Jeffery N. Wilkins, M.D.

Proper treatment for addiction is best informed by the substance of addiction. The main categories of substance addiction and proper treatment recommendations are reviewed.

Psychiatric Times February 2005 Vol. XXII Issue 2

Several medications are approved for the pharmacological treatment of substance abuse disorders including: disulfiram (Antabuse) and naltrexone (ReVia, Trexan, Nalorex) for alcohol dependence; methadone, l-a-acetylmethadol (OrLAAM), buprenorphine (Buprenex) and buprenorphine plus naloxone (Suboxone) for opioid dependence; and bupropion (Wellbutrin, Zyban) and nicotine in a patch (Nicoderm CQ/generic patches), gum (Nicorette/Nic Mint), spray (Nicotrol NS) or inhaler (Nicotrol Inhaler) for nicotine dependence. To be successful, pharmacotherapy is supplemented by psychosocial treatment modalities (e.g., 12-step, motivational enhancement and/or cognitive-behavioral therapy), including when substance abuse occurs in the context of mental illness.

Pharmacotherapy of Withdrawal States

The best practice model for treatment of severe/complex withdrawal and complex comorbid mental illness and substance abuse includes management by psychiatrists who are certified in addiction psychiatry or addiction medicine and who demonstrate appropriate training, experience and ongoing medical education in treatment of these conditions (Joint Statement of the American Society of Addiction Medicine and the American Managed Behavioral Healthcare Association, 2004).

Alcohol withdrawal. Alcohol withdrawal is best monitored with the Clinical Institute Withdrawal Assessment-Alcohol, revised (CIWA-Ar) (Sullivan et al., 1989). This scale determines initial and subsequent doses of benzodiazepine medication and serves as the basis for effective communication with nursing staff and other physicians. Benzodiazepines such as lorazepam (Ativan), diazepam (Valium) or chlordiazepoxide (Librium) are recommended using either symptom-triggered (Jaeger et al., 2001; Mayo-Smith, 1997) or fixed-dose (Mayo- Smith, 1997) regimens (Table 1). Symptom-triggered therapy has been shown to decrease the occurrence of withdrawal delirium/delirium tremens, as well as decrease the total amount of medication received by the patient (Jaeger et al., 2001).

Sedative-hypnotic-anxiolytic withdrawal. Much of the pharmacotherapy for sedative-hypnotic-anxiolytic withdrawal is similar to that for alcohol withdrawal (Table 2). Important differences include the use of clonazepam (Klonopin) as a front-line medication and the use of long-term outpatient tapering of clonazepam, diazepam or chlordiazepoxide as a means of minimizing post-abstinence syndrome.

GHB withdrawal. Cessation of chronic GHB (rohypnol) or GBL use leads to a discrete withdrawal syndrome resembling that of sedative-hypnotic withdrawal. Most cases of GHB withdrawal can be effectively managed through use of a long-acting benzodiazepine and tapering the dose after the symptoms have been controlled (Chin, 2001; Dyer et al., 2001).

Opioid withdrawal. The most significant recent advance in the United States for treating opioid withdrawal is the U.S. Food and Drug Administration approval of Suboxone (buprenorphine + naloxone) and Subutex (buprenorphine) for treatment of opioid dependence. Demonstrated as effective in office-based settings (Fudala et al., 2003), individual practitioners may obtain prescribing authority through sanctioned training or waiver (see htttp://buprenorphine.samhsa.gov). Methadone remains the primary agent for opioid maintenance and detoxification, although it must be administered in state- and federally approved clinics. Table 3 describes treatment with opioid agonists and non-opioid medications.

Clonidine (Catapres) and lofexidine (available in the United Kingdom), both α2-adrenoceptor agonists and similar in chemical structure, provide the psychiatrist with non-opioid medications to treat opioid withdrawal. Lofexidine may be preferred over clonidine due to a decreased risk for hypotension (van den Brink et al., 2003), although both may produce rebound hypertension if abruptly discontinued. Both medications reduce noradrenergic activity via stimulation of adrenergic autoreceptors, leading to decreases in withdrawal symptoms, including mydriasis, lacrimation, rhinorrhea, piloerection and yawning (Kosten and O'Connor, 2003). Supplementary medications can be employed to further reduce malaise (e.g., non-steroidal anti-inflammatory agents), muscle cramping (e.g., methocarbamol [Robaxin]), abdominal cramping (e.g., dicyclomine [Bentyl]), diarrhea (atropine/ diphenoxylate [Lomotil]), nausea and vomiting.

Stimulant withdrawal. Benzodiazepines such as lorazepam may be helpful for agitation or sleep disturbance. Severe suicidal ideation or persistent (greater than two to three weeks) depression may require antidepressant treatment (Schuckit, 1999). (Please refer to a summary of new approaches to cocaine addiction treatment, reviewed by Kyle M. Kampman, M.D., in this special report of Psychiatric Times, p38--Eds.)

Nicotine withdrawal. Despite concerns to the contrary, there is no compelling evidence that smoking cessation contributes to relapse to other substances. Furthermore, nicotine use is linked to other substance use. Recent strategies suggest that combining bupropion with the nicotine patch leads to improved treatment outcome (Jorenby et al., 1999) and that patients receiving atypical antipsychotics tolerate treatment with the nicotine patch (George et al., 2000) (Table 4). It is important to recognize that smoking cessation can significantly alter the pharmacokinetics of current psychotropic medications.

Intoxication-Related Psychopathology

Stimulant intoxication. Diazepam (10 mg to 30 mg PO or 2 mg to 10 mg IM or IV) or lorazepam (2 mg to 7 mg po, IM or IV) are preferred over neuroleptics to control severe agitation, anxiety or psychotic symptoms (Roth et al., 1997; Schuckit, 1999). Parenteral benzodiazepine dosing may be repeated every five to 10 minutes until sedation is achieved. If a neuroleptic is needed to control psychosis, a high-potency agent such as haloperidol (Haldol) (5 mg to 10 mg po, IM or IV) or droperidol (Inapsine) (2.5 mg to 5 mg IV) is preferred because of diminished anticholinergic activity.

MDMA, marijuana, hallucinogen intoxication. Benzodiazepines can ameliorate hyperthermia and agitation from MDMA ("ecstasy") intoxication. Neuroleptics should be avoided because they interfere with heat dissipation and lower the seizure threshold (Wilkins et al., 2003).

For patients whose marijuana-induced agitation or anxiety does not respond to reassurance, an oral benzodiazepine is preferred to neuroleptics, although psychosis usually responds promptly to low-dose antipsychotics (Wilkins et al., 2003).

Similarly, for patients whose hallucinogen-induced agitation or delirium does not respond to reassurance alone, an oral benzodiazepine, such as diazepam (10 mg to 30 mg), is the treatment of choice. When oral medication is too slow or the patient will not take oral medication, intramuscular lorazepam (2 mg, repeated hourly as needed) may be effective. If benzodiazepines are insufficient, low doses of a high-potency neuroleptic such as haloperidol are recommended.

Pharmacotherapy as an Adjunctive Treatment

Naltrexone. This µ-, κ-, σ-opioid receptor antagonist is approved in the United States and several European countries for the treatment of alcohol dependency as well as opioid dependence. Daily use (50 mg) has been demonstrated to reduce the craving for and the reinforcing euphoric effects of alcohol; reduce episodes of heavy drinking; decrease the number of drinking days; and decrease total amount of alcohol consumed (O'Brien, 1997).

Acamprosate. This medication, which was approved by the FDA last summer, is reported to lengthen the time to relapse, reduce drinking days and increase sustained abstinence (Wilde and Wagstaff, 1997) through actions at the N-methyl-D-aspartate receptors.

Combined naltrexone and acamprosate. Kiefer et al. (2003) studied 160 detoxified patients who were randomly assigned to receive naltrexone, acamprosate, naltrexone plus acamprosate or placebo for 12 weeks. Although study results were similar to the above reports for naltrexone or acamprosate alone, the combination demonstrated an increased number of days before relapsing to alcohol use.

Topiramate. In a study of 150 patients, 75 received topiramate (Topamax) and 75 received placebo in a 12-week, randomized, controlled trial with a two-group design: escalating topiramate and escalating placebo (Johnson et al., 2003). The patients who received topiramate significantly reduced their drinks per day, craving for alcohol and the number of heavy drinking days, and increased their number of days abstinent.

Stimulant dependence. A substantial effort has been made by the Medication Development Division of the National Institute on Drug Abuse to develop medications that will help patients initiate and maintain abstinence from cocaine and other stimulants, including methamphetamines. Whereas the dopamine D2 receptor agonists bromocriptine (Parlodel) and pergolide (Permax) have been found ineffective, indirect agonists including methylphenidate (Ritalin) (Grabowski et al., 1997), amantadine (Symmetrel) (Alterman et al., 1992) and propranolol (Inderal) (Kampman et al., 2001) have been reported to improve treatment retention.

Dr. Wilkins is vice chairperson of the department of psychiatry and director of addiction medicine at Cedars-Sinai Medical Center in Los Angeles.

References

Alterman AI, Droba M, Antelo RE et al. (1992), Amantadine may facilitate detoxification of cocaine addicts. Drug Alcohol Depend 31(1):19-29.

Chin RL (2001), A case of severe withdrawal from gamma-hydroxybutyrate. Ann Emerg Med 37(5):551-552 [letter].

Dyer JE, Roth B, Hyma BA (2001), Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 37(2):147-153 [see comments].

Fudala PJ, Bridge TP, Herbert S et al. (2003), Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Eng J Med 349(10):949-958 [see comments].

George TP, Ziedonis DM, Feingold A et al. (2000), Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry 157(11):1835-1842.

Grabowski J, Roache JD, Schmitz JM et al. (1997), Replacement medication for cocaine dependence: methylphenidate. J Clin Psychopharmacol 17(6):485-488.

Jaeger TM, Lohr RH, Pankratz VS (2001), Symptom-triggered therapy for alcohol withdrawal syndrome in medical inpatients. Mayo Clin Proc 76(7):695-701 [see comment].

Johnson BA, Ait-Daoud N, Bowden, CL et al. (2003), Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361(9370):1677-1685 [see comments].

Joint Statement of the American Society of Addiction Medicine and the American Managed Behavioral Healthcare Association (2004), ASAM Patient Placement Criteria. Available at: www.asam.org. Accessed Feb. 9.

Jorenby DE, Leischow SJ, Nides MA et al. (1999), A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 340(9):685-691 [see comments].

Kampman KM, Volpicelli JR, Mulvaney F et al. (2001), Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend 63(1):69-78.

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. Arch Gen Psychiatry 60(1):92-99.

Kosten TR, O'Connor PG (2003), Management of drug and alcohol withdrawal. N Engl J Med 348(18):1786-1795 [see comments].

Mayo-Smith MF (1997), Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA 278(2):144-151 [see comments].

O'Brien CP (1997), A range of research-based pharmacotherapies for addiction. Science 278(5335):66-70 [see comment].

Roth BA, Benowitz NL, Olson KR (1997), Emergency management of drug abuse-related disorders. In: Drug Abuse Handbook, Karch SB, ed. Boca Raton, Fla.: CRC Press, pp567-639.

Schuckit MA, (1999), Drug and Alcohol Abuse. A Clinical Guide to Diagnosis and Treatment, 5th Edition. New York: Kluwer Academic/Plenum.

Sullivan JT, Sykora K, Schneiderman J et al. (1989), Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84(11):1353-1357.

van den Brink W, Goppel M, van Ree JM (2003), Management of opioid dependence. Current Opinion in Psychiatry 16(3):297-304.

Wilde MI, Wagstaff AJ (1997), Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs 53(6):1038-1053.

Wilkins JN, Mellott K, Markvitsa R, Gorelick DA (2003), Management of Stimulant, Hallucinogen, Marijuana, Phencyclidine, and Club Drug Intoxication and Withdrawal. In: Principles of Addiction Medicine, Miller N, ed. Chevy Chase, Md.: American Society of Addiction Medicine.