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| New Developments in Treatment for Alcohol Dependence |
| Feature Articles - Treatment Strategies or Protocols | ||||||||
| Written by Kyle M. Kampman, MD and Christopher R. Wilkins, MHA | ||||||||
| Monday, 06 August 2007 | ||||||||
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Alcohol dependence is a complex and difficult disease to treat, often
requiring a sophisticated approach to treatment. Recent advances in
medications approved for treatment of alcohol dependence make
pharmacotherapies important therapeutic options for alcohol-dependent
individuals.
This is recognized in the 2005 guidelines from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which recommend medication use be considered for individuals who are actively alcohol dependent or who have stopped drinking but are experiencing slips and cravings (NIAAA, 2005). When used in combination with well-established psychosocial therapies, medications may provide additional benefits that complement patients’ efforts in therapy. This article presents highlights from a symposium at the 2006 Southeast Conference on Alcohol & Drug Addiction (SECAD) on Nov. 29, 2006, in Atlanta. Log on to www.extendmed.com/alcohol treatmentcme to review the symposium in its entirety and earn 2.0 CE/CME credits. Why pharmacotherapy? Biological, social, and psychological factors all may contribute to the development of alcohol dependence, but ultimately alcoholism is a disease of the brain. Alcohol affects the activity of many neurotransmitters and chemicals in the brain, including dopamine, GABA, glutamine and endogenous opioid peptides. Changes in the activity of these chemicals appear to contribute to the intoxicating and rewarding effects of alcohol, as well as the detrimental symptoms when drinking stops (De Witte, 2004; Gianoulakis, 2004; Koob, 1992; Tupala & Tiihonen, 2004). For example, GABA activity generally increases and glutamate activity decreases when alcohol is consumed (De Witte, 2004). Because GABA is an inhibitory neurotransmitter and glutamate is an excitatory neurotransmitter, the acute effects of alcohol result in sedation (Littleton, 1998). Changes in the activity of these neurotransmitters are also thought to contribute to the intoxicating effects of alcohol (Koob, 1992). The increased release of endogenous opioid peptides and dopamine in response to drinking alcohol appears to contribute to the euphoric and rewarding effects individuals derive from alcohol (Gianoulakis, 2004; Tupala & Tiihonen, 2004). Ultimately, alcohol-dependent individuals are abnormally driven to seek these rewarding effects from alcohol rather than from other sources (Kalivas & Volkow, 2005). These neurobiological changes largely occur in reward centers of the brain’s limbic system and are outside of conscious thought. Medications for alcohol dependence appear to act on these neurotransmitters and chemicals to reduce their effects on alcohol-dependent individuals’ drive to drink. However, the decision to drink is influenced both by these neurobiological changes and by the conscious decision making and higher executive functioning of the brain cortex. Thus, optimal treatment for alcohol dependence might best be conceptualized as targeting both the limbic system and the cortex (see Figure 1). This approach emphasizes the need for medication use, which primarily targets the limbic system, in conjunction with psychosocial therapies, which target the realm of conscious thought in the cortex. Medications approved for alcohol dependence treatment include oral naltrexone, extended-release (intramuscular) naltrexone, acamprosate and disulfiram (see Table 1). All are designed to be used in conjunction with psychosocial counseling in treatment. Oral naltrexone Naltrexone (both oral and injectable formulations) blocks opioid receptors, thus blocking the rewarding effects of alcohol mediated by endogenous opioid peptides. The high from alcohol is reduced by naltrexone, and craving for alcohol may also be limited (Monti et al., 1999; Volpicelli et al., 1995). Naltrexone has consistently proven to be effective in reducing relapse to heavy drinking. In an analysis of short-term studies (12 weeks), oral naltrexone was found to be significantly better than placebo in lowering the relapse rate (Bouza et al., 2004). As is true with most medications, adherence to treatment is vital to the efficacy of oral naltrexone, but adherence may be difficult because of potential side effects and the necessity of daily dosing regimens. A study by Volpicelli clearly demonstrated that naltrexone was significantly more effective than placebo in reducing relapse to heavy drinking (14 percent vs. 52 percent relapse rate, respectively) when participants adhered to naltrexone, which was defined as medication taken on 90 percent or more of study days (Volpicelli et al., 1997). However, naltrexone was no better than placebo in changing drinking behavior among those who did not adhere to treatment. Overall, oral naltrexone is well tolerated, with nausea being the most common side effect. Naltrexone is not toxic to the liver at recommended doses. Extended-release injectable naltrexone Extended-release injectable naltrexone (XR-NTX) is a once-a-month intramuscular injection designed to improve treatment adherence by removing the need for daily dosing with oral naltrexone. The injection is given by a health professional and produces therapeutic levels of naltrexone for about 30 days. XR-NTX is an opioid antagonist and works the same as the oral formulation of naltrexone, so their effects on drinking are similar. The pivotal trial for XR-NTX was conducted in over 600 alcohol-dependent individuals, most of whom were actively drinking at the time of treatment (Garbutt et al., 2005). In addition to medication (either active XR-NTX or placebo injections), all study participants received a form of psychosocial counseling known as BRENDA, which aims to help improve treatment adherence. (BRENDA is discussed in more detail later.) Individuals receiving XR-NTX plus counseling reduced their rate of heavy drinking 25 percent more than individuals receiving placebo and counseling. Among those who were abstinent for the week prior to treatment, the effects of XR-NTX were even greater: their risk for heavy drinking was reduced 80 percent more than initially abstinent individuals who received placebo (see Figure 2). Individuals who were abstinent also were more likely to remain abstinent over the six-month study duration when receiving XR-NTX compared with placebo (abstinence rates: 41 percent vs. 17 percent, respectively). As with oral naltrexone, the most common side effect of XR-NTX is nausea, though the vast majority of trial participants rated it as mild or moderate. Nausea usually disappeared after the first injection. Fatigue and injection site reactions also were reported (Garbutt et al., 2005). Adverse reactions at injection sites rarely necessitated discontinuation of the medication (Garbutt et al., 2005). Treatment completions rates (about 64 percent) were good, but studies to determine whether XR-NTX improves treatment adherence compared with oral naltrexone have not been completed. Acamprosate While naltrexone eliminates the reinforcing effects of alcohol, acamprosate is thought to relieve some of the negative symptoms that alcohol-dependent individuals experience after they stop drinking. When alcohol is chronically abused, the brain adapts so that glutamate (excitatory neurotransmitter) levels eventually rise to balance the increased activity of GABA and the sedative effects of alcohol (De Witte, 2004; Littleton, 1998). Once alcohol consumption stops, GABA activity declines, and brain nerve cells are left in a hyperexcited state as a result of persistently elevated glutamate levels (De Witte, 2004; Littleton, 1998). Acamprosate acts at two different glutamate receptors to reduce excitatory neurotransmission (De Witte et al., 2005). By restoring the balance of glutamate and GABA activity, acamprosate may reduce anxiety, irritability and other symptoms characteristic of the period following acute withdrawal from alcohol (De Witte et al., 2005; Littleton & Zieglgansberger, 2003). Therefore, acamprosate is meant to be used by individuals who have stopped drinking and are trying to remain abstinent. A meta-analysis showed that abstinent rates improved 88 percent compared with placebo (Bouza et al., 2004). Acamprosate produces very few side effects: diarrhea is most common (Bouza et al., 2004). Although acamprosate’s efficacy and superiority over placebo in helping individuals maintain abstinence has been demonstrated in several studies prior to its approval in the United States (Bouza et al., 2004; Mason, 2005), more recent trials have shown that acamprosate may not be better than placebo (Anton et al., 2006; Mason et al., 2006). For example, a study by Mason et al. found that in 601 alcohol-dependent individuals, those who received acamprosate had a similar number of abstinent days compared with those who received placebo (Mason et al., 2006). The study also found, however, that among individuals who had a goal of abstinence prior to treatment initiation, acamprosate was significantly better than placebo (58 percent days abstinent for placebo vs. 70 percent for 2g-dose acamprosate). This highlights the importance of assessing patient motivation for treatment and choosing therapies that are consistent with patients’ needs and goals. The recent large COMBINE study found that acamprosate was no better than placebo in improving abstinence (Anton et al., 2006); and combining acamprosate with oral naltrexone has not been found to be significantly better than using naltrexone alone (Anton et al., 2006; Kiefer et al., 2003). The discrepancy between study findings for acamprosate has not been fully explored or explained, but may be attributable to differences in study design (Kranzler, 2006). Disulfiram Disulfiram is the oldest of the approved medications for alcohol dependence, but unlike the others, its mechanism of action is based in the liver rather than the brain. Its inhibition of the liver enzyme aldehyde dehydrogenase interferes with the metabolism of alcohol and thus causes an aversive reaction when alcohol is consumed (Swift, 1999). The fear of the unpleasant disulfiram-alcohol reaction motivates individuals to avoid alcohol (Suh et al., 2006). Disulfiram does not appear to reduce craving for alcohol, and consequently, adherence is difficult. A study of U.S. veterans found that abstinent rates among disulfiram users were significantly higher among those individuals adherent to treatment versus those who were not consistently using disulfiram (Fuller et al., 1986). Among adherent participants, disulfiram significantly reduced the total number of drinking days compared with those who received inactive medication. Given these findings, it is recommended that disulfiram use be observed by a spouse or another reliable person in order to get the best results (Suh et al., 2006). Side effects from disulfiram (excluding those symptoms produced by the combination of disulfiram and alcohol) are not common, but include neuritis and hepatitis (Odyssey Pharmaceuticals, 2005). Integrating treatments: psychosocial therapy and medications There are several psychosocial techniques that have shown success in promoting recovery. Project MATCH, for example, found that cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), and 12-step facilitation therapy were all similarly effective in helping individuals cut down on drinking and abstain from alcohol during treatment and for the three years following treatment, even though each type of therapy uses different methods in its approach to recovery (Project MATCH Research Group, 1998). The approach and principles of these psychosocial techniques appear to complement the effects of medication. For example, CBT helps teach individuals how to deal with alcohol cravings and how to prevent slips from becoming relapses to heavy drinking. With its abilities to reduce the high from drinking, limit cravings for alcohol, and thus reduce the risk of relapse, oral naltrexone complements the goals of CBT (Anton et al., 1999; Monti et al., 1999; Volpicelli et al., 1995). One study revealed the potential synergy of oral naltrexone and CBT by demonstrating that the combination of the two is more effective than CBT alone in promoting abstinence, delaying relapse, and limiting alcohol consumption (Anton et al., 1999). Medication effects can wane with time, especially if medication use stops (Anton et al., 2006; Chick et al., 2003; O’Malley et al., 1996). For instance, cravings may return or increase, which is when coping skills developed in therapy are most vital to help individuals avoid relapse. Sustained treatment and commitment to behavioral change are needed for successful recovery. Clinicians need to caution and remind patients that relying on medication without addressing the psychological, social and spiritual components of their disease and recovery will lead to only temporary, if any, success. Recovery from addiction has been described as a process of behavioral change (Prochaska et al., 1992). Some individuals are not interested in changing their behaviors, while others are thinking about sobriety, and perhaps, even making plans to achieve it. Medication may help individuals in each stage of this process (DiClemente, 2003). For example, for those who are weighing the possibility of trying to become sober, medications may offer hope and prompt them to take action. For those who have already begun counseling for their drinking, medication may help remove some of the physical obstacles to their recovery, such as craving or the irritability and anxiety of the postwithdrawal stage, which can trigger a relapse to drinking. All approved medications for alcohol dependence treatment have demonstrated the ability to reduce the risk of relapse and/or maintain abstinence, which reinforces the efforts individuals are making in psychosocial therapy. Medication should not be thought of as a substitute for psychosocial counseling, which develops and encourages the sustained behavioral changes individuals need for long-term recovery. Proper use of medication and its integration with psychosocial therapy are vital to help ensure treatment success. Clinicians must counsel patients about what to expect from medications, and they must carefully monitor and manage medication side effects, which may discourage individuals from using medications or continuing treatment entirely. Patients who are aware in advance that a particular side effect might be common but short-lived may be more apt to continue therapy. Similarly, dosing regimens that are easier for individuals to follow will encourage adherence. Finally, counseling is particularly important when individuals may be disappointed by delayed onset of medication effects or limited efficacy. Medical management and BRENDA Certain counseling techniques specifically address medication issues in treatment, such as adherence to therapy. Two examples are medical management and BRENDA. Medical management is a brief, manualized form of therapy that initially involves discussion of alcohol dependence, the negative consequences of drinking, abstinence promotion, and appropriate referral to support groups (Pettinati et al., 2004). Follow-up sessions are usually shorter and focus on medication adherence and the individual’s drinking status. Medical management was effectively used in eight treatment groups in the COMBINE study to promote abstinence (Anton et al., 2006). The finding that those who received medical management as well as placebo effectively reduced their drinking, suggests that the act of taking medication (even inactive medication) and discussing issues of treatment and adherence with a health professional can promote successful recovery (Anton et al., 2006). BRENDA is a technique that combines motivational enhancement with medication management, especially adherence to medication (Volpicelli et al., 2001). It involves a biopsychosocial assessment of patients; reporting the assessment back to patients; taking an empathetic approach; identifying patient needs; providing direct advice to patients about their drinking; and assessing their adherence to treatment (Volpicelli et al., 2001). BRENDA is manualized and can be administered by many different health professionals, including counselors, psychologists, nurses and physicians. BRENDA has been effectively used in trials of oral (Pettinati et al., 2000) and extended-release naltrexone (Garbutt et al., 2005), and it has helped improved adherence to medication and commitment to treatment compared with other counseling (Pettinati et al., 2000). Summary Providing alcohol-dependent individuals with a variety of treatment options, including newer medications approved for treatment, should help engage them in the recovery process and improve the likelihood of treatment success. Clinical studies demonstrate that when medications for alcohol dependence are combined with psychosocial interventions, individuals have improved chances at achieving successful recovery. Optimal benefits from medications require proper instruction on their use, attention to adherence, and careful integration into counseling techniques. The following case studies highlight the experiences of three alcohol-dependent patients who used medications as part of their treatments. Each testimonial highlights factors contributing to successful treatment: • The hope patients describe when learning that medications may help with their treatment • The reduction in postwithdrawal cravings and physical symptoms achieved with the help of medication • The improved ability to focus on emotional, psychological and spiritual issues in counseling, once cravings were reduced • The difficulty of remaining adherent to treatment, especially with daily dosed medications • The patients’ beliefs that medications and counseling are both needed for their recoveries Kyle M. Kampman, MD is Medical Director of the Charles O’Brien Center for the Treatment of Addictions, Associate Professor of Psychiatry and Medical Director of the Treatment Research Center at the University of Pennsylvania in Philadelphia. He currently serves on the editorial board of the Journal of Addiction Medicine and is an active member of the American Society of Addiction Medicine, College on Problems of Drug Dependence and the Pennsylvania Society of Addiction Medicine. Christopher R. Wilkins, MHA is vice-president and chief operating officer of DePaul Addiction Services. He presides over inpatient, detoxification and outpatient programs for addiction and gambling treatment. He currently serves as president of the New York State Association of Substance Abuse Providers and board president of the Statewide Advocacy Association. References Anton, R.F., Moak, D.H., Waid, L.R., Latham, P.K., Malcolm, R.J. & Dias, J.K. (1999). Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. American Journal of Psychiatry 156(11),1758-64. Anton, R.F., O’Malley, S.S., Ciraulo, D.A. et al. (2006). Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. Journal of the American Medical Association 295(17),2003-17. Bouza, C., Magro, A., Munoz, A. & Amate, J.M. (2004). Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction(Abingdon,England) 99(7),811-28. Chick, J., Lehert, P. & Landron, F. (2003). Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol 17(4),397-402. De Witte, P. (2004). Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol. Addict Behav 29(7),1325-39. De Witte, P., Littleton, J., Parot, P. & Koob, G. (2005). Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 19(6),517-37. DiClemente CC. Addiction and change: how addictions develop and addicted people recover. New York, NY: Guilford Press; 2003. Fuller, R.K., Branchey, L., Brightwell, D.R. et al. (1986). Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. Journal of the American Medical Association 256(11),1449-55. Garbutt, J.C., Kranzler, H.R., O’Malley, S.S. et al. (2005). Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. Journal of the American Medical Association 293(13),1617-25. Gianoulakis, C. (2004). Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr Top Med Chem 4(1),39-50. Kalivas, P.W. & Volkow, N.D. (2005). The neural basis of addiction: a pathology of motivation and choice. American Journal of Psychiatry 162(8),1403-13. Kiefer, F., Jahn, H., Tarnaske, T. et al. (2003). Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo- controlled study. Archives of General Psychiatry 60(1),92-9. Koob, G.F. (1992). Neural mechanisms of drug reinforcement. Annals of the New York Academy of Sciences 654,171-91. Kranzler, H.R. (2006). Evidence-based treatments for alcohol dependence: new results and new questions. Journal of the American Medical Association 295(17),2075-6. Littleton, J. (1998). Neurochemical mechanisms underlying alcohol withdrawal. Alcohol Health and Research World 22(1),13-24. Littleton, J. & Zieglgansberger, W. (2003). Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. The American Journal on Addictions/American Academy of Psychiatrists in Alcoholism and Addictions 12 Suppl 1,S3-S11. Mason, B.J. (2005). Acamprosate in the treatment of alcohol dependence. Expert opinion on pharmacotherapy 6(12),2103-15. Mason, B.J., Goodman, A.M., Chabac, S. & Lehert, P. (2006). Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res 40(5),383-93. Monti, P.M., Rohsenow, D.J., Hutchison, K.E. et al. (1999). Naltrexone’s effect on cue-elicited craving among alcoholics in treatment. Alcoholism, Clinical and Experimental Research 23(8),1386-94. National Institute on Alcohol Abuse and Alcoholism (NIAAA). Helping Patients Who Drink Too Much. A Clinician’s Guide. 2005 Edition. Bethesda, Maryland: National Institutes of Health; 2005. O’Malley, S.S., Jaffe, A.J., Chang, G. et al. (1996). Six-month follow-up of naltrexone and psychotherapy for alcohol dependence. Archives of General Psychiatry 53(3),217-24. Odyssey Pharmaceuticals. Antabuse® tablets (Disulfiram Tablets, USP). Montvale, NJ: Thomson PDR; 2005. Pettinati, H.M., Volpicelli, J.R., Pierce, J.D., Jr. & O’Brien, C.P. (2000). Improving naltrexone response: An intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. J Addict Dis 19(1),71-83. Pettinati HM, Weiss RD, Miller WR, Donovan D, Ernst DB, Rounsaville BJ. Medical management treatment manual: a clinical research guide for medically trained clinicians providing pharmacotherapy as part of the treatment for alcohol dependence. Bethesda, MD: National Institute on Alcohol Abuse and Alcoholism; 2004 Aug. Report No.: DHHS Publication No. (NIH) 04-5289 Prochaska, J.O., DiClemente, C.C. & Norcross, J.C. (1992). In search of how people change. Applications to addictive behaviors. Am Psychol 47(9),1102-14. Project MATCH Research Group. (1998). Matching alcoholism treatments to client heterogeneity: Project MATCH three-year drinking outcomes. Alcoholism, Clinical and Experimental Research 22(6),1300-11. Suh, J.J., Pettinati, H.M., Kampman, K.M. & O’Brien, C.P. (2006). The status of disulfiram: a half of a century later. Journal of Clinical Psychopharmacology 26(3),290-302. Swift, R.M. (1999). Drug therapy for alcohol dependence. New England Journal of Medicine 340(19),1482-90. Tupala, E. & Tiihonen, J. (2004). Dopamine and alcoholism: neurobiological basis of ethanol abuse. Progress in neuro-psychopharmacology & biological psychiatry 28(8),1221-47. Volpicelli JR, Pettinati HM, McLellan AT, O’Brien CP. Combining Medication and Psychosocial Treatments for Addictions: The BRENDA Approach. New York: Guilford Press; 2001. Volpicelli, J.R., Rhines, K.C., Rhines, J.S., Volpicelli, L.A., Alterman, A.I. & O’Brien, C.P. (1997). Naltrexone and alcohol dependence: role of subject compliance. Archives of General Psychiatry 54(8),737-42. Volpicelli, J.R., Watson, N.T., King, A.C., Sherman, C.E. & O’Brien, C.P. (1995). Effect of naltrexone on alcohol “high” in alcoholics. American Journal of Psychiatry 152(4),613-5.             
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