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OPIOIDS IN TREATMENT OF
CHRONIC NON CANCER PAIN
Elias Veizi MD, PhD
Pain Medicine &Spine Care VAMC
Assistant Professor,
Departments of Anesthesiology, Pain Medicine
Case Western Reserve University
Cleveland, OH
OBJECTIVES
 Pharmacology of opioids
 Effects and side effects of opioids
 Review the state of opioid prescribing
 UDT in chronic pain patients
 DISCLOSURES: NONE
Nomenclature
 Opium: dried powdered mixture of 20 alkaloids
from the seed capsules of the poppy
 Opiate: any agent derived from opium (really only 3:
codeine, morphine, thebaine)
 Opioid: all substances with morphine like
properties
Heroin
HO- Group is needed for activity
2
AcO
2
HO
Easily enzymatically hydrolyzed to AcOH and HO-Ar
3
3
1
1
11
4
11
4
12
O
13
5
HO
10
15
O
9
14
H
8
6
16
12
H
13
5
N
CH3
AcO
10
15
9
14
H
8
6
16
H
N
CH3
7
7
Morphine (Astramorph)
HO- Group not important to activity
Heroin (Diamorphine)
(2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
I. Opioid Pharmacology
 Body has its own analgesic system
 This in-built analgesia provides short-term relief from pain
that enables an animal to escape from predators or extract
themselves from a dangerous situation without being crippled
with pain
 Opioid analgesics utilise this system to provide controlled
pain-relief
 This system is stimulated by other stimuli beside pain,
including exercise and stress
I. Opioid Pharmacology: Endogenous system
PROOPIOMELANOCORTIN
b-endorphin (m , d)
PROENKEPHALIN
Leu-enkephalin (d)
Met-enkephalin (d)
PRODYNORPHIN
Dynorphin A (k)
Dynorphin B (k)
a-neoendorphin (k)
b-neoendorphin (k)
Leu-enkephalin (d)
(ENDOMORPHINS)
????
I. Opioid Pharmacology:
Receptors
Characteristics
 Highly specific, high affinity binding sites
 Receptors subtypes
 mu (μ) – euphoria, analgesia, physical dependence,
respiratory depression
 µ1 = supraspinal analgesia; µ2 = spinal analgesia
 kappa (κ) – miosis, analgesia of pentazocine, sedation
 delta (δ) similar to μ receptors, enkephalins natural
agonists
 N/OFQ – newest opioid receptor; orphanin natural
agonists
I. Opioid pharmacology: mechanism of
action
Ca2+
Ca2+
Opioid
m opioid
receptor
Primary
afferent
nociceptor
terminal
Opioid
Secondary
ascending
neuron
Neurotransmitter
glutamate
m opioid
receptor
K+
K+
Functional Effects Associated with the
Main Types of Opioid Receptor
μ
δ
κ
Analgesia
Supraspinal
Spinal
Peripheral
+++
++
++
++
-
+
++
Respiratory depression
+++
++
-
Pupil constriction
++
-
+
Reduced GI motility
++
++
+
Euphoria
+++
-
-
Dysphoria
-
-
+++
Sedation
++
-
++
Physical dependence
+++
-
+
Morphine
25%
Morphine
acts here
NA
Cortico-Spinal
Receptors
5%
70%
Peripheral Nerve
5HT
Spino-thalamic
Activation of the μ receptor by an agonist
such as morphine
 analgesia
 sedation
reduced blood pressure
Itching
Nausea
 euphoria
 decreased respiration
 miosis (constricted pupils)
decreased bowel motility often leading to constipation
Classification of Agents
 Agonists
 Opium derivatives
 morphine
 codeine
 heroin (semi-synthetic)
 hydromorphone (Dilaudid), oxymorphone (Opana)
 semisynthetic derivatives of morphine
 hydrocodone (Vicodin), oxycodone (Percodan;
Oxycontin)
 semisynthetic derivatives of codeine
Classification of Agents
Synthetic opioids
meperidine (Demerol)
methadone (Dolophine)
propoxyphene (Darvon)
levorphanol (Levo-Dromoran)
Classification of Agents
 Opioid antagonists
 Drugs that bind to opioid receptors and may antagonize
(pure antagonists) or partially stimulate (partial agonists).
 Agonist – antagonists (partial agonists)
pentazocine (Talwin)
buprenorphine (Buprenex)
butorphanol (Stadol)
nalbuphine (Nubain)
Classification of Agents
Pure antagonists
naloxone (Narcan)
naltrexone (ReVia)
nalmefine (Revex)
Opioid Agonists
Morphine and its derivatives
 Morphine
 L-isomers are active form
 Extract of Papaver somniferum; chief phenanthrene
alkaloid in opium
 Standard analgesic for moderate to severe pain
Morphine Pharmacology
CNS effects
Analgesia
Selectively interfere with nociception of pain
Also interferes with forebrain mechanisms for affective
reaction to pain
Action mediated via receptors in:
 dorsal horn of spinal cord (substantia gelatinosa)
 periaqueductal gray (PAG)
 dorsal raphe nuclei
 and limbic regions
Morphine Pharmacology
CNS effects (cont.)
 Behavioral effects: dysphoria as initial experience followed by
euphoria – major contributor to abuse liability as well as relief of
pain and anxiety
 Sedation, drowsiness, and mental clouding
 Emetic:
 direct stimulation
 High doses depress vomiting center
 Antitussive: direct action on medulla cough center to suppress
cough reflex
Morphine Pharmacology
CNS effect (cont.)
 Respiratory depression: ↓ sensitivity of
respiratory center to CO2 drive. ↓ both rate
and depth of respiration. Overdose-death by
respiratory failure.
 Hypothalamus – slightly ↓ body temperature ↓ ACTH, FSH, LH, TSH
 Myosis (pin point pupils)
 ↑ tone to spinal motoneurons at high dose
(muscle rigidity)
 Excitatory effect at high doses, e.g., convulsion
Morphine Pharmacology
Peripheral actions
 GI tract - ↑ tone, ↓ peristalsis – constipation
(need to prevent and/or treat constipation in patients taking
opioids chronically)
 Biliary tract – gall bladder or bile duct spasm
due to ↑ biliary pressure
 Urinary tract - ↑ muscle tone → ↓ urinary
output
Morphine Pharmacology
 Peripheral actions
 Cardiovascular system – Most opioids have little direct effect on




the heart but may produce bradycardia
peripheral vasodilation and orthostatic hypotension as a result
of CNS actions, and histamine release.
Cerebral vasodilation, ↑ intracranial pressure
Indirect effect due to histamine release
 Itching, sweating, redness of eyes
 Bronchoconstriction, ↓ bronchial secretions
Immunologic – suppression of function of NK cells. However,
blocking pain with opioids may reverse pain-induced supression
of immune function.
Morphine and its Derivatives
Pharmacokinetics
Absorption
 im or sc: rapid absorption; peak plasma level within 30 min
 po: rapid absorption; significant first pass effect, relatively low
oral/parenteral ratio
Alternative routes of administration – an attempt to maximize benefit
and minimize side effects
 Patient controlled analgesia (PCA)
 Epidural
 Transdermal
 Transmucosal
 Intra-articular
Morphine Pharmacology
 Pharmacokinetics
 Metabolism
 Rapid glucuronide conjugation in liver and intestine
 80 - 90% may be metabolized during the first pass through the liver after
an oral dose
 Morphine-6-glucuronide (an active metabolite)
 4 – 6X more potent than morphine
 may contributes significantly to analgesia when morphine given
chronically by oral route or with renal failure
 Morphine-3-glucuronide lacks analgesic effect but can cause
dysphoric side effects or seizures
Morphine Pharmacology
Pharmacokinetics
Distribution – widely distributed
 Crosses placenta
 limited amounts slowly enters the brain (ABC transporters and
hydrophilicity limit entry)
Elimination
 Primarily biotransformation
 ~ 90% via kidney (as glucuronide)
 ~10% in feces via bile
Morphine Pharmacology
Acute toxic symptoms
 Triad
 coma, pinpoint pupils, respiratory depression
 Treatment:
 Maintain respiration
 Opioid antagonist, preferably iv naloxone (may precipitate
withdrawal symptoms), repeat as needed (naloxone has a
duration)
Morphine Pharmacology
Drug interactions
CNS depressant effects may be prolonged or
exaggerated by CNS depressants:
phenothiazines, MAOI, tricyclic antidepressants
Amphetamine in small dose may enhance
morphine effect (mechanism not clear)
Morphine Pharmacology
Contraindications/cautions
 Bronchial asthma
 Emphysema
 Liver damage
 Head injuries
 Acute alcohol use
 Previous dependence
 Convulsive disorders
 Abdominal pain of unknown origin
Synthetic Opioids
 Methadone (Dolophine)
 Primarily a μ agonist with actions similar to
morphine except
 Also glutamate antagonist at NMDA receptors
 Greater oral effectiveness
 Extended duration of action in suppressing
withdrawal
 Slow onset. Long duration (T1/2 22 hr) may
accumulate
8
8
Other Synthetic Opioids
Methadone (Cont.)
 Tolerance develops more slowly
 Withdrawal syndrome is long and relatively mild
 basis of “methadone detoxification”; wean addicts
off of other narcotics with oral methadone for a few
weeks.
 May cause torsades de pointes. Use with caution in
patient at risk for arrhythmias.
 Low cost so payers are encouraging its use
Methadone therapy
[prevention model considerations]
Appropriate selection of candidates based on medical and behavioral stability.
Methadone should not be used, or used very cautiously, in individuals with QTc
prolongation higher than 500 ms or cardiopulmonary abnormalities.
Additional risk factors for TdP are:
 History of unexplained syncope or seizures
 Other medication usage that affect QTc or CYP 3A4
 Pain patients likely to “doctor shop,” misuse methadone, or mix it with CNS
depressants are not good candidates for methadone.
Because a subgroup of pain patients experience substance use disorders, it is critically
important to assess for a history of substance use before initiating methadone treatment
for pain.
Although risk factors should be carefully considered, circumstances exist (e.g. end of
life) in which benefits of improving refractory pain may outweigh risks associated with
methadone
J Gen Intern Med 25(4):305–9 2010
Methadone dosing considerations
 Elderly, medically compromised, and opioid-naïve individuals starting on
methadone require special dosing considerations.
 Guidelines:
 Initial methadone doses for opioid-naïve patients should not exceed 15–30
mg a day for the first three days, and it may be as low as 1–2 mg in
medically vulnerable patients.
 In the US, the current package insert recommends starting methadone at
2.5–10 mg every 8–12 hours, with gradual titration, depending on efficacy
and tolerability
 Despite some variation in initial dosing, both guidelines advocate for a “start
low and go slow” approach, vigilance in assessing signs of toxicity, and slow
titrations upward when necessary.
 If pain persists, rescue doses may be required to improve analgesia during
initial stages of treatment.
 Patients are encouraged to monitor pain states, doses taken, quality of sleep,
mood, and activity level.
J Gen Intern Med 25(4):305–9 2010
Potential Risk Factors in Methadone
Deaths
Potential risk factors for respiratory
Potential risk factors for TdP:
depression
 Advancing age
 Medically compromised
 Female gender
 Liver or cardiac pathology
 Electrolyte imbalance
 Sleep apnea
 Liver or pulmonary pathology
 Polysubstance use
 Unexplained syncope or seizures
 Opioid-naïve/low tolerance
 High doses of methadone
 Rapid titration of methadone dosing
 Other drug and medication use,
especially those that impact QTc or
inhibit CYP 3A428
 High doses of methadone
 Prolonged QTc
Opioid Withdrawal
Other Synthetic Opioids
Tramadol (Ultram)
 not strictly an opioid analgesic
 produces part of its effects by binding to μ receptors.
 Also inhibits NE and 5HT reuptake.
 Risk of seizures
Understand the difference between
 Tolerance= less pain relief with the same dose (not a
contraindication for therapy)
 Physical dependence= withdrawal symptoms may occur
when mediation is stopped (it is not addiction)
 Addiction=compulsive behavior seeking the drugs
 Pseudo addiction=Iatrogenic drug seeking behavior
(inadequate treatment of pain?!)
The consequences of drugs of abuse on
the cellular elements of the CNS
A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of
drug abuse
Cerebral vascular changes in polydrug
abusers
Photomicrographs
illustrating
the
spectrum of cerebral vascular changes in
polydrug abusers.
(A) Small artery in occipital white matter
showing concentric wall thickening. The
surrounding perivascular space contains
occasional macrophages and pigment
deposition. H&E, original magnification
×200.
(B) Small vessel in the orbital white
matter with perivascular lymphocytic
aggregates. H&E, original magnification
×200.
(C) Endothelial proliferation in the dentate
nucleus, H&E, original magnification
×200.
(D) Endothelial hyperplasia in the
parietal
white matter, H&E, original
magnification ×200.
A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of
drug abuse
White matter of polydrug abusers a
widespread axonal damage
Immunohistochemistry
demonstrating
β-APPimmunopositive bundles and βAPP-immunopositive
globular
deposits in the pons of polydrug
abusers, counterstained with
haematoxylin,
original
magnification ×100.
A. Büttner (2011) Neuropathology and Applied Neurobiology37, 118–134 The neuropathology of
drug abuse
Dependence
(1) Physical dependence follows invariably tolerance to
repeated administration of an opioid (m type).
(2) Failure to continue administering the drug results in
withdrawal or abstinence syndrome.
(3) The signs and symptoms of withdrawal are: Rhinorrhea,
lacrimation,
chills,
gooseflesh
(piloerection),
hyperventilation, hyperthermia, mydriasis muscular
aches, vomiting, diarrhea, anxiety, and hostility.
OPIOID PRESCRIBING: Tremendous
increase in prescribing
 From 1997 to 2007, the milligram-per-person use of
prescription opioids in the U.S. increased from 74 milligrams
to 369 milligrams ↑ 402%
 In 2000, retail pharmacies dispensed 174 million
prescriptions for opioids; by 2009, 257 million prescriptions
were dispensed ↑ 48%
http://www.whitehouse.gov/ondcp/prescription-drug-abuse
Prescription opioid analgesic deaths nationwide, from 2001-2005.
Lanier W L , Kharasch E D Mayo Clin Proc. 2009;84:572575
© 2009 Mayo Foundation for Medical Education and Research
Increased prescription of opioids in million grams of
medication
between 1997 and 2006
Data taken from www.justice.gov/dea/index.htm
Crofford, L. J. (2010) Adverse effects of chronic opioid therapy for chronic musculoskeletal pain
Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.24
Opioid use - statistics
15% of chronic pain patients not treated with opioids had
illicit drug use vs. 34% illicit drug use in patients treated with
opioids.1
Patients with substance abuse are more likely to request &
be prescribed opioids?
Patients prescribed opioids are more likely to develop comorbid substance abuse issues?
1. Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Phys 2011;14:123-43
Who is prescribing these meds?
90% of patients are on opioids prior to presenting to a pain
center.1
Main prescribers of opioid analgesics are PCPs, followed by
dentists and orthopedic surgeons. The main prescribers for
patients age 10-19 are dentists.2
1. Manchikanti L, Damron KS, McManus CD, et al. Patterns of illicit drug use and opioid abuse in patients with chronic pain at
initial evaluation: a prospective, observational study. Pain Phys 2004;7:431-7. 2. Volkow ND, McLellan TA. Curtailing diversion
and abuse of opioid analgesics without jeopardizing pain treatment. JAMA 2011;305(13):1346-7
EVIDENCE??
A systematic review of randomized trials for
multiple opioids utilized for managing various
chronic pain conditions, showed fair evidence
for tramadol in managing osteoarthritis. For all
other conditions and all other drugs excluding
tramadol, the evidence was poor based on
either weak positive evidence or indeterminate
or negative evidence.
Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long-term opioid
management for chronic non-cancer pain. Pain Phys 2011;14:91-121.
PCP prescribing habits
PCPs assessed regarding following of nationally
accepted pain treatment guidelines before and after
2-hour intervention
What % of PCPs discussed….
Comorbid depression 35% → 44%
Functional status
38% → 49%
Substance use
25% → 34%
Side effects
14% → 20%
Corson K, Doak MN, Denneson L, et al. Primary care clinician adherence to guidelines for the management of chronic musculoskeletal pain: results
from the study of the effectiveness of a collaborative approach to pain. Pain Med 2011;12:1490-1501.
Aberrant behaviors (cont.)
 Going to ER for opioid medication refills
 Requesting early refills
 Reporting lost or stolen prescriptions
 Not following up with appointments that do not
involve dispensing opioids
 Motor vehicle accidents or arrests
 Abuse of illicit substances
 Reporting relief only from opioid medications
Consider opioid agreement for chronic
pain patients who:



Who are at risk for abuse or misuse
Who take opiates around-the-clock
Who get care from several providers
Monitoring based on Risk Level
Low
Moderate
High
5%
28%
90%
Monthly
Biweekly
Weekly
Yes
Yes
Yes
Other UDS
Randomly
Every visit
Every visit
Pill Counts?
No
Consider
Yes
Referral to
psychiatry/addictio
n?
No
Consider
Yes
Aberrant
behavior?
Frequency of
visits
UDS at initiation?
When to do Urine Drug Testing (UDT)
Consider testing for chronic pain patients:
 Who are on opiates and new to you
 Who have hx of prior substance abuse
 Who exhibit aberrant behaviors
 When starting new treatments
 To support a referral or a contract
8
WHY URINE?
 Urine allows longer
detection times than serum
(blood)1
 Good specificity, sensitivity,
low cost, ease of use2
 Currently we have the most
data on use of urine
1. Moeller K, Lee KC< Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc 2008;83:66-76. 2. Manchikanti L, Malla Y, Wargo B,
et al. Protocol for accuracy of point of care (POC) or in-office urine drug testing (immunoassay) in chronic pain patients: a prospective analysis of
immunoassay and liquid chromatography tandem mass spectroscopy (LC/MS/MS). Pain Physician 2010;13:E1-22.
Drug
Urine Detection Time
Heroin (6-MAM)
6-8 hours
Hydrocodone
1-2 days
Oxycodone
1-3 days
Morphine
3-4 days
Methadone
2-4 days
Benzodiazepines
Up to 30 days
Cocaine
1-3 days
Amphetamine
2-4 days
PCP
2-8 days
Marijuana
2-7 days for casual use
30 days for chronic use
IMPLEMENTATION
 Screening for opioid use/misuse helps build trust and
strengthens the patient-physician relationship
 Discuss at the first visit in a non-confrontational way that
this is like any other laboratory test
Cross-Reactivity
Drug
Cannabis
Opioids
Methadone
PCP
Benzodiazepine
s
Alcohol
Cross-Reactants
NSAIDs, protonix, marinol
Poppy seeds, chlorpromazine, rifampin,
dextromethorphan
Propoxyphene, quetiapine
Chlorpromazine, thioridazine, meperidine,
diphenhydramine
Oxaprozin (daypro)
Asthma inhalers
FALSE-POSITIVES FOR ILLICIT
DRUGS
A 2011 study on ~1,000 patients found1:
0% for cocaine
2% for marijuana
~1% for amphetamines
Plan may include no prescription until confirmation or a
limited supply (3-5 days)
1. Manchikanti L, Malla Y, Wargo BW, Fellows B. Comparative evaluation of the accuracy of immunoassay with liuqid
chromatography tandem mass spectrometry (LC/MS/MS) of urine drug testing (UDT) opioids and illict drugs in chronic pain
patients. Pain Physician 2011;14;175-88.
CONFIRMATORY TESTING
2009 retrospective study in 1 million patients utilizing UDT
found1:
75% were likely not taking medication as prescribed
38% had no detectable level of prescribed med
29% had a non-prescribed med
11% had illicit drugs.
While recommendations exist regarding use of UDT, none
exist regarding use of POC vs confirmatory testing.
1. Couto JE, Romney MC, Leider HL, et al. High rates of inappropriate drug use in the chronic pain population. Popul Health Mang 2009;12:185-90.
INTERPRETING RESULTS –
5 POSSIBILITIES
1. + for prescribed drugs and – for all other drugs
Normal result
2. - for prescribed drugs
3. + for non-prescribed drugs
4. + for illicit drugs
5. Urine specimen tampered with
Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Physician 2011;14:123-43.
URINE SPECIMEN TAMPERED
WITH
 Cold urine, wrong pH, abnormal creatinine, etc.
 Almost any possible explanation is incriminating
 Consider as grounds for discharge.
- FOR PRESCRIBED DRUGS


Send specimen for confirmation
More restrictive compliance monitoring
o
More frequent visits
o
Pill counts
o
Change in formulation
+ FOR NON-PRESCRIBED DRUG
False-positive
 Review cross-reactants
 Send for confirmation
 Metabolites
Opioids from another source
 Review state prescription reporting data [OARRS]
Metabolites
Drug
Hydrocodone
Metabolites
Hydromorphone, dihydrocodeine
Oxycodone
Oxymorphone, noroxycodone
Morphine
M-3-G, M-6-G, normorphine,
hydromorphone
Methadone
Hydromorphone
Oxymorphone
Codeine
Heroin
Fentanyl
EDDP
H-3-G, dihydromorphone
O-3-G, oxymorphol
Hydrocodone, norcodeine, morphine
Morphine, codeine, 6-MAM
Norfentanyl
+ FOR ILLICIT DRUGS
 ~46% of patient with CNCP have history of illicit drug
use and 8-23% are current users, 12% are actively abusing
opioids.1,2
 Continued illicit drug use is incompatible with opioid
therapy
 Discharge vs addiction medicine referral vs treatment.
1. Manchikanti L, Cash KA, Malla Y, et al. A prospective evaluation of psychotherapeutic and illicit drug use in patients presenting with chronic pain at the
time of initial evaluation. Pain Phys 2013;16:E1-13. 2. Manchikanti L, Damron KS, McManus CD, et al. Patterns of illicit drug use and opioid abuse in patients
with chronic pain at initial evaluation: a prospective, observational study. Pain Phys 2004;7:431-7
Opioid Therapy
Guidelines for opioid treatment
 Exhaust other conservative treatment options first
 Rule out contraindications to opioid use
 Single practitioner prescribes all the opioids
 Provide informed consent regarding side effects
 Opioid contract
 Assess degree of pain relief, functional improvement
 Pt should return at least monthly during dose titration
 Consider tapering and discontinuation if contract
breached
 Consider always alternative treatment
Thank you