Substance Abuse

From the 9th Annual Psychiatry Review, Pleasure and Motivation: Addiction, Impulsivity, and Compulsivity,
presented by the University of Minnesota Medical School

Educational Objectives

The goal of this program is to improve the recognition and treatment of substance abuse and dependence. After hear­ing and assimilating this program, the clinician will be better able to:

Identify patients at risk for dependence on prescription opioids, heroin, and alcohol.

Describe treatment strategies for opioid dependence.

Compare and contrast traditional and newer treatment strategies for alcohol abuse and dependence.

Explain some of the mechanisms, such as environmental cues, that contribute to nicotine addiction.

Discuss pharmacotherapy for nicotine addiction.

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, the following has been disclosed: Dr. Hatsukami is a consultant for Pfizer and Novartis and has received grant/research support from Nabi Bipopharmaceuticals. Dr. Fiellin and the planning committee reported nothing to disclose.

Acknowledgements

Drs. Fiellin and Hatsukami were recorded at the 9th Annual Psychiatry Review, Pleasure and Motivation: Addiction, Impulsivity, and Compulsivity, held September 18-19, 2008, in Minneapolis, MN, and sponsored by the University of Minnesota Medical School, Department of Psychiatry. The Audio-Digest Foundation thanks the speakers and UMMS for their cooperation in the production of this program.

Office-based Treatments for Opioid and Alcohol Dependence

David A. Fiellin, MD, Associate Professor of Medicine and Investigative Medicine, Department of Internal Medicine and General Medicine, Yale University School of Medicine, New Haven, CT

Introduction: majority of patients with opioid dependence use prescription opioids; estimated that 3 million individ­uals in United States who use prescription opioids meet criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for opioid dependence; heroin use less frequent (estimated that 2.4 million people have used heroin once, 1 million people dependent on it); heroin use usually via intranasal or smoking routes (potency of heroin has increased so much that most people no longer need to inject it); treatment for opioid dependence not readily available (in 2006 survey, 547   000 treated for addiction to pain relievers vs 466  000 for ad­diction to heroin)

DSM-IV criteria for opioid dependence: individual must meet ³3 criteria within 1 yr; physical dependence  —  tolerance; withdrawal; loss of control (addiction)    —  using larger amounts or for longer period than intended; in­ability or persistent desire to cut down or control usage; increased amount of time spent in activities necessary to obtain opioids (“for most of these patients, it’s like having a second job, just getting the money, getting the opioid, using, recovering; that takes 8-10 hr a day”); social, occupational, and/or recreational activities reduced or discon­tinued; continued use of opioids despite adverse consequences

Treatment strategies for opioid dependence: pharmacologic withdrawal (“detoxification”) has high relapse rate (£85% within 6 mo); <5% of those treated with naltrexone (opioid antagonist) able to adhere to treatment and of­ten relapse “fairly shortly”

Treatment with opioid agonist: rationale  —  cross-tolerance at opioid receptor prevents withdrawal and relieves craving for opioids, and provides narcotic blockade to attenuate euphoric effects of opioid; methadone  —  occupies opioid receptors to prevent withdrawal and to create narcotic blockade; buprenorphine  —  partial ago­nist at µ opioid receptor; combination buprenorphine plus naloxone  —  sublingual tablet; buprenorphine well-ab­sorbed and provides narcotic blockade; naloxone not well absorbed, but if individual grinds up pill, believing he or she can get euphoric effect from buprenorphine, naloxone causes opioid withdrawal; must be prescribed by qualifying physician (see below); usually taken once daily, but can also be used in directly observed therapy 3 times per week

Qualifying physician: must be certified in  addiction medicine or addiction psychiatry or complete 8-hr training course in treatment of opioid dependence; to date, buprenorphine and buprenorphine-naloxone combination only medications approved by Food and Drug Administration (FDA) for treatment of opioid dependence

How effective is office-based buprenorphine treatment? similar in efficacy to moderate doses (60-80 mg) of metha­done; in speaker’s study, within 1 to 2 wk, patients decreased use of prescription opioid or heroin from £5 doses/day to <1 day/wk; no dose-response effect seen with 2 levels of counseling, and no differences in treatment retention, urine toxicology reports, and self-reported opioid use; 50% to 55% of patients retained in study for 6 mo; highest retention rate and most prolonged abstinence seen in patients using only prescription opioids vs those using heroin only or heroin plus prescription opioids; at 2 yr, »40% of patients remained in treatment

Alcohol abuse and dependence: »40% of general population abstain, 35% are moderate drinkers, 20% are at risk or abusers, and 5% are alcohol-dependent; “moderate drinking” defined as >2 drinks/day for men £65 yr of age, and >1 drink/day for all women and for men >65 yr of age; “at risk” drinking defined as >14 drinks/wk or >4 drinks on any occasion for men, and 7 drinks/wk or >3 drinks on any occasion for women; “drink” defined as 14 g al­cohol (amount contained in 12 oz beer, 5 oz wine, or 1.5 oz distilled spirits)

At-risk drinking: brief interventions shown to be effective strategy for addressing drinking behavior; components of brief intervention  —  provide feedback to patient on clinical assessment and adverse effects of alcohol on his or her life; discuss adverse effects of alcohol consumption; compare patient’s consumption to national drinking norms; recommend specific drinking limits (see above); write prescription to “cut down on your drinking”; pro­vide patient education materials; have patient keep daily drinking diary; schedule repeat office visits for specific purpose of following up on drinking behavior

Alcohol abuse and dependence: disulfiram  —  blocks aldehyde dehydrogenase enzyme that converts acetaldehyde to acetate, causing flushing, headache, nausea, dizziness, and palpitations; in large study, found to be no better than placebo in maintaining abstinence; however, subset of patients who were older and more socially stable shown to drink less frequently when given disulfiram; greater efficacy shown with supervised administration of disulfiram; start at 250 mg/day and titrate up to 500 mg/day; contraindications include recent alcohol consump­tion, pregnancy, and cognitive impairment; side effects include hepatotoxicity and neuropathy; naltrexone  —opioid-receptor blocker that decreases euphoria, craving, and consumption of alcohol; start at 25 mg/day and ti­trate up to 50 mg/day; taken after meal, for 3 to 4 mo; depot form showed 25% reduction in number of days of heavy drinking; contraindicated in patients with opioid dependence or severe liver disease; side effects include nausea and headache; combined analysis of patients receiving concurrent psychotherapy showed 54% abstinence rate with naltrexone (31% with placebo); acamprosate  —  agonist at g-aminobutyric acid (GABA) receptors and antagonist at glutamate receptors; modulates action of alcohol at N-methyl-D-aspartate (NMDA) receptor; meta-analysis showed acamprosate improved ability to maintain continuous abstinence at 1 yr (23% vs 15% for pla­cebo); one study showed no significant effect on drinking, compared to placebo; recommended dosage 666 mg bid by mouth; start after period of abstinence; contraindications include impaired renal function and pregnancy; side effects include diarrhea; topiramate   —  reduces cortical mesolimbic dopamine release; acts as agonist at GABA receptor and antagonist at glutamate receptor; in United States, not approved for treatment of alcohol de­pendence; study found fewer patients reported days of heavy drinking with topiramate (reported by 44% of pa­tients taking topiramte vs 52% of patients receiving placebo); also, 10% to 38% increase in abstinence days seen with topiramate vs 9% to 29% with placebo; self-help groups  —  most well-known Alcoholics Anonymous (AA), with >36  000 groups in United States; AA considers alcohol dependence physical, emotional, and spiritual dis­ease; AA focuses on abstinence and participation in group; no randomized controlled trials have been done; pa­tients in outpatient treatment who also attend AA 50% more likely abstinent than non-attendees; observational studies show attendees have abstinence rates of 65% at 6 mo and 42% at 12 mo; “prescribe” attendance at AA for patients in need  —  develop familiarity with AA groups in local area (visit several meetings); keep AA litera­ture in office; provide list of meetings or refer patient to www.alcoholics-anonymous.org; provide rationale to pa­tient for referral to AA, and follow up on that referral

Summary: opioid and alcohol problems common; effective therapies available for opioid dependence and alcohol use disorders; office-based treatment of addictive disorders may increase access to treatment and decrease stigma

Nicotine Addiction: Translation of Science into Novel Treatments

Dorothy Hatsukami, PhD, Foster Family Professor in Cancer Prevention and Professor, Department of Psychiatry, Uni­versity of Minnesota Medical School, Minneapolis

Varenicline: in brain, nicotine targets nicotinic acetylcholine receptor, composed of 5 protein subunits, opening ion-gated channel that leads to release of number of neurochemicals and neurotransmitters; based on knowledge that nicotine targets different nicotinic acetylcholine receptor subtypes and leads to release of different neurotransmit­ters, therapies developed such as varenicline, which is partial agonist at a4b2 receptor subtype; varenicline has ag­onist and antagonist activities, results in lesser amount of dopamine being released from ventral tegmental area, and prevents nicotine from binding to a4b2 receptors; consequently, smoker does not get reinforcing effect from nico­tine; in studies, higher continuous abstinence seen with varenicline than with placebo; varenicline nearly signifi­cantly better than bupropion in one trial and had better cessation rates in another trial

Rimonabant: endocannabinoid system may play role in nicotine addiction; in animal studies, rimonabant (selective cannabinoid-1 [CB1] blocker) reduced nicotine self-administration and reduced nicotine-induced release of dopa­mine in nucleus accumbens; in human studies, greater long-term abstinence seen with rimonabant than with pla­cebo; rimonabant also seen to curtail weight gain that occurs in some people when they quit smoking; in trial, people who received rimonabant plus nicotine replacement had higher rate of success than those who received rimonabant plus placebo; cumulative weight loss also seen; rimonabant approved in Europe for treatment of obesity and metabolic syndrome, but not approved in United States (concern that it might promote neurodegenerative dis­eases)

Nicotine vaccine: abuse potential of nicotine depends on amount of nicotine that enters brain, how quickly it enters brain, and how quickly it clears brain; nicotine vaccine reduces amount of nicotine that enters brain; vaccine also slows rate at which nicotine enters brain and rate at which it clears brain; because nicotine molecule too small to stimulate immune system to create antibodies, vaccine designed to attach nicotine molecule to foreign carrier pro­tein; vaccination leads to development of anti-nicotine antibodies that capture nicotine molecules; this molecular complex too large to cross blood-brain barrier, resulting in less nicotine entering brain; low level of nicotine that enters brain may act as nicotine replacement therapy; however, not all people respond to vaccine; some generate many antibodies and some generate none; in study, those who developed high antibody levels (but did not quit smoking) had greater reduction in number of cigarettes smoked, compared to those who did not have high antibody levels or who were given placebo; results of study led to identification of most effective dose and schedule of vac­cine, recognition that antibody level predicts continuous abstinence and smoking reduction, and necessity of en­hancing antibody levels in greatest number of people; current research includes bivalent nicotine vaccine and combining vaccine with medications such as varenicline

Role of learning in nicotine addiction: cues in environment enhance reinforcing effects of nicotine but also promote nicotine-seeking behavior; in animal study, pairing availability of nicotine with environmental cues resulted in rapid and robust acquisition of nicotine self-administration behavior; if cues removed, self-administration of nico­tine not as robust; in human study, mere experience of cues led to same pattern of relapse as actually smoking ciga­rette; speaker suggests extinction therapy to reduce power of cues

Genetics of nicotine addiction: heritability coefficient for smoking initiation and nicotine dependence >70% in fe­male twins and »60% in male twins; candidate genes include polymorphisms in dopamine, serotonin, and nicotinic acetylcholine; some research shows that people who have slower rates of nicotine metabolism tend not to become nicotine-dependent; research beginning on pharmacogenetics

Trajectories of quitting smoking: different individuals, different patterns of quitting  —  some individuals quit; some do not quit; some quit for short while then relapse; some quit for long while then relapse; some quit permanently only after several unsuccessful attempts; current research focusing on how to deal with individuals who have lapses and relapses; study showed those who received nicotine replacement therapy (ie, nicotine gum) did better in sus­taining abstinence than those who received placebo; speaker suggests need to test medications to see how they may alter individual patterns of recovery

Summary: in past 10 yr, greater understanding of pathophysiology of nicotine addiction, critical importance of asso­ciative learning, genetic contributions to smoking and relapse, and individual differences in trajectories toward starting and quitting smoking

Suggested Reading

Allen SS et al: Effect of nicotine-replacement therapy on post-cessation weight gain and nutrient intake: a randomized con­trolled trial of postmenopausal female smokers. Addict Behav 30:1273, 2005; Anton RF: Naltrexone for the management of alcohol dependence. N Engl J Med 359:715, 2008; Baker TB et al: Transdisciplinary science applied to the evaluation of treatments for tobacco use. Nicotine Tob Res 5(Suppl 1):S89, 2003; Beich Aet al: Screening in brief intervention trials tar­geting excessive drinkers in general practice: systematic review and meta-analysis. Br Med J  327:536, 2003; Bertholet N et al: Reduction of alcohol consumption by brief alcohol intervention in primary care: systematic review and meta-analysis. Arch Intern Med  165:986, 2005; Bierut LJ et al: Novel genes identified in a high-density genome-wide association study for nicotine dependence. Hum Mol Genet 16:24, 2007; Bierut LJ et al: Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163, 2008; Fiellin DA et al:  Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med 355:365, 2006; Fleming MF et al: Brief physician advice for problem drink­ers: long-term efficacy and benefit-cost analysis. Alcohol Clin Exp Res 26:36, 2002; Fuller RK et al: Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. JAMA 256:1449, 1986; Garbutt JC et al: Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 293:1617, 2005; Hatsukami DK et al: Changing smokeless tobacco products new tobacco-delivery systems. Am J Prev Med 33(6 Suppl):S368, 2007; Hatsukami DK et al: Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther 78:456, 2005; Hatsukami DK et al: Tobacco addiction. Lancet 371:2027, 2008; Kendler KS et al: A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 29:299, 1999; Kotlyar M, Hatsukami DK: Managing nicotine addiction. J Dent Educ 66:1061, 2002; Lerman C et al: Changes in food reward following smoking cessation: a pharmacogenetic investigation. Psychopharmacology (Berl) 174:571, 2004; Moore BA et al: Primary care office-based buprenorphine treatment: comparison of heroin and prescription opioid dependent patients. J Gen Intern Med 22:527, 2007; Wallace P et al: Randomised controlled trial of general practi­tioner intervention in patients with excessive alcohol consumption. BR Med J 297:663, 1988; Wilk AIet al: Meta-analysis of randomized control trials addressing brief interventions in heavy alcohol drinkers. J Gen Intern Med 12:274, 1997.