Primary Psychiatry. 2009;16(8):47-52
Dr. Kampman is associate professor in the Department of Psychiatry at the University of Pennsylvania School of Medicine and medical director at the University of Pennsylvania Treatment Research Center in Philadelphia.
Disclosure: Dr. Kampman receives grant support from Alkermes and honorarium from Alkermes, Cephalon, and Reckitt Benkiser.
Off-label disclosure: This article includes discussion of unapproved/investigational treatments for drug dependence.
Please direct all correspondence to: Kyle M. Kampman, MD, Associate Professor, Department of Psychiatry, University of Pennsylvania School of Medicine, 3900 Chestnut St, Philadelphia, PA 19104; Tel: 215-222-3200; Fax: 215-386-6770; E-mail: email@example.com.
• Medications proven to be useful for the treatment of alcohol dependence include disulfiram, naltrexone, and acamprosate.
• Medications proven to be effective for the treatment of opioid dependence include methadone, buprenorphine, and naltrexone.
• Medications proven to be effective for the treatment of nicotine dependence include nicotine replacement, bupropion, and varenicline.
• There are no medications proven to be effective for cocaine, amphetamine, or marijuana dependence.
• Promising mediations for the treatment of cocaine and amphetamine dependence include modafinil, topiramate, γ-vinyl γ-aminobutyric acid, bupropion, and a cocaine vaccine.
Drug and alcohol dependence continue to be significant public health problems in the United States. The high rates of relapse associated with the psychosocial treatment of addiction have encouraged the development of medications to augment counseling for the prevention of relapse. Current medications have been developed to help prevent relapse by numerous different mechanisms, including making drug use aversive, reducing the euphoric effects of abused drugs, and reducing drug craving. Medications that can reduce drug craving have been the most effective. Effective medications for the treatment of alcohol dependence include disulfiram, naltrexone, and acamprosate. For opioid dependence, methadone, buprenorphine, and acamprosate have been shown to be effective. For nicotine dependence, nicotine replacement therapy is available as well as bupropion and varenicline. No medications have thus far been proven to be effective for stimulant dependence, but several promising leads have emerged.
The traditional treatments for the prevention of relapse in the treatment of drug and alcohol dependence have been individual or group counseling and participation in self-help groups. Although these treatments are often effective, not all patients benefit from these treatments and medications have been sought to augment the efficacy of psychosocial treatment. The medications that have thus far been proven to be effective work through one of three strategies. They either make continued drug use aversive, they block the euphoric effects of a drug, or they reduce drug craving. Medications that are able to reduce drug craving have been the most effective. This is probably because medications that do not significantly alter drug craving are less likely to be taken as directed and this lack of adherence significantly reduces their efficacy. Four effective medications are currently available for the treatment of alcohol dependence: disulfiram, oral naltrexone, long-acting injectable naltrexone, and acamprosate. Methadone, buprenorphine, and oral naltrexone are available for the treatment of opioid dependence, and bupropion, varenicline, and several types of nicotine replacement are available for the treatment of nicotine dependence. There are no drugs currently approved for the treatment of stimulant or marijuana dependence. However, there are several promising compounds in development for the treatment of stimulant dependence. New initiatives have recently begun to develop effective medications for marijuana dependence as well (Tables 1 and 2).
Why Do We Need Medications for the Treatment of Addictions?
Medications have been sought to augment individual and group counseling due to the high rates of relapse seen in the treatment of virtually all addictions when patients are treated with counseling alone. In a review1 of psychosocial treatment of alcohol dependence, it was found that 40% to 70% of patients relapsed to drinking in 1 year following treatment. For the treatment of opioid and stimulant addiction the relapse rates are often worse. For example, in a study2 involving 116 opioid-dependent veterans detoxified and referred to intensive outpatient treatment, investigators found that only 22% of patients completed 90 days of treatment and only 3% were abstinent from opiates at the end of 90 days. Dropout in cocaine treatment generally exceeds 50%3 and most cigarette smokers who try to quit will have relapsed within 6 months.4 The high dropout and relapse rates in addiction treatment demonstrate the need to find more effective treatments, and medications may answer this need.
Medications for the Treatment of Alcohol Dependence
For the treatment of alcohol dependence, there are now four medications that have been proven to be consistently effective. Disulfiram and oral naltrexone have been available for many years. In addition, two relatively newer medications are acamprosate and a long-acting injectable form of naltrexone.
The first medication for the treatment of alcohol dependence was disulfiram, approved by the Food and Drug Administration in 1951. Disulfiram has a simple mechanism of action. It makes the use of alcohol aversive. Disulfiram inhibits the enzyme aldehyde dehydrogenase, which is responsible for the conversion of acetaldehyde to acetate in the metabolism of alcohol. The accumulation of acetaldehyde produces an unpleasant disulfiram-alcohol interaction with symptoms including facial flushing, headache, palpitations, nausea, and vomiting. This aversive interaction deters further drinking. The usefulness of disulfiram has been limited by poor patient compliance. In a large, double-blind, placebo-controlled multicenter trial5 conducted in numerous Department of Veterans Affairs hospitals, only 20% of the patients took their study medication as prescribed, and there was no significant difference between disulfiram- and placebo-treated patients in the rate of abstinence from alcohol. However, with supervised dosing, or with patients highly motivated to stop drinking, disulfiram can be an effective treatment for the prevention of relapse in alcoholics.6-8
Oral naltrexone was approved for the treatment of alcohol dependence in 1994. Naltrexone is a mu opiate receptor antagonist. The effectiveness of oral naltrexone is postulated to be based on the reduction of the euphoric effects of alcohol in certain alcoholics caused by the alcohol-stimulated release of the endogenous opiate β-endorphin.9 In clinical trials and in human laboratory studies, naltrexone has been shown to reduce the “high” associated with drinking alcohol.10,11 Naltrexone has been shown in clinical trials to be effective mainly in reducing relapse to heavy drinking in alcoholics.12,13 Recently, pharmacogenetic analyses have demonstrated a specific mutation in the gene coding for the mu opiate receptor that predicts a good response to naltrexone.14
Extended-release naltrexone was developed because the efficacy of the oral form of naltrexone is very sensitive to the effects of medication adherence. Several investigators found that in clinical trials,15-17 naltrexone was superior to placebo only in subgroups of patients who took 70% to 90% of their study medications. A long-acting (monthly) injectable form of naltrexone would eliminate the need for patients to take a pill every day and could promote consistent blood levels of the medication. Extended-release naltrexone is such a long-acting injectable product. In this product, naltrexone is imbedded in polylactide-co-glycolide microspheres that are injected intramuscularly. Naltrexone adhering to the surface of the microspheres is released, and as the microspheres dissolve, more naltrexone is released. A 380 mg intramuscular dose of extended-release naltrexone results in a stable therapeutic dose of naltrexone for 28–30 days.
In clinical trials, long-acting injectable naltrexone has been shown to be safe, well tolerated, and efficacious for the treatment of alcohol dependence. In a large multicenter clinical trial18 involving 624 alcohol-dependent patients, extended-release naltrexone at a dose of 380 mg and 190 mg given monthly was compared to monthly injection of placebo. In this trial, 380 mg of the long-acting naltrexone was significantly better than placebo in reducing days of heavy drinking during the 6-month trial. The extended-release naltrexone was found to be well tolerated. Discontinuation rates were not significantly higher in either active medication group compared to the placebo group. The extended-release naltrexone appeared to have a more beneficial effect in patients who achieved 7 days of abstinence before starting the medication.
The last of the approved medications for alcoholism to be discussed is acamprosate. The exact mechanism of action of acamprosate is not known. One of the proposed mechanisms of action of acamprosate is reduction of glutamatergic activity in alcohol-dependent individuals during early abstinence. Glutamatergic activity in the brain is thought to be increased as a result of chronic alcohol administration.19 This increase in glutamatergic activity is thought to contribute to symptoms of alcohol withdrawal during early abstinence.19 By reducing glutamatergic activity, acamprosate may reduce symptoms of alcohol withdrawal during the post-acute phase and may reduce negatively reinforced relapses to drinking.20
Acamprosate was approved for use in the United States based on three double-blind, placebo-controlled trials21-23 conducted in Europe in which acamprosate was shown to be superior to placebo in promoting abstinence from alcohol from 3 months to 1 year. Although the one US trial was negative, a metanalysis24 of all controlled trials conducted with acamprosate supported its usefulness in helping patients detoxified from alcohol maintain abstinence.
Medications for the Treatment of Opioid Dependence
Methadone is the oldest of the approved medications for the treatment of opioid dependence. It is a long-acting full opiate agonist. It attaches to opiate receptors and activates them. Methadone is effective for the treatment of opioid dependence because, as an agonist, it can reduce opiate withdrawal symptoms and reduces opiate craving. If the dose of methadone is high enough, it will confer enough tolerance to opioids to significantly reduce the euphoric effects of street opioids such as heroin and oral opiate pain relievers. This makes methadone an extremely useful maintenance treatment. Methadone for the treatment of opioid dependence is high regulated and can only be prescribed for the treatment of opioid dependence in licensed methadone clinics. The dose of methadone prescribed for the treatment of opioid dependence is not derived from morphine dose equivalence tables.
Methadone effectiveness is very much affected by the way it is used. Methadone is most effective when used in well-regulated programs that monitor patients closely and provide other services, like drug counseling.25 Methadone has been shown in a number of trials to an effective treatment. It has been shown to reduce opiate use and other problems associated with opiate use such as criminal behavior.26 The annual mortality rate of untreated heroin addicts is ~5%. The annual mortality rate among heroin-dependent patients maintained on methadone is ~1.4%.27 Methadone saves lives.
There are numerous problems with methadone maintenance treatment, not the least of which is lack of availability. As a full opiate agonist, methadone has a relatively high abuse liability and can be a risk for overdose. Consequently, its use is highly restricted and it is available only at specialized clinics. This lack of availability has prompted the development of other agonist treatments that might be made available to patients at a physicians’ office. Buprenorphine is a partial mu opioid agonist that was first approved by the FDA in an injectable form to treat pain. It is currently available in a sublingual form for the treatment of opioid dependence. Unlike full agonists such as morphine and methadone, higher dosages of the partial agonist buprenorphine do not produce progressively greater opioid effects; thus, buprenorphine has less abuse potential and is less likely to produce an overdose.
Based on clinical trials to date, buprenorphine appears to be useful in the treatment of opioid addiction. Because of its good safety profile and less severe abuse liability, buprenorphine has significantly fewer restrictions placed on its use compared with methadone and has improve access to effective treatment for opiate-dependent patients. Unlike methadone, buprenorphine is available to qualified physicians to dispense from their offices. Because of the benefits of making it available for prescription outside of methadone treatment programs, it is important to reduce the risk of abuse of this medication. Therefore, the product proposed for use by office-based physicians is a combination of buprenorphine and naloxone. The addition of naloxone blocks the effects of buprenorphine if injected, but because of the poor oral bioavailability of naloxone, it would not impair the sublingual administration of buprenorphine. A large multicenter clinical trial28 of the combination of buprenorphine and naloxone showed that this medication was significantly better than placebo at reducing heroin craving and heroin use in opioid-dependent patients. Buprenorphine-naloxone has been approved for use as both a maintenance treatment and an aid for opiate detoxification. Physicians who wish to use buprenorphine for the treatment of opioid dependence must be trained in its use and obtain a license to do so from the Drug Enforcement Administration.
For patients who do not respond to agonist treatment, or who prefer not to be treated with agonists, one alternative is naltrexone. Naltrexone is an opioid antagonist. It binds to opiate receptors but it does not activate the receptor. Naltrexone is a relatively pure antagonist in that it produces little or no agonist activity at usual doses. Not only do pure antagonists fail to produce opiate effects, but their presence at the receptor also prevents opiate agonists from binding to the receptor and producing opiate effects. Because the antagonist competes for a binding site with the agonist, the degree of blockade depends on the relative concentrations of each and their relative affinity for the receptor site. Naltrexone has high receptor affinity, and thus it can block virtually all the effects of the usual doses of opioids. In the presence of naltrexone, there can be no opiate-induced euphoria, respiratory depression, pupillary construction, or any other opiate effect.
Naltrexone was approved by the FDA in 1984 on the basis of its clear pharmacologic activity as an opioid antagonist. Naltrexone is not effective when simply prescribed as a medication for street heroin-addicted patients in the absence of a structured rehabilitation program. Within a structured program, naltrexone appears to be effective, particularly with specific motivated populations. Patients with a history of recent employment and good educational backgrounds do well on naltrexone. Healthcare professionals generally have done well in naltrexone treatment programs.29 Long-acting injectable and implantable forms of naltrexone are currently being developed to help overcome the compliance problems that limit the effectiveness of oral naltrexone for the treatment of opioid dependence.
Because naltrexone is an opiate antagonist it can complicate pain management. In patients with chronic pain who need opiate pain relief, naltrexone should not be used. In cases of acute pain, non-narcotic management should be attempted. In situations requiring opioid analgesia, the amount of opioid necessary may be greater than usual. The use of opioid analgesia in a patient being treated with naltrexone should be undertaken with close monitoring by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.30
Medications for the Treatment of Nicotine Dependence
Physicians have several medication options for the treatment of nicotine dependence. First, there are many forms of nicotine replacement including patches, gum, inhalers, lozenges, and nasal sprays. The various forms of nicotine replacement differ in pharmacokinetics and therefore are useful for different aspects of treatment. For example, the nicotine patch is slow in onset but has the highest sustained levels of nicotine so it may be most efficacious for reducing withdrawal symptoms and effectively conferring tolerance. However, some of the other forms of nicotine replacement have a much faster onset, mimicking the rapid onset of nicotine seen in smoking. It turns out that these forms of nicotine replacement seem to work much better for helping patients deal with cue- or withdrawal-induced craving. Nicotine replacement has been shown to be useful for the treatment of nicotine dependence in numerous placebo-controlled trials.31
Bupropion sustained release is the first non-nicotine medication approved for the treatment of nicotine dependence. It has been proven to be safe and effective in numerous controlled trials.32 Bupropion is a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor, and an antagonist at nicotine receptors. It is thought to work by reducing withdrawal symptoms and by reducing the reinforcing effects of nicotine.
The newest medication approved for smoking cessation is varenicline. It was approved in 2006. It is a partial agonist at the α4β2 nicotine receptor subtype. Because it is a partial agonist, varenicline is effective at reducing nicotine withdrawal symptoms and reducing nicotine craving. However, because it is only a partial agonist it has some properties of an antagonist, including the ability to block the reinforcing effects of continued nicotine use. Varenicline has been shown to be superior to bupropion in two separate trials.33 Partial agonists appear to be extremely useful medications for the treatment of addictions as evidenced by the efficacy of varenicline for smoking and the efficacy of the mu opiate receptor partial agonist buprenorphine for the treatment of opioid dependence.
In clinical trials of varenicline for smoking cessation, the main side effect of varenicline was nausea, which was generally mild and not likely to cause discontinuation. Other side effects included headache and vivid dreams. In clinical trials, serious adverse events were rare and there were no deaths. However, post-marketing surveillance prompted the FDA to issue a warning about behavior changes associated with varenicline use, including agitation, depressed mood, and suicidal ideation. How many of these symptoms were actually caused by varenicline is not known. Therefore, patients given varenicline for smoking cessation and their families should be warned to be alert for possible neurospsychiatric adverse events.34
Medications for the Treatment of Stimulant and Marijuana Dependence
There are currently no medications approved for the treatment of stimulant or marijuana dependence. However, progress in the understanding of the neurobiology of drug dependence has led to the discovery of several promising medications that have already shown encouraging results in controlled clinical trials for cocaine and methamphetamine dependence.
Among the most promising medications for the treatment of cocaine dependence is modafinil. Modafinil is a medication approved for the treatment of narcolepsy. It may be useful for the treatment of stimulant-dependent patients by enhancing glutamate neurotransmission.35 Modafinil may be able to ameliorate glutamate depletion seen in chronic cocaine users.36 Modafinil was found to block the euphoric effects of cocaine in three independent human laboratory studies.37-39 In a pilot clinical trial,40 modafinil reduced cocaine use among cocaine-dependent patients. Most recently, modafinil was evaluated in a large multicenter trial41 involving 210 cocaine-dependent patients. In this 16-week trial, cocaine-dependent patients were treated with modafinil 200 mg/day, modafinil 400 mg/day, or placebo. In contrast to the pilot trials, in which none of the patients were both cocaine and alcohol dependent, in this trial 41% of the patients were both alcohol and cocaine dependent. In the group as a whole, modafinil was not superior to placebo in promoting abstinence from cocaine. However, among patients who were not also alcohol dependent, both doses of modafinil were superior to placebo for promoting abstinence from cocaine.
The mesocortical dopamine system plays a central role in the reinforcing effects of cocaine. Mesocortical dopaminergic neurons receive modulatory inputs from both γ-aminobutyric acid (GABA)ergic and glutaminergic neurons. GABA is primarily an inhibitory neurotransmitter in the central nervous system, and activation of GABAergic neurons tends to decrease activation in the dopaminergic reward system. Preclinical trials42,43 of medications that foster GABAergic neurotransmission have suggested that these compounds reduce the dopamine response to both cocaine administration and to conditioned reminders of prior cocaine use. Among the GABAergic medications that have shown promise for the treatment of stimulant dependence are γ-vinyl GABA (GVG) and topiramate.
GVG is an antiepileptic that has been in use in many countries throughout the world for numerous years and may soon be approved in the US for the treatment of certain forms of childhood epilepsy. It is an irreversible inhibitor of GABA transaminase and thus elevates brain GABA concentrations.
There have been two clinical trials44,45 of GVG for the treatment of stimulant dependence. They were both small open-label trials involving 20 and 30 patients, respectively, with either cocaine or amphetamine dependence. In these trials, treatment completers showed significant reductions in drug use. GVG has not been approved for use in the US due to an association between the use of GVG and visual field defects.
Topiramate may be an excellent medication for relapse prevention based on its effects on GABA neurotransmission. Topiramate increases cerebral levels of GABA, and facilitates GABA neurotransmission.46 In one small clinical trial,47 topiramate was found to be better than placebo in promoting abstinence from cocaine.
Bupropion may be efficacious for the treatment of methamphetamine in certain patients. Bupropion was tested for the treatment of methamphetamine dependence in a trial involving 151 methamphetamine-dependent patients. In the group as a whole, there was a nonsignificant trend towards more weeks of abstinence from methamphetamine treatment compared to placebo treatment. In a subgroup of patients with less methamphetamine use at baseline,48 bupropion treatment was associated with significantly more weeks of abstinence from methamphetamine compared to placebo treatment.
The last of the promising treatments for stimulant dependence to be discussed is a vaccine capable of stimulating the production of cocaine-specific antibodies. The vaccine (TA-CD) works by stimulating the production of cocaine-specific antibodies that bind to cocaine molecules and prevent them from crossing the blood-brain barrier. Since cocaine is inhibited from entering the brain, its euphoric and reinforcing effects are reduced.
Early human trials of TA-CD have been promising. In one trial,49 two different doses of TA-CD were tested in cocaine-dependent patients participating in a 12-week outpatient treatment program. Preliminary outcome data from that trial suggested that the vaccine reduced the euphoric effects of cocaine and the higher dose was associated with more cocaine abstinence compared to the lower dose.
Like cocaine and amphetamine, there are no medications approved for the treatment of marijuana dependence. A few medications have been evaluated for the treatment of marijuana dependence, mainly in human laboratory studies, and none have been shown to be efficacious.50 However, new initiatives are underway to promote further research into medications for the treatment of cannabis dependence.
There are numerous medications currently approved for the treatment of addictions. None of these medications are thought to be effective alone but rather are proposed as augmenters of counseling. Effective medications either make drug use aversive, reduce the euphoric effects of drugs, or block drug craving. Those that can block drug craving tend to have fewer problems with medication compliance and are generally more effective. Advances in our understanding of the brain reward system are leading to the discovery of new medications, including possible treatments for stimulant and marijuana dependence. PP
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