Download Pain Week Journal - Comprehensive Pain Medicine

vol. 2 q 2 2014
OPIOID-INDUCED HYPERALGESIAP.14 BULLYING IN MEDICINE: ARE YOU THE VICTIM OR
THE PERPETRATOR?P.20 WHIPLASH: TOWARDS NEW OBJECTIVE MARKERSP.30 STIFF &
STUCK: USING JOINT MOBILIZATION TO RESTORE MOVEMENT AND REDUCE PAINP.36
DIABETES AND GASTROINTESTINAL PAINP.42
Butrans — 7 Days of
Buprenorphine Delivery
Butrans is a Schedule III extended-release opioid analgesic
WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and
NEONATAL OPIOID WITHDRAWAL SYNDROME
Addiction, Abuse, and Misuse
Butrans exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient’s risk prior to prescribing Butrans, and monitor all patients regularly for the development of these behaviors or
conditions [see Warnings and Precautions (5.1) and Overdosage (10)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of Butrans. Monitor for respiratory depression, especially
during initiation of Butrans or following a dose increase. Misuse or abuse of Butrans by chewing, swallowing, snorting or injecting
buprenorphine extracted from the transdermal system will result in the uncontrolled delivery of buprenorphine and pose a significant
risk of overdose and death [see Warnings and Precautions (5.2)].
Accidental Exposure
Accidental exposure to even one dose of Butrans, especially by children, can result in a fatal overdose of buprenorphine [see Warnings
and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of Butrans during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not
recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required
for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that
appropriate treatment will be available [see Warnings and Precautions (5.3)].
Parentheses refer to sections in the Full Prescribing Information.
Butrans® (buprenorphine) Transdermal System is indicated for the management of pain severe
enough to require daily, around-the-clock, long-term opioid treatment and for which alternative
treatment options are inadequate.
Limitations of Use: Because of the risks of addiction, abuse and misuse with opioids, even at
recommended doses, and because of the greater risk of overdose and death with extended-release
opioid formulations, reserve Butrans for use in patients for whom alternative treatment options
(eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be
otherwise inadequate to provide sufficient management of pain. Butrans is not indicated as an
as-needed (prn) analgesic.
CONTRAINDICATIONS
■
Butrans is contraindicated in patients with:
significant respiratory depression; acute or severe
bronchial asthma in an unmonitored setting or in
the absence of resuscitative equipment; known or
suspected paralytic ileus; hypersensitivity (eg,
anaphylaxis) to buprenorphine
Neonatal Opioid Withdrawal Syndrome
■ Prolonged use of Butrans during pregnancy can
result in neonatal opioid withdrawal syndrome
which may be life-threatening to the neonate if
not recognized and treated, and requires
management according to protocols developed
by neonatology experts
Application Site Skin Reactions
■ In rare cases, severe application site skin reactions
with signs of marked inflammation including
“burn,” “discharge,” and “vesicles” have occurred
Anaphylactic/Allergic Reactions
■ Cases of acute and chronic hypersensitivity to
buprenorphine have been reported both in
clinical trials and in the post-marketing experience
Interactions with Central Nervous System
Depressants
Application of External Heat
■ Hypotension, profound sedation, coma,
■ Avoid exposing the Butrans application site and
Addiction, Abuse, and Misuse
respiratory depression, or death may result if
surrounding area to direct external heat sources.
■ Butrans contains buprenorphine, a Schedule III
Butrans is used concomitantly with other CNS
There is a potential for temperature-dependent
controlled substance. Butrans exposes users to
depressants, including alcohol or illicit drugs that
increases in buprenorphine released from the
the risks of opioid addiction, abuse, and misuse.
can cause CNS depression. Start with Butrans 5
system resulting in possible overdose and death
As modified-release products such as Butrans
mcg/hour patch, monitor patients for signs of
Use
in Patients with Gastrointestinal Conditions
deliver the opioid over an extended period of
sedation and respiratory depression, and
■ Avoid the use of Butrans in patients with paralytic
time, there is a greater risk for overdose and
consider using a lower dose of the concomitant
ileus and other GI obstructions. Monitor patients
death, due to the larger amount of buprenorphine
CNS depressant
with biliary tract disease, including acute
present. Addiction can occur at recommended
Use in Elderly, Cachectic, and Debilitated
pancreatitis, for worsening symptoms
doses and if the drug is misused or abused.
Patients and Patients with Chronic
Assess each patient’s risk for opioid addiction,
Pulmonary Disease
abuse, or misuse prior to prescribing Butrans, and ■
ADVERSE REACTIONS
Closely monitor elderly, cachectic, and debilitated
monitor all patients during therapy for the
■ Most common adverse reactions (≥5%) reported
patients, and patients with chronic obstructive
development of these behaviors or conditions.
by patients treated with Butrans in the clinical
pulmonary
disease
because
of
the
increased
risk
Abuse or misuse of Butrans by placing it in the
trials were nausea, headache, application site
of
life-threatening
respiratory
depression.
mouth, chewing it, swallowing it, or using it in
pruritus, dizziness, constipation, somnolence,
Consider the use of alternative non-opioid
ways other than indicated may cause choking,
vomiting, application site erythema, dry mouth,
analgesics in patients with chronic obstructive
overdose and death
and application site rash
pulmonary disease if possible
Life-Threatening Respiratory Depression
QTc
Prolongation
■ Serious, life-threatening, or fatal respiratory
■ Avoid in patients with Long QT Syndrome, family
depression has been reported with modifiedVisit
history of Long QT Syndrome, or those taking
release opioids, even when used as
Butrans.com
Class IA or Class III antiarrhythmic medications
for more information
recommended, and if not immediately recognized
or to print the Butrans
Hypotensive Effects
and treated, may lead to respiratory arrest and
Trial Offer and Butrans
■ Butrans may cause severe hypotension, including
death. The risk of respiratory depression is
Savings Cards
orthostatic hypotension and syncope in
greatest during the initiation of therapy or
ambulatory patients. Monitor patients during
following a dose increase; therefore, closely
dose initiation or titration
monitor patients for respiratory depression.
The first transdermal system to
Proper dosing and titration of Butrans are
Use in Patients with Head Injury or
deliver 7 days of buprenorphine
essential. Overestimating the Butrans dose when
Increased Intracranial Pressure
■ Monitor patients taking Butrans who may be
converting patients from another opioid product
can result in fatal overdose with the first dose.
susceptible to the intracranial effects of CO2
Accidental exposure to Butrans, especially in
retention for signs of sedation and respiratory
children, can result in respiratory depression and
depression. Avoid the use of Butrans in patients
with impaired consciousness or coma
death due to an overdose of buprenorphine
WARNINGS AND PRECAUTIONS
Please read Brief Summary of Full Prescribing Information on the following pages.
©2014 Purdue Pharma L.P.
Stamford, CT 06901-3431
H8365-A1 4/14
for transdermal administration
BRIEF SUMMARY OF PRESCRIBING INFORMATION
(For complete details please see the Full Prescribing Information and
Medication Guide.)
WARNING: ADDICTION, ABUSE and MISUSE; LIFE-THREATENING
RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL
OPIOID WITHDRAWAL SYNDROME
Addiction, Abuse, and Misuse
BUTRANS® exposes patients and other users to the risks of opioid
addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient’s risk prior to prescribing BUTRANS, and monitor all patients regularly for the development of these behaviors or
conditions [see Warnings and Precautions (5.1) and Overdosage (10)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur
with use of BUTRANS. Monitor for respiratory depression, especially
during initiation of BUTRANS or following a dose increase. Misuse
or abuse of BUTRANS by chewing, swallowing, snorting or injecting
buprenorphine extracted from the transdermal system will result in
the uncontrolled delivery of buprenorphine and pose a significant
risk of overdose and death [see Warnings and Precautions (5.2)].
Accidental Exposure
Accidental exposure to even one dose of BUTRANS, especially by
children, can result in a fatal overdose of buprenorphine [see Warnings
and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of BUTRANS during pregnancy can result in neonatal
opioid withdrawal syndrome, which may be life-threatening if not
recognized and treated, and requires management according to
protocols developed by neonatology experts. If opioid use is required
for a prolonged period in a pregnant woman, advise the patient of the
risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].
4 CONTRAINDICATIONS BUTRANS is contraindicated in patients with:
• Significant respiratory depression • Acute or severe bronchial asthma in an
unmonitored setting or in the absence of resuscitative equipment • Known or
suspected paralytic ileus • Hypersensitivity (e.g., anaphylaxis) to buprenorphine
[see Warnings and Precautions (5.12) and Adverse Reactions (6)]
5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse
BUTRANS contains buprenorphine, a Schedule III controlled substance. As an
opioid, BUTRANS exposes users to the risks of addiction, abuse, and misuse.
As modified-release products such as BUTRANS deliver the opioid over an
extended period of time, there is a greater risk for overdose and death, due
to the larger amount of buprenorphine present. Although the risk of addiction
in any individual is unknown, it can occur in patients appropriately prescribed
BUTRANS and in those who obtain the drug illicitly. Addiction can occur at
recommended doses and if the drug is misused or abused [see Drug Abuse
and Dependence (9)]. Assess each patient’s risk for opioid addiction, abuse,
or misuse prior to prescribing BUTRANS, and monitor all patients receiving
BUTRANS for the development of these behaviors or conditions. Risks are
increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major
depression). The potential for these risks should not, however, prevent the
proper management of pain in any given patient. Patients at increased risk
may be prescribed modified-release opioid formulations such as BUTRANS,
but use in such patients necessitates intensive counseling about the risks and
proper use of BUTRANS, along with intensive monitoring for signs of addiction,
abuse, or misuse. Abuse or misuse of BUTRANS by placing it in the mouth,
chewing it, swallowing it, or using it in ways other than indicated may cause
choking, overdose and death [see Overdosage (10)]. Opioid agonists such as
BUTRANS are sought by drug abusers and people with addiction disorders
and are subject to criminal diversion. Consider these risks when prescribing
or dispensing BUTRANS. Strategies to reduce these risks include prescribing
the drug in the smallest appropriate quantity and advising the patient on the
proper disposal of unused drug [see Patient Counseling Information (17)].
Contact local state professional licensing board or state controlled substances
authority for information on how to prevent and detect abuse or diversion of
this product. 5.2 Life-Threatening Respiratory Depression Serious, lifethreatening, or fatal respiratory depression has been reported with the use of
modified-release opioids, even when used as recommended. Respiratory
depression, from opioid use, if not immediately recognized and treated, may
lead to respiratory arrest and death. Management of respiratory depression
may include close observation, supportive measures, and use of opioid
antagonists, depending on the patient’s clinical status [see Overdosage (10)].
Carbon dioxide (CO2) retention from opioid-induced respiratory depression
can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of
BUTRANS, the risk is greatest during the initiation of therapy or following a
dose increase. Closely monitor patients for respiratory depression when initiating therapy with BUTRANS and following dose increases. To reduce the
risk of respiratory depression, proper dosing and titration of BUTRANS are
essential [see Dosage and Administration (2)]. Overestimating the BUTRANS
dose when converting patients from another opioid product can result in fatal
overdose with the first dose. Accidental exposure to BUTRANS, especially in
children, can result in respiratory depression and death due to an overdose
of buprenorphine. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged
use of BUTRANS during pregnancy can result in withdrawal signs in the
neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal
syndrome in adults, may be life-threatening if not recognized and treated,
and requires management according to protocols developed by neonatology
experts. If opioid use is required for a prolonged period in a pregnant woman,
advise the patient of the risk of neonatal opioid withdrawal syndrome and
ensure that appropriate treatment will be available. Neonatal opioid withdrawal
syndrome presents as irritability, hyperactivity and abnormal sleep pattern,
high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The
onset, duration, and severity of neonatal opioid withdrawal syndrome vary
based on the specific opioid used, duration of use, timing and amount of last
maternal use, and rate of elimination of the drug by the newborn. 5.4
Interactions with Central Nervous System Depressants Hypotension,
profound sedation, coma, respiratory depression, and death may result if
BUTRANS is used concomitantly with alcohol or other (CNS) depressants
(e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When
considering the use of BUTRANS in a patient taking a CNS depressant, assess
the duration of use of the CNS depressant and the patient’s response,
including the degree of tolerance that has developed to CNS depression.
Additionally, evaluate the patient’s use, of alcohol or illicit drugs that cause
CNS depression. If the decision to begin BUTRANS therapy is made, start
with BUTRANS 5 mcg/hour patch, monitor patients for signs of sedation and
respiratory depression and consider using a lower dose of the concomitant
CNS depressant [see Drug Interactions (7.2)]. 5.5 Use in Elderly, Cachectic,
and Debilitated Patients Life-threatening respiratory depression is more
likely to occur in elderly, cachectic, or debilitated patients as they may have
altered pharmacokinetics or altered clearance compared to younger,
healthier patients. Monitor such patients closely, particularly when initiating
and titrating BUTRANS and when BUTRANS is given concomitantly with other
drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use
in Patients with Chronic Pulmonary Disease Monitor patients with
significant chronic obstructive pulmonary disease or cor pulmonale, and
patients having a substantially decreased respiratory reserve, hypoxia,
hypercapnia, or pre-existing respiratory depression for respiratory depression,
particularly when initiating therapy and titrating with BUTRANS, as in these
patients, even usual therapeutic doses of BUTRANS may decrease respiratory
drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the
use of alternative non-opioid analgesics in these patients if possible. 5.7
QTc Prolongation A positive-controlled study of the effects of BUTRANS on
the QTc interval in healthy subjects demonstrated no clinically meaningful
effect at a BUTRANS dose of 10 mcg/hour; however, a BUTRANS dose of 40
mcg/hour (given as two BUTRANS 20 mcg/hour Transdermal Systems) was
observed to prolong the QTc interval [see Dosage and Administration (2.2) and
Clinical Pharmacology (12.2)]. Consider these observations in clinical decisions
when prescribing BUTRANS to patients with hypokalemia or clinically
unstable cardiac disease, including: unstable atrial fibrillation, symptomatic
bradycardia, unstable congestive heart failure, or active myocardial ischemia.
Avoid the use of BUTRANS in patients with a history of Long QT Syndrome
or an immediate family member with this condition, or those taking Class IA
antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or
Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide).
5.8 Hypotensive Effects BUTRANS may cause severe hypotension including
orthostatic hypotension and syncope in ambulatory patients. There is an
increased risk in patients whose ability to maintain blood pressure has already
been compromised by a reduced blood volume or concurrent administration
of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)
[see Drug Interactions (7.2)]. Monitor these patients for signs of hypotension
after initiating or titrating the dose of BUTRANS. 5.9 Use in Patients with
Head Injury or Increased Intracranial Pressure Monitor patients taking
BUTRANS who may be susceptible to the intracranial effects of CO2 retention
(e.g., those with evidence of increased intracranial pressure or brain tumors)
for signs of sedation and respiratory depression, particularly when initiating
therapy with BUTRANS. BUTRANS may reduce respiratory drive, and the
resultant CO2 retention can further increase intracranial pressure. Opioids
may also obscure the clinical course in a patient with a head injury. Avoid
the use of BUTRANS in patients with impaired consciousness or coma. 5.10
Hepatotoxicity Although not observed in BUTRANS chronic pain clinical
trials, cases of cytolytic hepatitis and hepatitis with jaundice have been
observed in individuals receiving sublingual buprenorphine for the treatment
of opioid dependence, both in clinical trials and in post-marketing adverse
event reports. The spectrum of abnormalities ranges from transient
asymptomatic elevations in hepatic transaminases to case reports of hepatic
failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.
In many cases, the presence of pre-existing liver enzyme abnormalities,
infection with hepatitis B or hepatitis C virus, concomitant usage of other
potentially hepatotoxic drugs, and ongoing injection drug abuse may have
played a causative or contributory role. For patients at increased risk of
hepatotoxicity (e.g., patients with a history of excessive alcohol intake,
intravenous drug abuse or liver disease), obtain baseline liver enzyme levels
and monitor periodically and during treatment with BUTRANS. 5.11
Application Site Skin Reactions In rare cases, severe application site skin
reactions with signs of marked inflammation including “burn,” “discharge,”
and “vesicles” have occurred. Time of onset varies, ranging from days to
months following the initiation of BUTRANS treatment. Instruct patients to
promptly report the development of severe application site reactions and
discontinue therapy. 5.12 Anaphylactic/Allergic Reactions Cases of acute
and chronic hypersensitivity to buprenorphine have been reported both in
clinical trials and in the post-marketing experience. The most common signs
and symptoms include rashes, hives, and pruritus. Cases of bronchospasm,
angioneurotic edema, and anaphylactic shock have been reported. A history
of hypersensitivity to buprenorphine is a contraindication to the use of
BUTRANS. 5.13 Application of External Heat Advise patients and their
caregivers to avoid exposing the BUTRANS application site and surrounding
area to direct external heat sources, such as heating pads or electric blankets,
heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing
the system because an increase in absorption of buprenorphine may occur
[see Clinical Pharmacology (12.3)]. Advise patients against exposure of the
BUTRANS application site and surrounding area to hot water or prolonged
exposure to direct sunlight. There is a potential for temperature-dependent
increases in buprenorphine released from the system resulting in possible
overdose and death. 5.14 Patients with Fever Monitor patients wearing
BUTRANS systems who develop fever or increased core body temperature
due to strenuous exertion for opioid side effects and adjust the BUTRANS
dose if signs of respiratory or central nervous system depression occur.
5.15 Use in Patients with Gastrointestinal Conditions BUTRANS is
contraindicated in patients with paralytic ileus. Avoid the use of BUTRANS in
patients with other GI obstruction. The buprenorphine in BUTRANS may cause
spasm of the sphincter of Oddi. Monitor patients with biliary tract disease,
including acute pancreatitis, for worsening symptoms. Opioids may cause
increases in the serum amylase. 5.16 Use in Patients with Convulsive or
Seizure Disorders The buprenorphine in BUTRANS may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate
seizures in some clinical settings. Monitor patients with a history of seizure
disorders for worsened seizure control during BUTRANS therapy. 5.17
Driving and Operating Machinery BUTRANS may impair the mental and
physical abilities needed to perform potentially hazardous activities such as
driving a car or operating machinery. Warn patients not to drive or operate
dangerous machinery unless they are tolerant to the effects of BUTRANS and
know how they will react to the medication. 5.18 Use in Addiction Treatment
BUTRANS has not been studied and is not approved for use in the management of addictive disorders. 6 ADVERSE REACTIONS The following
serious adverse reactions are described elsewhere in the labeling:
• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and
Precautions (5.2)] • QTc Prolongation [see Warnings and Precautions
(5.7)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and
Precautions (5.3)] • Hypotensive Effects [see Warnings and Precautions
(5.8)] • Interactions with Other CNS Depressants [see Warnings and
Precautions (5.4)] • Application Site Skin Reactions [see Warnings and
Precautions (5.11)] • Anaphylactic/Allergic Reactions [see Warnings
and Precautions (5.12)] • Gastrointestinal Effects [see Warnings and
Precautions (5.15)] • Seizures [see Warnings and Precautions (5.16)]
6.1 Clinical Trial Experience Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice. A total of
5,415 patients were treated with BUTRANS in controlled and open-label
chronic pain clinical trials. Nine hundred twenty-four subjects were treated for
approximately six months and 183 subjects were treated for approximately
one year. The clinical trial population consisted of patients with persistent
moderate to severe pain. The most common serious adverse drug reactions
(all <0.1%) occurring during clinical trials with BUTRANS were: chest pain,
abdominal pain, vomiting, dehydration, and hypertension/blood pressure
increased. The most common adverse events (≥2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence. The
most common adverse reactions (≥5%) reported by patients in clinical
trials comparing BUTRANS 10 or 20 mcg/hour to placebo are shown in
Table 2, and comparing BUTRANS 20 mcg/hour to BUTRANS 5 mcg/hour
are shown in Table 3 below:
Table 2: Adverse Reactions Reported in ≥5% of Patients during the
Open-Label Titration Period and Double-Blind Treatment Period:
Opioid-Naïve Patients
Open-Label
Double-Blind
Titration Period
Treatment Period
BUTRANS
BUTRANS
Placebo
MedDRA
(N = 1024)
(N = 256)
(N = 283)
Preferred Term
Nausea
23%
13%
10%
Dizziness
10%
4%
1%
Headache
9%
5%
5%
Application site
8%
4%
7%
pruritus
Somnolence
8%
2%
2%
Vomiting
7%
4%
1%
Constipation
6%
4%
1%
Table 3: Adverse Reactions Reported in ≥5% of Patients during the
Open-Label Titration Period and Double-Blind Treatment Period:
Opioid-Experienced Patients
Open-Label
Double-Blind
Titration Period
Treatment Period
BUTRANS
BUTRANS 20 BUTRANS 5
MedDRA
(N = 1160)
(N = 219) (N = 221)
Preferred Term
Nausea
14%
11%
6%
Application site
9%
13%
5%
pruritus
Headache
9%
8%
3%
Somnolence
6%
4%
2%
Dizziness
5%
4%
2%
Constipation
4%
6%
3%
Application site
3%
10%
5%
erythema
Application
3%
8%
6%
site rash
Application
2%
6%
2%
site irritation
The following table lists adverse reactions that were reported in at least
2.0% of patients in four placebo/active-controlled titration-to-effect trials.
Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/
Active-Controlled Clinical Trials with Incidence ≥2%
MedDRA Preferred Term BUTRANS (N = 392) Placebo (N = 261)
Nausea
Application site pruritus
Dizziness
Headache
Somnolence
Constipation
Vomiting
Application site erythema
Application site rash
Dry mouth
Fatigue
Hyperhidrosis
Peripheral edema
Pruritus
Stomach discomfort
21%
15%
15%
14%
13%
13%
9%
7%
6%
6%
5%
4%
3%
3%
2%
6%
12%
7%
9%
4%
5%
1%
2%
6%
2%
1%
1%
1%
0%
0%
The adverse reactions seen in controlled and open-label studies are presented
below in the following manner: most common (≥5%), common (≥1% to
<5%), and less common (<1%). The most common adverse reactions
(≥5%) reported by patients treated with BUTRANS in the clinical trials were
nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application
site rash. The common (≥1% to <5%) adverse reactions reported by patients
treated with BUTRANS in the clinical trials organized by MedDRA (Medical
Dictionary for Regulatory Activities) System Organ Class were: Gastrointestinal
disorders: diarrhea, dyspepsia, and upper abdominal pain General disorders
and administration site conditions: fatigue, peripheral edema, application
site irritation, pain, pyrexia, chest pain, and asthenia Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis Injury, poisoning and procedural
complications: fall Metabolism and nutrition disorders: anorexia Musculoskeletal
and connective tissue disorders: back pain, arthralgia, pain in extremity,
muscle spasms, musculoskeletal pain, joint swelling, neck pain, and
myalgia Nervous system disorders: hypoesthesia, tremor, migraine, and
paresthesia Psychiatric disorders: insomnia, anxiety, and depression
Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal
pain, and cough Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus Vascular disorders: hypertension Other
less common adverse reactions, including those known to occur with opioid
treatment, that were seen in <1% of the patients in the BUTRANS trials
include the following in alphabetical order: Abdominal distention, abdominal
pain, accidental injury, affect lability, agitation, alanine aminotransferase
increased, angina pectoris, angioedema, apathy, application site dermatitis,
asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level
of consciousness, depressed mood, disorientation, disturbance in attention,
diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry
skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence,
flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation,
hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of
consciousness, malaise, memory impairment, mental impairment, mental
status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal,
respiratory depression, respiratory distress, respiratory failure, restlessness,
rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary
hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation,
vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.
7 DRUG INTERACTIONS 7.1 Benzodiazepines There have been a number
of reports regarding coma and death associated with the misuse and abuse
of the combination of buprenorphine and benzodiazepines. In many, but not
all of these cases, buprenorphine was misused by self-injection of crushed
buprenorphine tablets. Preclinical studies have shown that the combination
of benzodiazepines and buprenorphine altered the usual ceiling effect on
buprenorphine-induced respiratory depression, making the respiratory effects
of buprenorphine appear similar to those of full opioid agonists. Closely
monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn
patients that it is extremely dangerous to self-administer benzodiazepines
while taking BUTRANS, and warn patients to use benzodiazepines concurrently
with BUTRANS only as directed by their physician. 7.2 CNS Depressants
The concomitant use of BUTRANS with other CNS depressants including
sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other
opioids, and alcohol can increase the risk of respiratory depression, profound
sedation, coma and death. Monitor patients receiving CNS depressants and
BUTRANS for signs of respiratory depression, sedation, and hypotension.
When combined therapy with any of the above medications is considered,
the dose of one or both agents should be reduced [see Dosage and
Administration (2.2) and Warnings and Precautions (5.4)]. 7.3 Drugs Affecting
Cytochrome P450 Isoenzymes Inhibitors of CYP3A4 and 2D6 Because
the CYP3A4 isoenzyme plays a major role in the metabolism of
buprenorphine, drugs that inhibit CYP3A4 activity may cause decreased
clearance of buprenorphine which could lead to an increase in
buprenorphine plasma concentrations and result in increased or prolonged
opioid effects. These effects could be more pronounced with concomitant
use of CYP2D6 and 3A4 inhibitors. If co-administration with BUTRANS is
necessary, monitor patients for respiratory depression and sedation at
frequent intervals and consider dose adjustments until stable drug effects
are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4
CYP450 3A4 inducers may induce the metabolism of buprenorphine and,
therefore, may cause increased clearance of the drug which could lead
to a decrease in buprenorphine plasma concentrations, lack of efficacy
or, possibly, development of an abstinence syndrome in a patient who
had developed physical dependence to buprenorphine. After stopping the
treatment of a CYP3A4 inducer, as the effects of the inducer decline, the
buprenorphine plasma concentration will increase which could increase
or prolong both the therapeutic and adverse effects, and may cause
serious respiratory depression. If co-administration or discontinuation of
a CYP3A4 inducer with BUTRANS is necessary, monitor for signs of opioid
withdrawal and consider dose adjustments until stable drug effects are
achieved [see Clinical Pharmacology (12.3)]. 7.4 Muscle Relaxants
Buprenorphine may enhance the neuromuscular blocking action of skeletal
muscle relaxants and produce an increased degree of respiratory depression.
Monitor patients receiving muscle relaxants and BUTRANS for signs of
respiratory depression that may be greater than otherwise expected. 7.5
Anticholinergics Anticholinergics or other drugs with anticholinergic activity
when used concurrently with opioid analgesics may result in increased risk
of urinary retention and/or severe constipation, which may lead to paralytic
ileus. Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concurrently with anticholinergic drugs. 8 USE
IN SPECIFIC POPULATIONS 8.1 Pregnancy Clinical Considerations
Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during
pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after
birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome,
such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and
manage accordingly [see Warnings and Precautions (5.3)]. Teratogenic Effects
- Pregnancy Category C There are no adequate and well-controlled studies
in pregnant women. BUTRANS should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. In animal studies,
buprenorphine caused an increase in the number of stillborn offspring, reduced
litter size, and reduced offspring growth in rats at maternal exposure levels
that were approximately 10 times that of human subjects who received one
BUTRANS 20 mcg/hour, the maximum recommended human dose (MRHD).
Studies in rats and rabbits demonstrated no evidence of teratogenicity following BUTRANS or subcutaneous (SC) administration of buprenorphine
during the period of major organogenesis. Rats were administered up to one
BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9, 12, & 15) or received
daily SC buprenorphine up to 5 mg/kg (gestation days 6-17). Rabbits were
administered four BUTRANS 20 mcg/hour every 3 days (gestation days 6, 9,
12, 15, 18, & 19) or received daily SC buprenorphine up to 5 mg/kg (gestation days 6-19). No teratogenicity was observed at any dose. AUC values for
buprenorphine with BUTRANS application and SC injection were approximately
110 and 140 times, respectively, that of human subjects who received the
MRHD of one BUTRANS 20 mcg/hour. Non-Teratogenic Effects In a peri- and
post-natal study conducted in pregnant and lactating rats, administration of
buprenorphine either as BUTRANS or SC buprenorphine was associated with
toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant
rats were administered 1/4 of one BUTRANS 5 mcg/hour every 3 days or
received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from
gestation day 6 to lactation day 21 (weaning). Administration of BUTRANS or
SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase
in the number of stillborns, reduced litter size, and reduced offspring growth
at maternal exposure levels that were approximately 10 times that of human
subjects who received the MRHD of one BUTRANS 20 mcg/hour. Maternal
toxicity was also observed at the no observed adverse effect level (NOAEL)
for offspring. 8.2 Labor and Delivery Opioids cross the placenta and may
produce respiratory depression in neonates. BUTRANS is not for use in women
during and immediately prior to labor, when shorter acting analgesics or other
analgesic techniques are more appropriate. Opioid analgesics can prolong
labor through actions that temporarily reduce the strength, duration, and
frequency of uterine contractions. However this effect is not consistent and
may be offset by an increased rate of cervical dilatation, which tends to shorten
labor. 8.3 Nursing Mothers Buprenorphine is excreted in breast milk. The
amount of buprenorphine received by the infant varies depending on the
maternal plasma concentration, the amount of milk ingested by the infant,
and the extent of first pass metabolism. Withdrawal symptoms can occur in
breast-feeding infants when maternal administration of buprenorphine is
stopped. Because of the potential for adverse reactions in nursing infants
from BUTRANS, a decision should be made whether to discontinue nursing
or discontinue the drug, taking into account the importance of the drug to the
mother. 8.4 Pediatric Use The safety and efficacy of BUTRANS in patients
under 18 years of age has not been established. 8.5 Geriatric Use Of the
total number of subjects in the clinical trials (5,415), BUTRANS was administered to 1,377 patients aged 65 years and older. Of those, 457 patients
were 75 years of age and older. In the clinical program, the incidences of
selected BUTRANS-related AEs were higher in older subjects. The incidences
of application site AEs were slightly higher among subjects <65 years of age
than those ≥65 years of age for both BUTRANS and placebo treatment groups.
In a single-dose study of healthy elderly and healthy young subjects treated
with BUTRANS 10 mcg/hour, the pharmacokinetics were similar. In a separate
dose-escalation safety study, the pharmacokinetics in the healthy elderly and
hypertensive elderly subjects taking thiazide diuretics were similar to those
in the healthy young adults. In the elderly groups evaluated, adverse event
rates were similar to or lower than rates in healthy young adult subjects,
except for constipation and urinary retention, which were more common in
the elderly. Although specific dose adjustments on the basis of advanced age
are not required for pharmacokinetic reasons, use caution in the elderly
population to ensure safe use [see Clinical Pharmacology (12.3)]. 8.6 Hepatic
Impairment In a study utilizing intravenous buprenorphine, peak plasma
levels (Cmax) and exposure (AUC) of buprenorphine in patients with mild and
moderate hepatic impairment did not increase as compared to those observed
in subjects with normal hepatic function. BUTRANS has not been evaluated
in patients with severe hepatic impairment. As BUTRANS is intended for
7-day dosing, consider the use of alternate analgesic therapy in patients with
severe hepatic impairment [see Dosage and Administration (2.4) and Clinical
Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled
Substance BUTRANS contains buprenorphine, a Schedule III controlled
substance with an abuse potential similar to other Schedule III opioids.
BUTRANS can be abused and is subject to misuse, addiction and criminal
diversion [see Warnings and Precautions (5.1)]. 9.2 Abuse All patients treated
with opioids require careful monitoring for signs of abuse and addiction, since
use of opioid analgesic products carries the risk of addiction even under
appropriate medical use. Drug abuse is the intentional non-therapeutic use
of an over-the-counter or prescription drug, even once, for its rewarding
psychological or physiological effects. Drug abuse includes, but is not limited
to the following examples: the use of a prescription or over-the-counter drug
to get “high”, or the use of steroids for performance enhancement and
muscle build up. Drug addiction is a cluster of behavioral, cognitive, and
physiological phenomena that develop after repeated substance use and
includes: a strong desire to take the drug, difficulties in controlling its use,
persisting in its use despite harmful consequences, a higher priority given to
drug use than to other activities and obligations, increased tolerance, and
sometimes a physical withdrawal. “Drug-seeking” behavior is very common
to addicts and drug abusers. Drug-seeking tactics include emergency calls
or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering
with prescriptions and reluctance to provide prior medical records or contact
information for other treating physician(s). “Doctor shopping” (visiting multiple
prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with
achieving adequate pain relief can be appropriate behavior in a patient with
poor pain control. Abuse and addiction are separate and distinct from
physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of
physical dependence in all addicts. In addition, abuse of opioids can occur in
the absence of true addiction. BUTRANS, like other opioids, can be diverted
for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal
requests, as required by state law, is strongly advised. Proper assessment
of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to
reduce abuse of opioid drugs. Risks Specific to the Abuse of BUTRANS
BUTRANS is intended for transdermal use only. Abuse of BUTRANS poses a
risk of overdose and death. This risk is increased with concurrent abuse of
BUTRANS with alcohol and other substances including other opioids and
benzodiazepines [see Warnings and Precautions (5.4) and Drug Interactions
(7.2)]. Intentional compromise of the transdermal delivery system will result
in the uncontrolled delivery of buprenorphine and pose a significant risk to
the abuser that could result in overdose and death [see Warnings and
Precautions (5.1)]. Abuse may occur by applying the transdermal system in
the absence of legitimate purpose, or by swallowing, snorting, or injecting
buprenorphine extracted from the transdermal system. 9.3 Dependence
Both tolerance and physical dependence can develop during chronic opioid
therapy. Tolerance is the need for increasing doses of opioids to maintain a
defined effect such as analgesia (in the absence of disease progression or
other external factors). Tolerance may occur to both the desired and undesired
effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be
precipitated through the administration of drugs with opioid antagonist
activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics
(pentazocine, butorphanol, nalbuphine). Physical dependence may not occur
to a clinically significant degree until after several days to weeks of continued
opioid usage. BUTRANS should not be abruptly discontinued [see Dosage
and Administration (2.3)]. If BUTRANS is abruptly discontinued in a physicallydependent patient, an abstinence syndrome may occur. Some or all of the
following can characterize this syndrome: restlessness, lacrimation, rhinorrhea,
yawning, perspiration, chills, myalgia, and mydriasis. Other signs and
symptoms also may develop, including: irritability, anxiety, backache, joint
pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting,
diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants
born to mothers physically dependent on opioids will also be physically
dependent and may exhibit respiratory difficulties and withdrawal symptoms
[see Use in Specific Populations (8.1)]. 10 OVERDOSAGE Clinical Presentation
Acute overdosage with BUTRANS is manifested by respiratory depression,
somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold
and clammy skin, constricted pupils, bradycardia, hypotension, partial or
complete airway obstruction, atypical snoring and death. Marked mydriasis
rather than miosis may be seen due to severe hypoxia in overdose situations.
Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled
ventilation if needed. Employ other supportive measures (including oxygen,
vasopressors) in the management of circulatory shock and pulmonary edema
as indicated. Cardiac arrest or arrhythmias will require advanced life support
techniques. Naloxone may not be effective in reversing any respiratory
depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70
kg, may be of limited value in the management of buprenorphine overdose.
The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram
hydrochloride (a respiratory stimulant) has also been used. Remove BUTRANS
immediately. Because the duration of reversal would be expected to be less
than the duration of action of buprenorphine from BUTRANS, carefully
monitor the patient until spontaneous respiration is reliably re-established.
Even in the face of improvement, continued medical monitoring is required
because of the possibility of extended effects as buprenorphine continues to
be absorbed from the skin. After removal of BUTRANS, the mean buprenorphine
concentrations decrease approximately 50% in 12 hours (range 10-24 hours)
with an apparent terminal half-life of approximately 26 hours. Due to this long
apparent terminal half-life, patients may require monitoring and treatment for
at least 24 hours. In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal.
The severity of the withdrawal produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is
made to treat serious respiratory depression in the physically dependent
patient with an opioid antagonist, administration of the antagonist should be
begun with care and by titration with smaller than usual doses of the
antagonist. 17 PATIENT COUNSELING INFORMATION Advise the patient to
read the FDA-approved patient labeling (Medication Guide and Instructions
for Use). Addiction, Abuse, and Misuse Inform patients that the use of BUTRANS,
even when taken as recommended, can result in addiction, abuse, and
misuse, which could lead to overdose and death [see Warnings and Precautions
(5.1)]. Instruct patients not to share BUTRANS with others and to take steps
to protect BUTRANS from theft or misuse. Life-Threatening Respiratory
Depression Inform patients of the risk of life-threatening respiratory depression,
including information that the risk is greatest when starting BUTRANS or when
the dose is increased, and that it can occur even at recommended doses [see
Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory
depression and to seek medical attention if breathing difficulties develop.
Accidental Exposure Inform patients that accidental exposure, especially in
children, may result in respiratory depression or death [see Warnings and
Precautions (5.2)]. Instruct patients to take steps to store BUTRANS securely
and to dispose of unused BUTRANS by folding the patch in half and flushing
it down the toilet. Neonatal Opioid Withdrawal Syndrome Inform female patients
of reproductive potential that prolonged use of BUTRANS during pregnancy
can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and Precautions (5.3)].
Interaction with Alcohol and other CNS Depressants Inform patients that
potentially serious additive effects may occur if BUTRANS is used with alcohol
or other CNS depressants, and not to use such drugs unless supervised by
a health care provider. Important Administration Instructions Instruct patients
how to properly use BUTRANS, including the following: 1. To carefully follow
instructions for the application, removal, and disposal of BUTRANS. Each
week, apply BUTRANS to a different site based on the 8 described skin sites,
with a minimum of 3 weeks between applications to a previously used site.
2. To apply BUTRANS to a hairless or nearly hairless skin site. If none are
available, instruct patients to clip the hair at the site and not to shave the area.
Instruct patients not to apply to irritated skin. If the application site must be
cleaned, use clear water only. Soaps, alcohol, oils, lotions, or abrasive devices
should not be used. Allow the skin to dry before applying BUTRANS. Hypotension
Inform patients that BUTRANS may cause orthostatic hypotension and syncope.
Instruct patients how to recognize symptoms of low blood pressure and how
to reduce the risk of serious consequences should hypotension occur (e.g.,
sit or lie down, carefully rise from a sitting or lying position). Driving or Operating
Heavy Machinery Inform patients that BUTRANS may impair the ability to
perform potentially hazardous activities such as driving a car or operating
heavy machinery. Advise patients not to perform such tasks until they know
how they will react to the medication. Constipation Advise patients of the
potential for severe constipation, including management instructions and
when to seek medical attention. Anaphylaxis Inform patients that anaphylaxis
has been reported with ingredients contained in BUTRANS. Advise patients
how to recognize such a reaction and when to seek medical attention.
Pregnancy Advise female patients that BUTRANS can cause fetal harm and
to inform the prescriber if they are pregnant or plan to become pregnant.
Disposal Instruct patients to refer to the Instructions for Use for proper disposal
of BUTRANS. Patients can dispose of used or unused BUTRANS patches in
the trash by sealing them in the Patch-Disposal Unit, following the instructions
on the unit. Alternatively, instruct patients to dispose of used patches by
folding the adhesive side of the patch to itself, then flushing the patch down
the toilet immediately upon removal. Unused patches should be removed from
their pouches, the protective liners removed, the patches folded so that the
adhesive side of the patch adheres to itself, and immediately flushed down
the toilet. Instruct patients to dispose of any patches remaining from a prescription as soon as they are no longer needed.
Healthcare professionals can telephone Purdue Pharma’s Medical Services
Department (1-888-726-7535) for information on this product.
Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431
Manufactured by: LTS Lohmann Therapy Systems Corp., West Caldwell,
NJ 07006
U.S. Patent Numbers 5681413; 5804215; 6264980; 6315854; 6344211;
RE41408; RE41489; RE41571.
© 2014, Purdue Pharma L.P.
This brief summary is based on BUTRANS Prescribing
Information 303135-0B, Revised 04/2014 (A)
GUEST EDITOR ROGER
PUBLISHER Aventine
B. FILLINGIM PhD
Co. 6 Erie Street, Montclair, NJ 07042
ART DIRECTOR DARRYL
FOSSA
EDITORIAL DIRECTOR DEBRA
WEINER
EDITORIAL BOARD
Charles E. Argoff MD, CPE
Professor of Neurology
Albany Medical College
Department of Neurology
Director
Comprehensive Pain Center
Albany Medical Center
Department of Neurology
Albany, NY
Peter A. Foreman DDS, DAAPM
Consultant
Rotorua Hospital and Private Practice
Rotorua, New Zealand
Steven D. Passik PhD
Director of Clinical Addiction Research and Education
Millennium Laboratories
San Diego, CA
Gary W. Jay MD, FAAPM , DAAPM
Medical Director
DNA Center
Daytona Beach, FL
John F. Peppin DO, FACP
Head of Global Medical Affairs, Pharmaceuticals
Mallinckrodt Pharmaceuticals
St. Louis, MO
Paul Arnstein RN , PhD, ACNS - BC , FNP-C, FAAN
Clinical Nurse Specialist for Pain Relief
Massachusetts General Hospital
Boston, MA
Mary Lynn McPherson PharmD, BCPS, CPE, FASPE
Professor and Vice Chair
University of Maryland School of Pharmacy
Department of Pharmacy Practice and Science
Hospice Consultant Pharmacist
Baltimore, MD
Joseph V. Pergolizzi MD
Adjunct Assistant Professor
Johns Hopkins University School of Medicine
Department of Medicine
Baltimore, MD
Senior Partner
Naples Anesthesia and Pain Medicine
Naples, FL
Said R. Beydoun MD, FAAN
Professor of Neurology
Director of the Neuromuscular Program
Keck Medical Center of
University of Southern California
Los Angeles, CA
Jennifer Bolen JD
Founder
Legal Side of Pain
Knoxville, TN
Paul J. Christo MD, MBA
Associate Professor
Johns Hopkins University School of Medicine
Department of Anesthesiology and
Critical Care Medicine
Baltimore, MD
Michael R. Clark MD, MPH, MBA
Vice Chair, Clinical Affairs
Johns Hopkins University School of Medicine
Department of Psychiatry and Behavioral Sciences
Director, Pain Treatment Programs
Johns Hopkins Medical Institutions
Department of Psychiatry and Behavioral Sciences
Baltimore, MD
Geralyn Datz PhD
Affiliate
University of Southern Mississippi
Department of Psychology
Clinical Director
Southern Behavioral Medicine Associates
Hattiesburg, MS
Srinivas Nalamachu MD
Clinical Assistant Professor
Kansas University Medical Center
Department of Rehabilitation Medicine
Kansas City, KS
President and Medical Director
International Clinical Research Institute
Overland Park, KS
Bruce D. Nicholson MD
Clinical Associate Professor
Department of Anesthesia
Penn State College of Medicine
Hershey Medical Center
Hershey, PA
Director of Pain Specialists
Lehigh Valley Health Network
Department of Anesthesiology
Allentown, PA
Marco Pappagallo MD
Director of Medical Intelligence
Grünenthal USA
Bedminster, NJ
Director
Pain Management & Medical Mentoring
New Medical Home for Chronic Pain
New York, NY
Robert W. Rothrock PA -C, MPA
University of Pennsylvania
Department of Anesthesiology and Critical Care
Pain Medicine Division
Philadelphia, PA
Michael E. Schatman PhD, CPE, DASPE
Executive Director
Foundation for Ethics in Pain Care
Bellevue, WA
Sanford M. Silverman MD, PA
CEO and Medical Director
Comprehensive Pain Medicine
Pompano Beach, FL
Thomas B. Strouse MD
Medical Director
Stewart and Lynda Resnick
Neuropsychiatric Hospital at UCLA
Los Angeles, CA
Kevin L. Zacharoff MD, FACPE, FACIP, FAAP
Faculty Clinical Instructor
SUNY Stony Brook School of Medicine
Stony Brook, NY
Director of Medical Affairs
Inflexxion Inc.
Newton, MA
PWJ is published by Aventine Co. Copyright © 2014, Aventine Co.
The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of Aventine or its publication staff.
Aventine Co. does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. Aventine Co. does not
assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be
from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent
upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.
All rights are reserved by Aventine Co. to accept, reject, or modify any advertisement submitted for publication. It is the policy of Aventine Co. to not endorse products.
Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.
Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education to physicians. Global Education Group designates this live activity for a minimum of 32.0 AMA PRA Category 1 Credit(s) TM. This activity will be approved for continuing
pharmacy, psychology, nurse practitioner, nursing and dentistry education. Applications for certification of social work NASW and family physician AAFP hours will be applied for. For more information and complete CME/CE accreditation details, visit our website at www.painweek.org.
/ PWJ / Q2 / 2014
11 | GUEST EDITOR’S LETTER
by roger b. Fillingim
FEATURES
14 | PAIN&CHEMICAL DEPENDENCY
OPIOID-INDUCED HYPERALGESIA
by sanford m. Silverman
20 | NADDI
BULLYING IN MEDICINE:
are you the victim or the perpetrator?
by lisa McElhaney
36 | PHYSICAL THERAPY
STIFF&STUCK:
using joint mobilization to restore movement
and reduce pain
by erica Sigman
42 | DIABETES&PAIN
DIABETES AND
GASTROINTESTINAL PAIN
by michael m. Bottros / narendren
Narayanasamy
56 | PUNDIT PROFILE
with kevin l. Zacharoff
30 | MUSCULOSKELETAL
WHIPLASH:
towards new objective markers
by james m. Elliott
8 | PWJ | www.painweek.org
Q2 | 2014
When 1st-line laxative therapy isn’t
enough for patients with advanced illness,*
OPIOID-INDUCED
CONSTIPATION MAY NEED
RELISTOR-INDUCED RELIEF.
• Opioid-induced constipation (OIC) is unique and
often unresponsive to laxative therapy1
• RELISTOR® (methylnaltrexone bromide) targets the
underlying cause of OIC without affecting analgesia2
• In a single-dose study, most patients experienced a
BM within 4 hours of the first dose and ≥3 weekly BMs
when dosed every other day in a multi-dose study2,3
• The most common adverse reactions in clinical
trials with RELISTOR were abdominal pain, flatulence,
nausea, dizziness, diarrhea, and hyperhidrosis 2
For more information, go to RELISTOR.com.
Indication
RELISTOR is indicated for the treatment of
opioid-induced constipation in patients with
advanced illness who are receiving palliative
care, when response to laxative therapy has not
been sufficient. Use of RELISTOR beyond four
months has not been studied.
Important Safety Information
about RELISTOR
RELISTOR® (methylnaltrexone bromide)
Subcutaneous Injection is contraindicated in
patients with known or suspected mechanical
gastrointestinal obstruction.
Cases of gastrointestinal (GI) perforation have
been reported in adult patients with opioid-induced
constipation and advanced illness with conditions
that may be associated with localized or diffuse
reduction of structural integrity in the wall
of the GI tract (i.e., cancer, peptic ulcer,
Ogilvie’s syndrome). Perforations have involved
varying regions of the GI tract (e.g., stomach,
duodenum, or colon). Use RELISTOR with caution
in patients with known or suspected lesions of
the GI tract. Advise patients to discontinue therapy
with RELISTOR and promptly notify their physician
if they develop severe, persistent, or worsening
abdominal symptoms.
If severe or persistent diarrhea occurs during
treatment, advise patients to discontinue therapy
with RELISTOR and consult their physician.
Use of RELISTOR beyond four months has not
been studied.
Safety and efficacy of RELISTOR have not been
established in pediatric patients.
The most common adverse reactions reported
with RELISTOR compared with placebo in
clinical trials were abdominal pain (28.5%),
flatulence (13.3%), nausea (11.5%), dizziness (7.3%),
diarrhea (5.5%), and hyperhidrosis (6.7%).
*Can include cardiovascular diseases, cancer, and COPD.
References
1. Thomas JR, Cooney GA. Palliative care and pain: new strategies for
managing opioid bowel dysfunction. J Palliat Med. 2008;11(suppl 1):S1-S19.
2. RELISTOR (prescribing information). Raleigh, NC: Salix Pharmaceuticals, Inc.
3. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced
constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343.
Please see Brief Summary of complete
Prescribing Information on the adjacent page.
www.salix.com
8510 Colonnade Center Drive, Raleigh, NC 27615
For additional information, call: 1-866-669-SLXP (7597)
To report adverse events, call: 1-800-508-0024
©2014 Salix Pharmaceuticals, Inc.
All rights reserved.
Printed in USA. REL39-0314
The rates of discontinuation due to adverse events during the
double-blind, placebo-controlled clinical trials (Study 1 and
Study 2) were comparable between RELISTOR (1.2%) and
placebo (2.4%).
The following is a brief summary only. See complete
Prescribing Information on www.Relistor.com or request
complete prescribing information by calling 1-800-508-0024.
INDICATIONS AND USAGE
RELISTOR is indicated for the treatment of opioid-induced
constipation in patients with advanced illness who are
receiving palliative care, when response to laxative therapy
has not been sufficient.
Limitation of use: Use of RELISTOR beyond four months has
not been studied in the advanced illness population.
CONTRAINDICATIONS
RELISTOR is contraindicated in patients with known or
suspected mechanical gastrointestinal obstruction.
WARNINGS AND PRECAUTIONS
Gastrointestinal Perforation
Cases of gastrointestinal (GI) perforation have been reported
in adult patients with opioid-induced constipation and
advanced illness with conditions that may be associated with
localized or diffuse reduction of structural integrity in the wall
of the GI tract (i.e., cancer, peptic ulcer, Ogilvie’s syndrome).
Perforations have involved varying regions of the GI tract
(e.g., stomach, duodenum, or colon).
Use RELISTOR with caution in patients with known or
suspected lesions of the GI tract. Advise patients to
discontinue therapy with RELISTOR and promptly notify
their physician if they develop severe, persistent, or
worsening abdominal symptoms.
Severe or Persistent Diarrhea
If severe or persistent diarrhea occurs during treatment,
advise patients to discontinue therapy with RELISTOR and
consult their physician.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates
observed in clinical practice.
The majority of patients had a primary diagnosis of incurable
cancer; other primary diagnoses included end-stage
COPD/emphysema, cardiovascular disease/heart failure,
Alzheimer’s disease/dementia, HIV/AIDS, or other advanced
illnesses. Patients were receiving opioid therapy (median
daily baseline oral morphine equivalent dose = 172 mg),
and had opioid-induced constipation (either <3 bowel
movements in the preceding week or no bowel movement
for 2 days). Both the methylnaltrexone bromide and placebo
patients were on a stable laxative regimen for at least
3 days prior to study entry and continued on their regimen
throughout the study.
The safety of RELISTOR was evaluated in two, double-blind,
placebo-controlled trials in patients with advanced illness
receiving palliative care: Study 1 included a single-dose,
double-blind, placebo-controlled period, whereas Study 2
included a 14-day, multiple-dose, double-blind, placebocontrolled period.
The most common adverse reactions (>5%) in patients
receiving RELISTOR are shown in the table below.
Adverse Reactions from all Doses in Double-Blind, PlaceboControlled Clinical Studies of RELISTOR in Adult Patients
with Opioid-Induced Constipation and Advanced Illness*
Adverse
Reaction
RELISTOR
N = 165
Placebo
N = 123
Abdominal Pain
47 (28.5%)
12 (9.8%)
Flatulence
22 (13.3%)
7 (5.7%)
Nausea
19 (11.5%)
6 (4.9%)
Dizziness
12 (7.3%)
3 (2.4%)
Diarrhea
9 (5.5%)
3 (2.4%)
Hyperhidrosis
11 (6.7%)
8 (6.5%)
* Doses: 0.075, 0.15, and 0.30 mg/kg/dose
Postmarketing Experience
The following additional adverse events have been identified
during post-approval use of RELISTOR. Because they are
reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. These events have
been chosen for inclusion due to either their seriousness,
frequency of reporting or causal connection to RELISTOR,
or a combination of these factors.
Gastrointestinal
Perforation, cramping, vomiting
General Disorders and Administrative Site Disorders
Diaphoresis, flushing, malaise, pain. Cases of opioid
withdrawal have been reported.
DRUG INTERACTIONS
Drugs Metabolized by Cytochrome P450 Isozymes
In healthy subjects, a subcutaneous dose of 0.30 mg/kg
of methylnaltrexone did not significantly affect the
metabolism of dextromethorphan, a CYP2D6 substrate.
In vitro methylnaltrexone did not significantly inhibit or induce
the activity of cytochrome P450 (CYP) isozymes CYP1A2,
CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4.
In vitro, methylnaltrexone did not induce the enzymatic
activity of CYP2E1.
Drugs Renally Excreted
Methylnaltrexone is actively secreted in the kidney. The
potential of drug interactions between methylnaltrexone
bromide and other drugs that are inhibitors of transporters
in the kidney has not been fully investigated.
Cimetidine
Cimetidine given 400 mg three times daily did not significantly
affect the systemic exposure to methylnaltrexone. The effect
of a higher cimetidine dose (e.g., 800 mg) on the systemic
exposure of methylnaltrexone has not been evaluated.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Reproduction studies have been performed in pregnant rats
at intravenous doses up to about 14 times the recommended
maximum human subcutaneous dose of 0.3 mg/kg based on
the body surface area and in pregnant rabbits at intravenous
doses up to about 17 times the recommended maximum
human subcutaneous dose based on the body surface
area and have revealed no evidence of impaired fertility or
harm to the fetus due to methylnaltrexone bromide. There
are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always
predictive of human response, methylnaltrexone bromide
should be used during pregnancy only if clearly needed.
Labor and Delivery
Effects of RELISTOR on mother, fetus, duration of labor, and
delivery are unknown. There were no effects on the mother,
labor, delivery, or on offspring survival and growth in rats
following subcutaneous injection of methylnaltrexone bromide
at dosages up to 25 mg/kg/day.
Nursing Mothers
Results from an animal study using [ 3H]-labeled
methylnaltrexone bromide indicate that methylnaltrexone
bromide is excreted via the milk of lactating rats. It is not
known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk, caution should be
exercised when RELISTOR is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of RELISTOR have not been
established in pediatric patients.
Geriatric Use
In the phase 2 and 3 double-blind studies, a total of 77 (24%)
patients aged 65-74 years (54 methylnaltrexone bromide,
23 placebo) and a total of 100 (31.2%) patients aged 75 years
or older (61 methylnaltrexone bromide, 39 placebo) were
enrolled. Pharmacokinetics of methylnaltrexone was similar
between the elderly (mean age 72 years old) and young adults
(mean age 30 years old). No overall differences in safety or
effectiveness were observed between these patients and
younger patients, and other reported clinical experience has
not identified differences in responses between the elderly
and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Based on pharmacokinetic data, and safety and efficacy data
from controlled clinical trials, no dose adjustment based on
age is recommended.
Renal Impairment
No dose adjustment is required in patients with mild or
moderate renal impairment. Dose reduction by one-half
is recommended in patients with severe renal impairment
(creatinine clearance less than 30 mL/min as estimated by
Cockcroft-Gault).
In a study of volunteers with varying degrees of renal
impairment receiving a single dose of 0.30 mg/kg
methylnaltrexone bromide, renal impairment had a marked
effect on the renal excretion of methylnaltrexone bromide.
Severe renal impairment decreased the renal clearance of
methylnaltrexone bromide by 8- to 9-fold and resulted in a
2-fold increase in total methylnaltrexone bromide exposure
(AUC). Cmax was not significantly changed. No studies were
performed in patients with end-stage renal impairment
requiring dialysis.
Hepatic Impairment
No dose adjustment is required for patients with mild or
moderate hepatic impairment. The effect of severe hepatic
impairment on the pharmacokinetics of methylnaltrexone
has not been studied.
Patient Counseling
Instruct patients not to continue taking RELISTOR and to
promptly notify their physician if they experience severe,
persistent, or worsening abdominal symptoms because
these could be symptoms of gastrointestinal perforation
[see Warnings and Precautions].
Instruct patients not to continue taking RELISTOR if they
experience severe or persistent diarrhea. Inform patients that
common side effects of RELISTOR include abdominal pain,
flatulence, nausea, dizziness, and diarrhea.
Advise patients to be within close proximity to toilet facilities
once the drug is administered.
Instruct patients with opioid-induced constipation and
advanced illness to administer one dose subcutaneously
every other day, as needed, but no more frequently than
one dose in a 24-hour period.
Instruct patients to discontinue RELISTOR if they stop taking
their opioid pain medication.
Instruct patients to use the RELISTOR single-use vial with a
27 gauge x ½-inch needle and 1 mL syringe.
You are encouraged to report negative side effects
of prescription drugs to the FDA. Visit www.fda.gov/
medwatch or call 1-800-FDA-1088.
To report adverse events, a product complaint, or for
additional information, call: 1-800-508-0024.
Manufactured for:
Salix Pharmaceuticals, Inc.
Raleigh, NC 27615
Under License from:
Progenics Pharmaceuticals, Inc.
Tarrytown, NY 10591
REL-RALAB6-062013
ROGER B.
FiLLiNGiM
PhD
T
his 4th issue of PWJ provides an abundance of valuable information
across several topics of importance to the frontline practitioner. The
variety of clinical conditions addressed serves as a reminder of the
broad array of issues faced by providers in offering high quality and
well-informed clinical care to patients suffering from chronic pain.
Those of us in the pain field are fond of quoting statistics attesting to
the staggering societal impact—100 million people are experiencing chronic pain, costing the US economy more than $600 billion
annually. Chronic pain is not one condition; as is made clear in this
issue of PWJ, chronic pain comprises multiple conditions that present
many different challenges. Knowledge represents the best weapon
the frontline practitioner can bring to his or her battle against the
manifold chronic pain conditions affecting patients. Therefore, enjoy
these articles, and continue to fight the good fight.
a motor vehicle accident do not experience persistent pain, Dr. Elliott
notes that a substantial minority (~25%) never fully recover. Considerable research has focused on the psychosocial and behavioral factors predicting chronic WAD symptoms, and biological factors have
been downplayed. Individuals who fail to recover show increased
fatty infiltrates on MRI, suggesting a potential biological mechanism.
This article discusses the available imaging methods that can be used
to better capture these changes and calls for a more comprehensive
biopsychosocial model to conceptualize WAD.
Dr. Erica Sigman addresses the use of joint mobilization to improve
mobility and reduce pain. She provides a clear description of the
different grades and notes that joint mobilization has been found to
be an effective adjunctive treatment for different forms of pain. In
addressing how it might improve both mobility and pain, Dr. Sigman
makes the important point that it can impact central pain processing,
thereby reducing pain and improving mobility in people with centralized pain. A case example is included, which illustrates the use
of joint mobilization to treat pain due to thoracic outlet syndrome.
Dr. Sanford Silverman discusses the phenomenon of opioid-induced
hyperalgesia (OIH ) in which opioids have the effect of increasing
rather than reducing pain. While the adverse personal and societal effects of opioids have received abundant attention in recent
years, OIH is often missing from this conversation, even though
there is abundant preclinical and clinical evidence. Dr. Silverman
distinguishes OIH from opioid tolerance, since the latter but not the
former can be overcome by increasing the dose of opioid. Information about neurobiology and the methods for diagnosis and treatment
all will help the frontline practitioner recognize and manage the
underappreciated clinical issue that is OIH.
Lisa McElhaney opens the discussion of bullying in the healthcare
setting. Several examples are provided, including a physician bullying a coworker to falsify medication dosages and a patient providing
sexual favors to physicians in exchange for pain medications. Bullying occurs in multiple directions and obviously can negatively impact
the workplace setting. Practitioners should be aware of these issues
and take steps to prevent bullying and maintain a nonhostile work
environment.
The increasing prevalence of diabetes is well known, and pain We want to thank all of the contributing authors for sharing their
associated with diabetic neuropathy is recognized as a significant knowledge and expertise with us. There is much to be learned in
clinical concern. Most attention has focused on painful symptoms these pages. We expect that these articles will answer some quesin the extremities; however, as Drs. Michael Bottros and Narendren tions while raising new ones. If you have feedback, or if there are
Narayanasamy note, chronic abdominal pain due to gastrointestinal other topics you would like to see in future issues of PWJ, please
involvement in diabetes is common yet underdiagnosed. Their article let us know.
highlights the high prevalence of GI symptoms in diabetes, including
abdominal pain. Several sources of diabetes-related GI symptoms are — ROGER B. FILLINGIM PHD
reviewed, including gastroparesis, esophageal symptoms, nonalcoholic fatty liver disease, and enteropathy. Diagnostic and treatment
considerations for each of these conditions are provided.
Dr. James Elliott presents the complex and controversial topic of whiplash associated disorders ( WAD). While most people who experience
Q2 | 2014
www.painweek.org | PWJ | 11
Michael M. Bottros MD
P.42
James M. Elliott PhD, PT
P.30
Lisa McElhaney P.20
Erica Sigman PT, DPT, OCS
P.36
Sanford M. Silverman MD
P.14
Michael Bottros is Assistant Professor of Anesthesiology, Division of Pain Medicine, in the Department of Anesthesiology
at Washington University School of Medicine in St. Louis, Missouri. He is founding Director, Acute Pain Service, at
Barnes-Jewish Hospital, St. Louis. His interests include treatments of both chronic and acute pain, and development of
various pain care paths across hospitals. He has been interviewed on television and satellite radio, and lectured nationally
and internationally on various pain conditions and their respective treatment options. Narendren Narayanasamy, MD, a
Fellow in Pain Medicine at the Washington University School of Medicine, is coauthor with Dr. Bottros on this article.
James Elliott is Assistant Professor in the Department of Physical Therapy and Human Movement Sciences, Feinberg
School of Medicine at Northwestern University in Chicago, Illinois, and the Principal Investigator of the Neuromuscular Imaging Research Lab (www.nirl.nu). He is also an Honorary Senior Fellow at the School of Health and Rehabilitation Sciences, the University of Queensland, Australia. His research program endeavors to identify the mechanisms
underlying the development/maintenance of chronic pain-related disability following traumatic spinal injuries...in
particular, motor vehicle collisions.
Lisa McElhaney is the National Vice President of NADDI, the National Association of Drug Diversion Investigators,
in Lutherville, Maryland. She is a sworn veteran of the Broward Sheriff’s Office in Fort Lauderdale, Florida, and is a
Detective Sergeant in the agency’s Public Corruption Unit. She has specialized in pharmaceutical and designer drug
investigations, prosecutions, and education for most of her 25-year career.
Erica Sigman is a physical therapist at the faculty practice on the Health Science Campus for the University of
Southern California’s (USC) Division of Biokinesiolgy and Physical Therapy. She specializes in treating patients
with headaches, temporomandibular joint-related issues, orthopedic disorders, and chronic pain. Dr. Sigman is board
certified by the American Board of Physical Therapy Specialties as an Orthopedic Clinical Specialist. Additionally,
she is an Instructor of Clinical Physical Therapy and the Coordinator of the Orthopedic Physical Therapy Residency
Program at USC.
Sanford Silverman is CEO and Medical Director of Comprehensive Pain Medicine in Pompano Beach, Florida. He
is Clinical Assistant Professor in the Department of Surgery, Division of Anesthesiology, at Nova Southeastern
University in Davie, Florida, and Affiliate Assistant Professor of clinical biomedical science at Charles E. Schmidt
College of Medicine, Florida Atlantic University in Boca Raton. Dr. Silverman is the immediate past president of the
Florida Society of Interventional Pain Physicians and president-elect of the Broward County Medical Association.
12 | PWJ | www.painweek.org
Q2 | 2014
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by SANFORD
e
M. SiLV RMAN MD
“Since
tolerance is characterized
by decreasing efficacy of a drug,
it can be overcome by increasing
the dose...OIH cannot be
overcome by increasing dosage,
however, because OIH is a form
of pain sensitization induced
by the drug...”
by SANFORD
Q2 | 2014
e
M. SiLV RMAN MD
www.painweek.org | PWJ | 15
As early as the nineteenth century, OIH was
observed in patients receiving morphine for
pain. It was recognized that a potent analgesic
such as morphine could actually result in an
increase in pain, as observed by Albutt in 1870:
“At
such times I have certainly
felt it a great responsibility
to say that pain, which I know
is an evil, is less injurious than
morphia, which may be an evil.
Here experience is needed.
Does morphia tend to
encourage the very pain it
pretends to relieve?
...in
the cases in question,
I have much reason to suspect
that a reliance upon hypodermic morphia only
ended in that curious state
of perpetuated pain.”1
*Sir Thomas Clifford Albutt (1836–1925): a British physician, researcher, and the author of Medical Thermometry.
PAiN&CHEMICAL DEPENDENCY
abstract: In the United States there is an epidemic of chronic pain that parallels the everincreasing utilization of opioids. This increase in opioid use has led to misuse and abuse
and has left in its wake thousands of fatalities. Yearly, there are greater than 15,000 deaths.2
Although the general consensus is that opioids can be prescribed safely and effectively
with prudent risk mitigation strategies, certain side effects/complications can be difficult
to treat. Addiction, abuse, and diversion are usually the focus of such efforts, and become
relatively straightforward when investigated. However, other side effects to opioid therapy
can be somewhat difficult to assess and even more so to treat. Opioid-induced hyperalgesia (OIH), related to but different from tolerance, is one such complication of opioid therapy. There is preclinical and clinical evidence for such, as well as the clinical implications
for the pain practitioner.3
e
e
e
TOL RANC VS PAiN S NSiTiZATiON
Tolerance is a pharmacologic concept. It occurs when there is a progressive lack of response to a drug thus requiring increased dosing.
Tolerance can occur with a variety of drugs including opioids.4,5 Tolerance may not only develop to the analgesia provided by opioids
but also to the undesirable side effects which are seen with opioid
administration, such as pruritus, nausea, sedation, and respiratory
depression.
Sensitization to pain occurs in several areas of the nervous system
involving the transmission of pain. Peripheral mechanisms have been
well documented with respect to neural injury involving mediators
of inflammation. This is known as primary hyperalgesia and is seen
clinically with peripheral nerve injuries. Secondary hyperalgesia, on
the other hand, occurs “downstream” from the initiating nociceptive
stimulus and peripheral injury. In the spinal cord, wide dynamic
Q2 | 2014
range neurons become sensitized through a variety of mechanisms
that may be mediated by neurotransmitters, such as calcitonin
gene-related peptide, vasoactive intestinal peptide, dynorphin, cholecystokinin, neuropeptide Y, and N-methyl-D-aspartate ( NMDA).6
Since tolerance is characterized by decreasing efficacy of a drug,
it can be overcome by increasing the dose. Unlike tolerance, OIH
cannot be overcome by increasing dosage, however, because OIH is a
form of pain sensitization induced by the drug, which occurs within
the central nerve system (CNS). It is a pro-nociceptive process that
is related to, but different from, tolerance. Pain is worsened with
increased opioid dosing and is improved by reducing or eliminating the opioid. Tolerance is a necessary condition for OIH, but the
converse is not true. Clinically this is an important distinction that
has obvious ramifications with respect to continued use of opioids
in a given patient.
www.painweek.org | PWJ | 17
PAIN&CHEMICAL DEPENDENCY
“Significant
pain reduction has
been demonstrated in patients
who have been detoxified from
high-dose opioids.”
Laboratory (preclinical) evidence exists for OIH. In several animal more often than not initially increase the dose of opioid to offset
studies, a progressive reduction in baseline pain threshold has been what they believe is tolerance. If the patient responds positively to
seen following administration of opioids through both intravenous such an increase, and sustains this over a period of time, then the
and intrathecal routes.7-10 Supporting evidence has shown that OIH diagnosis of tolerance is likely. However, if there is no improvement
occurs clinically outside the laboratory, and is seen after intraoper- or it is transient, then the clinician must consider OIH.
ative remifentanil infusion, resulting in decreased opioid efficacy.11
Significant pain reduction has been demonstrated in patients who There are other signs and symptoms that may be helpful in diagnoshave been detoxified from high-dose opioids.12 When challenged ing OIH. Typically, the pre-existing pain condition will be exacerwith cold pressor tests, opioid addicts maintained on methadone bated. The pain pattern will become more diffuse and less localized.
demonstrated increased pain sensitivity.13
The clinician must rule out further progression of the disease or
increased demand, which is perceived by the patient as increased
need for medication (often referred to as pseudotolerance).
N UROBiOLOGY OF HYP RALG SiA
There are several proposed mechanisms, many of them overlapping, In fact, most patients who are utilizing chronic opioid therapy are
that may explain the phenomenon of OIH. The 3 most commonly mildly hyperalgesic, particularly to acute pain. For example, a scenario with which most interventional pain physicians are familiar is
proposed are:
when a patient on chronic opioid therapy presents for a procedure.
Very often they do not tolerate even the local anesthetic and are less
1. The central glutamate system
tolerant of the acute pain experienced during the procedure. They
2. Elevated spinal dynorphin levels
3. Descending facilitation
often present with intolerance to acute surgical pain. Many surgeons
have discovered that these patients often require more opioid for a
Glutamate is an excitatory neurotransmitter that plays a central longer time postoperatively then the typical opioid naïve patient.
role in several disease states including chronic pain and chemical
dependency. The excitatory neurotransmitter NMDA binds to recep- However, if a patient on chronic opioid therapy (often at moderate to
tors throughout the CNS. With prolonged opioid administration, high doses) presents with diffuse pain, then OIH should be considNMDA receptors become activated. This activation can be inhibited ered. If an increase in opioid fails to address the problem, then OIH
with NMDA receptor antagonists and has been demonstrated to should be considered. If a reduction in opioid produces concomitant
reduction in pain, then certainly OIH is likely.
prevent the development of tolerance and OIH.14,15
e
e
e
Spinal dynorphin levels may increase with continued infusion
of µ-receptor agonists. This in turn leads to increased levels and
the release of spinal excitatory neuropeptides, such as calcitonin
gene-related peptide from primary afferents.16
e
e
e e
OIH TR ATM NT STRAT Gi S
When treating a chronic pain patient, it is important to recognize that
multimodal therapy produces the best results. Rational polypharmacy
to include nonopioid medications should be utilized, particularly in
Descending facilitation may influence OIH through subsets of neu- treating neuropathic pain. This in turn provides an opioid sparing
rons (on and off cells) in the rostral ventromedial medulla, which effect, reducing the total opioid dose and the concomitant opioid side
have the unique response to opioids.17,18 In addition, lesioning of effects. Interventional pain medicine along with behavioral therapy
these descending pathways in animals has been shown to prevent can accomplish similar goals in reducing pharmacotherapy.
increases seen in excitatory neuropeptides.19
If these options are not feasible, then the clinician may consider the
following approaches:
DiAGNOSiNG OPiOiD-INDUC D HYP RALG SiA
When a chronic pain patient demonstrates lack of efficacy to a given 1. Opioid rotation to a different chemical class of opioid
medication, the most common response is to increase the dose of that 2. Utilize NMDA receptor antagonists (ketamine, mematine)
medication. The presumed mechanism is tolerance. With opioids, 3. Reduce or eliminate the opioid and evaluate change in pain
however, does the lack of efficacy equal tolerance or OIH? Clinicians 4. Utilize opioids with unique properties that may mitigate OIH
e
18 | PWJ | www.painweek.org
e
e
Q2 | 2014
e
e e
OPiOiDS WiTH UNiQU PROP RTi S
Methadone is often utilized to treat chronic pain. It is a racemic mixture in which the D isomer is an NMDA receptor antagonist. Methadone displays incomplete cross tolerance unique from other µ-receptor
agonists, which may create a niche role for it in the treatment of OIH
and other forms of intractable pain, particularly neuropathic pain.
Incomplete cross tolerance of methadone has also led to its association
with multiple overdose deaths due to inappropriate escalation of the
dose or combining it with other opioids and CNS depressants.20
Buprenorphine has been used to treat chronic pain and has been
available in the US since the early 1980s. Commercially available
forms for chronic pain include a parenteral form (Buprenex®) and a
transdermal delivery system (Butrans®).
Buprenorphine has shown to be intermediate in its ability to induce
pain sensitivity in opioid addicts maintained on methadone and
control patients not utilizing opioids.13 Buprenorphine is a partial
agonist at the µ-receptor but an antagonist at the k-receptor. Spinal
dynorphin is a known k-receptor agonist that has been implicated
in OIH. Thus, buprenorphine may be unique in its ability to treat
chronic pain and OIH via k antagonism.
e
e
e
TR ATM NT CONSiD RATiONS
Weaning patients from high-dose opioid medications can be
time-consuming and sometimes impractical. For example, patients
often will experience more pain during the weaning process until
eventually they break through the hyperalgesic barrier. Physicians
will often have to adjust combinations of extended-release and
short-acting opioids during the weaning process. Patients may
become frustrated and eventually give up.
Breaking the cycle of pain and hyperalgesia is an attractive option for
the pain practitioner. Medically supervised withdrawal from highdose opioids utilizing sublingual buprenorphine is rapid and effective.
Sublingual buprenorphine is approved for the treatment of opioid
dependence. It requires a waiver from the Substance Abuse Mental
Health Administration and the Drug Enforcement Administration.
Patients who suffer from OIH can be transitioned to sublingual
buprenorphine just as patients suffering from opioid addiction are.
The buprenorphine can then be weaned accordingly.
CONCLUSiONS
Opioid therapy can be very effective for chronic nonmalignant pain.
However, like any other therapy, side effects and complications can
occur. The physician should have an exit strategy when initiating
opioids for the treatment of chronic pain. The potential for dealing
with complications such as opioid dependence, addiction, abuse, and
OIH are very real, and the pain practitioner must be prepared for
these challenges. As the number of patients treated with chronic
opioids increases, so do the complications. OIH should be considered
in the differential diagnosis when patients fail to respond to opioid
therapy, as part of a comprehensive assessment and informed consent/
agreement. Q2 | 2014
References
1. Albutt C. On the abuse of hypodermic injections of morphia. Practitioner.
1870;5:327–331.
2. Centers for Disease Control and Prevention. CDC vital signs: prescription painkiller overdoses in the US . November 2011. Available at: www.cdc.gov/VitalSigns/
PainkillerOverdoses/index.html.
3. Silverman S. Opioid induced hyperalgesia: clinical implications for the pain
practitioner. Pain Physician. 2009;12:679–684.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington, DC: American Psychiatric Press; 1994.
5. Compton P, Rollin M, Gallagher MD, et al. The neurophysiology of pain and
interfaces with addition. In: Principles of Addiction Medicine. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2009:1286–1287.
6. Yaksh TL , Malmberg AB . Central pharmacology of nociceptive transmission. In:
Wall P, Melzack R, eds. Textbook of Pain. 3rd ed. Edinburgh, UK: Churchill Livingstone;
1994:165–200.
7. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid
therapy. Pain. 2002;100:213–217.
8. Mao J, Price D, Mayer D. Mechanisms of hyperalgesia and morphine tolerance:
a current view of their possible interactions. Pain. 1995;62:259–274.
9. Celerier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in
rats: preventive effect of ketamine. Anesthesiology. 2000;92:465–472.
10. Celerier E, Laulin JP, Corcuff JB, et al. Progressive enhancement of delayed
hyperalgesia induced by repeated heroin administration: a sensitization process.
J Neurosci. 2001;21:4074–4080.
11. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative
remifentanil increases postoperative pain and morphine requirement. Anesthesiology.
2000;93:409–417.
12. Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients
after detoxification from high dose opioids. J Opioid Manag. 2006;2:277–282.
13. Compton P, Charuvastra VC , Ling W. Pain intolerance in opioid-maintained
former opiate addicts: effect of long acting maintenance agent. Drug Alcohol Depend.
2001;63:139–146.
14. Trujillo KA , Akil H. Inhibition of morphine tolerance and dependence by the
NMDA receptor antagonist MK-801. Science. 1991;251:85–87.
15. Marek P, Ben Eliyahu S, Gold M, et al. Excitatory amino acid antagonists
(kynurenic acid and MK-801) attenuate the development of morphine tolerance in the
rat. Brain Res. 1991;547:77–81.
16. Gardell LR , Wang R, Burgess SE, et al. Sustained morphine exposure induces
a spinal dynorphin-dependent enhancement of excitatory transmitter release form
primary afferent fibers. J Neurosci. 2002; 22:6747–6755.
17. Barbaro NM , Heinricher MM , Fields HL . Putative pain modulating neurons in the
rostral ventral medulla: reflex-related activity predicts effects of morphine. Brain Res.
1986;366:203–210.
18. Heinricher MM , Morgan MM , Fields HL . Direct and indirect actions of morphine
on medullary neurons that modulate nociception. Neuroscience. 1992;48:533–543.
19. Morgan MM , Heinricher MM , Fields HL . Circuitry linking opioid-sensitive
nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral
ventromedial medulla. Neuroscience. 1992;47:863–871.
20. Centers for Disease Control and Prevention. CDC vital signs: use and abuse
of methadone as a pain killer. Available at: http://www.cdc.gov/vitalsigns/
MethadoneOverdoses/.
www.painweek.org | PWJ | 19
“
Our society
appears to reward
humiliating and
demeaning
experiences,
promoting a
winner or loser
mentality that
encourages
dominance and
aggression.”
Are you the victim or the perpetrator
ANeY
H
L
e
c
LISA M
by NADDi
abstract: The increase of litigation in the healthcare industry has brought attention to issues
of workplace safety and the behaviors of medical professionals. Not only has there been
an increase in reported cases of patients being aggressive or violent towards healthcare
professionals, there has also been an increase in reported cases of staff members being
aggressive towards each other. Bullying contributes to deficiencies in the healthcare
workplace. Whether the healthcare professionals are on the contributing or the receiving
end of the mistreatment, there are significant decreases in job satisfaction and increases
in job-induced stress, anxiety, and a desire to leave employment, thus generating numerous legal repercussions for not only the retention of medical staff, but correspondingly the
aptitude of the staff to focus on and provide accurate medical treatment.
the societal expectations of the law enforcement profes- actions conveying fear of retribution if they “don’t” perform their
sion and the healthcare profession are focused on 2 basics principles: duties a certain way and express conditions of emotional or physical
to help those individuals in need and to do no harm. For the most intimidation and perceived bullying in their workplace. There are
part through the years, these 2 professions have worked shoulder many types of victims, and some have described a slow and deliberto shoulder to combat a variety of unpleasant circumstances, often ate transition from the status of “victim” to “perpetrator.”
calling upon each other for assistance. As industry oversight has
increased in the last few decades, law enforcement has been called
upon more to investigate criminal violations within the healthcare WHAT iS BULLYiNG?
field. Oftentimes the allegations are related to an issue of the diver- The Merriam-Webster Dictionary definition of bullying: to treat
sion of pharmaceutical drugs, a property crime, or an act of domestic another abusively, to affect by means of force or coercion, or to use
violence. More recent demands, however, have required in-depth browbeating language or behavior.1
investigations into the activities of rogue practitioners, their staff,
and their business practices.
Our society appears to reward humiliating and demeaning experiences, promoting a winner or loser mentality that encourages domDuring the course of various criminal investigations into the activ- inance and aggression. This attitude has been supported since the
ities of medical professionals, law enforcement has discovered a pat- period of the gladiators and is still popular in today’s reality televitern of coercion or bullying—both internal and external to the sion programs. While communities often attribute bullying behavpractice. Countless individuals interviewed defend their improper ior to adolescents, in truth incidents of violence have increased in
Q2 | 2014
www.painweek.org | PWJ | 21
NATIONAL ASSOCIATION OF DRUG DIVERSION INVESTIGATORS
both schools and workplaces in the past few decades. As a result,
greater focus has been directed to and acutely studied on the social
interactions in these environments. The term bullying has become
more recognized as a form of harassment, and has been acknowledged within a variety of workplace environments.
often requires viable consequences for any noncompliance. The
aggression is often passive and indirect, involving acts of disparaging treatment, such as engaging in bad-mouthing and gossip.
Incidents of sexual harassment and physical coercion between colleagues are not new to the healthcare industry. The consequences
most often revolve around a fiscal impact to the target employee
Bullying behavior consists of 4 basic types of abuse: emotional, verbal, such as the threat of loss of their job or position in the workplace.
physical, and cyber.2 Incidents of bullying behavior often begin in the The bullying behavior usually begins with a subtle approach that
early phases of personal development and usually end when individ- appears as a voluntary acceptance and gradually escalates to a situals being bullied become assertive and learn skills to protect them- uation through coercion where the targeted individual is afraid
selves. The societal hierarchies create an environment conducive to of any confrontation which will cause an act of reprisal. Thus the
the influences of power and control, and expectations of subservience. behavior continues and as such becomes a workplace norm that,
More often than not, the bullied feel somewhat responsible for being unchallenged, “validates” the perpetrator.
targeted and accept their perceived fate, convinced that they do not
have any options available to them.
The perpetrator of the behavior usually justifies their actions as
necessary to complete their respective goals. The sense of empowerment that builds within the perpetrator often fuels the escalation
of the bullying behavior, which is often displayed in the presence of
BULLYiNG B HAViOR
While bullying behavior in the workplace has been going on for cen- other employees, seeking validation of the bully’s perceived power.
turies, it has only gained recognition in the past decade. In 2010 the The other employees, not wanting to draw the same treatment from
Workplace Bullying Institute surveyed 1069 people of whom 98% the perpetrator, generally ignore the behavior as a personal interacsaid they were targets of workplace bullying.2 The survey sought tion between the targeted employee and the aggressor. Coworkers
to establish if the targets felt personal shame or stigma attached to frequently will listen to complaints from the victim and encourage
them to report the behavior or deal with it, but they will not intertheir bullying, and the following results were reported:
fere with the activity, fearing reprisal.
● 35% believed that “somehow I might have deserved
While the employers set the workplace tone, most develop an avoidthe criticisms”
ance of issues that may interfere with the productivity of the busi● 28% blamed themselves for “not being able to counter
ness. The bullied often attempt to do their job without disrupting
or confront” the bully
the status quo of the workplace and make efforts to deal with the
● 22% were embarrassed from “allowing it to happen to me”
● Only 13% felt no shame, saying they “did not invite or
bullying behavior. This bullying behavior can include various forms
deserve the assaults”
and degrees of verbal taunts, public humiliation, threats of reprisal,
and acts of segregation from other employees.
The study did not define whether the perpetrators of the bullying
behavior were internal colleagues of the recipient’s workplace or
if the individuals were encountered by the employees during the
course of their regular business obligations.
e
Another survey3 provided several key findings from participants:
● 37% of workers have experienced bullying firsthand
● 72% of bullies are bosses
● 60% of bullies are men
● 57% of targets are women, and women bullies target women
in 71% of cases
This survey also determined that bullying is 4 times more prevalent
than illegal harassment and more than half (62%) of employers ignore
the problem. A large percentage (40%) of the bullied individuals never
inform their employers of the activity, and only a small number (3%)
file lawsuits.
e
e
iNT RNAL WORKPLAC BULLYiNG
Internal workplace bullying— or staff-on-staff aggression—is
driven by the offenders’ need to control the target employee and
22 | PWJ | www.painweek.org
“AN OFFiCe ADMiNiSTRATOR
SeT UNReACHABLe GOALS
FOR OFFiCe PRODUCTiON,
CONTiNUOUSLY PeNALiZiNG
THe eMPLOYeeS’ PAY FOR NOT
ReACHiNG THe SeT GOALS.”
e
EXAMPL S
Specific examples of internal bullying include an anesthesiologist who
required a coworker to enter false amounts into the dose administration logs of patients; 2 previous employees who had challenged the
entries were subsequently transferred from the “elite” operating room
team to undesirable shifts. The coworker, not wanting to experience
the same fate as the previous employees, committed a felony violation
and falsified the records. In another instance, an office administrator
set unreachable goals for office production, continuously penalizing
the employees’ pay for not reaching the set goals. This practice was
a violation of federal wage laws. The employees expressed a need to
remain employed and thus endured the fiscal cuts.
Q2 | 2014
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NATIONAL ASSOCIATION OF DRUG DIVERSION INVESTIGATORS
A constant environment of harassment will leave the target individual feeling agitated, anxious, and waiting for bad things to happen;
the bullying behavior will in fact create a problem employee who
will suffer from emotional and social problems. Historically the
targeted individual receives little assistance or sympathy from
coworkers or human resources employees; the belief is that the
behavior isn’t illegal and the employees need to work it out amongst
themselves.
e e
XT RNAL BULLYiNG
External forms of bullying behavior—or patient-on-professional
aggression—are generally driven by perpetrators with a desire
for money or drugs who influence the providers or their staff with
assurances of either remuneration or retribution to gain their way.
Patients can often become assertive when they feel their needs are
not being met, applying pressure to the practitioner or the staff
in an effort to obtain specific requests. The aggression commonly
involves direct verbal abuse and at times, severe physical violence
driven by determination to obtain desired drugs or treatment.
“PATieNTS CAN OFTeN BeCOMe
ASSeRTiVe WHeN THeY FeeL THeiR
NeeDS ARe NOT BeiNG MeT,
APPLYiNG PReSSURe TO THe
PRACTiTiONeR OR THe STAFF iN
AN eFFORT…TO OBTAiN DeSiReD
DRUGS OR TReATMeNT.”
and recurring training for personnel. Mechanisms must be in a position to identify and accurately respond to bullying practices, and
awareness checks should be performed for acts of psychological violence, psychological harassment, personal harassment, status-blind
harassment, mobbing events, or emotional abuse in the workplace.4
Law enforcement often provides security training to businesses in
an effort to reinforce the professional responsibilities of providing
a safe working environment for their employees, as well as appropriate prescribing practices. A prevention plan is extremely important to protect the business’ interests, to provide a safe and secure
working environment, and to fulfill any local, state, and government requirements. The prevention plan is often combined with an
ethics or sexual harassment policy and assists in the development of
a strong organizational risk management strategy.
CONCLUSiON
Bullying decreases performance and productivity in the healthcare
workplace, leading to job dissatisfaction. Stress and anxiety increase,
making staff retention difficult. Employee aptitude declines and
legal repercussions arise.
By applying the necessary steps to prevent bullying activity, the
practitioner also secures the business’ reputation, principles, and
integrity. To maintain a secure, nonhostile work environment it is
important to plan for unforeseen incidents and to make sure that all
personnel are aware of the applicable policies and properly trained
in prevention and response procedures. e
EXAMPL S
Specific examples of external bullying include documented incidents of female patients providing sexual favors to physicians who
illegally compensate the patient with pain medications. Regrettably
if the physician decides to refuse to provide the requested drugs or
to cease future demands, the physician is threatened with a sexual
misconduct complaint to the licensing board. In most instances, the
illegal cycle of dispensing continues until law enforcement becomes
involved.
Another example focuses upon racketeers who manipulate practitioners and their staff with more money than either could earn in
a normal clinical situation. These organizations have been investigated by law enforcement for acts related to insurance fraud, illegal
drug distribution, and money laundering activities. Once the cycle
of activity begins, unless it is immediately reported by the receiver,
it will continue, and there rarely is an easy exit for the practitioners.
ee
PR V NTiON PLANS
According to the Workplace Bullying Institute, every healthcare
organization should have steps in place to handle bullying threats
or security vulnerabilities. Basic security measures include policies,
a defined prevention plan, mandatory reporting and documentation,
24 | PWJ | www.painweek.org
References
1. “Bullying.” Merriam-Webster’s Collegiate Dictionary. 11th ed. Springfield, MA:
Merriam-Webster Inc; 2003.
2. Workplace Bullying Institute. Self-defeating stigma an integral part of workplace bullying. November 9th, 2010. Available at: http://www.workplacebullying.
org/2010/11/09/shame/.
3. Workplace Bullying Institute. Results of the 2007 WBI U.S. Workplace Bullying
Survey. Available at: http://www.workplacebullying.org/wbiresearch/wbi-2007.
4. Ferris PA . The role of the consulting psychologist in the prevention, detection, and correction of bullying and mobbing in the workplace. Consult Psychol J.
2009;61(3):169–189.
Q2 | 2014
NOW APPROVED
NOW APPROVED
The onset you expect. The duration they deserve.
XARTEMISTM XR is the first and only FDA-approved oxycodone/acetaminophen
combination to provide immediate- and extended-release analgesia.1
INDICATIONS AND USAGE
XARTEMIS XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII) is
indicated for the management of acute pain severe enough to require opioid treatment and
for which alternative treatment options are inadequate. Because of the risks of addiction,
abuse, misuse, overdose, and death with opioids, even at recommended doses, reserve
XARTEMIS XR for use in patients for whom alternative treatment options (e.g., non-opioid
analgesics) are ineffective, not tolerated, or would be otherwise inadequate.
NEW
XARTEMIS™ XR (oxycodone HCl and acetaminophen) Extended-Release Tablets (CII)
The onset you expect.
The duration they deserve.
XARTEMIS™ XR is the first and only
FDA-approved oxycodone/acetaminophen
combination to provide immediate- and
extended-release analgesia.1
Delivers onset of pain relief in less than an hour
and lasts up to 12 hours.1,2
•
In the clinical trial, supplemental analgesia was available
to patients in the XARTEMIS XR and placebo groups.
•
Supplemental ibuprofen was used by less than 50% of the
XARTEMIS XR-treated patients after the first dose interval.
NEW
Dosed as 2 tablets, twice a day.1
•
On the first day of treatment, an additional dose may be
taken at 8 hours after initial dose if pain intensity requires it.
Visit xartemisxr.com/pwj
to discover a new approach to managing acute pain.
IMPORTANT RISK INFORMATION
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; and HEPATOTOXICITY
See full prescribing information for complete boxed warning.
•
XARTEMIS XR exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each
patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.
•
Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following
a dose increase. Instruct patients to swallow tablets whole to avoid exposure to a potentially fatal dose of oxycodone.
•
Accidental consumption of XARTEMIS XR, especially in children, can result in fatal overdose of oxycodone.
•
Prolonged use of XARTEMIS XR during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the
patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
•
XARTEMIS XR contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times
resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at
doses that exceed the maximum daily limit, and often involve more than one acetaminophen-containing product.
CONTRAINDICATIONS
•
ADVERSE REACTIONS
XARTEMIS XR is contraindicated in patients with:
•
- known hypersensitivity to oxycodone, acetaminophen,
or any other component of this product.
Serious adverse events may include respiratory depression
and hepatotoxicity.
•
Common adverse events may include nausea, dizziness,
headache, vomiting, constipation and somnolence.
- significant respiratory depression.
- acute or severe bronchial asthma or hypercarbia.
- known or suspected paralytic ileus.
See Brief Summary of Full Prescribing Information on the following pages. For additional Important Risk Information, including full
boxed warning, visit xartemisxr.com.
References: 1. XARTEMIS XR [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2014. 2. Singla N, Barrett T, Sisk L, Kostenbader K, Young J, Giuliani M. A randomized, double-blind,
placebo-controlled study of the efficacy and safety of MNK-795, a dual-layer, biphasic, immediate-release and extended-release combination analgesic for acute pain. Curr Med Res Opin. 2014;30(3):349-359.
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals
logo and other brands are trademarks of a Mallinckrodt company.
© 2014 Mallinckrodt. March 2014
BRIEF SUMMARY - Consult full
prescribing information before use.
XARTEMIS XR (oxycodone hydrochloride and acetaminophen)
Extended-Release Tablets, for oral use, CII
Initial U.S. Approval: 1976
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL
EXPOSURE; NEONATAL OPIOID
WITHDRAWAL SYNDROME; and HEPATOTOXICITY
Addiction, Abuse, and Misuse
XARTEMIS XR exposes patients and other users to the risks
of opioid addiction, abuse, and misuse, which can lead
to overdose and death. Assess each patient’s risk prior
to prescribing XARTEMIS XR, and monitor all patients
regularly for the development of these behaviors or
conditions [see Warnings and Precautions (5.1)].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of XARTEMIS XR. Monitor for
respiratory depression, especially during initiation
of XARTEMIS XR or following a dose increase. Instruct
patients to swallow XARTEMIS XR tablets whole; crushing,
chewing, or dissolving XARTEMIS XR can cause rapid
release and absorption of a potentially fatal dose of
oxycodone [see Warnings and Precautions (5.2)].
Accidental Exposure
Accidental ingestion of XARTEMIS XR, especially in
children, can result in a fatal overdose of oxycodone [see
Warnings and Precautions (5.2)].
Neonatal Opioid Withdrawal Syndrome
Prolonged use of XARTEMIS XR during pregnancy can
result in neonatal opioid withdrawal syndrome, which
may be life-threatening if not recognized and requires
management according to protocols developed
by neonatology experts. If opioid use is required for
a prolonged period in a pregnant woman, advise
the patient of the risk of neonatal opioid withdrawal
syndrome and ensure that appropriate treatment will be
available [see Warnings and Precautions (5.3)].
Hepatotoxicity
XARTEMIS XR contains acetaminophen. Acetaminophen has
been associated with cases of acute liver failure, at times
resulting in liver transplant and death. Most of the cases of
liver injury are associated with the use of acetaminophen
at doses that exceed the maximum daily limit, and often
involve more than one acetaminophen-containing product
[see Warnings and Precautions (5.7, 5.11)].
CONTRAINDICATIONS
XARTEMIS XR tablets are contraindicated in patients with
• Known hypersensitivity to oxycodone, acetaminophen, or
any other component of this product [see Warnings and
Precautions (5.12)].
• Significant respiratory depression
• Acute or severe bronchial asthma or hypercarbia
• Known or suspected paralytic ileus
WARNINGS AND PRECAUTIONS
XARTEMIS XR is not interchangeable with other oxycodone/
acetaminophen products because of differing pharmacokinetic
profiles that affect the frequency of administration.
Addiction, Abuse, and Misuse
XARTEMIS XR contains oxycodone, a Schedule II controlled
substance. As an opioid, XARTEMIS XR exposes users to the
risks of addiction, abuse, and misuse [see Drug Abuse and
Dependence (9)]. Although the risk of addiction in any individual
is unknown, it can occur in patients appropriately prescribed
XARTEMIS XR and in those who obtain the drug illicitly.
Addiction can occur at recommended doses and if the drug
is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse
prior to prescribing XARTEMIS XR, and monitor all patients
receiving XARTEMIS XR for the development of these behaviors
or conditions. Risks are increased in patients with a personal
or family history of substance abuse (including drug or alcohol
addiction or abuse) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the
prescribing of XARTEMIS XR for the proper management of pain
in any given patient. Patients at increased risk may be prescribed
modified-release opioid formulations such as XARTEMIS XR, but
use in such patients necessitates intensive counseling about
the risks and proper use of XARTEMIS XR along with intensive
monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of XARTEMIS XR by crushing, chewing,
snorting, or injecting the dissolved product will result in the
uncontrolled delivery of the oxycodone and can result in
overdose and death [see Overdosage (10)].
Life-threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has
been reported with the use of opioids, even when used as
recommended. Respiratory depression from opioid use, if not
immediately recognized and treated, may lead to respiratory
arrest and death. Management of respiratory depression may
include close observation, supportive measures, and use of
opioid antagonists, depending on the patient’s clinical status
[see Overdosage (10)]. Carbon dioxide (CO2) retention from
opioid-induced respiratory depression can exacerbate the
sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression
can occur at any time during the use of XARTEMIS XR, the risk
is greatest during the initiation of therapy or following a dose
increase. Closely monitor patients for respiratory depression
when initiating therapy with XARTEMIS XR and following
dose increases.
To reduce the risk of respiratory depression, proper dosing
and titration of XARTEMIS XR are essential [see Dosage and
Administration (2)]. Overestimating the XARTEMIS XR dose
when converting patients from another opioid product can
result in fatal overdose with the first dose.
Accidental consumption of XARTEMIS XR, especially by
children, can result in respiratory depression and death due to
an overdose of oxycodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of XARTEMIS XR during pregnancy can result in
withdrawal signs in the neonate. Neonatal opioid withdrawal
syndrome, unlike opioid withdrawal syndrome in adults, may
be life-threatening if not recognized and requires management
according to protocols developed by neonatology experts. If
opioid use is required for a prolonged period in a pregnant
woman, advise the patient of the risk of neonatal opioid
withdrawal syndrome and ensure that appropriate treatment
will be available.
Neonatal opioid withdrawal syndrome presents as irritability,
hyperactivity and abnormal sleep pattern, high pitched cry,
tremor, vomiting, diarrhea and failure to gain weight. The onset,
duration, and severity of neonatal opioid withdrawal syndrome
vary based on the specific opioid used, duration of use, timing
and amount of last maternal use, and rate of elimination of the
drug by the newborn.
Interactions with Central Nervous System Depressants
Hypotension, profound sedation, coma, respiratory depression,
and death may result if XARTEMIS XR is used concomitantly with
alcohol or other central nervous system (CNS) depressants (e.g.,
sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of XARTEMIS XR in a patient taking a
CNS depressant, assess the duration use of the CNS depressant
and the patient’s response, including the degree of tolerance
that has developed to CNS depression. Additionally, evaluate
the patient’s use of alcohol or illicit drugs that cause CNS
depression. If the decision to begin XARTEMIS XR is made, start
with XARTEMIS XR 1 tablet every 12 hours, monitor patients
for signs of sedation and respiratory depression, and consider
using a lower dose of the concomitant CNS depressant [see
Drug Interactions (7.1)].
Elderly, Cachectic, and Debilitated Patients
Life-threatening respiratory depression is more likely to occur
in elderly, cachectic, or debilitated patients as they may have
altered pharmacokinetics or altered clearance compared to
younger, healthier patients. Monitor such patients closely,
particularly when initiating and titrating XARTEMIS XR and
when XARTEMIS XR is given concomitantly with other drugs
that depress respiration [see Warnings and Precautions (5.2)].
Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and patients having
a substantially decreased respiratory reserve, hypoxia,
hypercapnia, or preexisting respiratory depression for
respiratory depression, particularly when initiating therapy and
titrating with XARTEMIS XR, as in these patients, even usual
therapeutic doses of XARTEMIS XR may decrease respiratory
drive to the point of apnea [see Warnings and Precautions (5.2)].
Consider the use of alternative non-opioid analgesics in these
patients if possible.
Hepatotoxicity
XARTEMIS XR contains oxycodone and acetaminophen.
Acetaminophen has been associated with cases of acute liver
failure, at times resulting in liver transplant and death. Most
of the cases of liver injury are associated with the use of
acetaminophen at doses that exceed 4000 milligrams per day,
and often involve more than one acetaminophen-containing
product. The excessive intake of acetaminophen may be
intentional to cause self-harm or unintentional as patients
attempt to obtain more pain relief or unknowingly take
other acetaminophen-containing products. The typical daily
acetaminophen contribution from XARTEMIS XR is 1300 mg.
The risk of acute liver failure is higher in individuals with
underlying liver disease and in individuals who ingest alcohol
while taking acetaminophen.
Instruct patients to look for acetaminophen or APAP on
package labels and not to use more than one product that
contains acetaminophen. Instruct patients to seek medical
attention immediately upon ingestion of more than 4000
milligrams of acetaminophen per day, even if they feel well.
Serious Skin Reactions
Rarely, acetaminophen may cause serious skin reactions
such as acute generalized exanthematous pustulosis (AGEP),
Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal. Inform patients about the
signs of serious skin reactions, and use of the drug should be
discontinued at the first appearance of skin rash or any other
sign of hypersensitivity.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of narcotics and their
capacity to elevate cerebrospinal fluid pressure may be
markedly exaggerated in the presence of head injury, other
intracranial lesions, or a pre-existing increase in intracranial
pressure. Furthermore, narcotics produce adverse reactions
which may obscure the clinical course of patients with
head injuries.
Hypotensive Effect
Oxycodone may cause severe hypotension particularly in
individuals whose ability to maintain blood pressure has been
compromised by a depleted blood volume, or after concurrent
administration with drugs which compromise vasomotor tone
such as phenothiazines. Administer XARTEMIS XR with caution
to patients in circulatory shock, since vasodilation produced
by the drug may further reduce cardiac output and blood
pressure. XARTEMIS XR may produce orthostatic hypotension
in ambulatory patients [see Drug Interactions (7.1)].
Use With Other Acetaminophen-containing Products
The typical daily acetaminophen-contribution from
XARTEMIS XR is 1300 mg. Due to the potential for acetaminophen hepatotoxicity at doses higher than 4000 milligrams/day,
XARTEMIS XR should not be used concomitantly with other
acetaminophen-containing products.
Hypersensitivity/Anaphylaxis
There have been post-marketing reports of hypersensitivity
and anaphylaxis associated with use of acetaminophen.
Clinical signs included swelling of the face, mouth, and throat,
respiratory distress, urticaria, rash, pruritus, and vomiting.
There were infrequent reports of life-threatening anaphylaxis
requiring emergency medical attention. Instruct patients to
discontinue XARTEMIS XR immediately and seek medical
care if they experience these symptoms. Do not prescribe
XARTEMIS XR for patients with acetaminophen allergy.
Difficulty Swallowing
Due to characteristics of the formulation that cause the tablets
to swell and become sticky when wet, consider use of an
alternative analgesic in patients who have difficulty swallowing
and patients at risk for underlying GI disorders resulting in a
small gastrointestinal lumen. Instruct patients not to pre-soak,
lick or otherwise wet XARTEMIS XR tablets prior to placing in the
mouth, and to take one tablet at a time with enough water to
ensure complete swallowing immediately after placing in mouth.
Gastrointestinal Effects
XARTEMIS XR is contraindicated in patients with known or
suspected paralytic ileus. Opioids diminish propulsive
peristaltic waves in the gastrointestinal tract and decrease
bowel motility. Monitor for decreased bowel motility in postoperative patients receiving opioids. The administration of
XARTEMIS XR may obscure the diagnosis or clinical course in
patients with acute abdominal conditions. Oxycodone may
cause spasm of the Sphincter of Oddi. Monitor patients with
biliary tract disease, including acute pancreatitis.
Cytochrome P450 3A4 Inhibitors and Inducers
Since the CYP3A4 isoenzyme plays a major role in the
metabolism of XARTEMIS XR, drugs that alter CYP3A4 activity
may cause changes in clearance of oxycodone which could
lead to changes in oxycodone plasma concentrations.
Inhibition of CYP3A4 activity by its inhibitors, such as macrolide
antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,
ketoconazole), and protease inhibitors (e.g., ritonavir), may
increase plasma concentrations of oxycodone and prolong
opioid effects. These effects could be more pronounced with
concomitant use of CYP 2D6 and 3A4 inhibitors.
Cytochrome P450 inducers, such as rifampin, carbamazepine,
and phenytoin, may induce the metabolism of oxycodone and,
therefore, may cause increased clearance of the drug which
could lead to a decrease in oxycodone plasma concentrations,
resulting in a potential lack of efficacy.
If co-administration is necessary, caution is advised when
initiating XARTEMIS XR treatment in patients currently taking,
or discontinuing CYP3A4 inhibitors or inducers. Evaluate these
patients at frequent intervals and consider dose adjustments
until stable drug effects are achieved [see Drug Interactions (7.4)].
Driving and Operating Machinery
XARTEMIS XR may impair the mental and/or physical abilities
required for the performance of potentially hazardous tasks
such as driving a car or operating machinery. The patient using
this drug should be cautioned accordingly.
ADVERSE REACTIONS
The following treatment-emergent adverse reactions are
discussed in more detail in other sections of the labeling:
• Respiratory Depression [see Contraindications (4), Warnings
and Precautions (5.2), and Overdosage (10)]
• Hepatotoxicity [see Warnings and Precautions (5.7)]
• Use With Other Acetaminophen-containing Products [see
Warnings and Precautions (5.11)]
• Interactions with Other CNS Depressants [see Warnings and
Precautions (5.4)]
Clinical Studies Experience
Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical
studies of a drug cannot be directly compared to rates in the
clinical studies of another drug and may not reflect the rates
observed in clinical practice.
In safety data from two Phase 3 (one placebo-controlled, one
open-label) trials where multiple doses of XARTEMIS XR were
administered for up to 42 days, the most common adverse
reactions (reported by ≥10% in any XARTEMIS XR dose group)
were: nausea, dizziness and vomiting. The most common
reasons for discontinuation due to AEs in these 2 studies
(reported by ≥1% in any XARTEMIS XR dose group) were
vomiting (4.8%) and nausea (4.1%); there were no reports of
these adverse reactions in the placebo-treated patients.
A total of 1028 subjects in 14 clinical studies were treated
with XARTEMIS XR during the clinical development program,
including 892 subjects treated with 15 mg oxycodone and
650 mg acetaminophen. This dosage regimen of XARTEMIS XR
was administered to 607 patients in two Phase 3 studies (one
placebo-controlled and one open-label).
In a placebo-controlled post-bunionectomy acute pain trial,
329 patients were dosed with 15 mg oxycodone and 650 mg
acetaminophen XARTEMIS XR or placebo orally every 12 hours,
for approximately 48 hours (blinded period) [see Clinical Studies
(14)]. Table 1 lists the adverse reactions reported by ≥1%
of XARTEMIS XR-treated patients and more frequently in
XARTEMIS XR-treated patients compared with placebo.
Table 1. Treatment-Emergent Adverse Reactions* Reported
by ≥1% of XARTEMIS XR-Treated Patients and More
Frequently than Placebo in XARTEMIS XR-Treated Patients
with Postoperative Bunionectomy Pain (blinded period)
Preferred Term
Nausea
Dizziness
Headache
Vomiting
Constipation
Somnolence
Rash
Blister
Dysuria
Edema peripheral
Erythema
Excoriation
Hot flush
Pruritus generalized
XARTEMIS XR
(N = 166)
%
31
13
10
9
4
4
2
1
1
1
1
1
1
1
Placebo
(N = 163)
%
6
1
5
0
3
<1
1
<1
0
0
0
0
<1
0
* A treatment-emergent adverse reaction refers to any
untoward medical event associated with the use of the drug
in humans, whether or not considered drug-related.
Other Adverse Reactions Observed During the Premarketing Evaluation of XARTEMIS XR
The following adverse drug reactions not listed above occurred
in ≥1% of XARTEMIS XR-treated patients in the pooled
safety data from two Phase 3 studies (including a placebocontrolled and an open-label non-controlled safety study)
where multiple-doses of XARTEMIS XR were administered
every 12 hours for up to 42 days:
Gastrointestinal disorders: dry mouth, dyspepsia, diarrhea
General disorders and administration site conditions: fatigue
Investigations: hepatic enzyme increased
Psychiatric disorders: insomnia
Respiratory, thoracic and mediastinal disorders: cough
The following adverse drug reactions occurred in <1% of
XARTEMIS XR-treated patients in the pooled safety data from
the two Phase 3 studies described above:
Cardiac disorders: palpitations
Eye and ear disorders: tinnitus, vision blurred
Gastrointestinal disorders: abdominal discomfort, abdominal
pain, esophageal spasm
General disorders and administration site conditions: asthenia,
chest discomfort, chills, contusion, fall, feeling jittery, malaise,
non-cardiac chest pain, thirst
Immune system disorders: hypersensitivity
Investigations: alanine aminotransferase increased,
aspartate aminotransferase increased, blood lactate
dehydrogenase increased, blood pressure increased, gammaglutamyltransferase increased, liver functional test abnormal
Metabolic and nutritional: decreased appetite
Musculoskeletal and connective tissue disorders: arthralgia,
musculoskeletal stiffness
Nervous system disorders: cognitive disorder, memory
impairment, migraine, myoclonus, paraesthesia, sedation,
tremor
Psychiatric disorders: anxiety, confusional state, disorientation,
euphoric mood, mood altered, sleep disorder, withdrawal
syndrome
Renal and urinary disorders: urine flow decreased
Respiratory, thoracic and mediastinal disorders: dyspnea,
hiccups, hypopnea, oropharyngeal pain, throat irritation
Skin and subcutaneous tissue disorders: dermatitis, ecchymosis,
hyperhidrosis, urticaria
Vascular disorders: flushing, hypertension
DRUG INTERACTIONS
CNS Depressants
The concomitant use of XARTEMIS XR with other CNS
depressants including sedatives, hypnotics, tranquilizers,
general anesthetics, phenothiazines, other opioids, and alcohol
can increase the risk of respiratory depression, profound
sedation, coma and death. Monitor patients receiving
CNS depressants and XARTEMIS XR for signs of respiratory
depression, sedation and hypotension.
When combined therapy with any of the above medications
is considered, the dose of one or both agents should be
reduced [see Dosage and Administration (2.2) and Warnings and
Precautions (5.4)].
Neuromuscular Blocking Agents
Oxycodone, as well as other opioid analgesics, may enhance
the neuromuscular blocking action of skeletal muscle relaxants
and produce an increased degree of respiratory depression.
Monoamine Oxidase Inhibitors
Monoamine Oxidase Inhibitors (MAOIs) have been reported to
intensify the effects of at least one opioid drug causing anxiety,
confusion, and significant depression of respiration or coma.
The use of XARTEMIS XR is not recommended for patients
taking MAOIs or within 14 days of stopping such treatment.
Agents Affecting Cytochrome P450 Enzymes
CYP3A4 Inhibitors
Because the CYP3A4 isoenzyme plays a major role in the
metabolism of oxycodone, drugs that inhibit CYP3A4 activity
may cause decreased clearance of oxycodone which could lead
to an increase in oxycodone plasma concentrations and result
in increased or prolonged opioid effects. These effects could be
more pronounced with concomitant use of CYP2D6 and 3A4
inhibitors. If co-administration with XARTEMIS XR is necessary,
monitor patients for respiratory depression and sedation at
frequent intervals and consider dose adjustments until stable
drug effects are achieved [see Clinical Pharmacology (12.3)].
CYP3A4 Inducers
CYP450 3A4 inducers may induce the metabolism of
oxycodone and, therefore, may cause increased clearance
of the drug which could lead to a decrease in oxycodone
plasma concentrations, lack of efficacy or, possibly,
development of a withdrawal syndrome in a patient
who had developed physical dependence to oxycodone.
If co-administration with XARTEMIS XR is necessary,
monitor for signs of opioid withdrawal and consider dose
adjustments until stable drug effects are achieved [see
Clinical Pharmacology (12.3)].
CYP2D6 Inhibitors
Oxycodone is metabolized in part to oxymorphone via
the Cytochrome P450 isoenzyme CYP2D6. While this
pathway may be blocked by a variety of drugs (e.g., certain
cardiovascular drugs, including amiodarone and quinidine,
and antidepressants), such blockade has not yet been shown
to be of clinical significance with this agent. However, clinicians
should be aware of this possible interaction [see Clinical
Pharmacology (12.3)].
Mixed Agonist/Antagonist Opioid Analgesics
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be
administered with caution to patients who have received
or are receiving a course of therapy with an opioid agonist
analgesic such as XARTEMIS XR. In this situation, mixed
agonist/antagonist analgesics may reduce the analgesic
effect of XARTEMIS XR and/or may precipitate withdrawal
symptoms in these patients.
See Brief Summary of Full Prescribing Information continued on adjacent page.
Anticholinergics
Anticholinergics or other medications with anticholinergic
activity when used concurrently with opioid analgesics may
result in increased risk of urinary retention and/or severe
constipation, which may lead to paralytic ileus.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of
XARTEMIS XR tablets or oxycodone/acetaminophen in
pregnant women. Epidemiological data on oral acetaminophen
use in pregnant women show no increased risk of major
congenital malformations. The incidence of malformations in
human pregnancies has not been established for oxycodone
as the data are limited. All pregnancies, regardless of drug
exposure, have a background risk of 2 to 4% for major birth
defects, and 15 to 20% for pregnancy loss.
No animal reproductive or developmental studies were
conducted with the combination of oxycodone and acetaminophen, the components of XARTEMIS XR. The following data are
based on findings from studies performed with the individual
components. Reproductive and developmental studies in rats
and mice from the published literature identified adverse
events at clinically relevant doses with acetaminophen.
Treatment of pregnant rats with doses of acetaminophen
approximately equal to the maximum human daily dose
(MHDD) showed evidence of fetotoxicity and increases in
bone variations in the fetuses. In another study, necrosis was
observed in the liver and kidney of both pregnant rats and
fetuses at doses approximately equal to the MHDD. In mice
treated with acetaminophen at doses within the clinical dosing
range, a reduction in number of litters of the parental mating
pair was observed as well as retarded growth and abnormal
sperm in their offspring and reduced birth weight in the next
generation. Reproductive studies in rats and rabbits with doses
of oxycodone greater than clinical doses did not show any
teratogenic or embryo-fetal toxic effects. XARTEMIS XR should
be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Prolonged maternal use of opioid analgesics during pregnancy
for medical or nonmedical purposes can result in physical
dependence in the neonate and neonatal opioid withdrawal
syndrome shortly after birth. Observe newborns for symptoms
of neonatal opioid withdrawal syndrome, such as poor feeding,
diarrhea, irritability, tremor, rigidity, and seizures, and manage
accordingly [see Warnings and Precautions (5.3)].
Labor and Delivery
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologic effects in neonates.
XARTEMIS XR is not recommended for use in women during or
immediately prior to labor. Neonates, whose mothers received
opioid analgesics during labor, must be observed closely for
signs of respiratory depression. An opioid antagonist such as
naloxone, must be available for reversal of opioid-induced
respiratory depression in the neonate.
Data
Human Data
Two large population based studies have evaluated the
safety of acetaminophen in pregnant women during the
first trimester; neither study showed an increased risk of
congenital malformations. Available published data
on oxycodone exposure during pregnancy and risk for
malformations are limited and do not allow conclusions
regarding a possible association.
Animal Data
No reproductive or developmental studies were conducted
with the combination of oxycodone and acetaminophen,
the components of XARTEMIS XR. The following data
are based on findings from studies performed with the
individual components.
Studies in pregnant rats that received oral acetaminophen
during organogenesis at doses up to 0.85 times the maximum
human daily dose (MHDD = 4 grams/day, based on a body
surface area comparison) showed evidence of fetotoxicity
(reduced fetal weight and length) and a dose-related increase
in bone variations (reduced ossification and rudimentary rib
changes). Offspring had no evidence of external, visceral,
or skeletal malformations. When pregnant rats received oral
acetaminophen throughout gestation at doses of 1.2-times
the MHDD (based on a body surface area comparison), areas
of necrosis occurred in both the liver and kidney of pregnant
rats and fetuses. These effects did not occur in animals that
received oral acetaminophen at doses 0.3-times the MHDD,
based on a body surface area comparison. In a continuous
breeding study, pregnant mice received 0.25, 0.5, or 1.0%
acetaminophen via the diet (357, 715, or 1430 mg/kg/day).
These doses are approximately 0.43, 0.87, and 1.7 times the
MHDD, respectively, based on a body surface area comparison.
A dose-related reduction in body weights of fourth and fifth
litter offspring of the treated mating pair occurred during
lactation and post-weaning at all doses. Animals in the high
dose group had a reduced number of litters per mating pair,
male offspring with an increased percentage of abnormal
sperm, and reduced birth weights in the next generation pups.
Reproduction studies in Sprague-Dawley rats and New Zealand
rabbits revealed that when oxycodone was administered orally
at doses up to 16 mg/kg (approximately 2 times the daily
oral dose of 90 mg for adults based on a body surface area
comparison) and 25 mg/kg (approximately 5 times the daily
oral dose of 90 mg based on body surface area comparison), it
was non teratogenic or embryo-fetal toxic.
Nursing Mothers
Oxycodone is present in human milk and may result in
accumulation and toxicities such as sedation and respiratory
depression in some infants. Acetaminophen is present in
human milk in small quantities. Based on data from more
than 15 nursing mothers, the calculated infant daily dose of
acetaminophen is approximately 1 to 2% of the maternal dose.
There is one well-documented report of a rash in a breast-fed
infant that resolved when the mother stopped acetaminophen
use and recurred when she resumed acetaminophen use.
Because of the potential for serious adverse reactions in
nursing infants from XARTEMIS XR, a decision should be made
whether to discontinue nursing or discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of XARTEMIS XR in pediatric patients
under the age of 18 years have not been established.
Geriatric Use
Of the 607 subjects in the Phase 3 studies treated with
XARTEMIS XR, 63 (10.3%) were older than age 65, of which
10 (1.6%) were older than age 75. No untoward or unexpected
adverse reactions were seen in the elderly patients who
received oxycodone hydrochloride/acetaminophen extendedrelease tablets. However, special precaution should be given
when determining the dosing amount and frequency of
XARTEMIS XR for geriatric patients, since a greater sensitivity to
oxycodone may be observed in this patient population when
compared to younger patients.
Hepatic Impairment
XARTEMIS XR contains oxycodone and acetaminophen, which
are extensively metabolized in the liver. Their clearance may
be decreased in patients with hepatic impairment. In patients
with hepatic impairment start with one tablet and adjust the
dosage as needed. Monitor closely for respiratory depression
[see Clinical Pharmacology (12.3)].
Renal Impairment
Information from oxycodone HCl indicates that patients
with renal impairment (defined as a creatinine clearance
<60 mL/min) had higher plasma concentrations of oxycodone
than subjects with normal renal function.
In patients with renal impairment start with one tablet and
adjust the dosage as needed. Monitor closely for respiratory
depression [see Clinical Pharmacology (12.3)].
DRUG ABUSE AND DEPENDENCE
Controlled Substance
XARTEMIS XR contains oxycodone, a mu-opioid agonist of
the morphine type and is a Schedule II controlled substance.
XARTEMIS XR is subject to misuse, abuse, addiction and
criminal diversion [see Warnings and Precautions (5.1)].
Abuse
All patients treated with opioids require careful monitoring for
signs of abuse and addiction, because use of opioid analgesic
products carries the risk of addiction even under appropriate
medical use.
Drug abuse is the intentional non-therapeutic use of an overthe-counter or prescription drug, even once, for its rewarding
psychological or physiological effects. Drug abuse includes,
but is not limited to the following examples: the use of a
prescription or over-the-counter drug to get “high,” or the use
of steroids for performance enhancement and muscle build-up.
Drug addiction is a cluster of behavioral, cognitive, and
physiological phenomena that develop after repeated
substance use and include: a strong desire to take the drug,
difficulties in controlling its use, persisting in its use despite
harmful consequences, a higher priority given to drug use than
to other activities and obligations, increased tolerance, and
sometimes a physical withdrawal.
“Drug-seeking” behavior is very common in persons with
substance abuse disorders. Drug-seeking tactics include
emergency calls or visits near the end of office hours, refusal
to undergo appropriate examination, testing or referral,
repeated “loss” of prescriptions, tampering with prescriptions,
and reluctance to provide prior medical records or contact
information for other treating healthcare provider(s). “Doctor
shopping” to obtain additional prescriptions is common among
drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical
dependence and tolerance. Healthcare providers should be
aware that addiction may not be accompanied by concurrent
tolerance and symptoms of physical dependence. In addition,
abuse of opioids can occur in the absence of true addiction.
XARTEMIS XR, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful
record-keeping of prescribing information, including quantity,
frequency, and renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices,
periodic re-evaluation of therapy, and proper dispensing and
storage are appropriate measures that help to limit abuse of
opioid drugs.
Risks Specific to the Abuse of XARTEMIS XR
XARTEMIS XR is intended for oral use only. Abuse of
XARTEMIS XR poses a risk of overdose and death. Abuse
may occur by taking intact tablets in quantities greater than
prescribed or without legitimate purpose, by crushing and
chewing, or snorting the crushed formulation, or by injecting
a solution made from the crushed formulation. The risk of
overdose and death is increased with concurrent abuse of
alcohol or other central nervous system depressants.
With intravenous abuse, the inactive ingredients in
XARTEMIS XR can result in death, local tissue necrosis, infection,
pulmonary granulomas, and increased risk of endocarditis
and valvular heart injury. Parenteral drug abuse is commonly
associated with transmission of infectious diseases such as
hepatitis and HIV.
Dependence
Patients may exhibit tolerance to some of the effects of
oxycodone. Tolerance is the need for increasing doses of
opioids to maintain a defined effect such as analgesia (in the
absence of disease progression or other external factors).
Tolerance may occur to both the desired and undesired effects
of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms
symptoms after abrupt discontinuation or a significant dose
reduction of a drug. Withdrawal also may be precipitated
through the administration of drugs with opioid antagonist
activity, e.g., naloxone or mixed agonist/antagonist
analgesics (pentazocine, butorphanol, buprenorphine,
nalbuphine). Physical dependence may not occur to a
clinically significant degree until after several days to weeks
of continued opioid usage.
The opioid abstinence or withdrawal syndrome is
characterized by some or all of the following: restlessness,
lacrimation, rhinorrhea, yawning, perspiration, chills,
myalgia, and mydriasis. Other symptoms also may develop,
including irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting,
diarrhea, or increased blood pressure, respiratory rate,
or heart rate. In patients suspected of having significant
physical dependence, withdrawal symptoms may be
reduced by tapering therapy.
Infants born to mothers physically dependent on opioids will
also be physically dependent and may exhibit respiratory
difficulties and withdrawal symptoms [see Use in Specific
Populations (8.1, 8.2)].
OVERDOSAGE
Signs and Symptoms
Following an acute overdosage, toxicity may result from the
oxycodone or the acetaminophen.
Oxycodone
Acute overdosage with opioids is often characterized by
respiratory depression, somnolence progressing to stupor
or coma, skeletal muscle flaccidity, cold and clammy skin,
constricted pupils, and, sometimes, pulmonary edema,
bradycardia, hypotension, and death. Marked mydriasis rather
than miosis may be seen due to severe hypoxia in overdose
situations [see Clinical Pharmacology (12.2)].
Acetaminophen
In acetaminophen overdosage, dose-dependent potentially
fatal hepatic necrosis is the most serious adverse effect. Renal
tubular necrosis, hypoglycemic coma, and coagulation defects
may also occur.
Early symptoms following a potentially hepatotoxic overdose
may include: nausea, vomiting, diaphoresis, and general
malaise. Clinical and laboratory evidence of hepatic toxicity
may not be apparent until 48 to 72 hours post-ingestion.
Treatment
A single or multiple drug overdose with oxycodone and
acetaminophen is a potentially lethal polydrug overdose,
and consultation with a regional poison control center is
recommended. Immediate treatment includes support
of cardiorespiratory function and measures to reduce drug
absorption. Oxygen, intravenous fluids, vasopressors, assisted
ventilation, and other supportive measures should be
employed as indicated.
Oxycodone
Primary attention should be given to the reestablishment
of adequate respiratory exchange through provision of a
patent airway and the institution of assisted or controlled
ventilation. The opioid antagonist naloxone hydrochloride is
a specific antidote against respiratory depression which may
result from overdose or unusual sensitivity to opioids, including
oxycodone. Since the duration of action of oxycodone may
exceed that of the antagonist, the patient should be kept
under continued surveillance, and repeated doses of the
antagonist should be administered as needed to maintain
adequate respiration.
Opioid antagonists should not be administered in the absence
of clinically significant respiratory or circulatory depression.
Administer opioid antagonists cautiously to persons who
are known, or suspected to be, physically dependent on
XARTEMIS XR. In such cases, an abrupt or complete reversal of
opioid effects may precipitate an acute abstinence syndrome. In
an individual physically dependent on opioids, administration
of the usual dose of the antagonist will precipitate an acute
withdrawal syndrome. The severity of the withdrawal syndrome
produced will depend on the degree of physical dependence
and the dose of the antagonist administered. If a decision is
made to treat serious respiratory depression in the physically
dependent patient, administration of the agonist should be
begun with care and by titration with smaller than usual doses
of the agonist.
Acetaminophen
Gastric decontamination with activated charcoal should be
administered just prior to N-acetylcysteine (NAC) to decrease
systemic absorption if acetaminophen ingestion is known or
suspected to have occurred within a few hours of presentation.
Serum acetaminophen levels should be obtained immediately
if the patient presents 4 hours or more after ingestion to assess
potential risk of hepatotoxicity; acetaminophen levels drawn
less than 4 hours post-ingestion may be misleading. To obtain
the best possible outcome, NAC should be administered as
soon as possible where impending or evolving liver injury
is suspected. Intravenous NAC may be administered when
circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication.
Procedures to limit the continuing absorption of the drug
must be readily performed since the hepatic injury is dosedependent and occurs early in the course of intoxication.
Inform patients not to adjust the dose of XARTEMIS XR without
consulting with a physician or other healthcare professional.
Inform patients not to not take more than 4000 milligrams of
acetaminophen per day and to call their doctor if they took
more than the recommended dose.
Addiction, Abuse, and Misuse
Inform patients that the use of XARTEMIS XR , even when
taken as recommended, can result in addiction, abuse, and
misuse, which can lead to overdose or death [see Warnings
and Precautions (5.1)]. Instruct patients not to share XARTEMIS
XR with others and to take steps to protect XARTEMIS XR from
theft or misuse.
Life-threatening Respiratory Depression
Inform patients of the risk of life-threatening of respiratory
depression, including information that the risk is greatest when
starting XARTEMIS XR or when the dose is increased, and that
it can occur even at recommended doses [see Warnings and
Precautions (5.2)]. Advise patients how to recognize respiratory
depression and to seek medical attention if breathing
difficulties develop.
Accidental Consumption
Inform patients that accidental exposure, especially in children,
may result in respiratory depression or death [see Warnings
and Precautions (5.2)]. Instruct patients to take steps to store
XARTEMIS XR securely and to dispose of unused XARTEMIS XR
by flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of XARTEMIS XR during pregnancy can result
in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated [see Warnings and
Precautions (5.3)].
Interactions with Alcohol and other CNS Depressants
Inform patients that potentially serious additive effects may
occur if XARTEMIS XR is used with alcohol or other CNS
depressants, and not to use such drugs unless supervised by
a health care provider.
Impairment of Mental or Physical Ability
Inform patients that XARTEMIS XR may cause drowsiness,
dizziness, or lightheadedness and may impair mental and/
or physical ability required for the performance of potentially
hazardous tasks (e.g., driving, operating heavy machinery).
Advise patients started on XARTEMIS XR or patients whose
dose has been adjusted to refrain from any potentially
dangerous activity until it is established that they are not
adversely affected.
Use During Pregnancy
Instruct females of reproductive potential who become or are
planning to become pregnant to consult a physician prior to
initiating or continuing therapy with XARTEMIS XR. Advise
patients that safe use in pregnancy has not been established.
Information Regarding Nursing
Advise women to not breastfeed as breastfeeding may cause
sedation in the infant.
Cessation of Therapy
If patients have been receiving treatment with XARTEMIS XR for
more than a few weeks and cessation of therapy is indicated,
counsel them on the possibility of withdrawal and provide
medical support for safe discontinuation of the product.
Common Side Effects
Advise patients taking XARTEMIS XR of the potential for severe
constipation; appropriate laxatives and/or stool softeners as
well as other appropriate treatments should be initiated from
the onset of opioid therapy.
Advise patients of the most common adverse reactions that
may occur while taking XARTEMIS XR: nausea, dizziness,
headache, vomiting, constipation and somnolence.
XARTEMIS is a trademark of Mallinckrodt LLC.
Mallinckrodt, the “M” brand mark, and the Mallinckrodt
Pharmaceuticals logo are trademarks of a Mallinckrodt
company.
© 2014 Mallinckrodt LLC
Issue: 03/2014
Manufactured for:
Mallinckrodt Brand Pharmaceuticals, Inc.
Hazelwood, MO 63042
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
Provide the following information to patients receiving
XARTEMIS XR or their caregivers:
Proper Administration
Inform patients that XARTEMIS XR is not interchangeable with
other forms of oxycodone/acetaminophen.
Inform patients XARTEMIS XR is a narcotic pain reliever and
must be taken only as directed.
Inform patients to take each tablet with enough water to
ensure complete swallowing immediately after placing in the
mouth, and not to pre-soak, lick, or otherwise wet the tablet
prior to placing in the mouth.
Inform patients that XARTEMIS XR tablets must be swallowed
whole. Do not crush or dissolve. Do not use XARTEMIS XR for
administration via nasogastric, gastric, or other feeding tubes
as it may cause obstruction of feeding tubes.
Inform patients that if they miss a dose to take it as soon as
possible. If it is almost time for the next dose, skip the missed
dose and take the next dose at the regularly scheduled time. Do
not take more than 2 tablets at once unless instructed by their
healthcare provider. If they are not sure about their dosing, call
their healthcare provider.
For additional Important Risk Information, including full boxed warning, visit xartemisxr.com.
by JAMES
e
M. LLiOTT PhD, PT
ee
MUSCULOSK L TAL
“ whiplash associated
disorders (WAD) from
motor vehicle collisions
afflict over 4 million
Americans annually…
reducing Quality of life
and costing $30 billion
for medical and
rehabilitative care.”
Data from the Centers for Disease Control indicates that millions of adult drivers
and passengers are treated in US emergency departments annually for whiplash as the
result of a motor vehicle collision. While it is expected that over half will recover within
the first months postinjury, a quarter will never fully recover. Estimated costs for medical
and rehabilitative care for those patients with poor functional recovery are in the billions
per year and no conservative treatments have shown to positively influence their outcomes.
Unfortunately, in the vast majority of whiplash cases, structural damage on objective imaging is rarely present. Currently, the prevailing opinion is that poor functional recovery is
largely influenced by social, psychological, and behavioral factors and not biological. While
this may be the case in some, emerging evidence (from the author’s lab) demonstrates the
rapid and early expression of muscle fatty infiltrates on MRI, signs of disturbed descending
control, and muscle weakness in the individuals with whiplash associated disorders and
poor functional recovery. The individuals that recover spontaneously following whiplash do
not manifest such signs and symptoms, suggesting a more severe injury with a biological
etiology in the chronic group. This article discusses the need for an integrated biopsychosocial model of these disorders and implications for clinical imaging research informing
assessment and ultimately management options.
abstract:
Q2 | 2014
www.painweek.org | PWJ | 31
MUSCULOSKELETAL PAIN SYNDROMES
hiplash associated disorders (WAD) from motor vehicle collisions (MVC) afflict over 4 million
Americans annually, tremendously reducing their quality of life and costing $30 billion for medical and
rehabilitative care.1 A majority of patients with WAD recover within 2 to 3 months postinjury with a fairly
uncomplicated clinical presentation.2 At the other end of the spectrum is a group of patients (25%) that
never fully recover, demonstrating a more complex clinical picture including severe pain-related disability,3
neck muscle degeneration,4 sensory deficits,5 muscle weakness,6 and psychological distress.7 A number of
psychosocial factors, including coping, expectations, anxiety, and depression have been identified as prognostic of WAD recovery.2 The pathophysiology underlying their chronic debilitating symptoms is unknown,
and the current best multimodal treatments have not shown to positively influence the rate of functional
recovery of both acute and chronic WAD.8-11 Furthermore, no structural cause of the acute or chronic disorder has been found, and traditional clinical imaging approaches yield inconsistent findings. However,
our previous and preliminary MRI work is at odds with this long-held position. We have observed and
quantified MRI findings of muscle degeneration in the neck that is specific to the 25% with poor functional
recovery.4 Such findings of muscle degeneration were not present in those that nominate full recovery or
in those with chronic nontraumatic idiopathic neck disorders,12 suggesting traumatic factors do play a role.
It’s difficult to determine cause and effect, and the precise mechanisms underlying muscle degeneration
and their influence on long-term recovery are unknown…at this time.
e
e
e
Due to the recurrent (and in some cases persistent) nature of symp- PATHOM CHANiCS OF TH WHiPLASH EV NT
toms in some subjects with traumatic3,13 and nontraumatic14 neck Whiplash injuries from a typical low-speed rear-end MVC are
disorders, our research remains focused on establishing a set of quan- defined by energy transfer to the cervical spine resulting from
tifiable measures to improve our understanding of the neuromuscular acceleration-deceleration forces that typically occur with rear-end
mechanisms underlying chronic WAD. We further aim to accurately vector impacts, with and without seat safety systems such as active
and consistently characterize the patient’s persistent pain-related head restraints or energy absorbing seats.16 Such forces, while sigdisability, all the while appreciating the biopsychosocial factors that nificantly reduced with active head restraints,16 can lead to the rapid
can, and likely do, contribute to the clinical course. Such practice development of nonphysiological stresses (producing an ephemcould circumvent the delivery of unnecessary and costly treatments eral S-shaped curve) on the cervical spine, which could result in
that could contribute to iatrogenic disability15 in patients expected to injury to many disparate regional tissues—facet joint capsules,
fully recover and could also provide foundation for the exploration discs, vascular tissues, dorsal root ganglia, nerve roots, and/or the
and development of more informed treatment strategies aimed at spinal cord.17-28 The effect of head position at the time of impact
retarding, if not preventing, the expression of persistent pain for has also been studied, and it has been determined that injury to a
number of vulnerable tissues, including the vertebral artery 29 and
high-risk patients.
32 | PWJ | www.painweek.org
Q2 | 2014
the craniocervical ligamentous tissues,30 are more likely to occur if imaging.34 It may be also possible to determine the severity of the
the head is rotated. Despite this knowledge, the consistent identifi- traumatic event, which may be contributing to their pain and discation of laboratory defined lesions with available imaging technol- ability and thus increase odds for developing a chronic condition.
ogy in patients with whiplash remains poor.31,32 Radiography lacks This work is also well underway.
sensitivity for ruling out bony lesions and the images lack the detail
to quantify the often suspected strain to zygapophyseal joint capsules and/or injured discs. Computed tomography (CT ) can identify AVAiLABL MRi M THODS AND
some cervical spine fractures but, to our knowledge, there are no POT NTiAL CLiNiCAL UTiLiTY
longitudinal studies to determine the prevalence of osseous fractures following a MVC .
MAGN TiZATiON TRANSF R RATiOS: MiCROSCOPiC SCAL
Conventional MRI has largely failed to consistently reveal the Magnetization transfer ratios (MTR) are being studied as semi-quanaxiomatic soft-tissue lesions in patients with traumatic whiplash.33 titative metrics for mild and traumatic brain injury41,42 and peripheral
The lack of specificity may relate to the widespread, and arguably neuropathy43 and are used clinically in diagnostic studies of neuronal
unnecessary,34 use of generic clinical protocols (typically with mag- degeneration in multiple sclerosis,44 Alzheimer’s,45-49 and Parkinson’s
nets at lower field strengths) and limitations in the resolution of the disease.50,51 MTR is an indirect measure of tissue stability, relying on
produced images.35 The advent of higher-field systems (3 Tesla and the exchange of magnetically saturated hydrogen molecules (protons)
greater) has provided a foundation for measuring physiologic pro- between water and solid tissue structures.52,53 MTR can be used as
a measure to characterize the demyelination/degeneration of spinal
cesses that could be associated with injured tissues.36,37
pathways in patients with spinal cord injury (SCI ) as a means to assess
Recent MRI evidence from our research across 2 continents (Aus- prognosis of functional rehabilitation.54 Magnetization transfer imagtralia and North America) has identified the unique expression of ing provides a more sensitive and specific marker of neural pathway
neck muscle degeneration (fatty infiltrates) between 4 weeks and pathology in the cervical cord when compared to traditional T1- and
3 months postwhiplash from a MVC .4 Interestingly, muscle changes T2-weighted signals. MTR measures of the dorsal and ventrolateral
were not present in patients with lower levels of initial pain or in spinal pathways in SCI have shown to be predictive of sensory and
patients with chronic nontraumatic neck pain,12 suggesting trau- motor disability levels, suggesting a noninvasive MRI measure of
matic factors play a role in altering the structure of the neck mus- cord degeneration and determination of impairment is possible.54
cles. Furthermore, the presence of a posttraumatic stress disorder MTR could also provide a sensitive measure of cellular level changes
( PTSD) response mediated the relationship between initial pain in the spinal cord, brain, and muscle tissues in patients with varying
levels and the development of neck muscle fat.4 While preliminary, levels of pain-related disability from a variety of neuromusculoskeletal
the relationship between symptoms of PTSD (a psychological find- disorders (eg, spinal pain and/or concussion).4,55,56
ing) and objective longitudinal data for muscle degeneration (a physical pathology), suggests multiple neuropsychobiological factors
influence recovery rates. Support for a neuropsychobiologic link is MUSCL FAT: MiCRO- AND MACROSCOPiC SCAL
available. While the acute chemical response to traumatic or stress- The quantification of muscle fatty infiltrates on T1-weighted imaging
ful events are beneficial, ongoing systemic stress can have a negative in chronic whiplash55-57 is interesting as such findings were not feaimpact at the level of the skeletal muscle system.38 Under the influ- tured in those with chronic idiopathic neck pain12 and their expression
ence of excessive sympathetic nervous system outflow, intramyo- (between 4 weeks and 3 months postinjury event) appears unique to
cellular oxidative stresses39 may be responsible for the observed those who develop chronic whiplash-related pain.4 It is suggested
muscle changes.39 The persistent presence of oxidative stress can that these muscle changes represent a biologic basis for the transition
dramatically affect skeletal muscle contractility as well as induce to chronic pain following whiplash injury. While the mechanisms
the expression of fibrotic tissues that have been observed in other remain unclear, it is possible that other available MRI techniques
painful conditions (such as fibromyalgia40 ) and possibly the fatty (MTR) could further help quantify earlier physiologic changes at
muscle changes observed in traumatic neck pain.4
the spinal cord and muscle cell that may precede observable muscle
changes on T1-weighted sequences. An earlier detection could prove
Our group has worked towards combining available MRI sequences essential for identifying the presence of select physiologic changes in
for identifying patients determined to be at high risk of poor func- spinal cord functioning with subsequent changes in muscle physioltional recovery. A comprehensive set of sequences provides both a ogy and the development of chronic pain-related disability.
microscopic and macroscopic view of the muscle system. Such findings, in tandem with clinical self-report measures of pain-related
disability, psychosocial risk factors, and psychological responses, FAT/WAT R S PARATiON IMAGiNG
could improve our ability to characterize high-risk patients. Accord- There are several ways to measure the fat composition in various tisingly, a more informed management schema could be explored, sues on MRI. One is to include a dual acquisition method, where an
developed, and tested in clinical trials. This noninvasive methodol- image is primarily water (fat suppressed)58 and a standard image is also
ogy may afford the clinician the ability to triage patients with confi- collected (fat and water). The challenge with this type of acquisition
dence and avoid costs associated with unwarranted and unnecessary remains its reliance on the uniform frequency difference between
e
e
e
e
e
e
e
e
e e
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www.painweek.org | PWJ | 33
MUSCULOSKELETAL PAIN SYNDROMES
water and fat across the whole volume of excitation, which is often
difficult to obtain especially at higher magnetic fields (3 Tesla and
above). A fat suppressed acquisition using a short tau inversion recovery (STIR) sequence is possible, but the quantity of fat has to be
assumed.59
An alternative is the Dixon method,60 where data is collected at
an echo time when water and fat are out of phase and at an echo
time when water and fat are in phase. The data can be collected and
combined in such a way that they generate a fat and water image.
This has been applied successfully in the liver and musculoskeletal
system using an iterative least squares solution called IDEAL.61,62
The method we have used in our studies collects multiple different
echo times sufficiently spaced on the unit circle to provide adequate
phase information for the variable projection ( VARPRO)a algorithm, which generates a globally optimal solution for the water/fat
decomposition.63,64
CONCLUSiONS
The observed temporal alterations in muscle structure and function in traumatic neck disorders provides preliminary evidence for
an objective marker of chronic WAD. Current studies indicate that
the physiologic measures assessed with a combination of available
imaging protocols show promise for detecting patients that may be
at risk for transitioning from acute to chronic WAD-related disability. While such measures hold promise for helping to characterize
the patient at risk for developing along a trajectory of chronicity,
they also provide hope for informing best clinical practice through
novel assessment and management regimens that avoid suggestions
of WAD being purely driven by psychosocial factors, as opposed to
a combined set of identifiable (and modifiable) biopsychosocial factors.65 Furthermore, clinicians across many disciplines may be able
to draw from these findings to improve outcomes among a majority
of their patients that are determined to be following a trajectory
of functional recovery by advising them to allow natural recovery
to occur, thereby circumventing the delivery of unnecessary, and
costly, treatments that have been suggested to contribute to iatrogenic disability.15 5. Sterling M, Jull G, Vicenzio B, et al. Sensory hypersensitivity occurs soon after
whiplash injury and is associated with poor recovery. Pain. 2003;104:509–517.
6. Sterling M, Jull G, Vicenzio B, et al. Development of motor dysfunction following
whiplash injury. Pain. 2003;103:65–73.
7. Sterling M, Jull G, Kenardy J. Physical and psychological factors maintain longterm predictive capacity post-whiplash injury. Pain. 2006;122:102–108.
8. Jull G, Sterling M, Kenardy J, et al. Does the presence of sensory hypersensitivity
influence outcomes of physical rehabilitation for chronic whiplash? A preliminary RCT.
Pain. 2007;129:28–34.
9. Jull G, Kenardy J, Hendrikz J, et al. Management of acute whiplash: a randomized controlled trial of multidisciplinary stratified treatments. Pain. 2013;154:1798–1806.
10. Lamb SE, Gates S, Williams MA , et al. Emergency department treatments and
physiotherapy for acute whiplash: a pragmatic, two-step, randomised controlled trial.
Lancet. 2013;381:546–556.
11. Michaleff ZA , Maher CG, Lin CW, et al. Comprehensive physiotherapy exercise
programme or advice for chronic whiplash (PROMISE ): a pragmatic randomised
controlled trial. Lancet. 2014:S0140–6736(14)60457–8. [Epub ahead of print.]
12. Elliott J, Sterling M, Noteboom JT, et al. Fatty infiltrate in the cervical extensor muscles is not a feature of chronic, insidious-onset neck pain. Clin Radiol. 2008;63:681–687.
13. Carroll LJ, Holm LW, Hogg-Johnson S, et al. Course and prognostic factors for
neck pain in whiplash-associated disorders ( WAD): results of the Bone and Joint
Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders. J Manipulative Physiol Ther. 2009;32:S97-S107.
14. Carroll LJ, Hogg-Johnson S, van der Velde G, et al. Course and prognostic
factors for neck pain in the general population: results of the Bone and Joint Decade
2000–2010 Task Force on Neck Pain and Its Associated Disorders. Spine (Phila Pa
1976). 2008;33:S75–82.
15. Cote P, Soklaridis S. Does early management of whiplash associated disorders
assist or impede recovery. Spine (Phila Pa 1976). 2011;36(25 suppl):S275-S279.
16. Ivancic PC , Sha D, Lawrence BD, et al. Effect of active head restraint on residual
neck instability due to rear impact. Spine (Phila Pa 1976). 2010;35:2071–2078.
17. Grauer JN, Panjabi MM , Cholewicki J, et al. Whiplash produces an S-shaped
curvature of the neck with hyperextension at lower levels. Spine (Phila Pa 1976).
1997;22:2489–2494.
18. Guez M, Hildingsson C, Rosengren L, et al. Nervous tissue damage markers in
cerebrospinal fluid after cervical spine injuries and whiplash trauma. J Neurotrauma.
2003;20:853–858.
19. Kaneoka K, Ono K, Inami S, et al. Motion analysis of cervical vertebrae during
whiplash loading. Spine (Phila Pa 1976). 1999;24:763–769; discussion 770.
20. Martin D, Schoenen J, Lenelle J, et al. MRI -pathological correlations in acute
traumatic central cord syndrome: case report. Neuroradiology. 1992;34:262–266.
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27. Winkelstein BA , Nightingale RW, Richardson WJ, et al. The cervical facet
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28. Chen HB, Yang KH, Wang ZG. Biomechanics of whiplash injury. Chin J Traumatol.
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29. Ivancic PC , Ito S, Tominaga Y, et al. Effect of rotated head posture on dynamic
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30. Kaale BR , Krakenes J, Albrektsen G, et al. Head position and impact direction in
whiplash injuries: associations with MRI -verified lesions of ligaments and membranes
in the upper cervical spine. J Neurotrauma. 2005;22:1294–1302.
31. Myran R, Kvistad KA , Nygaard OP, et al. Magnetic resonance imaging assessment of the alar ligaments in whiplash injuries: a case-control study. Spine (Phila Pa
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32. Siegmund GP, Winkelstein BA , Ivancic PC , et al. The anatomy and biomechanics
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33. Elliott JM , Noteboom JT, Flynn TW, et al. Characterization of acute and chronic
whiplash-associated disorders. J Orthop Sports Phys Ther. 2009;39:312–323.
34. Flynn TW, Smith B, Chou R. Appropriate use of diagnostic imaging in low back
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Sports Phys Ther. 2011;41(11):838–846.
49. Kabani NJ, Sled JG, Shuper A, et al. Regional magnetization transfer ratio
changes in mild cognitive impairment. Magn Reson Med. 2002;47:143–148.
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51. Tambasco N, Pelliccioli GP, Chiarini P, et al. Magnetization transfer changes of
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54. Cohen-Adad J, El Mendili MM , Lehericy S, et al. Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization
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muscles in persistent whiplash-associated disorders: a magnetic resonance imaging
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musculature: a preliminary investigation. Eur Spine J. 2009;18:1371–1378.
36. Curatolo M, Bogduk N, Ivancic PC, et al. The role of tissue damage in whiplash
associated disorders: discussion paper 1. Spine (Phila Pa 1976). 2011;36(25 suppl):S309–315.
58. Haase A, Frahm J, Hänicke W, et al. 1H NMR chemical shift selective (CHESS)
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inversion recovery. J Comput Assist Tomogr. 1985;9(6):1084–1089.
38. Passatore M, Roatta S. Influence of sympathetic nervous system on sensorimotor function: whiplash associated disorders ( WAD) as a model. Eur J Appl Physiol. 2006;98:423–449.
39. Jenkins RR . Exercise and oxidative stress methodology: a critique. Am J Clin Nutr.
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40. Gerdle B, Forsgren MF, Bengtsson A, et al. Decreased muscle concentrations of
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41. Bagley LJ, McGowan JC , Grossman RI, et al. Magnetization transfer imaging of
traumatic brain injury. J Magn Reson Imaging. 2000;11:1–8.
42. McGowan JC, Yang JH, Plotkin RC, et al. Magnetization transfer imaging in the detection of injury associated with mild head trauma. AJNR Am J Neuroradiol. 2000;21:875–880.
43. Sinclair CD, Morrow JM , Miranda MA , et al. Skeletal muscle MRI magnetisation
transfer ratio reflects clinical severity in peripheral neuropathies. J Neurol Neurosurg
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44. Filippi M, Rovaris M. Magnetisation transfer imaging in multiple sclerosis.
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45. Hanyu H, Asano T, Iwamoto T, et al. Magnetization transfer measurements of
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60. Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189–94.
61. Reeder SB, Wen Z, Yu H, et al. Multicoil Dixon chemical species separation with an
iterative least squares estimation method. Magn Reson Med. 2004;51:35–45.
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with echo asymmetry and least-squares estimation (IDEAL): application with fast spinecho imaging. Magn Reson Med. 2005;54:636–644.
63. Hernando D, Kellman P, Haldar JP, et al. Estimation of water/fat images, B0
field map and T2* map using VARPRO. In Proceedings of the 16th Annual Meeting of
ISMRM . Toronto, Canada. 2008:1517.
64. Elliott JM , Walton D, Rademaker A. Quantification of cervical spine muscle fat:
a comparison between T1-weighted and multi-echo gradient echo imaging using a
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Endnotes
a. Saurabh Shah, PhD, implemented the VARPRO algorithm and acquisition
sequence in the cardiovascular R&D team located at Northwestern University.
46. Hanyu H, Asano T, Sakurai H, et al. Magnetization transfer measurements of the
hippocampus in the early diagnosis of Alzheimer’s disease. J Neurol Sci. 2001;188:79–84.
47. Hanyu H, Shimizu S, Tanaka Y, et al. Differences in magnetization transfer ratios
of the hippocampus between dementia with Lewy bodies and Alzheimer’s disease.
Neurosci Lett. 2005;380:166–169.
48. Kabani NJ, Sled JG, Chertkow H. Magnetization transfer ratio in mild cognitive
impairment and dementia of Alzheimer’s type. Neuroimage. 2002;15:604–610.
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www.painweek.org | PWJ | 35
by Erica SiGMAN PT, DPT, OCS
“ Physical therapists…play a significant role in minimizing
the economic burden of chronic pain…and promote
optimal movement strategies, thereby decreasing pain
and improving QOL.”
by Erica SiGMAN PT, DPT, OCS
PHYSiCAL THERAPY
abstract: Joint mobilization and manipulation techniques are
used frequently by physical therapists in order to improve mobility and decrease pain. Joint mobilization, however, affects
more than just the joints. Recent evidence demonstrates how
these techniques go beyond the local level and into the central nervous system. This commentary describes techniques
and highlights supporting evidence for the use of this type of
manual therapy in the treatment of patients with chronic pain.
Chronic and centralized pain is a growing problem, calling for innovative and
cost-effective approaches to management. The prevalence of pain in the public is upwards
of 100 million with the estimated healthcare cost being more than $600 billion per year in
America alone.1 Chronic pain is also responsible for hundreds of thousands of lost work days
and greatly impacts overall quality of life (QOL). In fact, persons with migraine have been
shown to have QOL that is worse than or equal to persons with arthritis, asthma, diabetes,
or depression.1,2
Physical therapists are a part of many comprehensive pain programs that are more cost-effective than traditional medical treatment approaches3 and play a significant role in minimizing
the economic burden of chronic pain. While there are many treatment techniques employed
by physical therapists, joint mobilization and manipulation are widely used to supplement the
plan of care in order to restore pain-free mobility and promote optimal movement strategies,
thereby decreasing pain and improving QOL.
38 | PWJ | www.painweek.org
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Figure: Maitland Grades of Mobilization
Resting Position
Tissue Resistance
Anatomic Limit
Joint Range of Movement
Mobilization and
Manipulation Defined
How Does It Work?
Proposed Mechanisms of Action
The Guide to Physical Therapy Practice defines joint mobilization as
“a manual therapy technique comprised of a continuum of skilled
passive movements to the joints and/or related soft tissues that are
applied at varying speeds and amplitudes, including a small amplitude/high velocity therapeutic movement.” While there are varying
grades of mobilization that can be performed, all grades have the
potential to create change in the central nervous system. Joint mobilization activates mechanoreceptors which activate afferent neurons
that engage synapses in the dorsal column of the spinal cord. Once
this happens, the message is sent up to the thalamus in the brainstem
and then to the somatosensory cortex in the brain. The different
grades of mobilization are illustrated in the Figure (above).
Before understanding the mechanisms by which joint mobilization
and manipulation can help decrease pain, it’s important to review
the potential mechanisms of chronic musculoskeletal pain. Smart
et al describes the different types of pain nicely.4 Nociceptive pain
occurs with the activation of peripheral receptive terminals of primary afferents in response to a noxious stimuli. An example is facet
dysfunction in the cervical spine. Inflammation of the facet joint
causes pain with movement. No pain is present at rest or in a neutral
spinal position. Pain is usually localized to one side of the cervical
spine and reproduced with particular movements and/or postures.
Peripheral neuropathic pain is initiated and/or caused by a primary
lesion or dysfunction in the peripheral nervous system. An example
is cervical radiculopathy, which presents as pain in the cervical spine
and affected upper extremity due to impingement of a nerve at the
level of the root. In this case, the pain is more widespread, burning/
radiating in nature, but still related to particular movements and
positions that impinge upon the affected nerve root. Centralized pain,
in contrast to nociceptive and peripheral neuropathic pain, is fairly
constant. This pain is persistent due to altered pain processing in
the central nervous system. Another way to think of it: the pain is
lasting longer than what is to be expected given the involved tissues
Grades I and II activate type one cutaneous mechanoreceptors and
play a role in gating pain. Therefore grades I and II are used primarily
to help decrease pain at that region. Grade III moves into more tissue
resistance, activating more of the muscle and joint mechanoreceptors.
Grade IV is sustained motion into end range, changing joint capsule
extensibility. Therefore grades III and IV are used to directly improve
joint mobility. A grade V mobilization is a low amplitude/high velocity
thrust technique, otherwise termed manipulation.
Q2 | 2014
www.painweek.org | PWJ | 39
PHYSICAL THERAPY
“Joint mobilization and manipulation can
change central processing by optimizing
movement through improving painfree range of motion, appropriately
altering muscle activity, and improving
proprioception.”
and/or injury. A very clear example of this is phantom limb pain,
where a person continues to experience sensation and pain in a limb
that has been amputated.
There is a healthy sample of evidence supporting the use of joint
mobilization and manipulation to treat nociceptive and peripheral
neuropathic pain. For the purpose of this article, we will concentrate
on how joint mobilization and manipulation can aide in the management of centralized pain.
decreasing muscle tone and spasm.6,7 Joint mobilization and manipulation produces impulses in muscle spindle afferents, which help to
silence gamma motor neurons, thereby improving pain-free mobility
by decreasing muscle tone and spasm.7,8
In addition to silencing unwanted muscle tone, joint mobilization
and manipulation has also been shown to facilitate appropriate
muscle activation and timing in cases where these impairments lead
to pain.1,6,7 For example, persistent low back pain has been shown
to be associated with weakness and improper timing of the lumbar
multifidi and transverse abdominis.9-11 Ultrasound studies show an
increase in the thickness of these muscles with exercise after spinal
manipulation. This improvement of muscle function is positively
correlated with decreased pain and improved disability.9
How does a person get to the point of having persistent and centralized pain? If an injury occurs, whether it’s a macro- or microtrauma, it alters movement in an effort to avoid pain. This altered
movement strategy can impair joint mobility and alter muscle activity, which ultimately affects and changes central processing of that
particular body region.5 Similarly, if there is impaired joint mobility Finally, we can improve movement and normalize central processin the absence of pain (for example, in the case of decreased ankle ing by improving joint and body proprioception.5 A classic example
mobility after a sprain 3 years earlier), it can alter movement, which of disturbed proprioception in a case of chronic pain is a whiplash
changes central processing and can facilitate the development of type of injury, where there is inflammation and pain. This changes
persistent pain.5 Regardless of the pathway, the alteration in central muscle spindle sensitivity, which disturbs the afferent activity in the
processing has been shown to play a large role in centralized pain. region. This alters cortical representation and muscle function of the
Joint mobilization and manipulation can change central process- cervical spine, which leads to disturbances in head-neck awareness,
ing by optimizing movement through improving pain-free range postural stability, oculomotor control, and neck movement control.
of motion, appropriately altering muscle activity, and improving This cascade of events contributes to prolonged pain, dizziness, and
proprioception.
headache.12,13 Since joint mobilization and manipulation activates
proprioceptive afferents, it is a great adjunct to exercise and balance
Mobilization and manipulation can increase pain-free range of training, in order to improve movement void of dysfunction and/
motion and mobility by improving joint capsule extensibility and or pain.14
40 | PWJ | www.painweek.org
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Case Example
A 25-year-old female diagnosed with right thoracic outlet syndrome
reported having pain for 2 years, taking 60 mg of Cymbalta® daily,
and using Lidoderm® patches as needed. Upon the initial physical
therapy evaluation, she reported pain on the right side, which started
in the periscapular region and traveled down the posterior aspect of
the brachium, into the medial aspect of the forearm and last 2 digits
of the hand. She stated that her pain averaged 7/10 and ranged from
4 to 8/10, and was “burning” and “achy.” She also mentioned allodynia in the forearm and hand. Aggravating factors included sitting or
typing more than 30 minutes and any weight-bearing through the
right upper extremity. The outcome questionnaire used was DASH,
the Disabilities of the Arm, Shoulder, and Hand scale. Her score
indicated 58.3% disability of the right arm due to pain.
The neurologic screen, including upper extremity deep tendon
reflexes, dermatome and myotome testing, was symmetric and
normal bilaterally. Cervical spine range of motion was only slightly
limited; however, her arm pain was reproduced with flexion, right
rotation, and left sidebend.
The patient attended a total of 6 physical therapy visits, 30-minutes
each, over the course of 2.5 months. Treatment included patient education regarding ergonomics, activity pacing, and ways to unload her
right upper extremity in all functional positions. Additionally, she was
placed on an exercise program focusing on postural strengthening
and endurance training, cardiovascular endurance, relaxation techniques, diaphragmatic breathing, and movement reeducation. Manual
therapy techniques included manipulation to the thoracic spine and
cervicothoracic junctional region, joint mobilization of the right first
rib, and soft tissue mobilization to the scalenes and pectoralis minor.
The patient was then taught how to perform similar mobilization
techniques at home using tennis balls, a foam roll, and a towel.
After 2.5 months the patient’s average pain was decreased to 3/10 and
the pain ranged from 0 to 4/10. Her pain was located proximally and
never extended distal to the elbow. DASH improved to only 20% disability. Cervical spine range of motion was pain-free and she was able
to sit and type for up to 1.5 hours without symptoms. Additionally,
she had not taken Cymbalta or any other pharmacological treatment
for approximately a month.
Conclusion
References
1. Institute of Medicine. Relieving Pain in America: a Blueprint for Transforming
Prevention, Care, Education, and Research. Washington, DC: National Academies
Press; 2011.
2. Torrance N, Smith BH, Bennett MI, et al. The epidemiology of chronic pain of
predominantly neuropathic origin. Results from a general population survey. J Pain.
2006;7(4):281–289.
3. Gatchel RJ, Okifuji A. Evidence-based scientific data documenting the treatment
and cost-effectiveness of comprehensive pain programs for chronic nonmalignant
pain. J Pain. 2006;7(11):779–793.
4. Smart KM , Blake C, Staines A, et al. Clinical indicators of ‘nociceptive’, ‘peripheral neuropathic’ and ‘central’ mechanisms of musculoskeletal pain. A Delphi survey
of expert clinicians. Man Ther. 2010;15:80–87.
5. Butler DS, Mosley LG. Explain Pain. Adelaide, Australia: Noigroup Publications;
2003.
6. Coronado RA , Gay CW, Bialosky JE, et al. Changes in pain sensitivity following
spinal manipulation: a systematic review and meta-analysis. J Electromyogr Kinesiol.
2012;22(5):752–767.
7. Pickar JG. Neurophysiological effects of spinal manipulation. Spine J.
2002;2:357–371.
8. Martinez-Segura R, De-la-Llave-Rincón AI, Ortega-Santiago R, et al. Immediate
changes in widespread pressure pain sensitivity, neck pain, and cervical range of
motion after cervical or thoracic thrust manipulation in patients with bilateral chronic
mechanical neck pain: a randomized controlled trial. J Orthop Sports Phys Ther.
2012;42(9):806–814.
9. Koppenhaver SL , Fritz JM , Hebert JJ, et al. Association between changes in
abdominal and lumbar multifidus muscle thickness and clinical improvement after
spinal manipulation. J Orthop Sports Phys Ther. 2011;41(6):389–399.
10. MacDonald DA , Dawson AP, Hodges PW. Behavior of the lumbar multifidus
during lower extremity movements in people with recurrent low back pain during
symptom remission. J Orthop Sports Phys Ther. 2011;41(3):155–164.
11. Teyhen DS, Bluemle LN, Dolbeer JA , et al. Changes in lateral abdominal muscle
thickness during the abdominal drawing-in maneuver in those with lumbopelvic pain.
J Orthop Sports Phys Ther. 2009;39(11):791–798.
12. Kristjansson E, Treleaven J. Sensorimotor function and dizziness in neck
pain: implications for assessment and management. J Orthop Sports Phys Ther.
2009;39(5):364–377.
13. O’Leary S, Falla D, Elliott JM , et al. Muscle dysfunction in cervical spine
pain: implications for assessment and management. J Orthop Sports Phys Ther.
2009;39(5):324–333.
14. Haavik H, Murphy B. The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. J Electromyogr Kinesiol.
2012;22:768–776.
15. Aure OF, Nilsen JH, Vasseljen O. Manual therapy and exercise therapy in
patients with chronic low back pain. Spine. 2003;28(6):525–532.
16. Evans R, Bronfort G, Nelson B, et al. Two-year follow-up of a randomized clinical
trial of spinal manipulation and two types of exercise for patients with chronic neck
pain. Spine. 2002;27(21):2383-2389.
Joint mobilization and/or manipulation has been found to be an
effective adjunct to the treatment of chronic and persistent pain.
Both Aure and Evans found a combination of manual therapy and
exercise to be more beneficial than manual therapy alone.15,16 There
are many healthcare practitioners who perform joint mobilization
and manipulation techniques, and it’s important for patients and
those referring to make sure the techniques are being performed as
a part of a comprehensive treatment program.
Q2 | 2014
www.painweek.org | PWJ | 41
by Michael
M. BOTTROS MD/Narendren NARAYANASAMY MD
ee
DiAB T S&PAiN
“Neuropathy of the
GI system could manifest
as nausea, bloating,
abdominal pain,
vomiting, diarrhea,
constipation, and
delayed gastric emptying.”
abstract: An epidemiological world survey estimated an over-
all prevalence of 2.8% diabetics in the year 2000. By 2030,
this number is estimated to increase to 4.4% worldwide, with
the United States ranking third among all countries.1 The
metabolic derangement of diabetes afflicts multiple organ
systems. Neuropathy of the gastrointestinal (GI) system could
manifest as nausea, bloating, abdominal pain, vomiting, diarrhea, constipation, and delayed gastric emptying. The purpose of this review on diabetes is to understand:
1) Gastric emptying physiology; 2) Pathophysiology of gastric
neuronal degeneration and gastroparesis; 3) GI symptom
prevalence; 4) Clinical overview of GI sequelae to diabetes
Q2 | 2014
www.painweek.org | PWJ | 43
DIABETES&PAIN
GASTRiC FUNCTiONAL ANATOMY
Effective gastric emptying is accomplished by the coordinated action of the stomach and
proximal small intestine at a structural and molecular level. A cascade of events takes place
when food particles enter the fundus, which primarily accommodates the contents without
increasing intragastric pressure. This process is enabled mainly by the release of nitric oxide
( NO) via vagal efferent output. Following gastric distension, the interstitial cells of Cajal ( ICC)
generate slow waves in smooth muscles. A membrane potential gradient is established that
ultimately triggers rapid circumferential and longitudinal contractions of smooth muscles
that sweep throughout the body and antrum of the stomach. Macrophages that are normally
present in the gastric lining exert oxidative protective effects on the gastric mucosa by expressing antioxidants like heme oxygenase-1, which produces carbon monoxide. Gastric emptying
finally occurs by antral contractions and from enterogastric reflexes and release of hormones
like cholecystokinin from the duodenum. Food particles less than 3 mm in size enter the
duodenum by a filtration process from antral contractions.2
e
GASTROPAR SiS PATHOPHYSiOLOGY
A major GI complication of diabetes is gastroparesis, which was originally thought to be a
direct result of delayed gastric emptying. However, there seems to be an inconclusive correlation between symptoms and gastric emptying, with weak diagnostic evidence to demonstrate
the abnormality in relation to gastroparesis.
Abdominal pain experienced by diabetics could be due to discordant GI contractions as a result
of autonomic neuropathy. Myenteric and submucous plexus of the enteric nervous system
govern normal gut function by maintaining a balance between the excitatory neurotransmitters, acetylcholine and substance P, and the inhibitory neurotransmitters, vasoactive intestinal
peptide ( VIP), and NO generated from nitric oxide synthase (nNOS). Advanced glycation
products formed due to increased oxygen radicals produced in diabetes could inhibit the
myenteric plexus decreasing n NOS production.2 Studies also show altered chemical coding
leading to neuronal remodeling. These changes occur in the stomach, caecum, ileum, and
proximal colon in 2 phases, an initial neuronal loss followed by a later regeneration.3 These
neuronal changes could be seen as early as 1 week (proximal colon) of diabetes. The inhibitory
neurons (n NOS, VIP and neuropeptide Y) are affected severely while the cholinergic excitatory neuronal density is increased leading to heightened contractility in diabetes. Further, a
sensory neuropeptide, calcitonin gene-related peptide (CGRP) that is colocalized with the
excitatory neurotransmitter substance P is decreased in diabetes. Another factor that is thought
to contribute to gastroparesis in diabetes is loss of ICC that is damaged from impaired upregulation of the antioxidant heme oxygenase-1. Further, a survival factor for ICC, the insulin-like
growth factor-1, is deficient, and relative insulin deficiency in diabetes causes smooth muscle
atrophy that leads to ICC depletion causing gastric dysrhythmias (bradygastria and/or tachygastria). Decreased gastric secretion, blunted pancreatic polypeptide response, reduced pyloric
relaxation, and vagus nerve dysfunction are other manifestations of diabetic neuropathy.2
e e
ee
GI SYMPTOM R Vi W iN DiAB T S
Upper and lower gastrointestinal symptoms are highly prevalent in patients with diabetes. A
population-based survey of 15,000 adults to determine the prevalence of GI symptoms in diabetes showed that the duration of diabetes or the type of treatment were not significantly associated
with the prevalence. Five symptom complexes were analyzed: esophageal, upper dysmotility,
any bowel symptoms, diarrhea, and constipation symptom complex. A significant association
of symptoms of fecal incontinence, dysphagia, and vomiting with odds ratios (OR) of 2.74, 2.71,
and 2.51, respectively, at a 95% confidence interval were shown in patients with diabetes.4
Poor glycemic control could also be associated with a higher prevalence of symptoms in diabetes.
Age and sex adjusted OR for symptoms such as lumpy or hardy stools (OR 3.75), urgency (OR 3.12),
and upper GI dysmotility (OR 1.97) were shown to be independent risk factors in patients with
44 | PWJ | www.painweek.org
Q2 | 2014
poor glycemic control.4 In a multiple logistic regression analysis, glycemic control as represented
by the HbA1C estimation was shown to be the only independent risk factor for the prevalence of
upper GI symptoms.5 Further, patients with HbA1C values >8% had higher prevalence of these
symptoms compared to patients with HbA1C <6% suggesting that strict glycemic control could
play a significant role in decreasing the prevalence of bothersome GI symptoms in diabetic patients.
e
GASTROPAR SiS: clinical overview
ee
PR S NTATiON
Gastroparesis is largely prevalent in women (82%) with a mean age of occurrence at 34 years
of age.6 Slow gastric emptying was seen more commonly in women than men, suggesting a
decreased threshold in the development of gastroparesis in women. The reason for the gender
susceptibility to this pathology is unknown. The clinical presentation is highly variable with
mostly nonspecific symptoms. Usually, patients complain of abdominal pain or discomfort that
is burning, vague, or crampy in nature. Very few patients localize this pain to the epigastric
region; symptoms usually occur after a meal or during nighttime sleep. See Table 1 for possible
etiologies for chronic abdominal pain.
DiAGNOSiS
SCINTIGRAPHY—Abnormal gastric emptying still remains the only objective method to demon-
strate neuromuscular abnormality of the GI system in diabetic gastroparesis. The most commonly used method is scintigraphy, which is the radiographic measurement of a solid meal tagged
with a radiolabeled compound at specific time points from the time of intake. The amount of
food particles measured as a percentage is used to indirectly estimate normal vs abnormal gastric
emptying time. The disadvantages of this test are that it is relatively expensive, involves exposure
to some radiation, and is not standardized across medical centers in the country.1
Other possible tests used in the diagnosis of gastroparesis are:
Gastric emptying breath test using 13C:
89% sensitive and 80% specific
● Gastroduodenal manometry: expensive
and invasive, uncomfortable, with very
limited availability
● Transabdominal ultrasound: requires technical expertise, with limited availability
●
e
MRI: expensive and correlates well with
scintigraphy
● Nondigestible capsules: 87% sensitive
and 92% specific, designed to record pH,
temperature, and pressure
●
e
TR ATM NT
NUTRITION —Though there are no randomized controlled trials done to validate the importance of diet in the management of gastroparesis, studies in healthy volunteers show that
fatty foods could slow gastric emptying. Frequent small meals, chewing well, less fiber, and
a low-fat diet are some recommendations to improve gastric emptying. Further, patients are
encouraged to consume more liquid-based meals such as stew and soups, as this diet seems
to preserve gastric emptying.2
NONPHARMACOLOGIC —These
options are generally used as adjuvants to medications:
Biofeedback therapy
Relaxation therapy
● Physical and occupational therapy
● Cognitive and behavioral strategies
including guided imagery
Q2 | 2014
●
●
●
●
Acupuncture
Transcutaneous electrical nerve
stimulation (time consuming and
some patients find it challenging to
operate the device)
www.painweek.org | PWJ | 45
DIABETES&PAIN
“Chronic abdominal pain due to GI involvement
in diabetes is prevalent, underdiagnosed, and a
complex symptomatology to manage and treat. Hence,
it is imperative for healthcare providers to have an
in-depth understanding of this entity.”
Table 1. Differential Diagnosis for Chronic Abdominal Pain7
Pathology
Comments
Peptic ulcer disease
Epigastric burning pain related to meals
Inflammatory bowel disease
Diffuse abdominal pain, confirmed by upper and lower GI endoscopy
Chronic appendicitis
Underdiagnosed; right lower quadrant pain, retrocolic appendiceal
inflammation diagnosed by digital rectal examination
Diverticular disease and diverticulosis
Usually diagnosed incidentally during colonoscopy or sigmoidoscopy
Nephrolithiasis
Intermittent abdominal pain, migratory symptoms, hemoglobin or red blood
cells in the urine, stones or pelvicalyceal distension seen in ultrasound
Abdominal aortic aneurysm or
mesenteric ischemia
DM II is prone to develop atherosclerosis, confirmed by ultrasound of
abdominal aorta or CT of abdomen
Infectious diseases
Patients on hemodialysis are susceptible to tuberculosis, yersiniosis,
Whipple’s disease, helminthic or other tropical GI infectious diseases
presenting with chronic abdominal pain
Partial intestinal obstruction
Incarcerated hernia, intra-abdominal adhesions, and partial intussusception
Painful rib syndrome (rare)
Common in women; lower chest, upper abdomen, or coastal margin
discomfort, rib pressure reproduces pain
Wandering spleen syndrome (rare)
Torsion of the structures (including blood vessels) that attach to the spleen
leading to splenic infarcts and abdominal pain
Abdominal migraines (rare)
Usually have concomitant migraine headaches
Eosinophilic gastroenteritis (rare)
Present with abdominal pain, nausea, vomiting, and diarrhea;
histopathology of tissue biopsy needed to confirm diagnosis
The Fitz-Hugh–Curtis syndrome (rare)
Right upper quadrant pain in young women due to perihepatic inflammation from Chlamydia trachomatis or Neisseria gonorrhoeae infection
Hereditary angioedema (rare)
C1 esterase inhibitor defect, present in young adolescents as colicky
abdominal pain with nausea, vomiting, and diarrhea associated with
mucosal swelling, usually dissipates spontaneously in 2 to 4 days
Abdominal malignancies or metastatic disease
to abdomen (rare)
Associated systemic symptoms
Somatization disorder (rare)
Psychogenic in origin
46 | PWJ | www.painweek.org
Q2 | 2014
(fenoprofencalciumcapsules) 400 mg
Fast and Effective, Move On With Nalfon
Safety Information
Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Cardiovascular Risk
• Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular
disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG)
surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation
of stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms.
Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).
Nalfon® is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon® should not be given to patients who
have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like
reactions to NSAIDs have been reported in such patients. Nalfon® is contraindicated for the treatment of perioperative pain in the setting of
coronary artery bypass graft (CABG) surgery. Nalfon® is contraindicated in patients with a history of significantly impaired renal function.
Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing
the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs.
Copyright © 2014, Xspire Pharma, Ridgeland, MS 39157
42195-308-09
(fenoprofencalciumcapsules) 400 mg
What makes NALFON a unique and different
non-steroidal anti-inflammatory patient option?
NALFON is Safe...
During clinical studies, Nalfon had less than 2% discontinuation rate due to
gastrointestinal adverse reactions.
NALFON is Effective...
• Nalfon has more clinician use and prescriptions than any other branded NSAID with
over 40 years of use and in excess of 37 million prescriptions.
• Nalfon reaches peak plasma levels within 2 hours of administration.
Peak Levels (2 hours)
0
1
2
3
90% of a single oral dose is
eliminated within 24-hours as
fenoprofen glucuronicle and
4-hydroxfenoprofen glucuronide,
the majority urinary metabolites
of fenoprofen.
4
5
6
7
8
9
NALFON is Flexible...
Unlike other commonly prescribed NSAIDs with QID dosing, Nalfon is dosed
TID for better patient compliance.
NALFON is Cost Effective...
• Nalfon is covered by 90% of all commercial plans with a patient co-pay.
• Nalfon is covered by Medicare-D plans and Tri-Care.
• Only Nalfon offers patients a “Pay No More Than $15” instant pharmacy rebate.
Safety Information
Nalfon® is indicated for relief of mild to moderate pain in adults and for relief of the signs and
symptoms of rheumatoid arthritis and osteoarthritis.
Cardiovascular Risk
• Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious
cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may
increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at greater risk (see WARNINGS).
• Nalfon® is contraindicated for the treatment of perioperative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events (see WARNINGS).
For more information on Nalfon 400 mg,
visit www.nalfon.com
(fenoprofencalciumcapsules) 400 mg
TM
Technology
• Nalfon is the only fenoprofen calcium available in a capsule preparation.
• Nalfon is rapidly absorbed with a 30-minute onset of action.
• Nalfon is readily bound to plasma proteins at 99%.
Recommended Dosing
Carefully consider the potential benefits and risks of Nalfon and other treatment
options before deciding to use Nalfon. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals.
Nalfon is indicated:
• For relief of mild to moderate pain in adults.
• For relief of the signs and symptoms of rheumatoid arthritis.
• For relief of the signs and symptoms of osteoarthritis.
After observing the response to initial therapy with Nalfon,
the dose and frequency should be adjusted to suit an
individual patient's needs.
• The dose should be tailored to the needs of the
patient and may be increased or decreased
depending on the severity of the symptoms.
• Total daily dosage should not exceed 3200 mg.
• Nalfon may be administered with meals or with milk.
• The smallest dose that yields acceptable
control should be employed.
(feno
profen
calcium
capsule
s) 400 m
Disp
*
NALFON 400 mg EP 123
*Not actual size
Use this Nalfon 400 mg capsule for identification.
g
90 C
aps
Take
1 Cap
Q8 H
PRN
rs
Pain
Infla
a
n
d
mma
tion
Contraindications
Nalfon® is contraindicated in patients who have shown hypersensitivity
to fenoprofen calcium. Nalfon® should not be given to patients who
have experienced asthma, urticaria, or allergic-type reactions after
taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like
reactions to NSAIDs have been reported in such patients. Nalfon®
is contraindicated for the treatment of perioperative pain in the setting
of coronary artery bypass graft (CABG) surgery. Nalfon® is
contraindicated in patients with a history of significantly impaired renal function.
Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
After observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to
suit an individual patient's needs.
Nalfon ©2011
is a registered
trademark of Xspire
Pharma.
WraSer Pharmaceuticals
R1NF0210ZJ02
NALFON ®
(fenoprofen calcium capsules, USP) 200 mg and 400 mg
Rx ONLY
Cardiovascular Risk
• Non-Steroidal Anti-Inflammatory (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke,
which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be
at greater risk (See WARNINGS).
• Nalfon® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of stomach or intestines, which
can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at great-er risk for serious gastrointestinal events (see WARNINGS).
DESCRIPTION Nalfon® (fenoprofen calcium capsules, USP) is a nonsteroidal, anti-inflammatory, antiarthritic drug. Nalfon capsules contain fenoprofen calcium as the dihydrate in an amount equivalent to 200 mg (0.826 mmol) or 400 mg (1.65 mmol) of fenoprofen. The 200 mg capsules contain cellulose, gelatin,
iron oxides, silicone, titanium dioxide, and other inactive ingredients. The 400mg capsules contain gelatin, sodium lauryl sulfate, iron oxide yellow, FD&C Blue
1, titanium dioxide, FD&C Red 40, crospovidone, talc, and magnesium stearate. Chemically, Nalfon is an arylacetic acid derivative. Nalfon is a white crystalline powder that has the structural formula C30H26CaO6•2H2O representing a molecular weight of 558.65. At 25°C, it dissolves to a 15 mg/mL solution in
alcohol (95%). It is slightly soluble in water and insoluble in benzene. The pKa of Nalfon is a 4.5 at 25°C.
CLINICAL PHARMACOLOGY Nalfon is a nonsteroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact
mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Results in humans demonstrate that fenoprofen has both antiinflammatory and analgesic actions. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of Nalfon, aspirin, and indomethacin were each compared with those of a placebo. All 3 drugs demonstrated antierythemic activity. In all patients with rheumatoid arthritis, the anti-inflammatory action of Nalfon has been evidenced by relief of pain, increase in grip strength, and reductions in joint
swelling, duration of morning stiffness, and disease activity (as assessed by both the investigator and the patient). The anti-inflammatory action of Nalfon has
also been evidenced by increased mobility (i.e., a decrease in the number of joints having limited motion). The use of Nalfon in combination with gold salts or
corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement
is obtained by adding Nalfon to maintenance therapy with gold salts or steroids. Whether or not Nalfon used in conjunction with partially effective doses of a
corticosteroid has a “steroid-sparing” effect is unknown. In patients with osteoarthritis, the anti-inflammatory and analgesic effects of Nalfon have been demonstrated by reduction in tenderness as a response to pressure and reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both
the patient and the investigator). These effects have also been demonstrated by relief of pain with motion and at rest and increased range of motion in involved joints. In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown Nalfon to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal reactions (nausea, dyspepsia) and tinnitus occurred less frequently in patients treated with Nalfon
than in aspirin-treated patients. It is not known whether Nalfon causes less peptic ulceration than does aspirin. In patients with pain, the analgesic action of
Nalfon has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect. Under
fasting conditions, Nalfon is rapidly absorbed, and peak plasma levels of 50 μg/mL are achieved within 2 hours after oral administration of 600 mg doses.
Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About
90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxyfenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin. The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does
not interfere with absorption of Nalfon. There is less suppression of collagen-induced platelet aggregation with single doses of Nalfon than there is with aspirin.
INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to use Nalfon. Use the
lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Nalfon is indicated: • For relief of mild to
moderate pain in adults. • For relief of the signs and symptoms of rheumatoid arthritis. • For relief of the signs and symptoms of osteoarthritis.
CONTRAINDICATIONS Nalfon is contraindicated in patients who have shown hypersensitivity to fenoprofen calcium. Nalfon should not be given to patients
who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to
NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma). Nalfon is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS). Nalfon is contraindicated in
patients with a history of significantly impaired renal function (see WARNINGS – Advanced Renal Disease).
WARNINGS - CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of
up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be
fatal. All NSAIDs, both COX-2 selective and nonselective, may give a similar risk. Patients with known CV disease or risk factors for CV disease may be at
greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest
duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients
should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent
use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS - Gastrointestinal Effects). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension NSAIDs, including Nalfon, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to
the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs,
including Nalfon, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID
treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients
taking NSAIDs. Nalfon should be used with caution in patients with fluid retention, compromised cardiac function or heart failure. The possibility of renal involvement should be considered. Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Nalfon, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can
be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients,
who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in
approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use,
increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of
peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports
of fatal GI events are in elderly or de-bilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for
an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians
should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a
serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients,
alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and,
secondarily, in renal blood flow, which may precipitate overt renal decomposition. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery
to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Nalfon in patients with
advanced renal disease. There-fore, treatment with Nalfon is not recommended in patients with advanced renal disease. (See CONTRAINDICATIONS).
Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Nalfon. Nalfon should not be
given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Nalfon, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hyper-sensitivity. Pregnancy Starting at 30-weeks gestation, Nalfon and other NSAIDs should be
avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Ocular Studies to date have not shown changes in the eyes
attributable to the administration of Nalfon. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking Nalfon. Central Nervous System Caution should be exercised by patients whose activities require alertness if they experience CNS side effects while taking Nalfon. Hearing Since the safety of Nalfon has not been established in patients with
impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with Nalfon.
PRECAUTIONS - General Nalfon cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Nalfon in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients
taking NSAIDs including Nalfon. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable
elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them
with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred,
should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Nalfon. If clinical signs and symptoms consistent
with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Nalfon should be discontinued. Hematological Effects Anemia is
sometimes seen in patients receiving NSAIDs, including Nalfon. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described
effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Nalfon, should have their hemoglobin or hematocrit checked if they exhibit
any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their
effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Nalfon who may be adversely affected by alterations in
platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients
with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm
which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such
aspirin-sensitive patients, Nalfon should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients - Patients should be informed of the following information before initiating therapy with an NSAID and periodically during
the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. 1. Nalfon, like other NSAIDs, may cause serious CV side effects, such as myocardial infarction (MI) or stroke, which may result in hospitalization and
even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of
breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the
importance of this follow-up (see WARNINGS, Cardiovascular Effects). 2. Nalfon, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side
effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can oc-
cur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be
apprised of the importance of this follow-up (see WARNINGS - Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).
3. Nalfon, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hy-persensitivity such as itching, and should ask for medical advice when observing any indicative
signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as
soon as possible. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. 5. Patients
should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant
tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. 6. Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS). 7. Starting at 30-weeks gestation, Nalfon and other NSAIDs should
be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur.
Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs
or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically.
If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if
abnormal liver tests persist or worsen, Nalfon should be discontinued.
Drug Interactions - ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction
should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin The coadministration of aspirin decreases
the biologic half-life of fenoprofen because of an increase in metabolic clearance that results in a greater amount of hydroxylated fenoprofen in
the urine. Although the mechanism of interaction between fenoprofen and aspirin is not totally known, enzyme induction and displacement of
fenoprofen from plasma albumin binding sites are possibilities. As with other NSAIDs, concomitant administration of fenoprofen calcium and
aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that Nalfon can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has
been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely
for signs of renal failure (see WARNINGS - Renal Effects), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation
of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID.
Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The
effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher
than users of either drug alone. Phenobarbital Chronic administration of phenobarbital, a known enzyme inducer, may be associated with a
decrease in the plasma half-life of fenoprofen. When phenobarbital is added to or withdrawn from treatment, dosage adjustment of Nalfon may
be required. Plasma Protein Binding In vitro studies have shown that fenoprofen, because of its affinity for albumin, may displace from their
binding sites other drugs that are also albumin bound, and this may lead to drug interactions. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore,
signs of toxicity from these drugs. Drug/Laboratory Test Interactions Amerlex-M kit assay values of total and free triiodothyronine in patients
receiving Nalfon have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroidstimulating hormone, total thyroxine, and thyrotropin-releasing hormone response are not affected. Carcinogenesis, Mutagenesis, and
Impairment of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of fenoprofen. Studies
have not been conducted to determine the effect of fenoprofen on mutagenicity or fertility.
Pregnancy - Teratogenic Effects. Pregnancy Category - C Prior to 30-Weeks Gestation; Category D starting at 30-Weeks Gestation.
Starting at 30-weeks gestation, Nalfon and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus
in the fetus may occur. Nalfon can cause fetal harm when administered to a pregnant woman starting at 30-weeks gestation. If this drug is used
during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus. There are no adequate and well-controlled
studies in pregnant women. Prior to 30-weeks gestation, Nalfon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities when
given daily oral doses of 50 or 100 mg/kg fenoprofen calcium, respectively (0.15 and 0.6 times the maximum human daily dose of 3,200 mg
based on body surface area comparisons). However, animal reproduction studies are not always predictive of human response. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Labor and Delivery The effects of Nalfon on labor and delivery in
pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing
infants from Nalfon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.
Pediatric Use Safety and effectiveness in pediatric patients under the age of 18 have not been established.
Geriatric Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
ADVERSE REACTIONS During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics,
complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in
6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266
patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly
lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System—
During clinical trials with Nalfon, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving
Nalfon as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3%
Nalfon vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and
diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarkeing studies. Nervous System —The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs.
6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Nalfon was discontinued
in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appen-dages—Increased sweating (4.6% vs.
0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Nalfon was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses—Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and
decreased hearing (1.6% vs. none) were reported. Nalfon was discontinued in less than 0.5% of patients because of adverse effects related to
the special senses during premarketing studies. Cardiovascular—Palpitations (2.5% vs. 0.4%). Nalfon was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous—Nervousness (5.7% vs. 1.5%), asthenia
(5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs.
5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients During Clinical Trials Digestive
System—Gastritis, peptic ulcer with/without perforation, gastrointestinal hemorrhage, anorexia, flatulence, dry mouth, and blood in the stool.
Increases in alkaline phosphatase, LDH, SGOT, jaundice, and cholestatic hepatitis, aphthous ulcerations of the buccal mucosa, metallic taste,
and pancreatitis (see PRECAUTIONS). Cardiovascular—Atrial fibrillation, pulmonary edema, electrocardiographic changes, and supraventricular tachycardia. Genitourinary Tract—Renal failure, dysuria, cystitis, hematuria, oliguria, azotemia, anuria, interstitial nephritis, nephrosis,
and papillary necrosis (see WARNINGS). Hypersensitivity—Angioedema (angioneurotic edema). Hematologic—Purpura, bruising, hemorrhage,
thrombocytopenia, hemolytic anemia, aplastic anemia, agranulocytosis, and pancytopenia. Nervous System—Depression, disorientation,
seizures, and trigeminal neuralgia. Special Senses—Burning tongue, diplopia, and optic neuritis. Skin and Appendages—Exfoliative dermatitis,
toxic epidermal necrolysis, Stevens-Johnson syndrome, and alopecia. Miscellaneous—Anaphylaxis, urticaria, malaise, insomnia, tachycardia,
personality change, lymphadenopathy, mastodynia, and fever.
OVERDOSAGE Signs and Symptoms—Symptoms of overdose appear within several hours and generally involve the gastrointestinal and
central nervous systems. They include dyspepsia, nausea, vomiting, abdominal pain, dizziness, headache, ataxia, tinnitus, tremor, drowsiness,
and confusion. Hyperpyrexia, tachycardia, hypotension, and acute renal failure may occur rarely following overdose. Respiratory depression
and metabolic acidosis have also been reported following overdose with certain NSAIDs.Treatment—To obtain up-to-date information about the
treatment of overdose, a good resource is your certified Regional Poison Con-trol Center. Telephone numbers of certified poison control centers
are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction
among drugs, and unusual drug kinetics in your patient. Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor
and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than lavage; consider charcoal instead of or in
addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard
the patient’s airway when employing gastric emptying or charcoal. Alkalinization of the urine, forced diuresis, peritoneal dialysis, hemodialysis,
and charcoal hemoperfusion do not enhance systemic drug elimination.
DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of Nalfon and other treatment options before deciding to
use Nalfon. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After
observing the response to initial therapy with Nalfon, the dose and frequency should be adjusted to suit an individual patient's needs. Analgesia
For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given
orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity
of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage
should not exceed 3,200 mg. Nalfon may be administered with meals or with milk. Although the total amount absorbed is not affected, peak
blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of Nalfon than do those with
osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many
patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy.
HOW SUPPLIED Nalfon® (fenoprofen calcium capsules, USP) are available in: The 200 mg* capsule is opaque yellow No. 97 cap and opaque
white body, imprinted with “RX681” on the cap and body. NDC 42195-308-10 Bottles of 100. The 400 mg* capsule is opaque green cap and
opaque blue body, imprinted with “NALFON 400 mg” on the cap and “EP 123” on the body. NDC 42195-308-09 Bottles of 90 *Equivalent to
fenoprofen. Preserve in well-closed containers. Store at 20° - 25° C (68° - 77° F). (See USP Controlled Room Temperature).
ATTENTION DISPENSER: Accompanying Medication Guide must be dispensed with this product.
NSAID medicines that need a prescription
Generic Name
Trade Name
Celecoxib
Diclofenac
Diflunisal
Etodolac
Fenoprofen
Flurbiprofen
Ibuprofen
Indomethacin
Ketoprofen
Ketorolac
Mefenamic Acid
Meloxicam
Nabumetone
Naproxen
Oxaprozin
Piroxicam
Sulindac
Tolmetin
Celebrex
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Dolobid
Lodine, Lodine XL
Nalfon, Nalfon 200
Ansaid
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone)
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Oruvail
Toradol
Ponstel
Mobic
Relafen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Daypro
Feldene
Clinoril
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
*Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC
NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.
Manufactured by:
Emcure Pharmaceuticals, USA
East Brunswick, NJ 08896
Manufactured for:
Xspire Pharma
Ridgeland, MS 39157
Rev. 08/2012
References
1. Wk Prescription Sales Data, 2012
2. Podiatry Today, Vol. 19, Issue 3
3. Nalfon Package Insert, July 2009
4. Medispan, 2012
PHARMACOLOGIC —The
medical management of gastroparesis is listed in Table 2.
Table 2. Treatment of Gastroparesis8
Prokinetics
Antiemetics
Adjuvants
»» Metoclopramide (central and
peripheral dopamine-2 receptor
antagonist, only FDA-approved
drug for gastroparesis)
»» Domperidone (peripheral
dopamine-2 receptor antagonist,
investigational drug)
»» Erythromycin (motilin receptor agonist)
»» Compazine (phenothiazine
derivatives)
»» Ondansetron (serotonin 5-HT3
receptor antagonist)
»» Metoclopramide and domperidone
(dopamine receptor antagonist)
»» Diphenhydramine, promethazine,
meclizine (H1 receptor antagonist)
»» Lorazepam (benzodiazepines)
»» Nortriptyline, amitriptyline (tricyclic
antidepressants)
»» Gabapentin, levetiracetam
(anticonvulsants)
e e
INT RV NTiONS
Botox injection of the pylorus to relax
its resistance may be considered to
decrease gastric emptying. However,
randomized controlled trials failed to
validate the usefulness of this injection.8
● Gastric electrical stimulation (GES): in
patients with refractory nausea and
vomiting in gastroparesis, the FDA
approved implantation of a low energy
and high frequency GES device in 2000.
●
e
Note: No specific study has evaluated
the use of these adjuvants. However, these
agents have been used with reasonable
success for neuropathic pain.
Electrodes are connected to the antrum
that stimulate autonomic vagal function
allowing for more gastric accommodation, and possibly modulate gastric
biomechanical activity. This modality has
been shown to improve quality of life and
nutritional status. The downside of GES
is that it is invasive and predisposes to
complications related to implantation of
the electrode and the generator.8
e
ee
SOPHAG AL COMPLiCATiONS
OF DiAB T S: clinical overview
In long-standing diabetes, the myenteric plexus that constitutes the autonomic innervation
of the esophagus could be affected causing diabetic neuropathy as seen in gastroparesis. This
neuronal degeneration along with structural remodeling of the esophageal musculature
could result in spontaneous contractions, abnormal peristalsis, and reduced lower esophageal
sphincter tone predisposing diabetic (DM I and II ) patients to develop esophageal dysmotility,
dysphagia, GERD, and heartburns. The prevalence of esophageal dysmotility and GERD
were shown to be as high as 63% and 41%, respectively. However, only a minority of patients
seem to present with symptoms of dysphagia and heartburn.9-11
DiAGNOSiS
Tests used in the diagnosis are12:
Esophageal pH monitoring and
conventional manometry
● Wireless Bravo ® pH capsule
(newer modality with impedance
pH monitoring)
● Catheter-based technique (detects acid
and nonacid reflux in the esophagus)
●
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High-resolution manometry (uses multipressure sensors that project spatiotemporal esophageal pressure changes)
● Impedance manometry (direct
manometric measurement of a bolus)
●
www.painweek.org | PWJ | 51
DIABETES&PAIN
e
e
TR ATM NT
Table 3 summarizes treatment options.
Table 3. Treatment of Esophageal Complications of Diabetes12
Prokinetic drugs
Metoclopramide and proton pump inhibitors
Erythromycin
2-week course reduces mean esophageal transit and gastric emptying time in DM II
Consumption of sufficient fluids
Prevents pill-induced esophagitis
e
NONALCOHOLiC FATTY LiV R
DiS AS (NAFLD): clinical overview
e e
NAFLD commonly develops in obese patients as well as those with DM II. It is defined as
hepatic steatosis confirmed by histology and imaging in the absence of secondary causes like
significant alcohol intake, steatogenic medications, or hereditary causes.13
NAFLD is the most common cause of chronic liver disease in North America. Most patients
remain asymptomatic, while some present with malaise and right upper quadrant pain. Acanthosis nigricans may be present in children. Hepatomegaly is usually the only sign in patients
with NAFLD.12
DiAGNOSiS
The exclusion criteria to diagnose NAFLD are listed in Table 4. Confirmatory tests of
NAFLD are shown in Table 5.
Table 4. Exclusion Criteria for the Diagnosis of NAFLD12
Exclusion Criteria
Comment
Alcohol intake
>20 gm/day
Nutritional causes
Total parenteral nutrition and rapid weight loss
Metabolic
Glycogen storage disorders
Chronic hepatitis C
Especially genotype 3
Other chronic liver diseases
Autoimmune, Wilson’s, and hemochromatosis
Endocrine
Polycystic ovarian syndrome, hypopituitarism and hypothyroidism
e
e
TR ATM NT12
Lifestyle modification and weight loss
● Insulin sensitizing agents
● Vitamin E
●
52 | PWJ | www.painweek.org
Incretin mimetics
Omega-3 fatty acids
● Bariatric surgery
●
●
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Table 5. Diagnosis of NAFLD12
Liver biopsy
Confirmatory diagnosis of NAFLD
Novel biomarker cytokeratin-18 fragment
78% sensitive and 87% specific
Transient elastography
Noninvasive measure of liver stiffness, high failure rate in obese
individuals
NAFLD fibrosis score
Evaluate the presence of fibrosis in NAFLD by using 6 variables:
»» Age
»» BMI
»» Hyperglycemia
»» Platelet count
»» Albumin
»» Aspartate aminotransferase/alanine aminotransferase ratio:
90% sensitive and 60% specific to rule out
67% sensitive and 97% specific to rule in
eNTeROPATHY: clinical overview
Autonomic neuropathy and fibrosis of intestinal musculature are common in patients with
long-standing diabetes. This enteropathy could present as constipation (60%), diarrhea (due
to small intestinal bacterial overgrowth [SIBO]), or fecal incontinence.11
DiAGNOSiS12
Tests for fecal incontinence: endoanal
ultrasound, anorectal manometry
●
e
●
Hydrogen breath test for SIBO:
40% sensitive and 80% specific
e
TR ATM NT
Table 6 summarizes the treatment options of enteropathy.
Table 6. Treatment of Enteropathy12
Constipation
Diarrhea
»» Symptom relief, correction
»» Hydration, exercise, increased fiber
of fluid and electrolyte
»» Lactulose and osmotic laxatives for
deficits, improvement of
severe cases
nutrition and glycemic
»» Lubiprostone stimulates colonic
control
water and electrolyte secretion
»» Antidiarrheal agents should
through activation of type 2 chloride
be avoided; may precipitate
channels in enterocytes
»» Prucalopride, a selective 5-HT4-receptor toxic megacolon
agonist enhances colonic transit
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Fecal Incontinence
SIBO
»» Loperamide
»» Rifaximin: shown to
eradicate bacterial
overgrowth in up to
84% of patients
www.painweek.org | PWJ | 53
DIABETES&PAIN
CONCLUSiON
Chronic abdominal pain due to GI involvement in diabetes is prevalent, underdiagnosed,
and a complex symptomatology to manage and treat. Hence, it is imperative for healthcare
providers to have an in-depth understanding of this entity. While significant advances have
been made in demonstrating the pathophysiology of gastroparesis, the treatment options
are limited. Basic and clinical science research are warranted in formulating and validating
drugs with specific targets: insulin-like growth factor-1, oxidation, ICC , n NOS, and immune
cells.2 Further, ongoing regenerative medicine research could offer promising solutions in
the future with respect to restoration of the deranged molecular and structural integrity of
the GI system in diabetes. References
1. Wild S, Roglic G, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
Diabetes Care. 2004;27(5):1047–1053.
2. Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years.
Gut. 2010;59(12):1716–1726.
3. Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil.
2007;19(12):951–960.
4. Bytzer P, Talley NJ, Leemon M, et al. Prevalence of gastrointestinal symptoms associated with diabetes mellitus:
a population-based survey of 15,000 adults. Arch Intern Med. 2001;161:1989–1996.
5. Kim JH, Park HS, Ko SY, et al. Diabetic factors associated with gastrointestinal symptoms in patients with type 2
diabetes. World J Gastroenterol. 2010;16(14):1782–1787.
6. Keld R, Kinsey L, Athwal V, et al. Pathogenesis, investigation and dietary and medical management of
gastroparesis. J Hum Nutr Diet. 2011;24(5):421–430.
7. Panagoulias G, Tentolouris N, et al. Abdominal pain in an adult with type 2 diabetes: a case report. Cases J.
2008;1:154.
8. Tang DM , Friedenberg FK . Gastroparesis: approach, diagnostic evaluation, and management. Dis Mon.
2011;57(2):74–101.
9. Gustafsson RJ, Littorin B, Berntorp K, et al. Esophageal dysmotility is more common than gastroparesis in
diabetes mellitus and is associated with retinopathy. Rev Diabet Stud. 2011;8:268–275.
10. Wang X, Pitchumoni CS, Chandrarana K, et al. Increased prevalence of symptoms of gastroesophageal reflux
diseases in type 2 diabetics with neuropathy. World J Gastroenterol. 2008;14:709–712.
11. Lluch I, Ascaso JF, Mora F, al. Gastroesophageal reflux in diabetes mellitus. Am J Gastroenterol.
1999;94:919–924.
12. Krishnan B, Babu S, Walker J, et al. Gastrointestinal complications of diabetes mellitus. World J Diabetes.
2013;4(3):51–63.
13. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease:
Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–2023.
54 | PWJ | www.painweek.org
Q2 | 2014
WHERE OTHERS SEE COMPLEX PROBLEMS,
MALLINCKRODT SEES UNIQUE SOLUTIONS
Today’s Mallinckrodt Pharmaceuticals combines more
than 146 years of expertise with the determined focus
needed to solve the complex specialty pharmaceutical
challenges of today. Whether it’s the production of
medicines for pain or ADHD, or the development of
drugs that treat CNS conditions, we are working to make
complex products simpler, safer and better for patients.
Learn more at www.mallinckrodt.com
Mallinckrodt, the “M” brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt.
with
Kevin L.
Zacharoff
MD, FACPE, FACIP, FAAP
Kevin L. Zacharoff
is Faculty Clinical
Instructor, at
SUNY Stony Brook
School of Medicine,
Department of
Preventive Medicine,
in New York,
and Director of
Medical Affairs at
Inflexxion, Inc.
56 | PWJ | www.painweek.org
Q2 | 2014
“When I was in junior high school,
in print shop I printed up
business cards that said
Kevin Zacharoff, Young Doctor.”
What inspired you to become a healthcare
provider?
I was that kid who wanted to be a doctor
from the beginning—since I was 7 years old. When
I was in junior high school, in print shop I printed up
business cards that said Kevin Zacharoff, Young Doctor.
I never had to worry about what my career was
going to be, just how to get there.
Why did you focus on pain management?
When you’re treating someone for pain, there’s a
certain connection between you and the patient that’s
different than other medical conditions. It’s almost as
if, at that given time, you have only one patient. It’s
that focus that I like best. In all caps— FOCUS. I liked
giving all of myself to one patient at a time.
Who were your mentors?
My mentors have always been my patients.
There have been many times in my career that I got
“schooled” about what I thought I had down to a
science. I’ve had many professional people to look up
to in my career, but the ones I remember most are the
patients—they taught me the art of medicine.
If you weren’t a healthcare provider, what
would you be?
A radio disc jockey. When the medical school
applications went out, there was an application to the
Connecticut School of Broadcasting standing by just in
case. I was a DJ for 4 years in college and I love music.
Q2 | 2014
What is your most marked characteristic?
What I want on my tombstone: that I care.
It’s okay if nobody remembers me as the smartest,
just the most caring.
What do you consider your greatest
achievement?
Being a father to my daughter. Nothing else even
comes close…except maybe being a good husband
to my wonderful wife (she might read this...).
What is your favorite language?
Music.
If you had to choose one book, one film, and
one piece of music to take into space for an unde‑
termined amount of time, what would they be?
The book would be Stephen King’s The Stand.
The film would be One Flew Over the Cuckoo’s Nest.
The song, Stairway to Heaven
What would you like your legacy to be?
That I treated people with respect more than not,
that I was generous to a fault, and that I cared about
everything I did.
What is your motto?
“I’d rather be me.”
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GRALISE® (gabapentin) tablets
BRIEF SUMMARY: For full prescribing information, see package insert.
INDICATIONS AND USAGE
GRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable
with other gabapentin products because of differing pharmacokinetic profiles that affect the
frequency of administration.
DOSAGE AND ADMINISTRATION
Postherpetic neuralgia
• GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets
should be swallowed whole. Do not split, crush, or chew the tablets.
• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done
gradually over a minimum of one week or longer (at the discretion of the prescriber).
• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used
in patients with CrCl less than 30 or in patients on hemodialysis.
• In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows:
Table 1 GRALISE Recommended Titration Schedule
Day 1
Day 2
Days 3-6
Days 7-10
Days 11-14
Day 15
Daily dose 300 mg 600 mg
900 mg
1200 mg
1500 mg
1800 mg
CONTRAINDICATIONS
GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.
Table 2 GRALISE Dosage Based on Renal Function
Once-daily dosing
Creatinine clearance (mL/min)
GRALISE dose (once daily with evening meal)
≥ 60
1800 mg
30-60
600 mg to 1800 mg
< 30
GRALISE should not be administered
Patients receiving hemodialysis
GRALISE should not be administered
WARNINGS AND PRECAUTIONS
GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles
that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has
not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active
ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any
indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening
of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient
in Gralise) in the Pooled Analysis
Indication
Epilepsy
Psychiatric Other
Total
Placebo patients with events per 1000 patients
1.0
5.7
1.0
2.4
Drug patients with events per 1000 patients
3.4
8.5
1.8
4.3
Relative risk: incidence of events in
drug patients/incidence in placebo patients
3.5
1.5
1.9
1.8
Risk difference: additional drug patients
with events per 1000 patients
2.4
2.9
0.9
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for
psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with
the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components
that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated
with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and
behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms
in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be
informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of
suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the
signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should
be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar
adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In
clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years
of age, new tumors were reported in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2
years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to
provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin
therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed
tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events
have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological
abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present.
Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important
to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though
rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE
should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests
Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use
of GRALISE. The value of monitoring gabapentin blood concentrations has not been established.
ADVERSE REACTIONS
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with
postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical
studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE
and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE
treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of
GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse
reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at
least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the
incidence was greater than in the placebo group.
Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain
Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and
More Frequent Than in the Placebo Group)
Body system—preferred term
GRALISE N = 359, %
Placebo N = 364, %
Ear and Labyrinth Disorders
Vertigo
1.4
0.5
Gastrointestinal Disorders
Diarrhea
3.3
2.7
Dry mouth
2.8
1.4
Constipation
1.4
0.3
Dyspepsia
1.4
0.8
General Disorders
Peripheral edema
3.9
0.3
Pain
1.1
0.5
Infections and Infestations
Nasopharyngitis
2.5
2.2
Urinary tract infection
1.7
0.5
Investigations
Weight increased
1.9
0.5
Musculoskeletal and Connective
Tissue Disorders
Pain in extremity
1.9
0.5
Back pain
1.7
1.1
Nervous System Disorders
Dizziness
10.9
2.2
Somnolence
4.5
2.7
Headache
4.2
4.1
Lethargy
1.1
0.3
In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain
relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia.
Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the
placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension,
joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory
infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the
adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been
reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not
been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The
listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated
liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events
following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently
reported events were anxiety, insomnia, nausea, pain and sweating.
DRUG INTERACTIONS
Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced
hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this
interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at
other doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered
2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin
AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The
pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after
morphine. The magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide
and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%,
but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at
least 2 hours following antacid administration. There are no pharmacokinetic interactions between gabapentin and
the following antiepileptic drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine
300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect
of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically
significant. Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics
of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmax of
norethindrone was increased by 13%. This interaction is not considered to be clinically significant. Gabapentin
immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that
gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.
USE IN SPECIFIC POPULATIONS
Pregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed
ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and
well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure
to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North
American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number
1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at
the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk
following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day
of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are
nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in
the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric
Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic
neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were
similar across age groups except for peripheral edema, which tended to increase in incidence with age. GRALISE
is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made in patients
with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment Because
gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal
Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in
patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and
30 or in patients undergoing hemodialysis [see Dosage and Administration].
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of GRALISE has not been evaluated in human studies.
OVERDOSAGE
A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg.
Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute
oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double
vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care.
Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose
cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.
CLINICAL PHARMACOLOGY
Pharmacokinetics Absorption and Bioavailability Gabapentin is absorbed from the proximal small bowel by a
saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased,
bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three
times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax and lower
AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration
(Tmax) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200,
600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant
increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the
high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations
of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma
concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma
concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell
carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding
to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced
pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells
in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether
gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans.
Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. No adverse
effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the
maximum recommended human dose on an mg/m2 basis).
© December 2012, Depomed, Inc. All rights reserved. GRA-410-P.1
GRALISE (gabapentin) tablets are indicated for
the management of postherpetic neuralgia (PHN).
PLEASE
GRALISE ME!
Offer effective 24-hour pain control for PHN1
• Rapid titration to an effective dose*1-3
• Statistically significant reduction in pain scores†1,2
• Once-daily dosing with the evening meal
• The most common adverse reaction (≥ 5% and twice
placebo) to GRALISE (gabapentin) is dizziness1
* 2-week titration to 1800 mg/day.
†
In a 10-week clinical trial, approximately one-third of GRALISE (gabapentin) patients achieved a 50%
reduction in pain from baseline and approximately one-half achieved a 30% reduction in pain with an
1800 mg once-daily dose (mean baseline pain score was 6.6 for GRALISE-treated patients).1,3
Indication and Usage
GRALISE (gabapentin) tablets are indicated for the management of
postherpetic neuralgia (PHN). GRALISE is not interchangeable with
other gabapentin products because of differing pharmacokinetic
profiles that affect the frequency of administration.
Important Safety Information
GRALISE is contraindicated in patients who have demonstrated
hypersensitivity to the drug or its ingredients.
Antiepileptic drugs (AEDs) including gabapentin, the active ingredient
in GRALISE, increase the risk of suicidal thoughts or behavior in
patients taking these drugs for any indication. Patients treated with
any AED for any indication should be monitored for the emergence or
worsening of depression, suicidal thoughts or behavior, and/or any
unusual changes in mood or behavior.
Across all GRALISE clinical trials, the other most common adverse
reactions (≥ 2%) are somnolence, headache, peripheral edema,
diarrhea, dry mouth, and nasopharyngitis.
Dosage adjustment of GRALISE is necessary in patients with impaired
renal function. GRALISE should not be administered in patients with
a creatinine clearance rate < 30 mL/min or in patients undergoing
hemodialysis.
Because every moment counts in PHN
Please see adjacent page for Brief Summary
of Prescribing Information. Full Prescribing
Information and Medication Guide are available
at GRALISE.com.
References:
1. GRALISE [prescribing information]. Newark, CA: Depomed Inc.;
December 2012. 2. Sang CN, et al. Gastroretentive gabapentin (G-GR)
formulation reduces intensity of pain associated with postherpetic
neuralgia (PHN). Clin J Pain. 2013;29:281-288. 3. Data on file,
Depomed Inc.
January 2014, Depomed Inc. All rights reserved. GRA-409-P.2