For decades, the principal treatment for substance use disorders has been psychological therapies. Twelve-step facilitation therapy, modeled after Alcoholics Anonymous, and motivational enhancement therapy are currently the two most widely used.
Although disulfiram (Antabuse) hit the U.S. market in 1951, addiction pharmacotherapy was underwhelming for many years. Methadone (Dolophine) eventually arrived in the 1960s to treat opioid dependence and there have been notable introductions of medications ever since.
As with other mental disorders, treatment of addiction is a “both/and” rather than “either/or” proposition. In other words, clients can benefit from both psychological therapies and pharmacotherapies. While psychological therapies remain essential, adding medications to treatment plans can improve overall success. Medication-assisted therapy, as augmentation is called in addiction circles, is finally gaining wider currency as providers see its benefits.
Addiction in a Nutshell
Addiction, reduced to its essence, is when individuals continue compulsive substance use despite harming themselves. DSM-IV-TR (and the long awaited DSM-5) criteria reflect the many domains in which impairment can occur.
Addiction involves dysregulation of three interconnected brain regions: the reward-antireward system, located mainly in the midbrain; the prefrontal cortex; and the extended amygdala.
The reward-antireward system serves as the body’s emotional thermostat and processes reward functions. Dopamine—the drugs, sex, and rock ‘n’ roll neurotransmitter—and endogenous opioids (endorphins and their cousins) are some major players in the addiction process.
The prefrontal cortex serves various executive functions including inhibitory control, self-regulation, and problem-solving. It’s engaged in constant conversation: the reward circuitry, located in the mesolimbic pathway of the midbrain, says “Go!” (encouraging risk taking and experimentation) to which the prefrontal cortex replies “Stop!” (advocating harm avoidance and risk reduction). In the normal brain, this running dialog keeps us out of trouble. As you’d expect, the addicted brain has too much “Go!” and not enough “Stop!” The extended amygdala is critical for emotional learning and memory. It processes various sensory stimuli, often below the level of consciousness, and presents this information to the reward-antireward system and prefrontal cortex for further consideration. Our emotions and behaviors often arise out of this complex three-way conversation that takes place in the brain.
The addicted brain has a host of problems that propagate substance use (see Figure 1). Negative affect, which is still underappreciated by many mental health professionals, was recognized way back in 1939 by Dr. William Silkworth, an early specialist in the treatment of alcoholism. In the first edition of the “Big Book” of Alcoholics Anonymous, he famously described alcoholics as “restless, irritable, and discontented.” While there is likely a complex interplay of psychological and neurobiological factors involved, from the perspective of modern neurobiology there is evidence that this is due to an imbalance in the reward-antireward system (Gardner EL, Adv Psychosom Med 2011;30:22–60; Koob GF and LeMoal M, Annu Rev Psychol 2008;59:29–53). This imbalance causes people to feel crummy and compulsively use substances in an attempt to feel normal. The imbalance persists when a person achieves abstinence and is a potent driver for relapse.
Clients with addiction are vulnerable to stress. Laboratory studies have demonstrated that stress triggers substance cravings in those with addiction, but not healthy controls (Fox HC et al, Neuropsychopharmacology 2008;33(4):796–805). The addicted brain is also particularly sensitive to environmental cues related to substance use—people, places, and things that act as triggers. In functional imaging studies, drug-related images “light up” the brain, even if subliminally presented (Yalachkov Y et al, Neurosci Biobehav Rev 2012;36(2):825–835; Childress AR et al, PLoS One 2008;3:e1506).
There are presently eight FDA-approved medications to treat addiction, some of which are available in multiple formulations (see Table 1). Here are some common types of addictions and the drugs used to treat them:
Alcohol is still public enemy number one in many cultures. Excessive drinking causes about 79,000 deaths per year in the U.S. and costs $224 billion in terms of negative economic impact, according to statistics from the Centers for Disease Control and Prevention (CDC). That translates to a cost of $746 per person or $1.90 per drink in economic costs. Excessive alcohol use places drinkers at risk for many harmful health effects, including motor vehicle crashes, intimate partner violence, risky sexual behaviors, fetal alcohol spectrum disorders, and chronic conditions such as alcohol dependence, liver disease, high blood pressure, heart attack, stroke, and certain kinds of cancer, according to the CDC.
According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), heavy drinking for men is defined as more than four drinks per day or more than 14 drinks per week; for women, the corresponding thresholds are three drinks per day or more than seven per week. Exceeding either the daily or the weekly limits defines heavy drinking (also referred to as at-risk drinking).
Disulfiram (Antabuse) works by causing a nasty reaction if an individual consumes alcohol: flushing, palpitations, nausea, vomiting, and dizziness. Intuitively, this should strongly discourage drinking; however, the data on its effectiveness are pretty plus-minus. The most recent meta-analysis, which acknowledged issues with the underlying data (eg, all the available studies were of moderate, rather than high quality), demonstrates that disulfiram may slightly increase abstinence in the short-term (Jørgensen CH et al, Alcohol Clin Exp Res 2011;35(10):1749–1758). A prior analysis indicated that disulfiram reduces drinking frequency, but did not achieve a higher rate of abstinence (Garbutt JC et al, JAMA 1999;281(14):1318–1325). This questionable efficacy must be weighed against possible harm to clients. Disulfiram can cause psychosis and may be dangerous for clients who can’t tolerate the disulfiram reaction due to age or chronic medical conditions.
Alcohol causes euphoria, in part, via the body’s endogenous opioids or morphine-like substances. Naltrexone (ReVia, Vivitrol) works on this end of the drinking equation by blocking the brain’s opioid receptors. This blunts the pleasurable effects of drinking for some clients and thus decreases positive reinforcement.
On average, naltrexone reduces heavy drinking by 17% and drinking days by 4%, but does not increase abstinence (Rösner S et al, Cochrane Database Syst Rev 2010[Dec 8];(12):CD001867). Naltrexone is available as a pill that clients can take several times per week or daily; a once-a-month injection became available in 2006.
Acamprosate (Campral) received FDA approval in 2004 after years of use in Europe. Its mechanism of action is a bit of a mystery. However, the prevailing theory is that acamprosate normalizes GABA-glutamate balance—two major “workhorse” neurotransmitters in the brain—which is especially important in early recovery when there is too much glutamate and not enough GABA.
The most rigorous meta-analyses suggest that acamprosate reduces lapse/relapse by 14% compared to placebo but does not impact heavy drinking (Rösner S et al, Cochrane Database Syst Rev 2010[Sep 8];(9):CD004332). (Relapse is defined as the reinstatement of abusive or dependent alcohol use; lapse or a “slip” is drinking that does not meet DSM criteria for addiction.) Depending on the trial, acamprosate is either inferior or superior to naltrexone, with no difference between the two when data are pooled.
Unintentional drug overdose deaths have increased exponentially since the early 1990s, according to the CDC. Although prescription opioid analgesic Medications—what we all know as painkillers—are the main driver of this trend, heroin use also remains a major part of the problem. In 2008, drug overdoses in the United States caused 36,450 deaths, according to the CDC. Opioid pain relievers were involved in 14,800 deaths (73.8%) of the 20,044 prescription drug overdose deaths. The overdose death rate from opioid pain relievers in 2008 was nearly four times the rate in 1999, according to CDC statistics. Opioid dependence was seemingly impossible to treat before methadone became available as a treatment option (Dole VP and Nyswander M, JAMA 1965;193(8):646–650). Methadone works by occupying and activating opioid receptors, thereby preventing withdrawal and cravings. It also blocks other opioids and positively effects hedonic tone, thereby addressing negative affect.
On average, methadone reduces opioid abuse by 34% compared to medication-free interventions and at least triples retention in treatment (Mattick RP et al, Cochrane Database Syst Rev 2009[Jul8];(3):CD002209).
Despite methadone’s clinical effectiveness, access to care has been a huge issue. It is only available in federally licensed opioid treatment programs (OTPs or “methadone clinics”), which tend to be clustered in large urban centers. Federal legislation was passed in 2000 that allowed the use of buprenorphine (Suboxone, Subutex) by specially licensed or “waivered” prescribers in office-based settings. For the first time, physicians are able to treat patients from their private offices or other clinical settings, which is a desirable treatment option for those unwilling or unable to seek help in drug treatment clinics. Patients can now be treated in the privacy of their doctor’s office. Buprenorphine has a similar mechanism of action as methadone.
Subutex and Suboxone are formulated for sublingual use (ie, dissolves when placed under the tongue). Subutex contains buprenorphine, while Suboxone contains the opioid antagonist, naloxone, in addition to buprenorphine. Suboxone is designed to deter intravenous use of buprenorphine. Clinical data (as seen in the Prescribing Information) indicate that when administered intravenously (but not when administered sublingually), the ingredients of Suboxone were perceived as unpleasant and dysphoric.
When compared head-to-head, methadone has a higher retention in treatment (Mattick RP et al, Cochrane Database Syst Rev 2009[Apr 16];(2):CD002207). Of clients remaining in treatment, both medications are equally effective at suppressing illicit opioid and cocaine use.
Naltrexone, while also FDA-approved for opioid dependence, generally runs a distant third as a treatment method. Unlike methadone and buprenorphine, it does not suppress withdrawal or correct underlying problems with hedonic tone, although it may modestly reduce cravings. Compliance with the oral formulation tends to be poor and retention in treatment is disappointingly low (Minozzi S et al, Cochrane Database Syst Rev 2011[Apr 13];(4):CD001333). The long-acting, injectable formulation has shown promise (Krupitsky E et al, Lancet 2011;377:1506–1513), but hasn’t been directly compared to methadone or buprenorphine.
Tobacco use causes about 443,000 deaths in the U.S. each year and $200 billion in negative economic impact, according to the CDC. Despite these facts, 47 million American adults are nicotine users.
Nicotine replacement therapy increases the rate of quitting by 50% to 70% compared to placebo (Stead FL et al, Cochrane Database Syst Rev 2008[Jan 23];(1):CD000146). Many formulations are available—patches, gum, lozenges—and they are all roughly equally effective. Individuals commonly start smoking again when they stop replacement therapy.
Varenicline (Chantix), a long-acting nicotine analog, received FDA approval in 2006. It prevents cravings and symptoms of withdrawal, and blocks the effects of nicotine if a client attempts to smoke or chew tobacco. Varenicline doubles the chances of quitting compared to placebo and compares favorably to traditional nicotine replacement therapy (Cahill K, et al, Cochrane Database Syst Rev 2012[Apr 18];(4):CD006103). Some neuropsychiatric side effects—depression, aggression, suicide, and Nightmares—have been getting a lot of attention. In my experience, these are dose-related and a gentle introduction of the medication is advisable, rather than the manufacturer’s suggested ramp-up over seven days.
Bupropion, the antidepressant known as Wellbutrin, was re-launched for smoking cessation in 1997 as Zyban. It is equivalent to nicotine replacement therapy, but less effective than varenicline (Hughes JR, et al, Cochrane Database Syst Rev 2007[Jan 24];(1):CD000031). There is a small risk of seizure with bupropion. We generally withhold therapy from patients with a history of seizure, which excludes a number of patients with alcohol dependence who have had withdrawal seizures. Bupropion should also not be used for patients with a history of eating disorders. In addition, the Prescribing Information presents cautions concerning the increased risk of seizures in many circumstances, a couple of which are: excessive use of alcohol or sedatives, and concomitant use of medications known to lower seizure threshold.
TCPR's Verdict: Addiction pharmacotherapy reduces substance abuse and helps keep clients in treatment. The benefits of addiction pharmacotherapy are maximized when it is applied as part of a comprehensive program of recovery that includes psychosocial interventions, often encompassing several modalities, including individual, family, and/or group counseling, and peer support groups.