Download Pharmacodynamic Profile of Enadoline, A Selective Kappa (k

1
Use of Buprenorphine in the
Pharmacological Management of Opioid
Dependence
Sponsored jointly by:
American Academy of Addiction Psychiatry and the
American Osteopathic Academy of Addiction
Medicine
and
Center for Substance Abuse Treatment/Substance
Abuse and Mental Health Services
2
Physician Clinical Support System for
Buprenorphine (PCSS-B)
A national mentoring network for physicians treating
opioid dependence with buprenorphine
Offered by
American Academy of Addiction Psychiatry
American Osteopathic Academy of Addiction Medicine
American Psychiatric Association
To get involved or get assistance
Go to the website: www.pcssb.org
Sponsored by CSAT/SAMHSA
3
Overview to the Course
Lectures
Small groups with case discussions
4
Overview to the Course
Legislation: Overview of the
Drug Addiction Treatment Act of
2000
Epidemiology
5
Amended Controlled Substances Act
• Drug Addiction Treatment Act of 2000: “Waiver Authority
for Physicians Who Dispense or Prescribe Certain
Narcotic Drugs for Maintenance Treatment or
Detoxification Treatment” (H.R. 4365, Children’s Health
Act of 2000)
• Revision in legislation allows a physician to prescribe
narcotic drugs in schedules III, IV, V, or combinations of
such drugs, for the treatment of opioid dependence
• Drugs and practitioner must meet certain requirements
6
Amended Controlled Substances Act
“Qualifying physician”:
A licensed physician who meets one or more of
the following:
1. ABPN Added Qualification in Addiction
Psychiatry
2. Certified in Addiction Medicine by ASAM
3. Certified in Addiction Medicine by AOA
4. Investigator in buprenorphine clinical trials
7
Amended Controlled Substances Act
“Qualifying physician” (continued):
Meets one or more of the following:
5. Has completed 8 hours training provided by
ASAM, AAAP, AMA, AOA, APA (or other
organizations which may be designated by HHS)
6. Training/experience as determined by state
medical licensing board
7. Other criteria established through regulation by
the Secretary of Health and Human Services
8
Amended Controlled Substances Act
Practitioner requirements:
“Qualifying physician”
Has capacity to refer patients for appropriate counseling and ancillary services
No more than 30 patients (individual)
The limit on the number of patients that can be treated by an individual physician has been increased
to 100 patients as part of the Office of National Drug Control Policy Reauthorization Act of 2006 (P.L
109-469. ONDCPRA). Physicians who meet the following criteria may notify the Secretary of Health
and Human Services (HHS) of their need and intent to treat up to 100 patients at any one time:
1. the physician must currently be qualified under DATA 2000
2. at least one year must have elapsed since the physician submitted the initial notification for
authorization
3. the physician must certify their capacity to refer patients for appropriate counseling and other
appropriate ancillary services
4. the physician must certify that the total number of patients at any one time will not exceed the
applicable number
No limit for group practices (August 2005)
9
Amended Controlled Substances Act
Practitioner:
Must notify the Secretary of HHS in writing:
- His/her name
- DEA registration
- If in a group practice, names of others in the
practice and DEA registrations
- Practice Location
- Criteria under which practitioner qualifies
- Certification of capacity to refer to appropriate
ancillary services
10
Amended Controlled Substances Act
• Submit required information on form provided by Center
for Substance Abuse Treatment (SAMHSA)
• “Notification of Intent to Use Schedule III, IV, or V Opioid
Drugs for the Maintenance and Detoxification Treatment
of Opiate Addiction Under 21 USC 823(g)(2)”
• Notifications can be submitted by mail, fax, online
(www.buprenorphine.samhsa.gov)
11
Amended Controlled Substances Act
Practitioner:
- DHHS has 45 days to determine if the physician
meets all the requirements
- The DEA will assign an identification (DEA) number
(the “x” number) to the practitioner; this number is
assigned after 45 days if DHHS does not act
- Violations will put the physician’s DEA registration
at risk
12
Amended Controlled Substances Act
Narcotic drug:
Approved by the FDA for use in
maintenance or detoxification
treatment of opioid dependence
Schedule III, IV, or V
Drugs or combinations of drugs
13
Amended Controlled Substances Act
Methadone treatment programs:
- Practitioner can also prescribe these drugs (i.e.,
Schedule III, IV, or V; approved for maintenance or
detoxification treatment) under a methadone
program registration
- No limit on number of patients when used in the
methadone treatment program setting according to
methadone regulations
14
Amended Controlled Substances Act
State legislation:
- A state may not preclude a practitioner
from dispensing or prescribing
buprenorphine for opioid dependence
treatment unless the state enacts a law
prohibiting the practitioner from doing so
15
Amended Controlled Substances Act
Evaluation period:
- During the first three years, DHHS and
DEA evaluated safety and efficacy
- Safety includes protection of the public
health against diversion of the drug
16
Amended Controlled Substances Act
DHHS evaluated:
- Whether the treatment is effective in the office
setting
- Whether access to treatment has been increased
- Whether there have been adverse consequences
for the public health
17
Amended Controlled Substances Act
• DEA evaluated:
- The extent of violations of the 30 patient limit
- The extent of diversion of the medication
- Physician record keeping and security measures
related to on-site buprenorphine storage
- OBOT audit
- DEA to visit two buprenorphine prescribers in each
DEA District every 18 months
18
Amended Controlled Substances Act
• Evaluation period:
- Very little diversion (this is changing)
- Few toxicity reports from DAWN (toxicity reports in
young children increasing)
- Access to treatment has improved, but needs
further expansion
- Buprenorphine will continue to be available (but
physicians need to be aware of the potential problems and
give careful thought to each treatment plan)
19
Overview to the Course
Legislation
Epidemiology
20
Opioid Abuse: Epidemiology
Prevalence: Heroin
- In 2006, 560,000 Americans age 12 and older
reported use of heroin at least once
- www.samhsa.gov
- 0.8% of 8th graders, 0.8% of 10th graders, and
0.9% of 12th graders had abused heroin at
least once in the year prior to being surveyed
- www.monitoringthefuture.org
21
Past Year: Dependence or Abuse By Drug
Class
(NSDUH, 2002)
22
Abuse of Prescription Opioids
In 2006, 16.2 million Americans age 12 and older took a prescription pain
reliever, tranquilizer, stimulant, or sedative for nonmedical purposes at
least once in the year prior to being surveyed.
1.64 million prescription narcotic users meet diagnostic criteria for opioid
abuse or dependence (second only to marijuana (4.17 million) )
New users of prescription opioids now exceeds that of marijuana use
2.15 million vs. 2.06 million (2006)
National Survey on Drug Use and Health, 2006
23
Number of New Non-medical Users of Therapeutics
24
Past Month Nonmedical Use of Prescription Drugs
(Psychotherapeutics) among Persons 12+:2002-2006
Percent Using in Past Month
3
2
1.9
+
2.0
1.9
2002
2005
2.1
2003
2006
2004
1.8+
2
1
0.8 0.8
0.5 0.5 0.5
1
0.4
0.7 0.7 0.7
0.5
0.2
0.1 0.1 0.1
0.2
0
Pain Relievers
+
Stimulants
Sedatives
Tranquilizers
Difference between this estimate and the 2006 estimate is statistically significant at the .05 level.
25
Rates of Prescription Narcotic Abuse
Prescription Narcotic Abuse Prevalence:
12th graders:
1992: 3.3%
2007: 9.2%
 179% increase over 15 years
OxyContin
Vicodin
8th
1.8%
8th
2.7%
10th
3.9%
10th
7.2%
12th
5.2%
12th
9.6%
Source: Monitoring the Future, 2007.
26
Highest Prevalence in Young Adults
Lifetime Nonmedical Use of Prescription Opioids (2006):
Pain Relievers:
Age 12-17
10.4%
Age 18-25
25.5%
Age 26 +
12%
OxyContin:
Age 12-17
1.3%
Age 18-25
Age 26 +
5.1%
1.1%
Between 2004 and 2005, the proportion of teens who thought there
was a great risk in trying prescription pain relievers fell from
48% to 44%
27
Fatal Drug Poisoning
Between 1999 and 2002, the number of opioid analgesic
poisonings on death certificates rose 91.2%
During this time period, poisoning from opioid analgesics
surpassed both cocaine and heroin poisoning as the
most frequent type of drug poisoning found on death
certificates in the U.S.
Source: Paulozzi, L.J., Budnitz, D.S., Xi, Y, 2006. Increasing deaths from opioid analgesics in the
United States. Pharmacoedidemiology and Drug Safety 15, 613-7.
28
Distribution of first-listed specified drugs among
unintentional drug overdose deaths, US, 2005
100%
Methadone, 16.2%
80%
60%
40%
Other opioid
painkillers, 22.0%
Benzo./antidepress, 6.5%
Cocaine, 25.1%
Heroin, 7.7%
20%
0%
Meth / amphet., 6.4%
Other specified
drugs, 16.1%
29
Unintentional drug overdose deaths
by specific drug type, United States, 1999-2004
8000
Number of deaths
7000
6000
5000
prescription opioid
cocaine
heroin
4000
3000
2000
1000
0
'99
'00
'01
'02
Year
'03
'04
30
Source Where Pain Relievers Were Obtained for Most Recent
Nonmedical Use among Past Year Users Aged 12 or Older: 2006
Source Where Respondent Obtained
Bought on
Drug Dealer/ Internet
0.1%
Stranger
More than 3.9%
One Doctor
1.6%
Other 1
4.9%
Free from
Friend/Relative
55.7%
One Doctor
19.1%
Bought/Took
from Friend/Relative
14.8%
Source Where Friend/Relative Obtained
More than One Doctor
3.3%
Free from
Friend/Relative
7.3%
One
Doctor
80.7%
Bought/Took from
Friend/Relative
4.9%
Drug Dealer/
Stranger
1.6%
Other 1
2.2%
Note: Totals may not sum to 100% because of rounding or because suppressed estimates are not shown.
1
The Other category includes the sources: “Wrote Fake Prescription,” “Stole from Doctor’s
Office/Clinic/Hospital/Pharmacy,” and “Some Other Way.”
31
Gaps in current treatment of opioid dependence
• Approx. 600,000 heroin users
• At least 6.4 million abuse prescription narcotics (2003)
• Increasing prevalence in those under age 25
• 260,000± patients receiving methadone maintenance
• Restrictions on OTPs
• Detoxification of limited long-term effectiveness
• Access to treatment restricted
32
Summary – Epidemiology
• Prevalence of opioid dependence is increasing
• The need for opioid dependence treatment far
exceeds what is currently available
• Office-based buprenorphine is intended to:
•
address unmet treatment needs
•
to place the treatment of opioid dependence
in the mainstream of medical care
33
Review of Opioids and
Treatment of Opioid
Dependence
34
Opioid Dependence –
Goals of Review
• Historical Information
• Neurobiology
• Types of opioids and their effects
• Pharmacology of opioids
• Treatment modalities
• Pregnancy and other special groups
35
Opioids
• Opioids: opium and opium-derived
compounds as well as semisynthetic and
synthetic compounds that resemble the
structure and/or function of the naturally
occurring forms
• Opioids are medically used for relief of pain and
cough suppression, and many have an abuse
potential
36



Historical Perspective of Opioid
Abuse
Late 19th and early 20th century: Women/high income
Americans: high rates of morphine addiction. Most introduced
to the drugs by their physicians for menstrual pain and
menopausal symptoms.
20th century: U.S. adopted severe policies toward addiction;
criminalized addiction
Harrison Act (1914): prohibition on prescription of narcotics
(opiates) to addicts.
 Many physicians prosecuted
 physicians fear opioid prescribing
 increased drug trafficking and crime associated with opiate
and cocaine addiction
37
Historical Perspective
• 1974: first methadone maintenance programs for
opioid addiction; serve approximately 260,000
patients
• Large increases in prescription opioid addiction
starting in late 1990s to present
• DATA 2000: Office-based treatment of opioid
dependence; requirement for physician training
to engage in OBOT
38
Opioid Pharmacology
Types of opioid receptors:
Mu
Kappa
Delta
• Addictive effects of opioids occur through
activation of mu receptors
• Role of kappa and delta receptors in addictive
process not well defined
39
Opioid Receptors
Drugs and medications that activate mu receptors:
morphine
heroin
methadone
LAAM
hydromorphone buprenorphine
codeine
oxycodone
fentanyl
hydrocodone
40
Function at Receptors: Full Opioid Agonists
Mu
receptor
Full agonist binding …
 activates the mu receptor
 is highly reinforcing
 is the most abused opioid type
 includes heroin, oxycodone, methadone, & others
41
Function at Receptors: Partial Agonists
Mu
receptor
Partial agonist binding …
 activates the receptor at lower levels
 is relatively less reinforcing
 is a less abused opioid type
 includes buprenorphine
42
Function
at Receptors: Opioid Antagonists
Mu
receptor
Antagonist binding …
 occupies without activating
 is not reinforcing
 blocks abused agonist opioid types
 includes naloxone and naltrexone
43
Comparison of Activity Levels
100
90
Full Agonist
(e.g. heroin)
80
70
60
%
Mu Receptor
Intrinsic
Activity
Partial Agonist
(e.g. buprenorphine)
50
40
Maximum opioid agonist
effect is never achieved
Even when all mu receptors
occupied
30
20
10
Antagonist (e.g. naloxone)
0
no drug
low dose
DRUG DOSE
high dose
44
Pharmacology of Opioids
• First pass after oral ingestion varies: morphine only 15%
orally available, but methadone 80-90%
• Duration of analgesia 3-6 hours but constipation or respiratory
depression may last longer in drugs such as methadone
• Metabolized by liver (glucuronidation or P450 CYP 2D6, 2B6,
3A4)
• Opioids are excreted in urine and bile
• Impaired hepatic function could increase bioavailability and
impaired renal function could cause accumulation of
metabolites
45
Repeated Dosing: Opioid Tolerance and
Withdrawal
• Tolerance:
– Need more for same effect
– Less effect with same amount
– Occurs for euphoria, sedation, respiratory depression, vomiting,
analgesia
– Minimal tolerance to constipation, miosis, sweating
– Can attain high levels of tolerance with gradual increases to doses
that would otherwise be lethal
• Withdrawal
– upon reduction or cessation of opioid use/administration
46
Opiate Withdrawal
Physical dependence is typically shown through the signs
and symptoms of opioid withdrawal
- Dysphoric mood
Pupillary dilation
- Nausea or vomiting
Sweating
- Muscle aches/cramps
- Lacrimation
Gooseflesh
- Rhinorrhea
Diarrhea
- Insomnia
Yawning
- Hypertension
Tachycardia
- Can use standardized scales to measure:
- e.g.: COWS, OOWS
47
Repeated Administration and Withdrawal
• Physical dependence and syndrome of dependence (as in
DSM-IV) are importantly different:
- Physical dependence indicates physiological change or
adaptation in an organism in response to repeated
administration of a drug
- A “syndrome of dependence” is a group of signs and
symptoms indicating a pattern of pathologic use or
“addiction”
48
Repeated Administration and Withdrawal
• Spontaneous Withdrawal
- Occurs when a person physically dependent on mu
agonist opioids suddenly stops or markedly
decreases the amount of use
- For short-acting opioids (e.g., heroin, hydrocodone,
oxycodone): usually begins 6-12 hours after last
dose, peaks at 36-72 hours, and lasts about 5 days
(with possible protracted withdrawal?)
49
Repeated Administration and Withdrawal
• Spontaneous Withdrawal (continued)
- For opioids with longer half-lives (e.g., methadone), there
is a longer period before onset (methadone: 36-72
hours), longer period before peak effects occur
- Medications with longer half-lives generally have less
severe spontaneous withdrawal syndrome-but longer
withdrawal syndrome
50
Opioid Overdose
• Respiratory depression - usual cause of death
• Coma, hypotension, pinpoint pupils (may dilate with
hypoxia)
• Noncardiogenic pulmonary edema
• High-dose meperidine (Demerol) or propoxyphene
(Darvon) can cause seizures
–Note: FDA Advisory Panel recently voted to
recommend removal of propoxyphene from market
• Antidote for heroin overdose: naloxone (i.m. or i.n. work
equally well); note: naloxone does not work well for
buprenorphine
51
Etiology of Opioid Abuse: Neurobiology of Addiction
Cortex
Prefrontal Cortex
Thalamus
VTA
NAc
Mu opioid receptors are distributed widely in the brain. While binding in the
thalamus produces analgesia, binding in the cortex produces impaired
thinking/balance; binding in prefrontal cortex contributes to an individual’s
decision about how important use of the drug is to him/her (salient value of the
cue) and ventral tegmental area (VTA)/nucleus accumbens (NAc) is associated with
52
Clinical Treatment of Opioid Use Disorders
DSM-IV Criteria for Opioid Abuse
A maladaptive pattern of substance use leading to clinically significant
impairment or distress, as manifested by one (or more) of the following
occurring within a 12-month period:
Recurrent substance use resulting in a failure to fulfill major role
obligations at work, school, or home

Recurrent substance use in situations in which it is physically
hazardous

Recurrent
substance-related legal problems
Continued substance use despite having persistent or recurrent
social or interpersonal problems caused or exacerbated by the effects

53
DSM-IV Criteria for Opioid Dependence
Three (or more) of the following occurring at any time in the same 12month period:
Tolerance, as defined by either of the following:
• A need for markedly increased amounts of the substance to achieve
intoxication or the desired effect, or
• Markedly diminished effect with continued use of the same amount
of the substance
Withdrawal, as manifested by either of the following:
• The characteristic withdrawal syndrome for the substance, or
• The same (or closely related) substance is taken to relieve or avoid
withdrawal symptoms
The substance is often taken in larger amounts or over a longer period
than was intended
54
DSM-IV Criteria for Opioid Dependence
• There is a persistent desire or unsuccessful efforts to cut down
or control substance use
• A great deal of time is spent in activities necessary to obtain the
substance, use the substance, or recover from its effects
• Important social, occupational, or recreational activities are
given up or reduced because of substance use
• The substance use is continued despite knowledge of having a
persistent or recurrent physical or psychological problem that is
likely to have been caused or exacerbated by the substance
55
Pharmacological Treatments for Opioid
Dependence
• Short-Term:
–Medical Withdrawal (Detoxification)
• Opioid and non-opioid
• Long-Term
–Opioid antagonist
–Opioid agonist or partial agonist
56
Opioid Detoxification - Efficacy
• 1988, Ball: methadone tapered, but 82% relapsed within
12 months
–45% in first 3 months
• Minimal follow-up data for ultra-rapid detox
• Overall, HIGH RELAPSE RATE for medical withdrawal
procedures
• Risk of overdose
57
Detoxification Using Opioids
• Stabilize on methadone (e.g.: 40 mg/d) and taper
• Stabilize on buprenorphine (variable doses have been
reported to be effective) and taper
– May have less withdrawal
– Short vs. prolonged taper
58
Non-Opioid Detoxification
• Clonidine or Lofexidine (not available U.S.)
• Alpha-2 adrenergic agonists suppress increased noradrenergic activity
from locus ceruleus caused by withdrawal of opioid
• Clonidine
– FDA approved for hypertension; limiting side effect is hypotension
– Helps autonomic symptoms
– Reduces withdrawal symptoms
better than placebo
– Most commonly used non-opioid approach over past 20 years
• Sedation, dry mouth, hypotension
• Sometimes accelerated with naltrexone
59
Ultra-Rapid Opioid Withdrawal
• Deep sedation and administer opioid antagonists to provoke W/D
– Inpatient advised
• Manage emergent symptoms with:
– Clonidine
– Benzodiazepines
– Antiemetics
– Antidiarrheals
• W/D reportedly resolved in 2-3 days with patient on full dose of
antagonist (naltrexone) if patient completes treatment. Withdrawal has
been reported 1 week out from procedure. High drop-out rate
• Risk of SAEs: aspiration pneumonia, renal failure
60
Opioid Dependence Maintenance Therapy
Naltrexone (antagonist therapy)
Why antagonist therapy?
•
•
•
•
•
•
•
•
Block effects of a dose of opiate
Prevent impulsive use of drug
Relapse rates high (90%) following detoxification with no
medication treatment
Dose (oral): 50 mg daily, 100 mg every 2 days, 150 mg every
third day
Blocks agonist effects
Side effects: hepatotoxicity, monitor liver function tests every 3
months
Biggest issue is lack of compliance –works well in motivated
patients
Injectable naltrexone not currently approved for opioid
dependence, but likely to also be effective
61
Long-Acting Opioid Treatment Options
• Methadone
– Schedule II
– Highly regulated
– Narcotic Treatment Program settings
– Approved for pregnancy
• LAAM (l-alpha acetyl methadol) – taken off market after
problems with arrhythmias
• Buprenorphine
– Schedule III
– Can be prescribed from physician offices
– Safer in overdose
62
Opioid
Dependence Maintenance Therapy: Agonist
Treatment
What is agonist therapy?
Use of a long acting medication in the same class as the abused drug
(once daily dosing)
• Prevention of Withdrawal Syndrome
• Induction of Tolerance
– What agonist therapy is not:
• Substitution of “one addiction for another”
Who is appropriate for opioid agonist therapy?
• > 18 years (for methadone ; exceptions for 16-17 y.o. with
parental consent and special methadone treatment programs)
• Greater than 1 year of opioid dependence
• Medical compromise
• Infectious disease
• Pregnant women
63
Opioid Dependence Maintenance Therapy
Determine opiate dependence
•
•
•
•
•
History (including previous records)
Signs of dependence (withdrawal symptoms, tracks)
Urine toxicology
Naloxone challenge can be given if unsure of opioid dependence
Prior to starting methadone:
ECG: determine if pre-existing prolonged QT interval, ECG
after 30 days to compare to baseline; methadone prolongs
QT in approx. 2%; 500 msec or greater—reduce dose
*Risk appears greater with doses over 100 mg/d
64
Methadone Dosing
• Once daily
• Start low, go slow
• Look for signs of withdrawal prior to Dose 1
• Regulation:1st dose <30 mg; 1st day NTE 40 mg; for person with low
tolerance: 10-15 mg Day 1
• If no evidence of opiate withdrawal; given no more than 10-15 mg Day 1
• Usual starting dose 20-30 mg
• Watch in clinic after first dose approximately 2 h
• Dose increases: every 5-7 days
• If in withdrawal at peak; increase dose by 5-10 mg
• If comfortable at peak; maintain dose
• If intoxicated at peak; reduce next day dose by 5-10 mg and evaluate at
time of peak daily to determine if intoxication continues/increases
65
Methadone Dosing
• Target range 60-100 mg
– Stop withdrawal, avoid sedation/euphoria
– Doses should be individualized but higher doses
generally more effective
• Beware accumulation in first 5-10 days; do
not make rapid dose changes
• Methadone 40 mg will block withdrawal in
everyone—won’t address craving, but will
block withdrawal; therefore no need to
rapidly increase the dose
66
Methadone Side Effects
• Minimal sedation once tolerance achieved
• Constipation - talk to patients about a bowel program
• Increased Appetite/Weight Gain
• Lowered Libido; May decrease gonadal hormone levels
• Exhaustively studied in all other organ systems with no
evidence of harm with long-term use
67
Opioid Dependence Maintenance Therapy
Methadone
Benefits:
• Lifestyle stabilization
• Improved health and nutritional status
• Decrease in criminal behavior
• Employment
• Decrease in injection drug use/shared
needles
68
Drug Interactions: Methadone
Decreased methadone concentrations:
• Pentazocine
• Phenytoin
• Carbamazepine
• Rifampin
• Efavirenz
• Nevirapine
• Lopinavir (Kaletra)
• Opiate withdrawal syndrome
•
Increased methadone concentrations:
• Ciprofloxacin
• Fluvoxamine
• Drugs that inhibit 2D6, 3A4, 2B6 (some SSRIs)
• Or Discontinuation of inducing drugs
• Cognitive impairment
• Respiratory depression
• QTc prolongation; Torsade de Pointes
69
Opioid Dependence Maintenance Therapy
Buprenorphine
•
•
•
•
•
•
Partial agonist
Binds opioid receptors; slow to dissociate
Dosing may be daily, every other day or three times
weekly
Average dose 8/2-16/4 mg daily
Little effect on respiration or cardiovascular responses
at high doses
Induct upon observation of withdrawal symptoms
70
Opioid Dependence Maintenance Therapy
Buprenorphine
•
•
•
•
•
•
•
Mild withdrawal syndrome
Maintenance form: buprenorphine/naloxone combination; except
pregnant women: use mono-formulation
Primary care physicians are expected to be providers of this
treatment as well as addiction specialists
Abuse by injection may be problem
Deaths reported when buprenorphine injected with BZDs
Drug Interactions: Atazanavir/ritonavir: increases buprenorphine
concentrations; rifampin: decreases buprenorphine concentrations;
opiate withdrawal possible
Buprenorphine certification (CSAT/DEA) required to prescribe
71
Buprenorphine – methadone: treatment retention
100
90
80
Percent
70
60
50
40
30
Buprenorphine
20
Methadone
10
0
1
2
4
6
8
10
12
14
16
Week
(Strain et al., 1994)
Buprenorphine vs. Withdrawal and Drug-Free
Treatment for Heroin Dependence
Kakko, Lancet 2003
Remaining in treatment
72
20
15
4 Subjects in Control Group Died
10
5
0
Detoxification
Maintenance
0
50 100 150 200 250 300 350
Treatment duration (days)
73
Zubieta et al., 2000
74
Opioid Dependence:
Additional Treatment Components
• Psychosocial Services
– Individual and group therapy
– Family therapy
– 12 Step
– Higher psychiatric severity patients more responsive to increased services
• Contingency treatments very useful
– E.g.: Take-home medication
75
Opioid Dependence:
Additional Treatment Components
• Opioids detected in blood, urine, saliva, and hair
• Random Urine Toxicology Screening: Gold standard
• Heroin is excreted in urine as morphine
• 6-monoacetyl morphine (6-MAM) detected for 12 hours –
evidence of recent heroin use
• Routine screens may not detect meperidine, oxycodone,
fentanyl, tramadol, buprenorphine
• Poppy seeds contain trace amounts of codeine and
morphine. Even small amounts of poppy seeds can give
positive morphine in urine
76
Opioid Replacement Therapy In Pregnancy
and in the Neonatal Period
• Methadone maintenance is considered the gold standard and
strongly advised
– Removes mother from drug-using environment
– More likely to get prenatal obstetrical care
– Reduces obstetrical complications
– Improves maternal/fetal nutrition
– Increases birth weight
• Need structure and psychosocial support
• Opioids not shown to be teratogenic
77
Opioid Dependence and Pregnancy
• Methadone Dosing during Pregnancy
– High enough dose to stop use and block craving
– Detoxification safest weeks 14-32
– Withdrawal may precipitate miscarriage in 1st trimester or
premature labor in 3rd
– Methadone: may need split dose or higher dose as pregnancy
progresses
– Convert buprenorphine/naloxone to buprenorphine if woman
wants to continue buprenorphine treatment
• Neonatal Abstinence Syndrome often occurs (in up to 90% and 50%
will need treatment):
– Irritability, fever, diarrhea, hyperreflexia, seizure
– Treatment: Tincture of opium
78
Opioid Dependence and Pregnancy
• NAS in buprenorphine-maintained women: offspring show signs of
NAS earlier and symptoms milder than for methadone
• Infants of methadone maintained women more likely to
experience NAS than for buprenophine maintained women (78%
vs. 40% with 53% vs 15% requiring treatment)
• Buprenorphine: higher birth weights, fewer hospital days
• Methadone and buprenorphine are excreted into breastmilk
• Breastfeeding should be encouraged unless there are other
conditions that would be a contraindication
• Methadone in breast milk may help with NAS
• Buprenorphine in breast milk not well absorbed; not likely to help
with NAS
79
HIV and Opioid Dependence
• Opioid replacement therapy obvious harm reduction
– Reduced high risk behavior: reduced needle use, less chaotic life
style
• Treatment of HIV pain may become issue: neuropathy:
anticonvulsants, avoid CBZ
• Buprenorphine interactions with antiretroviral medications
have not been clinically significant, except for significant
increase in buprenorphine and metabolite with
atazanavir/ritonovir, may be associated with sedation,
possibly cognitive impairment
See PCSSmentor.org Guideline on Opioid Therapies, HIV disease, and Drug
Interactions by McCance-Katz
80
Opioid Dependence and Acute Pain
• Acute pain in methadone patients
– Usual methadone dose will not provide analgesia
– Increasing methadone dose acts too slowly
– Give regular dose of methadone for addiction plus short-acting medication
for pain
• Acute pain in buprenorphine patients
• Blocks most mu agonists - may depend on dose
• Challenge to provide adequate analgesia
• Consider non opioid alternatives first line
• For severe pain: regional anesthetic, high potency opioid such as fentanyl, or
switching to full agonist and then re-induce when pain condition stops
• Watch for relapse risk. Use short term prescriptions and
coordination of care
81
Opioid Dependence and Chronic Pain
Limited evidence of usefulness of long term opioid therapy for chronic,
non-malignant pain
• Treatment Agreement /Informed Consent (documentation of
risk/benefit) advised
• Treatment Agreement to stipulate:
– One physician/one pharmacy
– UDS when requested
– Agreement to return for pill count when asked to do so
– Medication Levels
– Number/frequency of all refills
– Reason for discontinuation (violation of agreement, misuse of medication, abuse
of other substances)
• Chronic pain with opioid addiction may do better with methadone
maintenance
82
Opioid Dependence and Adolescents
• Increasing problem, but limited data
• Experiment with prescription analgesics but may
progress to heroin
• Usual treatment is non-pharmacologic following
medical withdrawal
• Office buprenorphine may be better than
methadone clinic
• Extended medication-assisted
(buprenorphine/naloxone) treatment shown to be
better than detoxification
Woody, G et al. JAMA 2008; 300(17):2003-2011
83
Conclusions
• Opioid addiction is a growing problem in the US mainly due to
large increases in prescription opioid dependence
• Chronic opioid abuse produces physical dependence
–Medication treatment needed:
• Medical withdrawal (but not usually best treatment if addiction has
been present for extended period or patient has failed previous
detoxification attempts)
• Maintenance therapy (for as long as patient benefits and wishes to
continue
• Psychosocial treatments are necessary with medication treatments
84
Patient Assessment & Selection
85
Commonly Abused Opioids
Diacetylmorphine (Heroin)
Hydromorphone (Dilaudid)
Oxycodone (OxyContin, Percodan, Percocet,
Tylox)
Meperidine (Demerol)
Hydrocodone (Lortab, Vicodin)
86
Commonly Abused Opioids (continued)
Morphine (MS Contin, Oramorph)
Fentanyl (Sublimaze)
Propoxyphene (Darvon)
Methadone (Dolophine)
Codeine
Opium
87
Commonly Abused Opioids
Opioids are abused by all routes of administration
including oral, inhalation, smoking, and injection.
Heroin is most commonly used intravenously, but
can be inhaled, smoked, or injected
intramuscularly or subcutaneously.
Opium is usually smoked.
The pharmaceutical opioids are usually taken orally
(but may also be injected).
88
Evaluation of the Patient
Attitude of the interviewer:
Matter-of-fact, non-judgmental, curious, respectful
Acknowledge that some information is difficult to talk about
Assure the patient that you are asking because of concern
for his/her health
Try to avoid using labels or diagnoses
Follow up on “qualified” answers
Assure confidentiality (as long as no risk of harm to
self/others)
89
Evaluation of the Patient
History of drug use:
Start with first substance used
Ask about all substances (including licit and illicit)
Determine changes in use over time (frequency,
amount, route)
Assess recent use (past several weeks)
No slang
Try to get collateral information when possible
90
Evaluation of the Patient
Tolerance, intoxication, withdrawal:
Explain what is meant by tolerance
Determine the patient’s tolerance and withdrawal
history
Ask about complications associated with
intoxication and withdrawal
91
Evaluation of the Patient
Relapse/attempts to abstain:
Determine if the patient has tried to abstain, and
what happened
Ask what was the longest period of abstinence
Identify triggers to relapse
92
Evaluation of the Patient
Consequences of use:
Determine current and past levels of functioning
Identify consequences to drug/alcohol use (such
as):
Medical
Family
Employment
Legal
Other
93
Evaluation of the Patient
Craving and control:
Ask if the patient experiences craving to
use and/or a compulsive need to use
Determine if patient sees loss of control
over use
94
Evaluation of the Patient
Substance use disorder treatment history:
Treatment episodes (detoxifications – medically
and non-medically supervised; maintenance;
counseling)
Response following each treatment intervention
Attendance at 12 step (or other self-help)
meetings
95
Evaluation of the Patient
Psychiatric history:
Inpatient and/or outpatient treatment episodes
Untreated episodes of psychiatric illness
Treatment with psychiatric medications
Ask about treatment delivered by nonpsychiatrists (e.g., an antidepressant
prescribed by a family physician,
psychotherapy provided by a psychologist)
96
Evaluation of the Patient
Medical history:
Past and/or present:
Significant medical illnesses
Hospitalizations
Operations
Accidents/injuries
Drug allergies
Current medications: Prescription and OTC
97
Evaluating the Patient
Physical examination:
Needle marks
Sclerosed veins (track marks)
Cellulitis/Abscess
Evidence of hepatitis or HIV
98
Evaluation of the Patient
Personal (or social) history:
Birth and early development
Education
Employment and occupations
Marital status and children
Living situation
Legal status
Family history of psychiatric or substance use d/o
99
DSM-IV Criteria for Opioid Dependence
A maladaptive pattern of substance use, leading to clinically significant
impairment or distress, as manifested by three (or more) of the following,
occurring at any time in the same 12-month period:
1. Tolerance, as defined by either of the following:
a) a need for markedly increased amounts of the substance to achieve
intoxication or the desired effect, or
b) markedly diminished effect with continued use of the same amount of
the substance
2. Withdrawal, as manifested by either of the following:
a) the characteristic withdrawal syndrome for the substance, or
b) the same (or closely related) substance is taken to relieve or avoid
withdrawal symptoms
100
DSM-IV Criteria for Opioid Dependence
3. The substance is often taken in larger amounts or over a longer
period than was intended
4. There is a persistent desire or unsuccessful efforts to cut down
or control substance use
5. A great deal of time is spent in activities necessary to obtain the
substance, use the substance, or recover from its effects
6. Important social, occupational, or recreational activities are
given up or reduced because of substance use
7. The substance use is continued despite knowledge of having a
persistent or recurrent physical or psychological problem that is
likely to have been caused or exacerbated by the substance
101
DSM-IV Criteria for Opioid Dependence
Diagnosis can include modifiers indicating if
the patient is physiologically (or physically)
dependent on the substance (i.e., has
evidence of tolerance or withdrawal), is in
various stages of remission, is on agonist
treatment, or is in a controlled environment
102
Opioid Physical Dependence
Important Clinical Features of Opioid Physical
Dependence
Physical dependence can occur after
relatively short periods of daily use (e.g., 2
weeks)
Opioid physical dependence is characterized
by regular administration to avoid
withdrawal
103
Other Substance Use, Abuse, Dependence
Reason to assess for other substance use
Co-morbid substance use disorders are
common in patients with opioid dependence
Important to assess when initially evaluating
the patient, as their presence/absence can
guide whether or not office-based treatment is
appropriate
104
Types of Other Substance Use
Alcohol
Sedative-hypnotics
Cocaine
Methamphetamine
Cannabis
PCP
Nicotine
“Club Drugs” (Ecstasy, Ketamine, GHB)
Non-controlled (clonidine, etc.)
105
Detecting Other Substance Use
Self-report of use, reason
Multiple trauma
Hospitalization
Infections
Body fluid testing (e.g., urine)
106
Detecting Other Substance Use
Examination:
Track or puncture marks
Infection (abscesses, cellulitis)
Constricted pupils (opioid intoxication)
Dilated pupils (opioid withdrawal)
Confusion, disorientation
107
Detecting Other Substance Use
Laboratory methods:
-
Blood
-
Urine testing for presence of drugs of abuse
-
Hair, saliva, sweat – limited and primarily
experimental
liver function test abnormalities
elevated mean corpuscular volume on CBC
108
Types of Other Substance Use
In a study of opioid dependent people (n=716) seeking
methadone treatment :
lifetime
cocaine dependence 64.7
cocaine abuse
12.4
cannabis dependence 50.8
cannabis abuse
14.9
alcohol dependence 50.3
alcohol abuse
13.0
sedative-hypnotic abuse 13.0
current
40.2
3.4
16.2
2.4
24.7
1.8
1.5
109
Co-morbid Medical Disorders
Important to assess for such, since (like other comorbid disorders), their presence can influence the
decision to provide office-based treatment of opioid
dependence
Advantage: One-stop treatment for opioid
dependence and other medical needs
Disadvantage: Management of co-morbidity can be
complicated and require specialized services
Separate section on this topic
110
Co-morbid Psychiatric Disorders
Most common to find depression, anxiety and
personality disorders
Presence of comorbid mental illness can influence the
decision to provide office-based treatment of opioid
dependence
Poor BUP candidates:
Active psychosis
Suicidal or homicidal
Cognitive impairment or dementia
111
Psychiatric Assessment – Induced, Independent
Distinguish between substance-induced
disorders versus independent psychiatric
disorders
Substance-induced: Disorders related to the
use of psychoactive substance; typically
resolve with sustained abstinence
Independent: Disorders which present during
times of abstinence; symptoms not related to
use of psychoactive substance
112
Psychiatric Assessment – Induced
Substance-induced disorders
-
Patient’s history suggests symptoms occur
only when he/she is actively abusing drugs
-
Symptoms are related to intoxication,
withdrawal, or other aspects of active use
-
Onset and/or offset of symptoms are
preceded by increases or decreases in
substance use
-
Goal should be sustained abstinence followed
by re-evaluation of symptoms
113
Psychiatric Assessment – Independent
Independent disorders
-
Patient’s history suggests symptoms occur during
periods when not using or abusing psychoactive
substances, or during periods of steady use without
change in amount or type
-
May also find a family history of the disorder
Goal of substance abuse treatment should still be
cessation of substance use, but treatment may also
address psychiatric symptoms simultaneously
114
Psychiatric Assessment – Areas to Assess
Depressive and anxiety symptoms
Common for opioid dependent patients to
report high rates of depressive and anxiety
symptoms at time of treatment entry
Symptoms often resolve within few days
after entry (i.e., substance-induced)
115
Treatment Principles – Depression, Anxiety
Patients with opioid dependence and
independent depressive and anxiety
disorders can respond to medication
treatments for depressive and anxiety
conditions (similar to the general population)
Generally avoid use of benzodiazepines, since
risk of abuse and possibility of interactions
with buprenorphine
116
Treatment Principles – Depression, Anxiety
Don’t overlook importance of nonpharmacological approaches to treatment
(e.g., cognitive-behavioral therapy),
especially in patients with mild/moderate
anxiety
117
Appropriateness for Office-based Buprenorphine
Consider these factors
1. Does the patient have a diagnosis of
opioid dependence?
2. Is the patient interested in office-based
buprenorphine treatment?
3. Does the patient understand the
risks/benefits of buprenorphine treatment?
118
Appropriateness for Office-based Buprenorphine
Consider these factors (continued)
4. Is he/she expected to be reasonably
compliant?
5. Is he/she expected to follow safety
procedures?
6. Is the patient psychiatrically stable?
119
Appropriateness for Office-based Buprenorphine
Consider these factors (continued)
7. Are the psychosocial circumstances of the patient
stable and supportive?
8. Can the office provide the needed resources for the
patient (either on or off site)?
9. Is the patient taking other medications that may
interact with buprenorphine (naltrexone,
benzodiazepines, other sedative-hypnotics?
120
Appropriateness for Office-based Buprenorphine
Patient is less likely to be an appropriate candidate
for office-based buprenorphine treatment
1. Dependence on high doses of
benzodiazepines, alcohol, or other CNS
depressants
2. Significant psychiatric co-morbidity
3. Active or chronic suicidal or homicidal ideation
or attempts
121
Appropriateness for Office-based Buprenorphine
Patient is less likely to be an appropriate candidate
for office-based buprenorphine treatment
(continued)
4. Multiple previous treatments and relapses
5. Non-response to buprenorphine in the past
6. High level of physical dependence (risk for
severe withdrawal)
7. Patient needs cannot be addressed with
existing office-based resources
122
Appropriateness for Office-based Buprenorphine
Patient is less likely to be an appropriate
candidate for office-based buprenorphine
treatment (continued)
8. Pregnancy
9. Current medical condition(s) that could
complicate treatment
10. Poor support systems
123
Matching the Treatment Plan and Resources
The decision to provide treatment from the
office should be based upon the suitability of
the patient for this level of service and the
availability of other resources in case
complications in the office-based treatment
arise.
124
Summary
Determination of suitability for office-based
buprenorphine treatment begins with the
presence of a diagnosis of opioid dependence
In addition, many patient factors (such as comorbid conditions) will guide the decision of
whether or not to treat in the office with
buprenorphine
Final decision is whether the patient’s needs can
be addressed by the resources available through
the office
125
Clinical Use of Buprenorphine:
Induction
Stabilization
Maintenance
Withdrawal
126
Buprenorphine Induction
Overview: Goal of induction
To find the dose of buprenorphine at which
the patient:
- discontinues or markedly reduces use of
other opioids,
- experiences no cravings,
- has no opioid withdrawal symptoms, and
- has minimal/no side effects
127
Buprenorphine Induction
Overview: Practical Issues with Induction
Buprenorphine/naloxone supply options:
-
keep a supply of medication in the office for induction
administration
-
have the patient fill a prescription for the induction
doses and bring the medication to the office where it
will be administered
128
Buprenorphine Induction
Office medication supply:
• physician must keep the records required by
federal and state law for maintaining
supplies of controlled substances for
administration or dispensing
• Records may be audited by the DEA
129
Buprenorphine Induction: Giving a
Prescription for the Induction Doses
Prescription for the first/second day’s doses (e.g.: eight
2/0.5 mg tablets and one 8/2 mg tablet):
Day 1: 2 doses of two 2/0.5 mg tablets
Day 2: Depending on symptoms: up to 16/4 mg (up to
four 2/0.5 mg tablets and 1 8/2 mg tablet)
After induction Day 2 write scrip for daily dose until
next visit
• Risk that a patient might not return with the filled
prescription
130
Buprenorphine Induction – Day 1
Patients dependent on short-acting opioids
No opioid use for 12-24 hours (must be in mildmoderate withdrawal at time of first
buprenorphine dose)
Can use an opioid withdrawal scale to assess
severity of withdrawal when the patient arrives
at the office and to track the patient's response
to first day’s dose
For withdrawal scales, see Appendix B of CSAT Clinical Guidelines for the
Use of Buprenorphine in the Treatment of Opioid Addiction 2004
CLINICAL OPIATE WITHDRAWAL SCALE (COWS)
Buprenorphine/naloxone induction: Enter scores at time zero, 1-2 h after first dose, and at
additional times that medication is given over the induction period.
131
DATE:
Resting Pulse Rate: (record beats per minute) Measured after patient is
sitting/lying for one minute.
0 pulse rate 80 or below
1 pulse rate 81-100
2 pulse rate 101-120
4 pulse rate greater than 120
Sweating: Over past ½ hour not accounted for by room temperature or
patient activity.
0 no report of chills of flushing
1 one subjective report of chills or
flushing 2 flushed or observable moistness on face 3 beads of sweat
on brow or face
4 sweat streaming off face
Restlessness: Observation during assessment.
0 able to sit still 1 report difficulty sitting still, but is able to do so
3 frequent shifting or extraneous movements of legs/arms
5 unable to sit still for more than a few seconds
Pupil Size:
0 pupils pinned or normal size for room light 1 pupils possibly larger
than normal for room light 2 pupils moderately dilated 5 pupils so
dilated that only rim of the iris is visible
Bone or Joint aches: If patient was having pains previously, only the
additional component attributed to opiate withdrawal is scored.
0 not present
1 mild diffuse discomfort
2 patient reports
severe diffuse aching of joints/muscles
4 patient is rubbing joints
or muscles and is unable to sit still because of discomfort
TIME:
TIME:
TIME:
132
Runny nose or tearing: Not accounted for by cold symptoms or allergies.
0 not present
1 nasal stuffiness or unusually moist eyes
2 nose running or tearing
4 nose constantly running or tears
streaming down cheeks
GI Upset: Over last ½ hour
0 no GI symptoms 1 stomach cramps 2 nausea or loose stools
vomiting or diarrhea 5 multiple episodes of diarrhea or vomiting
Tremor: Observation of outstretched hands
0 no tremor
1 tremor can be felt, but not observed
observable
4 gross tremor or muscle twitching
3
2 slight tremor
Yawning: Observation during assessment
0 no yawning 1 yawning once or twice during assessment
2 yawning three or more times during assessment
4 yawning several times/minute
Anxiety or Irritability
0 none
1 patient reports increasing irritability or anxiousness
2 patient obviously irritable, anxious 4 patient so irritable or anxious
that participation in the assessment is difficult
Gooseflesh skin
0 skin is smooth
3 piloerection of skin can be felt or hairs standing up
on arms 5 prominent piloerection
Total Score
Observers Initials
Dose of Buprenorphine/naloxone given
133
Buprenorphine Induction – Day 1
Patients dependent on short-acting opioids
- If patient is not in opioid withdrawal :
-
assess time of last use
- consider either having him/her return another
day or wait in the office until evidence of
withdrawal is seen
134
Buprenorphine Induction – Day 1
Patients dependent on short-acting opioids
First dose: 2/0.5-4/1 mg sublingual
buprenorphine/naloxone
Monitor in office for 1-2 hours after first dose
The length of time the patient is monitored in the
office can vary depending upon the clinician’s
familiarity with the patient, and the clinician’s
familiarity with using buprenorphine.
135
Buprenorphine Induction – Day 1
Patients dependent on short-acting opioids
If opioid withdrawal appears (worsens) shortly
after the first dose: consider precipitated
withdrawal
Greatest severity of buprenorphine-related
precipitated withdrawal occurs in the first few
hours (1-4) after a dose, with a decreasing (but
still present) set of withdrawal symptoms over
subsequent hours
136
Buprenorphine Induction – Day 1
If a patient has precipitated withdrawal consider:
-giving another dose of buprenorphine
attempting to provide enough agonist effect from
buprenorphine to suppress the withdrawal
or
-stopping the induction, provide symptomatic
treatments for the withdrawal symptoms, and
have patient return the next day.
137
Buprenorphine Induction – Day 1
Patients dependent on short-acting
opioids
- Can re-dose if needed (every 1-4
hours, if opioid withdrawal
subsides then reappears)
- Maximum first day dose of 8/2 mg
buprenorphine/naloxone
138
Buprenorphine Induction – Day 1
Patients dependent on short-acting opioids
Can initiate therapy starting with
buprenorphine/naloxone combination tablets
139
Buprenorphine Induction – Day 1
Patients dependent on long-acting opioids
Patients should have dose decreases until they are
down to ≤40 mg/d of methadone or the equivalent
Begin induction 24- 48 hours after last dose of
methadone: Key is to see objective withdrawal
signs
Give no further methadone once buprenorphine
induction is started; confirm with MMP/prescriber
140
Buprenorphine Induction – Day 1
Patients dependent on long-acting opioids
Use similar procedure as that described
for short acting opioids
Expect total first day dose of up to 8/2 mg
sublingual buprenorphine/naloxone
141
Buprenorphine Induction – Day 2+
Patients dependent on short- or long-acting
opioids
After the first day of buprenorphine
induction for patients who are dependent
on either short-acting or long acting
opioids, the procedures are essentially
the same
142
Buprenorphine Induction – Day 2
Patients dependent on short- or long-acting
opioids
On Day 2, have the patient return to the office,
if possible, for assessment and Day 2 dosing
Adjust dose according to the patient’s
experiences on first day
143
Buprenorphine Induction – Day 2
Patients dependent on short- or long-acting opioids
Adjust dose according to the patient’s experiences:
lower dose if patient was over-medicated at end
of Day 1 (rare)
higher dose if there were withdrawal symptoms
after leaving your office and/or if patient used
opioid agonists
Don’t assume abstinence after the first day’s dose
144
Buprenorphine Induction – Day 2
Patients dependent on short- or long-acting opioids
Continue adjusting dose by 2/0.5-4/1 mg increments
until an initial target dose of 12/3-16/4 mg is achieved
for the second day
Increasing dose after achieving 12/3-16/4 dose should be
following steady state which can take about 10 days;
24/6 mg/d is max. daily recommended dose according
to FDA approved package insert
Note: 16/4 is most used maintenance dose; rarely are
much higher doses needed
145
Buprenorphine Induction
Patients not physically dependent on opioids
Examples:
- A patient at high risk for relapse to opioid use,
such as a person who had been incarcerated
and was recently released
- A patient with history of opioid dependence
documented in medical records who is at high
risk for relapse
146
Buprenorphine Induction
Patients not physically dependent on opioids
First dose: 2/0.5 mg sublingual buprenorphine/naloxone
Monitor in office after first dose
The length of time the patient is monitored in the
office can vary depending upon the clinician’s
familiarity with the patient, and the clinician’s
familiarity with using buprenorphine
Gradually increase dose over days; increase in
increments of 2/0.5 mg
147
Buprenorphine Induction
Conversion to buprenorphine/naloxone
In virtually all circumstances, induction can
(and should) begin with the combination
tablet
For pregnant patients for whom buprenorphine
is being used, induction and maintenance
should be with monotherapy tablets
If induction was begun with monotherapy
tablets, switch to combination tablets after 23 days
148
Buprenorphine Stabilization / Maintenance
Stabilize on once daily sublingual dose (no
divided doses)
Expect average daily dose will be somewhere
between 8/2 and 16/4 mg of
buprenorphine/naloxone
Higher daily doses more tolerable if tablets are
taken sequentially rather than all at once
149
Buprenorphine Stabilization / Maintenance
Most patients will be dosed daily
Alternative:
Once stabilized, the patient can be shifted to alternate day
dosing (e.g., every other day, MWF, or every third day, MTh)
(for IOP/monitored dosing)
Increase dose on dosing day by amount not received on other
days (e.g., if on 8 mg/d, switch to 16/16/24 mg MWF)
(note: daily dosing is recommended, alternate day dosing may
be useful for those attending treatment programs where
medication is administered or for those not wanting to take
medication daily)
150
Withdrawal Using Buprenorphine
WITHDRAWAL IN </= 3 DAYS (rapid)
Withdrawal over 4 to 30 days (moderate
period)
Withdrawal over more than 30 days (long
term)
151
Withdrawal Using Buprenorphine
Withdrawal in </= 3 days (rapid)
Reports show buprenorphine suppresses
opioid withdrawal signs and symptoms
(better than clonidine)
152
Withdrawal Using Buprenorphine
Withdrawal in </= 3 days
Using sublingual tablets:
First day: 8/2-12/3 mg sl
Second day: 8/2-12/3 mg sl
Third (last) day: 6/1.5 mg sl
153
Withdrawal Using Buprenorphine
Withdrawal in </= 3 days
Buprenorphine is effective in suppressing
opioid withdrawal symptoms
Long-term efficacy is not known, and is likely
limited
Studies of other withdrawal modalities have
shown that such brief withdrawal periods are
unlikely to result in long-term abstinence
154
Withdrawal Using Buprenorphine
Withdrawal in </= 3 days (rapid)
WITHDRAWAL OVER 4 TO 30 DAYS
(MODERATE PERIOD)
Withdrawal over more than 30 days (long
term)
155
Withdrawal Using Buprenorphine
Withdrawal over 4-30 days
Although there are few studies of buprenorphine
for such time periods, buprenorphine has been
shown more effective than clonidine over this
time period
However, outcomes not as good as for longer
periods of buprenorphine withdrawal treatment
(longer than 30 days)
156
CTN Buprenorphine Withdrawal Protocol
Study Day
Buprenorphine-Naloxone Dose
(mg)
1
4 + additional 4 as needed
2
8
3
16
4
14
5
12
6
10
7
8
8
6
9
6
10
4
11
4
12
2
13
2
157
Withdrawal Using Buprenorphine
Withdrawal in </= 3 days (rapid)
Withdrawal over 4 to 30 days (moderate
period)
WITHDRAWAL OVER MORE THAN 30 DAYS
(LONG TERM)
158
Withdrawal Using Buprenorphine
Withdrawal over >30 day (long term)
Not a well studied topic
Literature on opioid withdrawal can provide guidance;
suggests longer, gradual withdrawal more effective than
shorter withdrawal
Tapering schedule: 50% daily to 8 mg; then slower taper
depending on clinical judgment
Many iterations of above are effective
Medical withdrawal from buprenorphine associated with
much milder withdrawal than for full mu agonists
159
Summary
Buprenorphine is effective and safe when used for
maintenance treatment of opioid dependence
Monitor patient during induction with buprenorphine;
best to keep patient at office after first dose to gauge
effectiveness and tolerability
Efficacy of buprenorphine in management of
withdrawal not well determined, but withdrawal from
buprenorphine may be milder than withdrawal from
other opioids; probably best if conducted over
longer periods
160
Clinical Management
161
Problem Behaviors
importance of preparation and anticipation, so that
the clinician is not making sudden decisions about
how to handle these situations.
Occur rarely, especially in stable patients, and can
occur in patients being treatment for any condition
(not only opioid dependence)
162
Prior to the Initial Visit
In a phone call with the patient:
Briefly discuss your office’s general treatment
philosophy
Determine insurance coverage
Find out the pharmacy he/she uses
Explain cost of medication (if uninsured), urine
testing, etc.
Explain amount of time that may be required for
the initial visit
163
The Initial Visit with the Patient
Goal: Establish a relationship in which patient can
be open and confident that he/she can report
difficulties
Be prepared for defensiveness
Address concerns about disclosure, confidentiality
164
The Initial Visit with the Patient
Major Task to be Completed:
Part of the initial visit is to review rules and
expectations with the patient, making sure that the
patient understands them before buprenorphine
treatment is initiated
Part of the patient assessment is to form a judgment
about whether the person can comply with the rules
– whether the medication will be taken as prescribed
and will be kept safe.
165
Information for the Patient
Provide written information to your patients:
Information about buprenorphine (e.g., brochure)
Copy of rules/expectations to be signed by patient
Physician’s name, address, phone number, office
hours
Emergency contact information
Payment procedures
166
Rules and Expectations for the Patient
General principles for rules and expectations
Provide clear guidelines and expectations for patients
Must clearly outline consequences of infractions
Lay the groundwork for confronting patients about
problematic behaviors
Must be clear to all involved with patient’s care
Must be flexible, when necessary
If you are uncertain, ask a colleague and/or lawyer
167
Rules and Expectations For Staff
Address staff concerns and preconceptions
Help staff understand relevant issues before
the patient’s first visit
As a group, determine reasonable and
realistic consequences of unacceptable
behavior
Assure that everyone is on board
168
Rules and Expectations for Office Staff
Inform your staff members about:
How to maintain patient confidentiality
Treatment philosophy (particularly the
goals of treatment)
Providing medication (particularly storage
and administration procedures)
Role of non-pharmacological treatments
169
Examples of Rules and Expectations for the Patient
Prescription procedures
How many day’s medication is provided in a prescription
How you respond to lost buprenorphine prescriptions
How to store the medication safely
Need for full and prompt disclosure of use of nonprescriptive psychoactive substances
Urine testing procedures
Illicit drug, problematic alcohol use
If the patient cancels an appointment
170
Rules and Expectations for the Patient
Conveying rules and expectations
Do both in writing and verbally
Give the patient a copy
Convey that failure to comply will result in
consequences
Review periodically (as needed) with patients
Review (and revise as needed) periodically with
staff
171
Boundaries in Patient-Staff Interactions
Boundaries are important for the physician and the
physician’s office staff to consider
Maintain professional relationship
Acknowledge away from office only if patient does so
Careful avoidance of excessive familiarity with patients
Do not accept gifts from patients
172
Problematic Behavior: General Principles
Preparation and anticipation are crucial, as are
consistency and flexibility in responding to
problems
Evaluate the problem
Consider the length of time in treatment; history of
patient’s treatment success, patient’s motivation,
options available
Be aware of impact on staff and other patients if it is
perceived that there is no consequence to the
patient
173
General Principles
Consider a range of options tailored to the
specific problematic behaviors:
Increased office visits, to physician and/or
counselor
Referral to more intensive level of service
such as counseling or intensive outpatient program
Change in dosing schedule
Transfer to opioid treatment program (OTP)
174
General Principles
Negotiating skills and problematic
behaviors
Negotiate from strength
Defend the integrity of treatment
Consider violations in the context of the
patient’s condition and situation
Be aware of your own feelings
175
Examples of Problematic Behaviors
Intoxication at the office
Loitering
Diversion of medication
Drug dealing
Aggressive acts
Such actions occur rarely – but if they do
occur, it is important that the office be
prepared to respond in a therapeutically
appropriate and consistent way
176
Office-Based Practice Necessary Resources: Urine
Testing
Why conduct urine drug testing?
Drug abuse a chronic disorder – relapse can
occur
Patients may deny or minimize use
Urine testing an integral part of on-going
evaluation and treatment planning
Purpose is not to punish the patient, but to
provide a therapeutically appropriate
response
177
Office-Based Practice Necessary Resources: Urine
Testing
Capacity to get valid urine test results
Collection procedures (in office or off-site)
If off-site testing, system for shipment of
specimens
Procedures if you will do on-site testing
Sending specimens out for testing versus quick
test in office
Random versus scheduled collection
Observed versus non-observed
178
Urine Testing
Different laboratory methods for drug
screening and testing
Thin Layer Chromatography (TLC)
positive result on this screening test
should be confirmed using another
method
Gas chromatography/mass spectrometry
Enzyme immunoassay (EIA)
179
Urine Testing
Detection time limits for drugs of abuse using urine
testing
Amphetamine/methamphetamine: 2-4 days
Benzodiazepines: up to 30 days
Cocaine: 1-3 days
Heroin/morphine: 1-3 days;
Methadone: 2-4 days
Marijuana: chronic use, up to 30 days; occasional
use, 1-3 days
Alcohol: 2-4 days
180Office-Based Practice Necessary Resources: Medication
Storage
Medication availability, security and storage
-
You can keep buprenorphine in the office and administer it to patients
if you comply with the DEA (and any State) rules for keeping and
administering a supply of it
-
Check with your state on dispensing laws
-
These strict requirements may be a disincentive to keeping
buprenorphine in the office
-
May be easier to write a prescription for first doses of buprenorphine
(for induction)
-
In advance, confirm that a local pharmacy stocks buprenorphine
Medication may be delivered to your office; or patient can fill
prescription and bring it to your office for initial supervised dosing
181
Office-Based Practice Necessary Resources
Coverage
Be realistic – one person providing 24 hour
coverage, 7 days per week is not sustainable
Covering physician should be knowledge and
experienced in using buprenorphine, and be
familiar with your office policies and
procedures; if will prescribe buprenorphine,
then needs a DATA waiver
182
Office-Based Practice Necessary Resources
Referral resources
-
Different levels of substance abuse treatment
services:
- group counseling programs
- methadone treatment programs
- partial hospitalization
- intensive outpatient
-
Psychiatric or medical services
-
Self-help groups such as AA, NA in your
community
183
Financial Issues
Financing of methadone treatment
To understand potential payment sources, it
may be helpful to look at how payment for
methadone treatment is provided. There
are several different payment sources:
Out-of-pocket payments by the patient
The patient’s insurance providing
reimbursement
Medicaid (in some states)
State treatment grants (in some states)
184Financial
Issues
Fees for office-based treatment
Consider these services, among others,
when determining the fees:
Routine office visits of varying lengths
Record-keeping and billing
Medications
Counseling
Urine testing
Physical examinations
Laboratory work
185
Financial Issues
Fees for office-based treatment (continued)
Physicians use CPT codes they are
accustomed to using for outpatient
‘evaluation and management’:
Outpatient new patient (99201)
Outpatient consultation (99241)
Outpatient: established patient revisit
(99211)
186
Financial Issues
Fees for office-based treatment (continued)
Psychiatrists usually choose regular
psychiatric CPT codes
Outpatient New Patient (90801)
Outpatient Consultation (99251)
Outpatient Medication Management (90862)
Outpatient Psychotherapy (90804)
Outpatient Group Psychotherapy (90853)
187
Financial Issues
Fees for office-based treatment
Psychiatrists’ CPT codes are time-based
Other physicians’ CPT codes are
complexity-of-service based
Services provided within the context of
Intensive Outpatient Services can use
Group Therapy codes, but most
physicians will submit an MD/DO-specific
charge vs. having charges wrapped into
IOP charges
188
Financial Issues
Determining how the patient plans to pay for
treatment
It is important for the office staff to determine
how the patient plans to pay for treatment,
and arrange to bill the patient directly or to
bill a third party payer, or both.
If patient has insurance, make sure
buprenorphine is covered (on the formulary)
189Financial
Issues
Determining how the patient plans to pay for
treatment
Note that the patient may have insurance that
covers some but not all aspects of treatment
For example, an initial office visit with history
and physical examination, regular office
visits to monitor medications for chronic
conditions, associated laboratory tests, etc.,
but not on-site counseling
190
Clinical Tools for Office-Based Practice
See CD ROM in course materials
1. Informing patients/families
2. Office staff Intake Questionnaire
3. Releases of Information
4. Buprenorphine Treatment Agreement
5. Medical History/PE form
6. Progress Note Example
7. Billing Information
8. Ongoing Treatment: Protocol for Follow Up Appointments,
Signs of Relapsive Behavior or Relapse
9. Drug Inventories (for office dispensing)
191
Summary
Most patients treated in an office-based setting
will be cooperative, stable
Having rules helps patients and office staff
prepare responses to problematic acts
The physician should have options in how to
respond – not every infraction should result
in discharge from treatment
192
Confidentiality and Medical Record
Keeping
193
Specific Federal regulations govern disclosure of a
patient’s identity and treatment information, and
states may have further such regulations.
Title 42, Part 2, Code of Federal Regulations
[42 CFR Part 2]
Knowledge of these statutes is important for those
providing substance abuse treatment as the rules
may apply to their practice.
194
Rationale for Development of Confidentiality
Statutes Specific to Those Seeking Substance
Abuse Treatment
The logic behind these regulations is that
persons with substance abuse
problems are more likely to seek and
succeed at treatment if they know their
need for treatment will not be disclosed
unnecessarily
195
Scope of the Law
Strictness of Regulations
Federal confidentiality regulations more
strict than most other confidentiality rules
They apply whether the individual:
- Seeking the information already has it
- Is seeking it for judicial or administrative
proceedings
- Is a law enforcement or other government official
- Has a subpoena or a search warrant
- Is the spouse, parent, relative, employer, or friend
196
Scope of the Law
Consequences of Violating or
Disregarding
Criminal penalty
For a program, could lose license or
certification
Patients may sue
197
General Rules: Definitions of Terms in Statutes
Patient
Anyone who has applied for or received a
diagnostic examination or interview,
treatment, or referral for treatment at a drug or
alcohol program
Applicants for services are covered even if they
fail to show for their initial appointment, or
elect to not follow up with treatment
Includes current, former, and deceased patients
198
General Rules: Definition of Terms in Statutes
Programs
Definition of a program: federally assisted
organizations and individual practitioners
(MDs, psychologists, others)
Specialize in providing, in whole or in part,
individualized alcohol or drug abuse
diagnosis, treatment, or referral for treatment
Receive Federal support or operated by gov’t
199
General Rules
Disclosure
Communication that directly or indirectly
identifies someone as being, having been in, or
having applied for substance abuse treatment
Occurs when a program or practitioner:
discloses patient’s record;
allows an employee to testify about a patient’s
treatment;
allows a receptionist to confirm that a person
is a patient in the program;
uses identifying stationery;
discloses anecdotal information
200
Disclosure: Exceptions
• Internal communications
• Consent
• Anonymous or non-patient identifying information
• Qualified service organization agreement
• Crimes on premises or against personnel
• Medical emergencies
• Mandated reports
• Research
• Audit and evaluation
• Court orders
201
HIPAA and Substance Abuse Treatment
HIPAA: Health Insurance Portability and
Accountability Act (1996) became effective on
April 14, 2003, providing national standards for
protecting health information.
It is important to be aware of HIPPA for all patients
in treatment (not just those with a substance
abuse disorder)
202
HIPAA and Substance Abuse Treatment
HIPAA shifts control of health information from
providers to patients (to a great degree)
Covers providers who transmit health information
electronically (essentially everyone)
Key feature of HIPAA is the definition of
“Protected Health Information” (PHI) –
individually identifiable information (e.g., name,
date of birth, Social Security Number)
203
Medical Record Keeping
The medical record is the ongoing narrative of a
patient’s healthcare and memorializes the past
history for purposes of continuity of current and
future treatment.
Remember: if it isn’t written down, it didn’t happen.
204
Overview to the Medical Record
The medical record should document
-
Initial diagnosis and treatment plan information
- Complete history
-
Physical examination results
-
On-going history and physical examination
-
Assessment of pharmacological efficacy
Comparisons with initial presentation for progress or regression (with
corresponding modifications, if needed, in the treatment plan)
Lab tests and results
Consults
Compliance with treatment plan
Urine and blood drug screening: Collection and results
Medications prescribed
Inventory and dispensing of controlled substances
205Documentation
and Buprenorphine
When planning to prescribe buprenorphine for opioid
dependence treatment, it is important to document:
- Evidence showing patient is opioid dependent
(including physical signs/symptoms, urine
toxicology results)
- Length and severity of patient’s opioid dependence
- Number, type, and intensity of previous treatments
for opioid dependence
- Any legal consequences to the patient because of
opioid use
206
Storage of Records
Must keep available for at least 2 years
Can be kept at a central location (but
must notify DEA)
Must be kept in a locked, secure place
when not in use
207
Storage of Buprenorphine
• Buprenorphine must be stored in the
physician’s office
• Buprenorphine must be stored under locked
conditions
• Tracking record must be maintained that
provides information on who received
buprenorphine and quantity of drug
dispensed
208
Summary
Documentation and immaculate record
keeping are extremely important – for the
well being of both the patient and the
physician.
The record is a legal document that may be
reviewed by outside agencies.
209
Medical Co-Morbidity
210
Addiction and health behavior
Opioid dependence frequently associated with other medical
conditions
Consequences of injection drug use/shared needles
Direct toxic effect of opioids and/or inert substances mixed
with heroin
Consequences of risky sexual behavior
Lack of attention to preventive health care
Need to screen for comorbid medical illness and provide
treatment or make referral when needed
211
Outline for This Talk
I. Hepatitis B
II. Hepatitis C
III. HIV/AIDS
IV. Tuberculosis
V. Preventive health care for opioid
dependent patients
VI. Summary
212
Hepatitis B
Epidemiology
Blood borne viral pathogen
Estimated 1.25 million chronically infected in U.S.
Approximately 300,000 new cases per year; 15,00030,000 chronic infection
Transmission by blood borne (parenteral), sexual,
or perinatal routes
Approximately 50% of active injection drug users
have serological evidence of prior exposure to
HBV
213
Hepatitis B
Clinical course
Early and mild viral hepatitis manifests with
symptoms of hepatic inflammation and
damage with elevated serum transaminases
(can rise to 10-20x normal)
Chronic viral hepatitis manifests as chronic
liver disease with portal hypertension and
poor hepatic synthetic function
214
Acute Hepatitis B Infection with Recovery
Symptoms
anti-HBe
HBeAg
Total anti-HBc
Titer
0
4
anti-HBs
IgM anti-HBc
HBsAg
8
12
16
20
24
28
32
36
Weeks after Exposure
52
100
215
Hepatitis B
Clinical course (continued)
Likelihood of developing chronic
infection is related to age:
80 to 90% of infants infected develop
chronic disease
only 2 to 10% of infected adults
progress to chronic disease
216
Progression to Chronic Hepatitis B Infection
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Total anti-HBc
Titer
IgM anti-HBc
0
4
8 12 16 20 24 28 32 36
Weeks after Exposure
52
Years
217
Hepatitis B
Treatment
Interferon is administered subcutaneously
daily three times per week, for 16 weeks
Metaanalysis of 16 randomized controlled trials
found loss of HBeAg and HBV DNA in 33 to
37% of interferon treated patients compared
with 12 to 17% of controls
Lamivudine: oral, resistance develops,
seroconversion response in nearly 33% of
patients after one year
218
Hepatitis B
Treatment (continued)
Famciclovir less effective than lamivudine and
is also limited by the development of
resistance
Adefovir possesses added benefit of exhibiting
no resistant mutations
Vaccination is crucial – a three part series over
6 months
219
Hepatitis C
Definition
Hepatitis C (HCV) is the most common
bloodborne infection in the U.S.
The viral pathogen established as the
major cause of hepatitis previously
called nonA, nonB hepatitis
220
Hepatitis C
Epidemiology: United States
New infections (cases) per year:
1985 to 1989:
242,000 (42,000)
1998:
40,000 (6,500)
Seroprevalence studies reveal that
approximately 1.8% of the U.S. population are
infected with HCV
Deaths from acute liver failure are rare
221
Hepatitis C
Epidemiology: United States (continued)
Of the estimated 3.9 million people in the U.S.
who are HCV antibody positive, 2.7 million are
chronically infected with detectable RNA levels
Chronic liver disease – HCV-related: 40% - 60%
Deaths from HCV chronic disease/year: 8,00010,000
Most common cause (~40%) of liver transplant in
U.S.
222
Hepatitis C
Epidemiology (continued)
HCV is more prevalent and more infectious than HIV
with 170 million people infected with HCV worldwide
Greater than 90% of injection drug users have
antibodies to HCV
In injection drug users, infection results from contact
with contaminated needles, syringes, paraphernalia
Blood and blood products are more infectious than
saliva, vaginal secretions, or semen
223
Hepatitis C: Prevalence by Selected Groups
(U.S.)
Hemophilia
Injecting drug users
Hemodialysis
STD clients
Gen population adults
Surgeons, PSWs
Pregnant women
Military personnel
0
10
20
30
40
50
60
70
Average Percent Anti-HCV Positive
80
90
224
Hepatitis C
Clinical course: Acute hepatitis C
Incubation period averages 6 to 8 weeks during which time
antibodies are undetectable
Symptoms develop in only 25% to 35% patients:
Nonspecific
Jaundice in only 20% to 30%
Diagnosis rarely established during acute phase
85% develop persistent infection
Majority develop chronic hepatitis with persistent viremia
and intermittently elevated liver function tests
225
Hepatitis C: Acute Infection with Recovery
anti-HCV
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
3
4
Months
5
6
1
Time after Exposure
2
3
Years
4
226
Hepatitis C
Clinical course: Chronic hepatitis C
Symptoms: 50% of patients report chronic fatigue
and right upper quadrant abdominal discomfort
Serum transaminases: Persistently elevated in 43%,
intermittently elevated in 42%, normal in 15%
Risk factors for disease progression include:
Alcohol use
Co-infection with Hepatitis B virus and/or HIV
Early onset infection (<40 years old)
Male sex
227
Hepatitis C: Progression to Chronic Infection
anti-HCV
Symptoms +/-
Titer
HCV RNA
ALT
Normal
0
1
2
3
4
Months
5
6
Time after Exposure
1
2
3
Years
4
228
30 Year Progression of Chronic Hepatitis C
Acute hepatitis C
>85% (10 years)
Chronic hepatitis C
20% - >50% (20 years)
Cirrhosis
< 20%
< 20%
Hepatic failure HCC (30 years)
229
Hepatitis C
Clinical course: HCV and HIV co-infection
(continued)
HIV has a significant effect on progression
of liver disease in HCV-infected patients
Must balance hepatotoxicity of HIV therapy
with need to treat HIV in HCV-infected
patients, while HIV therapy can worsen the
symptoms of HCV
230
Hepatitis C
Treatment: Pretreatment assessment
HCV RNA: Lower viral RNA levels (viral load) appear to
predict better treatment response
HCV genotyping:
Has impact on response to treatment
70% of HCV-infected in U.S. have genotype 1, rest are
genotypes 2, 3, and 4
Genotype 1 has less favorable prognosis and decreased
likelihood for treatment response – requires longer
duration of therapy
231
Hepatitis C
Treatment: Pretreatment assessment (continued)
Liver biopsy: Provides information regarding degree of
inflammation, fibrosis, or cirrhosis
Rules out other causes of liver disease
Sustained virological response (SVR)=absence of detectable
RNA at end of treatment and 24 weeks after end of
treatment
Interferon plus ribavirin produced SVR=38 to 43% after 48
weeks of therapy
Pegylated interferon plus ribavirin produced SVR=54-56%
after 48 weeks of therapy (82% in genotypes 2 and 3,
42% in genotype 1)
232
Hepatitis C
Treatment: Drug users and treatment for HCV
Standard recommendation: > 6 months
“clean”
Arguments for not treating: poor adherence,
side effects, re-infection, non-urgent
treatment – but data supporting these
arguments are lacking, some drug users may
do well
Treatment should be based on individual riskbenefit assessments
233
Hepatitis C
Treatment:
Management of HCV-infected injecting drug users is
enhanced by linkage to drug treatment programs
Promotion of collaboration between HCV experts
and providers specializing in substance abuse
treatment
HCV treatment of active injecting drug users should
be considered on a case-by-case basis
Active injecting drug use should not exclude
patients from HCV treatment
234
Prescribing Buprenorphine in Hepatitis
Mechanism of hepatitis associated with
buprenorphine:
Buprenorphine inhibits hepatic mitochondrial
function at high concentrations
May cause elevation of transaminases
No documented cases of fulminant liver
failure due solely to buprenorphine
235
Studies of Buprenorphine in Hepatitis
120 patients treated with buprenorphine > 40 days:
HCV: ALT and AST increased by 8-9 times upper
limit of normal
non-HCV: no change in ALT or AST
Case reports (5):
Transaminase increases, 30-50 times normal, with
intravenous buprenorphine in patients infected
with Hepatitis C
236
Prescribing Buprenorphine in Hepatitis
Buprenorphine may elevate transaminases
especially in patients with HCV
especially when administered IV
but less likely when administered sublingually
Monitor liver enzyme levels in patients with hepatitis,
especially those on Buprenorphine/Naloxone
Warn patients not to use Buprenorphine intravenously
237
HIV/AIDS
Definition
A blood-borne retroviral infection caused by the
human immunodeficiency virus (HIV)
AIDS diagnosis made using 1993 CDC
classification and case definition system:
CD4 < 200
% CD4 <14%
AIDS defining diagnoses (indicator conditions)
238
HIV/AIDS
Epidemiology
Worldwide 58 million people infected with HIV (15,000 new
cases/d)
HIV-1 predominates in the U.S.; HIV-2 found in West Africa
1.1 million cases in the US (45,000 new cases per year)
1993-1999 the number of injecting drug users living with
AIDS increased from 48,244 to 88,540
15-20% long-term injecting drug users infected
0.7-34% (median 15%) seroprevalence entering substance
abuse treatment
43% AIDS in women secondary to injection drug use
239
HIV/AIDS
Clinical course
Primary HIV infection can be asymptomatic or result in an
acute “viral” syndrome: fever 96%, adenopathy 74%,
pharyngitis 70%, rash 70%, myalgia/arthralgia 54%,
diarrhea 32%, headache 32%, nausea/vomiting 27%,
H/Smegaly 14%, thrush 12%
Initial infection is followed by active viral replication
primarily in lymphoid tissue
Course followed clinically with CD4 lymphocyte counts and
viral RNA (viral load)
240
HIV/AIDS: Natural History of HIV-1 Infection
241
HIV/AIDS
Clinical course: Risk of disease progression
Low CD4 is the strongest predictor of the
development of opportunistic infections (OIs)
Most OIs occur at CD4<50 (at least for patients
receiving PCP prophylaxis)
HIV RNA >20,000 confer greater OI risk for any given
CD4 count
High HIV RNA is an independent predictor of disease
progression
242
Indications for Treatment (www.hivatis.org)
New data suggests offering treatment to all regardless of disease
status (2010)
Clinical
Category
CD4
HVL
Recommend
Symptomatic
AIDS
Any value Any value Treat
Asymptomatic
AIDS
<200
Any value Treat
Asymptomatic
<350
Any value Offer treatment
Asymptomatic
>350
>55,000
Offer treatment
Asymptomatic
>350
<55,000
Defer therapy
3 yr risk <15%
243
HIV/AIDS
Treatment
Standard is at least a three-drug regimen (called
highly active antiretroviral therapy – HAART)
Three classes of medications are effective in
helping to decrease retroviral replication:
a) Nucleoside reverse transcriptase inhibitors
(e.g., zidovudine)
b) non-nucleoside reverse transcriptase
inhibitors (e.g., efavirenz)
c) protease inhibitors (e.g., indinavir)
244
HIV/AIDS
Treatment (continued)
Adherence to HAART can be difficult
Complications of HAART can include nephrolithiasis, anemia,
pancreatitis, neuropathy, lipid abnormalities, and fat redistribution
Poor adherence to HAART predicts treatment failure and can lead to
development of viral resistance
Clinical trials have demonstrated non-detectable viral loads in 80%
of patients receiving HAART
Patients with good adherence to HAART regimens have decreased
morbidity, mortality, hospitalization rates, and viral replication
245
HIV/AIDS
Treatment: HIV and injecting drug users
High risk for non-receipt of antiretrovirals:
2-3 times as likely not to be on antiretroviral
treatment if not in SA treatment
High risk for non-adherence:
1998 CDC guidelines recommend delaying HAART
until active opioid use has been addressed
However, drug interactions between methadone and
antiretrovirals can decrease adherence!
246
HIV/AIDS
Treatment: Buprenorphine in HIV+ injecting drug users; MANIF
2000 cohort (France):
Risk for HAART non-adherence:
Non-adherent
Adherent
OR (adjusted)
Buprenorphine 7 (21%)
25 (78%)
1.00
No current IDU 39 (35%)
74 (65%)
2.32 (0.8-6.5)
Active IDU
8 (42%)
5.1 (1.3-20.1)
11 (58%)
247
HIV/AIDS
Treatment: Buprenorphine in HIV+ injecting drug users; MANIF
2000 cohort (France):
6 month follow-up (median values):
Buprenorphine(n=20) Ex-IDU(n=83) P
Age
32
34
.04
CD4 (pre)
287
347
.16
CD4 (post)
344
457
.17
Viral Load (pre)
4.8
4.4
.17
Viral Load (post)
2.7
3.3
.91
Mos. on HAART
3.7
4.0
.34
Mos. Buprenorphine
10
NA
NA
248
Tuberculosis
Epidemiology
Worldwide, approximately 2 billion people (1/3 of world
population) are infected with M. tuberculosis
Since the HIV pandemic began in the U.S. in the mid1980s, there has been increased concern about TB
since it is more common in this population
Tuberculosis is also more common in injection drug
users in general and in patients with alcohol use
disorders
249
Tuberculosis
Clinical presentation
Tuberculosis infection without disease: PPD+
Tuberculosis infection with disease: most
commonly this involves pulmonary infection,
although other sites can be involved as well.
This is referred to as extra-pulmonary
tuberculosis (and can involve sites such as
bone, lymph node, kidneys, and other intraabdominal organs)
250
Tuberculosis
Screening for tuberculosis infection
Should be performed annually on all patients with a
history of a substance use disorder who have
previously been PPD negative and have no prior
history of tuberculosis
Patients who have had a previously positive PPD
should not receive repeat PPD testing, but should
be followed with annual chest x-rays
251
Tuberculosis
Interpretation of PPD results
PPD read as positive if:
5 mm of induration: Patients with HIV infection, those
with close contact to documented cases, and those
who have chest x-rays suggestive of tuberculosis
10 mm of induration: Individuals from population
groups with a high prevalence of tuberculosis
infection including immigrants, injection drug users,
homeless persons, immigrants from endemic areas
15 mm of induration: Individuals with no known risk
factors for tuberculosis
252
Tuberculosis
Assessment of patients with a positive PPD
History and physical exam focusing on risk
factors for tuberculosis
Chest x-ray
Sputum studies (AFB smear and culture in
individuals with chest x-ray evidence of
possible tuberculosis)
253
Tuberculosis
Treatment: No evidence of active disease (continued)
Isoniazid (INH) 300 mg po qd (plus daily vitamin B6)
for nine mos. is the standard therapy in
immunocompetent patients
Isoniazid (INH) 300 mg po qd (plus daily vitamin B6)
for 9 mos. is the standard therapy for HIV+ patients
INH hepatotoxicity is a concern, especially in patients
with other reasons to have liver disease.
Regular monitoring of liver enzymes (e.g., monthly)
254
Tuberculosis
Treatment: Evidence of active disease
Most common presentation is pulmonary tuberculosis
Multidrug regimens utilized: may include isoniazid (INH),
rifampin, pyrazinamide, ethambutol, and other agents
Note: Rifampin induces opiate withdrawal in both methadone
and buprenorphine maintained patients; will need to use
rifabutin as alternative medication
Directly observed therapy may be particularly important when
treating substance users who have active tuberculosis and
Potential for drug resistant strains of M. tuberculosis may
require additional treatment as appropriate
255
Summary
Patients with opioid dependence frequently have comorbid
medical conditions, especially infectious diseases
Important to screen for these disorders, and to provide
treatment and prevention, or to be aware of and familiar
with screening, treatment, and prevention services if they
are done elsewhere
Linkage of substance abuse treatment with medical
treatments and prevention for comorbid disorders can
enhance medical treatment outcomes
256
Risk Evaluation and Mitigation
• Buprenorphine has been diverted to the community
• The DEA is monitoring OBOT practices
• Buprenorphine appears to be abused by non-medical
use for treatment of withdrawal
• The generic form of buprenorphine is currently only
available in mono formulation
• Use wth Benzodiazepines, alcohol and other sedatives is
associated with complications
257
2004 DAWN REPORT
• 2004 the Drug Abuse Warning Network data estimated
495,732 emergency department visits for nonmedical use
of prescription medications, of which 236 (0.05%) were
reports of nonmedical use of buprenorphine and or the
buprenorphine/naloxone combination.
• During this same time, there were no reports of
buprenorphine associated with suicide attempts.
258
DIVERSION ISSUES OF BUPRENORPHINE
• T Cicero, JAMA, 2006, provided information demonstrating low
levels of buprenorphine diversion.
• Finland report of the street value of buprenorphine/naloxone,
compared to buprenorphine mono in Finland, once
buprenorphine/naloxone was introduced due to buprenorphine mono
formulation abuse.
• 80% of Finnish IV users said that the IV buprenorphine/naloxone
experience was "bad". The street value of buprenorphine/naloxone
was less than 50% of buprenorphine mono formulation.
259
Buprenorphine 2001-7
John Renner MD Feb 2008 Buprenorphine Summit
• 4.1 million prescriptions
• 585,000 patients treated
• 30% Detox
• 70% Maintenance
• 16,232 Physicians trained
• 13,318 Waivered
260
Emerging Issues
• ED visits 2003 (1) vs 2007 (Q1-3) 368
• Compared to methadone (6000) and oxycodone
(9000)
• Toxic exposures higher in children BUP 2% vs
methadone, oxycodone or heroin 0.5%
• 27% of all reported toxic exposures to BUP were
under the age of 6 vs methadone 7% and
oxycodone 8%
• Six deaths in 2006-7 all with EtOH or sed
hypnotics
261
Baltimore Sun Articles
• 1-17-08 …October, its consultants found
that half the doctors they surveyed were
aware of an illegal trade in Buprenorphine
and their numbers have been climbing”
• 1-25-08 “..addicts using the drug on the
street mostly say they do so to avoid
withdrawal, not to get high.”
262
RADARS Dasgupta Feb 2008 Bup Summit
• Governmental non-profit operation
• Rocky Mountain Poison and Drug Center
• Reckitt Benckiser did support the Pediatric data
analysis in an educational grant
• 11 of 60 US Centers (18%) 2003 Q1
• 43 of 60 US Centers (72%) 2007 Q2
263
RADARS BUPRENORPHINE ABUSE
• 125 cases were reviewed for abuse per
methodology
• Mean age 27
• Male 65%
• 7% chronic buprenorphine abuse
• 34% ingestion, 28% parenteral, 18%
inhalation
264
RADARS Mortality Data
• “associated medical outcome”
• 2003 to 2007Q3 data set
• Not causally linked to death
• 5 deaths related to BUP with intentional
use/abuse No PEDS Deaths
• Methadone has 126 deaths in the same time
frame
• 3/5, 60% were intentional self harm
265
RADARS Peds Data 2003-6
BUP
Hydrocodone
Fentanyl
Oxycodone
N=176
N=6003
N=123
N=2036
Age (SD)
2.1 (0.9)
2.3 (1.2)
2.0 (1.2)
2.1 (1.1)
Male (%)
99 (56.3)
3232 (53.9)
64 (52.5)
1081 (53.5)
Site Home %
169 (96)
5581 (93)
111 (90.2)
1821 (89.4)
Ingest %
174 (99.4)
5993 (99.8)
77 (62.6)
2020 (99.1)
266
Ceiling effect on respiratory depression
17
Breaths/Minute
16
Human respiratory rate
15
14
13
12
11
10
0
PL
1
2
4
8
16
32
Buprenorphine (mg, sl)
Adapted from Walsh et al., 1994
267
Buprenorphine-Benzodiazepine
Relative Contraindication
 CNS depressants and sedatives (eg,
benzodiazepines):
 All opioids have additive sedative effects when used in
combination with other sedatives
 Increased potential for respiratory depression, heavy
sedation, coma, and death (France, IV aprazolam and
buprenorphine)
 Despite favorable safety, use caution with
concomitant psychotropics (eg, benzodiazepines)
268
Special Treatment Populations
269
Outline for This Talk
Adolescents
Pregnant patients
Geriatric patients
HIV positive patients
Acute and chronic pain patients
Summary
270
Prevalence of any illicit drug use
In 2002, for 12-17 year olds:
Ever used any illicit drugs: 30.9%
Used illicit drugs in past year: 11.6%
In 2002, for 18-25 year olds:
Ever used illicit drugs: 59.8%
Used illicit drugs in past year: 20.2%
2002 National Survey on Drug Use and Health (NSDUH)
271
Prevalence of non-medical use of an Rx
pain reliever
In 2002, for 12-17 year olds:
Ever used: 11.2%
Used in past year: 3.2%
In 2002, for 18-25 year olds:
Ever used: 22.1%
Used in past year: 4.1%
2002 National Survey on Drug Use and Health (NSDUH)
272
Special diagnostic and treatment considerations
Length of time illicit opioids used
Relatively short?
Route of administration
Injecting? Nasal? Oral?
At risk for HIV or other infections?
273
Special diagnostic and treatment considerations
Use versus abuse versus dependence
Severity of use?
Evidence of physical dependence?
Evidence or indication that use will become
dependence despite other interventions?
Goals of treatment intervention
Withdrawal off opioids?
Maintenance?
274
Use of Buprenorphine with Adolescents
While extensive use of buprenorphine in adults, limited
use in adolescents
Guidelines for dose induction and withdrawal
recommended for adults should, in general, be used
with adolescents
Assess level of physical dependence, adjust dose
accordingly for adolescents, just as for adults
275
Use of Buprenorphine with Adolescents
Buprenorphine may be a good match for patients with
lower levels of physical dependence (such as
adolescents)
A history of multiple relapses (e.g., after medically
supervised opioid withdrawals) is an indicator for a
trial of buprenorphine maintenance treatment
Buprenorphine’s possible mild withdrawal syndrome
may also make it particularly useful in adolescents
276
Use of Buprenorphine with Adolescents
Buprenorphine may have a mild withdrawal
syndrome (this has been frequently hypothesized,
but not tested by well-controlled studies)
If buprenorphine does have a mild withdrawal
syndrome, this may be an advantage for its use
with adolescents (especially if the goal is eventual
withdrawal off the medication)
277
Use of Buprenorphine with Adolescents
Supervision of take home doses of medication
Watch for risk of diversion, abuse
Regular assessment for pregnancy
Provide or refer for other psychosocial
treatment; medication will not be enough
278
The Opioid Dependent Pregnant Patient
1997: 5,000-10,000 infants born to opioid
dependent mothers
Important to know about specialized
treatment services in your community
available for pregnant, opioid dependent
patients
Management of the patient will depend on the
availability of such services
279
Initial Management of the Pregnant Patient
It is important to know about specialized
treatment services available for
pregnant, opioid dependent patients in
your community. Management of the
patient will depend on the availability of
such services.
280
Initial Management of the Pregnant Patient
If specialized treatment program is available:
New patient – refer to the program
Buprenorphine/naloxone-maintained patient
who is now pregnant:
switch to buprenorphine alone vs. change to
methadone
consider referral to the program
281
Initial Management of the Pregnant Patient
If no specialized treatment program is available
and it is a new patient – consider referral to
methadone treatment (even if there is no
program specifically for pregnant women)
and it is a buprenorphine/naloxone maintained
patient who is now pregnant – switch to
buprenorphine monotherapy and consider
referral to methadone treatment (standard of
care for pregnant opioid dependent patients)
282
Evaluation of the Pregnant Patient
Factors to consider in the evaluation:
Is the patient dependent on opioids?
Is there other drug use?
Medical problems?
Psychiatric problems?
Family and social situation?
283
Buprenorphine versus Methadone
Methadone approved for use in
pregnancy, and substantial
experience with it
Not a similar amount of experience
with buprenorphine use in pregnancy
284
Buprenorphine versus Methadone
Minimal information about need for dose adjustments
of buprenorphine during pregnancy
Pregnant women treated with buprenorphine have
had good withdrawal suppression with once daily
dosing
Maintain clinical flexibility during pregnancy –
consider dose adjustments, split dosing, if indicated
285
Use of Buprenorphine versus Methadone
Buprenorphine may have milder withdrawal
syndrome for infant
Plasma to breast milk ratio is approximately 1
(limited data on this)
Poor oral bioavailability when buprenorphine
swallowed
Should not use buprenorphine/naloxone
286
Use of Buprenorphine versus Methadone
Like methadone, some evidence of a neonatal
abstinence syndrome (NAS) for infants born of
mothers maintained on buprenorphine (not all
infants, and not systematically studied)
Buprenorphine NAS starts in first two days,
peaks in 3-4 days, lasts up to one week
Buprenorphine via breast milk will probably not
suppress neonatal abstinence syndrome
287
In Utero Exposure to Buprenorphine
Limited experience with buprenorphine in pregnancy
(primarily case reports and small series of patients)
At least 21 published reports (case reports, prospective
studies, open-labeled controlled studies) of 15 cohorts
of infants exposed to buprenorphine in utero
No significant adverse effects on fetus noted
In general, full term births, normal birth weights
Neonate is dependent on opioids if mother is
maintained on buprenorphine
288
In Utero Exposure to Buprenorphine
Of approximately 300 infants exposed, 62%
experienced a neonatal abstinence syndrome (NAS),
with 48% requiring treatment
However, neonatal abstinent syndrome (NAS) minimal
and short lived in buprenorphine-exposed infants
Buprenorphine appears to be at least equivalent to
methadone for treatment of pregnant , opioid
dependent women (Jones et al, 2010 pending pub)
289
Geriatric (Over age 60) Population: Prevalence of
Opioid Misuse
There is no good epidemiological information available about rates
of opioid misuse in the elderly
National Household Survey/National Survey of Drug Use and
Health generally does not specify data for older persons
Drug Abuse Warning Network classifies as 55+ years old
There are anecdotal reports of older patients in methadone
treatment
Dependence on psychoactive substances can certainly be present
in this age group
290
Special Diagnostic Considerations
Our index of suspicion may be too low; we
don’t usually think of drug use in the elderly
Effects of drug use may be mistakenly
attributed to aging
The usual diagnostic criteria may be less
appropriate for the elderly (for example,
those related to violations of social norms)
291
Use of buprenorphine with geriatric patients
No data on buprenorphine for opioid
dependence in the elderly
Consider more gradual dose induction and
closer monitoring (versus routine practice in
non-elderly)
Watch for medication interactions (elderly may
have comorbid medical conditions and be
taking other prescribed medications)
292
Pain Treatment
in Patients with an Addiction
These patients suffer thrice:
1. from the painful disease
2. from the addiction, which makes pain
management difficult
3. from the health care provider’s
ignorance
293
Pain Treatment
in Patients with an Addiction
Must consider:
1. High tolerance to medications
2. Low pain threshold
3. High risk for relapse
294
Pain Treatment
in Patients with an Addiction
1.
Explain potential for relapse
2.
Explain the rationale for the medication
3.
Educate the patient and the support system
4.
Encourage family/support system
involvement
5.
Frequent follow-ups
6.
Consultations and multidisciplinary approach
295Acute
and Chronic Pain Patients
General Points Regarding Pain Treatment
Buprenorphine is an effective parenteral analgesic,
but its duration of analgesia is relatively short
(necessitating multiple dosing daily)
Buprenorphine’s analgesic potency is
approximately 30x that of morphine
A bell-shaped dose response curve has been
reported for buprenorphine’s analgesic effects
296
General Points Regarding Pain Treatment
Usual analgesic dose regimens are 0.3-0.6 mg q 6-8 hrs
(parenteral)
Duration of analgesia is about 6-8 hours
Ceiling analgesic dose is approximately 1.5-5 mg
Onset of analgesia is approximately 30 minutes
Peak analgesia occurs at approximately 3 hours
In U.S., sublingual form has not been developed for analgesic
purposes and not FDA approved for analgesic indication
Use of full opioid agonists to treat pain in patients maintained on
buprenorphine may be complicated
297
Acute Pain in Buprenorphine Maintained Patients
Make sure some form of opioid maintenance medication is
continued
The patient’s acute pain will not be treated by their once
daily maintenance dose of buprenorphine – other
management of pain will be required
Initially try non-opioid analgesics (ketorolac, NSAIDs, or
Cox-II inhibitors)
If opioid analgesics required, consider switching off
buprenorphine (e.g., to methadone)
298
Acute Pain in Buprenorphine Maintained Patients
Alternately, could try to obtain analgesic
effect with an increased dose of
buprenorphine – that is, small
supplemental doses of sublingual
buprenorphine periodically throughout the
day in addition to their once daily dose of
maintenance buprenorphine
299
Acute Pain in Buprenorphine Maintained Patients
Additional strategies to consider:
Titrate down buprenorphine dose and transfer
patient to full opioid agonist temporarily, then
return to buprenorphine
Use of regional anesthesia such as epidural
blockade
Use of other methods of pain control such as
TENS (Transcutaneous Electrical Nerve
Stimulator)
300
Chronic Pain Patients
In general, when treating a patient with
chronic pain:
Consider consulting a pain medicine
specialist
Consider multidisciplinary team approach
Try non-opioids and adjuvant analgesics
Begin with non-pharmacologic therapies
301
Chronic Pain Patients
If chronic opioid analgesics are required for pain
control:
Buprenorphine may cause precipitated withdrawal
Buprenorphine maintenance may need to be
discontinued
Patient’s opioid dependence may be better treated
with methadone maintenance (avoids
complications of possible precipitated withdrawal
by buprenorphine)
Buprenorphine: Considerations for Pain
Management
302
Rolley E Johnson et al. Journal of Pain and Symptom Management, Vol 29, No 3, March 2005,
pp297-326
303
Parental Morphine Equivalency
Morphine
Buprenorphine
10mg
0.3mg
Methadone
10mg
Oxycodone
10-15mg
Pentazocine
30mg
Codiene
120mg
304
Non Pharmacologic Interventions
1.
Behavioral Interventions-ie guided imagery, biofeedback
2.
Meditation
3.
Osteopathic Manipulation, Chiropractic, Body work, etc
4.
Acupuncture with or without stimulation
5.
Physical Therapy modalities
6.
Regional anesthetic blocks- epidural injections
7.
Tran-cutaneous Nerve Stimulation
8.
Hypnosis
305
Treatment of Chronic Pain
in Patients with an Addiction
1.
Search for physical causes
2.
Identify and address possible non-pain
sustaining factors
3.
Address and improve functional status
4.
Treat associated symptoms, if indicated
5.
Case management
306
Buprenorphine maintained patients
1.If non-opioids are ineffective, may
need to increase the BUP or stop
buprenorphine and add a pure Mu
agonist for pain (OR-fentanyl)
2.May need to switch to pure Mu
agonist for maintenance (baseline
requirements)
3.Care needed if/when buprenorphine
is restarted for maintenance
307
Chronic Pain Patients
Goals of treatment
1. Pain reduction
2. Functional improvement
3. Safe and Tolerable side effects
4. Prevention of addiction or relapse
308
Patients with Renal Failure
Few studies of buprenorphine in patients with renal failure;
ones available are primarily single dose or short duration
of treatment (for example, for analgesia)
No significant difference in kinetics of buprenorphine in
patients with renal failure versus healthy controls
No significant side effects in patients with renal failure
It should be suitable to use buprenorphine in patients with
renal failure – consistent with buprenorphine’s
metabolism being hepatic (not renal)
309
Summary
Limited information about the use of buprenorphine for
the treatment of opioid dependence in special
populations of patients
This reflects, in part, the lack of studies with these groups
(for any treatment intervention, not just buprenorphine)
While caution should be exercised in the use of
buprenorphine with any of these groups,
buprenorphine’s safety profile is an advantage to its
use in these populations
310
Waiver Notification
Process
311
Submitting Notification of Intent
www.buprenorphine.samhsa.gov/bwns/howto.html
• Printable HTML Notification of Intent Form
• Printable PDF Notification of Intent Form
• Submit Notification of Intent Form Online
A Notification of Intent Form is also included in the Additional
Reprints/Resources section of your notebook.
Record of your completion of this training kept by AOAAM who
will notify SAMHSA of qualification for waiver
312
Notification of Intent
The complete form is 2 pages.
313
Waiver Notification Process
314
For More Information
For more information about DATA 2000, buprenorphine, or about
how to submit a waiver notification, call the CSAT Buprenorphine
Information Center at 866-BUP-CSAT (866-287-2728), or e-mail
[email protected].
Live operators are available to answer calls Monday through
Friday from 8:30 a.m. to 5:00 p.m. EST.
View the approval announcement and other information about
Suboxone® and Subutex® on the FDA Web site
(www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm)
or call the FDA at 888-INFO-FDA for consumer inquiries and 301827-6242 for media inquiries.