PSYCHIATRY
Volume 44, Issue 05
March 7, 2015
Pharmacologic Management of Addiction
From Addiction Medicine Weekend, sponsored by Albany Medical College
Petros Levounis, MD, MA, Chair, Department of Psychiatry, Rutgers New Jersey Medical School,
and Chief of Service, Department of Psychiatry, University Hospital, Newark, NJ
Background: treatment of addiction relies primarily on psychosocial modalities (eg, individual or group psychotherapy,
counseling, inpatient rehabilitation, outpatient programs, partial hospitalization and halfway houses, cognitive behavioral
therapy, motivational interviewing, mentalization-based therapy, 12-step programs and facilitation, mutual help groups);
however, safe and effective medications can augment these
treatments
Pharmacotherapeutic treatment of addiction: most effective
for opioids and tobacco; moderately effective for alcohol; minimally effective for stimulants, cannabis, inhalants, and majority of other unlisted substances
Refusal of psychosocial support: medications most effective
when patients engage in counseling and discuss their problem;
speaker recommends treatment with medication in patients
with opioid or tobacco addiction who refuse psychosocial treatment, since these agents (eg, buprenorphine, nicotine patch)
sufficiently effective as monotherapies; however, speaker does
not recommend this approach for patients with alcoholism
(since evidence does not support efficacy of, eg, acamprosate
in absence of other forms of support); speaker cautions strongly
against prescribing unapproved medications (eg, methylphenidate, bupropion) to patients with addiction to stimulants
Anton et al (2006): large (>1000 patients) multicenter study with
excellent design and execution; efficacy of acamprosate alone
or naltrexone alone compared with that of acamprosate plus
naltrexone as well as that of placebo in patients who received
or did not receive psychotherapy (9 cells); all cells had favorable outcomes, although patients who received psychotherapy
alone fared slightly worse (possibly because study advertised
as medication trial); speaker attributes these outcomes to powerful psychosocial interventions received by all participants
(eg, weekend hours, childcare services, provision of one-onone care by research assistants)
Opioid µ receptor gene polymorphism: significantly increases
efficacy of naltrexone in patients with alcoholism
Tobacco
Physician advice: simple advice to quit smoking has measurable
effects and favorable outcomes; briefest possible intervention;
approach may have decreased in efficacy over time, since most
patients who continue smoking in modern era (despite contemporary stigmas) have severe forms of addiction
Educational Objectives
The goal of this program is to improve the pharmacologic management of addiction. After hearing and assimilating this program, the clinician will be better able to:
1.Identify patients whose addictions are most likely to
respond favorably to medication.
2.Select appropriate intervention for treating nicotine
addiction.
3.Explain the mechanisms by which alcohol induces
dependency-promoting effects and protracted withdrawal
syndrome.
4. Distinguish between medications that block, do not block,
or partially block opioid receptors.
5. Evaluate medications used to treat cocaine addiction.
Practices lacking base of evidence: selective serotonin reuptake
inhibitors (although some patients may be using tobacco to
self-medicate for depression and anxiety, which may warrant
psychiatric evaluation and treatment); massage therapy; acupuncture; herbal supplements; Nicotine Anonymous (however,
some physician-based groups have shown efficacy)
Nicotine replacement therapy (NRT): patches deliver steady
dose of nicotine; chewing gum addresses acute cravings; inhalers mimic hand-mouth activity of smoking; sprays have largely
fallen into disuse, as their potent initial delivery of nicotine
could impair driving and cause jitteriness and excessive activation; issues with gum — often difficult for patients to chew
(particularly those with, eg, temporomandibular joint disorder) and learn how to use properly; issues with nicotine inhalers — may exacerbate underlying condition in patients with
bronchospasms
Bupropion (eg, Aplenzin, Wellbutrin, Zyban): easy to use;
treats tobacco use and depressive disorders (common in smokers) at same dose levels; risks — may exacerbate significant
forms of anxiety (due to activating dopaminergic properties);
carries seizure warnings, but relevance greater for immediaterelease preparations (risk for seizure significantly decreased
in patients taking extended-release preparation once or twice
daily [rates comparable to those of most other antidepressants])
Varenicline: oral medication; partial agonist of nicotinic acetylcholine receptors; strength of receptor stimulation 30%
to 40% that of nicotine or other full agonists; “feeds” addiction while reducing cravings; side effects — include primarily
self-limiting forms of, eg, nausea and constipation; however,
major neuropsychiatric consequences prompt concern in many
patients, and have resulted in black box warning for increased
suicidality; reports of suicidality associated with varenicline
have increased since issuing of this warning, which may be
attributable to increased awareness or related to “me too” effect
and high rates of underlying depression seen in contemporary
smokers
Gunnell et al (2009): study included ≈80,000 smokers from
United Kingdom who received bupropion, varenicline, or
NRTs; no differences in suicidality found between groups; only
2 completed suicides recorded, and these occurred in patients
using nicotine NRTs
Cessation rates at >6 mo: bupropion, varenicline, and all forms
of NRT help with cessation; varenicline appears to be slightly
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support,
Audio Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within
the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that
this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported
nothing to disclose. In his lecture, Dr. Levounis presents information that is related to the off-label or investigational use of a
therapy, product, or device.
Audio Digest Psychiatry 44:05
superior to bupropion, but only when including data from studies funded by manufacturer of varenicline
Nicotine vaccination: causes immune system to surround nicotine molecules with antibodies, which prevents nicotine from
crossing blood-brain-barrier; approach has shown poor clinical
efficacy
Electronic cigarettes: risks and benefits have not been established (more research needed); since prominent researchers
from, eg, Centers for Disease Control, view electronic cigarettes as significantly promising, speaker recommends keeping open mind toward this approach; disadvantages — hazards
related to electricity and potential burns; can be used to inhale
dangerous substances (eg, “bath salts,” synthetic cannabinoids); no infrastructure exists to enforce labeling or regulation
Managing anxiety and excessive activation associated with
bupropion: speaker warns against use of benzodiazepines,
since it may end up legitimizing potentially catastrophic form
of substance abuse
Alcohol
Risk of combining caffeine with alcohol: sedating properties of
alcohol normally act as protective mechanism by preventing
users from drinking excessively or causing them to lose consciousness after reaching certain level of intoxication; caffeine
negates this protection by allowing users to remain alert and
continue drinking
Pharmacodynamics: extremely small molecule penetrates all
areas of body and, thus, can destroy many different types of
tissues; “dirty” substance affects many neurotransmitter systems, but primarily promotes activity of γ-aminobutyric acid
(GABA; inhibitory molecule) and inhibits glutamate (excitatory molecule); by synergistically promoting inhibitory system and antagonizing excitatory system, alcohol use results
in overall sedation and depression of central nervous system;
lower doses show preferential selection for and suppression of
frontal lobes, and thus cause disinhibited behavior (eg, belligerence, inappropriateness, apparent excitability) despite triggering sedative processes in brain
Disulfiram (Antabuse): blocks metabolism of acetaldehyde
(toxic substance) into acetate (neutral substance); accumulation of acetaldehyde (even after consumption of small amount
of alcohol) causes severe illness and discourages future consumption; pharmacodynamics — irreversible inhibitor of
acetaldehyde dehydrogenase (patients must wait 1-2 wk after
discontinuation of disulfiram before resuming consumption
of alcohol); clinical use — limited due to lack of compelling
evidence; significantly more helpful when used under supervision (including daily mouth checks) or in highly controlled
environment (eg, physician assistant programs ); speaker views
disulfiram as outdated approach because of its punitive effects
(motivational interviewing and recent shifts in psychosocial
treatment of addiction have shown that punitive approaches
fail to benefit patients)
Alcohol-induced cravings: reward craving — occurs when
patient feels perfectly fine; initial intake causes strong desire
to consume increasing quantities of alcohol, which leads to
intoxication; abstinence craving — opposite of reward craving; when patients stop drinking, they experience protracted
withdrawal syndrome resulting in anxiety, irritability, insomnia, restlessness, and malaise; this syndrome causes patients to
drink in order to normalize mental state; physiology — opioid
and dopamine systems mediate reward cravings, whereas glutamate primarily mediates abstinence cravings
Naltrexone: blocks opioid system, and thus primarily affects
reward cravings for alcohol; effects on alcoholism — patients
who attempt to abstain from alcohol may experience lapses;
without medication, consumption of even small amounts of
alcohol causes activation of opioid system, leading to excitement, reward cravings, and full relapse; in patients who receive
naltrexone (50 mg/day orally or 380 mg intramuscularly), these
small lapses less productive of excitement and euphoria; thus,
patients have better chance of resuming their sobriety; particularly effective for reducing heavy drinking
Acamprosate: affects abstinence cravings by interfering with
glutamate system, thus reducing misery associated with protracted withdrawal syndrome and preventing patients from taking their first drink (ie, maintaining abstinence)
Naltrexone vs acamprosate: neither agent has substantial efficacy; slightly greater quantity of evidence supports naltrexone
over acamprosate; although acamprosate highly successful in
Europe, results in United States (US) poor
Opioids
Origins of opioid epidemic: in US, emergency department
admissions related to prescription opioids have increased dramatically since 1999; physicians have significant responsibility
for epidemic, since medical students have been taught to prescribe opioids for any kind of pain without hesitation (ignoring
concerns about addiction); pharmaceutical industry has capitalized on these attitudes among physicians, which has further
contributed to problem
Contemporary changes in opioid prescribing and use: widespread addiction to synthetic opioids has led to new regulations
that make prescriptions more difficult to obtain; physicians
now take courses on risk evaluation and mitigation strategies;
New York has established Internet System for Tracking OverPrescribing (I-STOP); new formulations of medications more
difficult to crush and inject; these changes have led to decrease
in abuse of oxycodone (OxyContin) but have caused many
individuals with ongoing opioid addiction to switch to heroin
(which has led to escalating rates of use)
Cicero et al (2014): in 1960s, for most individuals, addiction to
opioids started with heroin use; entry point to addiction gradually shifted toward prescription opioids; trend has reversed in
recent years, with heroin increasingly considered substance
of choice by younger individuals because of its widespread
availability
Pharmacologic treatment options: methadone (full agonist);
naltrexone (full antagonist); buprenorphine (partial agonist);
opioid agonists — may be highly reinforcing, and can cause
addiction or respiratory depression; prescribing methadone thus
requires high level of competency, as miscalculated dosages
can result in death; opioid antagonists — block opioid receptors, and thus have no potential for addiction; since patients do
not receive reinforcement from use, compliance may be major
issue; buprenorphine — most successful option; partial agonist
with high affinity for opioid µ receptor and slow dissociation;
strength of receptor stimulation ≤40% that of full agonists
Comparing effects of pharmacologic agents: methadone (full
agonist) activates opioid receptors with 100% efficiency (associated with euphoria, relief of physical and emotional pain, and
respiratory depression); even at high doses, naltrexone does not
activate opioid receptors (no association with addiction, euphoria, pain relief, or respiratory depression); buprenorphine has
ceiling effect, wherein strength of receptor stimulation 40%
that of full agonists even at extremely high doses
Advantages of buprenorphine: prescribed in physician’s office
(no specialized clinic required); lethal overdose virtually
impossible (because of ceiling effect)
Other Substances of Abuse
Khat: mild stimulant; popular in Somalia and Saudi Arabia
before being brought to US; active molecules have been modified for use in bath salts preparations containing synthetic versions of khat
Dackis et al (2012): for first 12 wk of study, modafinil found to
be superior to placebo in patients with addiction to cocaine;
however, no difference between modafinil and placebo seen
at 24 wk; speaker warns against trusting results of short-term
studies
Audio Digest Psychiatry 44:05
Mariani et al (2012): topiramate showed efficacy for patients
with addiction to cocaine; however, speaker expresses hesitation over findings because of short length of study (12 wk)
Cocaine vaccine: results disappointing
Disulfiram for cocaine addiction: secondary mechanism
of action centrally blocks dopamine β-hydroxylase, which
increases levels of dopamine; disulfiram must be avoided in
patients with schizophrenia; because disulfiram amplifies
already significant increases in dopamine caused by cocaine, it
causes jitteriness and unpleasant overexcitation in brain (thus
acting as aversive agent)
Synthetic cannabinoids: significantly more dangerous than tetrahydrocannabinol (THC; active molecule in marijuana); frequently available in, eg, gas stations and gift stores; increasing
levels of THC in natural cannabis plants have been associated
with psychosis; risk of inducing psychosis even greater with
new synthetic cannabinoids
Dronabinol: synthetic form of THC showing limited promise;
cannabis-using patients given dronabinol tend to stay in treatment for longer periods of time than do patients given placebo (toxicologic examinations of urine showed no difference
between dronabinol and placebo)
Acknowledgments
Dr. Levounis was recorded at Addiction Medicine Weekend, held November 7-8, 2014, in Albany, NY, and sponsored by Albany Medical College. For information about upcoming CME activities from Albany Medical College, please visit www.amc.edu. The Audio
Digest Foundation thanks Dr. Levounis and Albany Medical College for their cooperation in the production of this program.
Suggested Reading
Anton RF et al: Combined pharmacotherapies and behavioral
interventions for alcohol dependence: the COMBINE study: a
randomized controlled trial. JAMA 295:2003, 2006; Baxter LE
Sr et al: Safe methadone induction and stabilization: report of
an expert panel. J Addict Med 7:377, 2013; Cicero TJ et al: The
changing face of heroin use in the United States: a retrospective
analysis of the past 50 years. JAMA Psychiatry 71:821, 2014;
Dackis CA et al: A double-blind, placebo-controlled trial of
modafinil for cocaine dependence. J Subst Abuse Treat 43:303,
2012; Gunnell D et al: Varenicline and suicidal behaviour: a
cohort study based on data from the General Practice Research
Database. BMJ 339:b3805, 2009; Kraus ML et al: Statement
Accreditation: The ­Audio Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing
medical education for physicians.
Designation: The ­
Audio Digest Foundation designates this enduring
material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians
should claim only the credit commensurate with the extent of their participation in the activity.
­Audio Digest Foundation is approved by the American Psychological
Association to sponsor continuing education for psychologists. ­
Audio
Digest Foundation maintains responsibility for this program and its content. Each A
­ udio Digest Psychiatry home study activity is offered for 2 CE
credits for psychologists.
The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities designated for AMA PRA
Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum
of 2 AAPA Category 1 CME credits for each ­Audio Digest activity completed successfully.
­Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC’s)
Commission on Accreditation. ­Audio Digest designates each activity for
2.0 CE contact hours.
of the American Society Of Addiction Medicine Consensus
Panel on the use of buprenorphine in office-based treatment of
opioid addiction. J Addict Med 5:254, 2011; Mariani JJ et al:
Extended-release mixed amphetamine salts and topiramate for
cocaine dependence: a randomized controlled trial. Biol Psychiatry 72:950, 2012; Mcfarlane V, Christie G: Synthetic cannabinoid withdrawal: A new demand on detoxification services. Drug
Alcohol Rev 2015 Jan 15. [Epub ahead of print]; Rech MA et
al: New Drugs of Abuse. Pharmacotherapy 2014 Dec 4. [Epub
ahead of print]; Skinner MD et al: Disulfiram efficacy in the
treatment of alcohol dependence: a meta-analysis. PLoS One
9:e87366, 2014.
­ udio Digest Foundation is approved as a provider of nurse practitioner
A
continuing education by the American Academy of Nurse Practitioners
(AANP Approved Provider number 030904). ­Audio Digest designates each
activity for 2.0 CE contact hours, including 0.5 pharmacology CE contact
hours.
The California State Board of Registered Nursing (CA BRN) accepts
courses provided for AMA PRA Category 1 Credit™ as meeting the continuing education requirements for license renewal.
Expiration: This CME activity qualifies for AMA PRA Category 1
Credit™ for 3 years from the date of publication.
Cultural and linguistic resources: In compliance with California Assembly Bill 1195, Audio Digest Foundation offers selected cultural and linguistic resources on its website. Please visit this site: www.audiodigest
.org/CLCresources.
Estimated time to complete the educational process:
Review Educational Objectives on page 1
Take pretest
Listen to audio program
Review written summary and suggested readings
Take posttest
5 minutes
10 minutes
60 minutes
35 minutes
10 minutes
Audio Digest Psychiatry 44:05
Pharmacologic Management of Addiction
To test online, go to www.audiodigest.org and sign in to online services.
To submit a test form by mail or fax, complete Pretest section before listening and Posttest section after listening.
1. Pharmacologic treatment is least effective for patients who abuse which of the following substances?
(A) Tobacco
(B) Opiates
(C) Alcohol
(D) Stimulants**
2. Opioid µ receptor gene polymorphism significantly increases the efficacy of naltrexone in patients with:
(A) Opioid addiction
(B) Alcoholism**
(C) Cocaine addiction
(D) All the above
3. The dose of bupropion prescribed to treat smoking cessation is _______ the dose of bupropion prescribed to treat depression.
(A) Higher than
(B) Lower than
(C) Equal to**
4. Which of the following medications carries a black box warning because of reports of increased suicidality?
(A) Bupropion
(C) Naltrexone
(B) Varenicline**
(D) Acamprosate
5. Disulfiram produces its aversive effects by causing the accumulation of which of the following substances?
(A) Acetaldehyde**
(B) Acetaldehyde hydrogenase
(C) Acetate
(D) Glutamate
6. Acamprosate mediates abstinence cravings and the symptoms of protracted withdrawal syndrome by interfering with which
of the following neurotransmitter systems?
(A) γ-aminobutyric acid
(B) Glutamate**
(C) Dopamine
(D) Noradrenaline
7. Which of the following treatments for alcoholism is backed by the greatest amount of evidence?
(A) Disulfiram
(B) Naltrexone**
(C) Acamprosate
(D) Bupropion
8. Which of the following medications shows the highest rates of success in patients with opioid dependency?
(A) Methadone
(B) Naltrexone
(C) Buprenorphine**
9. Which of the following medications is contraindicated in patients with schizophrenia because of its ability to increase levels
of dopamine?
(A) Varenicline
(B) Bupropion
(C) Disulfiram**
(D) Acamprosate
10. Which of the following medications has been shown to make cocaine use more unpleasant and potentially produce an
aversive response?
(A) Varenicline
(B) Bupropion
(C) Naltrexone
(D) Disulfiram**
Answers to Audio Digest Psychiatry Volume 44, Issue 04: 1-A, 2-C, 3-B, 4-C, 5-C, 6-D, 7-B, 8-B, 9-D, 10-A
ⒸⓅ 2015 Audio Digest Foundation • ISSN 0271-1311 • www.audiodigest.org
Toll-Free Service Within the U.S. and Canada: 1-800-423-2308 • Service Outside the U.S. and Canada: 1-818-240-7500
Remarks represent viewpoints of the speakers, not necessarily those of the Audio Digest Foundation.