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Benzodiazepines for substance abusers

Yes? No?

Do addiction worries outweigh the need for effective treatment? A sobriety-based algorithm addresses both concerns.

S. Pirzada Sattar, MD ow should you treat anxiety in substance- Assistant professor of psychiatry H abusing patients: deny them benzodi- Associate director of residency training azepines and risk under-treatment, or Creighton/University of Nebraska psychiatry prescribe benzodiazepines for the residency program effect and risk contributing to addiction? Staff psychiatrist, Treatment Center VA Medical Center, Omaha, NE There is no definitive answer, but one thing is clear: Among psychiatric patients, substance Subhash Bhatia, MD abusers are most likely to abuse benzodiazepines and become addicted to them. Professor of psychiatry Creighton University School of Medicine Some argue that the abuse potential is over- Chief of and Behavioral Science stated, but only limited data suggest that benzo- VA Medical Center, Omaha, NE diazepines can be safely prescribed to patients who are abusing or . In this article, we discuss benzodiazepine use in these patients and offer a sobriety-based treatment approach. continued

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Table 1 benzodiazepine and cloza- Benzodiazepines’ potency and half-lives, pine.1 including half-lives of active metabolites Overdose and withdrawal symptoms. Benzodiazepine Potency Shorter half-life (hr) Longer half-life (hr) overdose is characterized by slurred speech, seda- High (6 to 12) (18 to 50) tion, memory impairment, (10 to 20) incoordination, respirato- (2) ry depression, hypoten- Low (4 to 15) (5 to 30) [36 to 200]* sion, stupor, and . (8 to 22) [36 to 200]* Abrupt withdrawal may produce life-threatening (20 to 100) [36 to 200]* , hallucinations, [40 to 250]* grand mal , and * [active metabolite] symptoms similar to those Source: Ashton CH. Benzodiazepine equivalence table. Available at www.benzo.org.uk of alcohol withdrawal (insomnia, anxiety, , hyperactivity, nausea, BENEFITS AND RISKS vomiting, and ).1 Considered a safe substitute for , ben- zodiazepines were heralded as wonder drugs ABUSE PATTERNS when they were introduced in the 1950s. Reports The few empiric studies examining benzodi- of their addictive potential surfaced in the 1970s, azepines’ abuse potential in substance abusers and since then researchers have disagreed on have shown inconsistent results. However, it is whether benzodiazepines should be prescribed to generally accepted that: substance-abusing or -dependent patients. • long-term benzodiazepine use may lead Clinical utility. Benzodiazepines are used in many to tolerance and physiologic dependence clinical situations because of their: • withdrawal symptoms can occur if benzo- • anxiolytic, , , diazepines are stopped suddenly, especially antipanic, , amnestic, anes- after long-term (months to years) use. thetic, and antispastic effects Even though most benzodiazepine prescrip- • relatively mild side effects, when com- tions are not abused,2 a history of alcohol and pared with alternatives such as barbiturates. abuse suggests high potential for benzodi- In psychiatry, benzodiazepines are used to azepine abuse. Also, long-term users of pre- treat anxiety disorders, agitation, and . scribed benzodiazepines often develop tolerance Because of cross-tolerance with alcohol and bar- and may escalate their doses to get the same biturates, benzodiazepines also are used to man- desired effects. If their supply is threatened, these age alcohol or withdrawal. patients may seek benzodiazepines illicitly. Interactions. Benzodiazepines can interact with Benzodiazepines may enhance or prolong other psychotropics, including , antipsy- the elation (“high”) associated with other drugs chotics, and selective serotonin reuptake or mitigate the depression (“crash”) that follows a inhibitors (SSRIs). Respiratory arrest has been “high.” Sometimes benzodiazepines reported in patients taking both a high-potency are the drug of choice, as high doses of potent, continued on page 29

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continued from page 26 short-acting agents may provide a Table 2 stimulant “high.” Should benzodiazepines be prescribed to substance abusers? WHO ABUSES BENZODIAZEPINES?

Alcohol and substance abusers tend YES: Arguments for to ingest benzodiazepines for recre- • Studies showing risks of benzodiazepine abuse ational purposes. Thirty to 50% of in substance users were based on faulty data alcoholics undergoing detoxification (Maletzky & Klotter).17 and 44% of IV drug abusers also • Long-term benzodiazepine treatment of anxiety— may be abusing benzodiazepines.3 even in substance abusers—is similar to treatment Benzodiazepines are cross-toler- of other chronic conditions (Lader).18 ant with alcohol, and alcoholics may • Studies suggesting that alcoholics and drug use them with alcohol or as a substi- abusers are at high risk of benzodiazepine abuse tute when alcohol is unavailable. are inconclusive (Ciraulo et al).19 They also may self-medicate with • Abuse potential is minimal, and undue restrictions benzodiazepines to ease alcohol’s cause patients to suffer needlessly (Berner).20 withdrawal symptoms. , am- • Prolonged benzodiazepine use decreases morbidity in phetamine, and abusers may chronic conditions (Schatzberg).21 use benzodiazepines with their drugs • Other treatments are often ineffective (Lader).22 of choice, as may younger abusers of NO: Arguments against MDMA (“Ecstasy”) and LSD. • Prescribing benzodiazepines promotes drug abuse Even patients who begin taking (Sellers et al).23 benzodiazepines for legitimate rea- • Physiologic tolerance and dependence occurs with sons may end up abusing them. In every long-term benzodiazepine use, and these risks 24 one study of 2,600 patients prescribed are compounded in substance abusers (Hamlin). diazepam, up to 60% had abused • Long-term benzodiazepine use may cause structural brain damage (Piesiur-Strehlow et al).25 and/or become dependent on it.4 Benzodiazepine abuse may start • Guilt and failure to spend enough time with patients with other /hypnotic abuse are the main reasons physicians prescribe benzodi- 26 or as experimentation with drugs or azepines (Bendtsen et al). alcohol, typically around age 13 or • Benzodiazepines should be reserved for detoxification and withdrawal in individuals with 14.5 The average benzodiazepine type 2 (Linnoila).27 abuser is age 19 to 31, and the male- to-female ratio is about 2:1.6 Multi-drug abuse. Benzodiazepines are usually not the preferred or sole previous week.8 Other studies suggest that up to drug of abuse. Roughly 80% of benzodiazepine 90% of users regularly abuse benzodi- abuse may be a component of poly-drug abuse, azepines, often at high doses.9 most commonly with addiction.7 A 2-year National Institute on Drug Abuse study of ILLICIT USE POTENTIAL abusers suggested that 15% also abused benzodi- Prescriptions are the primary source of supply for azepines daily for more than 1 year, and 73% had benzodiazepine abusers. These patients are doc- abused benzodiazepines several times during the tor shoppers and often change pharmacies. They

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visit emergency rooms frequently and may feign diazepoxide has been reported to produce a lower symptoms to obtain benzodiazepine prescrip- “high” than other benzodiazepines.14 Among the tions. They fill prescriptions for personal use or short half-life benzodiazepines, oxazepam may sell the drugs to illicit sources to support their have a relatively low abuse potential.14 Clon- addictions. azepam—a high-potency benzodiazepine with a long half-life—is gener- Without convincing data, psychiatrists must decide ally safe and may have a the merits of using benzodiazepines, usually case by case. lower abuse or addiction potential, although its abuse has been report- On the street, brand-name benzodiazepines ed.15 Similarly, oxazepam, clorazepate, and chlor- are worth much more than generics because they diazepoxide may be less reinforcing than other can be identified by photographs of brand-name benzodiazepines, although reports have linked benzodiazepines on the Internet or in reference these agents to abuse as well.16 books. In many cities, the street value of the Xanax or Klonopin brands may be $5 to $10 per pill. A 5- TO PRESCRIBE OR NOT TO PRESCRIBE mg tablet of Valium-brand diazepam may sell for Opponents blame benzodiazepines for promot- $5, and 10-mg tablets are worth up to $10. ing the and argue that prescribing Higher abuse potential. All benzodiazepines have benzodiazepines promotes drug abuse. Advocates abuse potential, and most have been reported in of benzodiazepine contend that restrict- the literature as being abused. Those most likely ing an effective and safe is unethical, to be abused have a short half-life10 (Table 1) or even in substance abusers. Arguments from each rapidly cross the blood brain barrier, such as perspective are summarized in Table 2.17-27 alprazolam.11 In 1990, an American Psychiatric Association Alprazolam and lorazepam are popular task force concluded that alcohol and substance among benzodiazepine abusers. In experienced abusers could be prescribed benzodiazepines but nondependent users, 1 mg of alprazolam pro- with very close monitoring but did not recom- duces a sense of elation and carries an abuse mend specific standards.28 potential similar to that of 10 mg of dextroam- phetamine.12 Lipophilic agents such as diazepam RECOMMENDATIONS also have a high abuse and addiction potential. Prescribing benzodiazepines to substance abusers In the United States, diazepam and alprazo- is not absolutely contraindicated, despite an ele- lam appear to be the most abused benzodi- vated relative risk of abuse or dependence. In the azepines.13 has become popular absence of convincing data, physicians must among high school students and drug addicts, decide on their own—usually case by case—the particularly in the south and southwest. This merits of using benzodiazepines to treat anxiety potent benzodiazepine is not approved for use in in substance abusers. the United States but is diverted from Latin A sobriety-based approach. Our group at the America or Europe in the . Substance Abuse Treatment Center, VA Medical Lower abuse potential. Benzodiazepines with Center, Omaha, Nebraska, has developed a treat- longer half-lives generally are less likely to be ment algorithm for substance abusers presenting abused, although diazepam—with a half-life of with anxiety (see Algorithm). It is based on clini- up to 100 hours—is the exception. Chlor- cal experience, more than 200 relevant articles,

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Algorithm Sobriety-based protocol for treating anxiety in substance abusers

Substance-abusing patient with anxiety presents for treatment

▼ ▼ Willing to commit to sobriety Not willing to commit to sobriety ▼ Detoxification (in- or outpatient) ▼ Refer to substance ▼ abuse program If anxiety persists, first-line treatments include , SSRIs, ▼ , , Consider involuntary treatment , , and if patient meets criteria other sedating

▼ ▼ If no improvement, Motivational enhancement consider adjunctive therapy long-acting benzodiazepine at adequate dosages ▼ ▼ Individual or group therapy, Follow prescribing precautions Alcoholics/

(below), and monitor ▼ Anonymous adherence to ongoing substance abuse treatment

Precautions for prescribing benzodiazepines • Inform patient of planned duration • Attempt to taper dosage after 3 to 6 of therapy months—even if patient resists—and monitor • Prescribe for brief periods (weeks to for objective withdrawal months), with follow-up at least monthly • If no objective withdrawal, terminate • No refills without follow-up, and no benzodiazepine; continue other refills over the phone • If objective withdrawal, continue • Use random urine toxicology benzodiazepine and reattempt taper in 3 to 6 screening every 1 to 3 months to monitor months; continue Alcoholics/Narcotics for relapse Anonymous

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and the consensus of psychiatrists trained and Observe prescribing precautions (see certified by the American Board of Psychiatry and Algorithm), and screen patients’ urine randomly Neurology and the American Society of every 1 to 3 months to monitor their adherence to . substance abuse treatment. We suggest that you begin by encouraging Keep patient records current, with attention to dates of visits and pre- scriptions and quantity Keep patient records current, with attention to dates of benzodiazepines pre- of visits and quantity of benzodiazepines prescribed scribed. To ensure proper continued use of benzo- sobriety and referring willing patients to detoxifi- diazepines, consider consulting with physicians cation. Because most addicts deny or greatly who have expertise in treating similar patients. minimize their substance abuse, investigate all Watch for possible signs of benzodiazepine potential drug or thoroughly and dependence and abuse, such as requests for dose address it appropriately. increases or early refills. If anxiety persists after detoxification, begin drug therapy with : • Diphenhydramine, 50 to 100 mg/d, may Related resources reduce anxiety and often improves , but Parran TV. Prescription drug abuse. A question of balance. Med consider its side effects Clin North Am 1997;81:967-78. before prescribing. Lader M, Russell J. Guidelines for the prevention and treatment of benzodiazepine dependence: summary of a report from the Mental • Some SSRIs and venlafaxine are used Health Foundation. Addiction 1993;88(12):1707-8. to treat anxiety, but they generally take National Institute on Drug Abuse. www.nida.nih.gov weeks to produce a therapeutic effect and National Institute on Alcohol Abuse and Addiction. some patients cannot wait that long. www.niaaa.nih.gov • Mirtazapine, 15 to 30 mg/d, provides DRUG BRAND NAMES relatively rapid sedation and helps with Alprazolam • Xanax Gabapentin • Neurontin sleep and anxiety. Buspirone • BuSpar Lorazepam • Ativan Chlordiazepoxide • Librium Mirtazapine • Remeron • Buspirone may reduce anxiety, especially Clonazepam • Klonopin Oxazepam • Serax when given at 30 to 60 mg/d. Clorazepate • Tranxene Temazepam • Restoril Diazepam • Valium Triazolam • Halcion • Gabapentin, 100 to 300 mg tid or higher, Flurazepam • Dalmane Venlafaxine • Effexor may reduce anxiety and help with sleep.

• antidepressants may be DISCLOSURE considered, but watch for cardiac and anti- This work was supported by the Attorney General’s Office, Commonwealth cholinergic side effects and overdose risks. of Massachusetts and the United States Department of Veterans Affairs. Dr. Sattar has received grant funding from Abbott Laboratories and is a If anxiety does not improve with an adequate speaker for AstraZeneca and Eli Lilly and Co. trial of first-line agents, consider adding long-act- Dr. Bhatia is a speaker for AstraZeneca, Eli Lilly and Co., Janssen ing benzodiazepines at sufficient dosages, such as Pharmaceutica, and Bristol-Myers Squibb Co. clonazepam, 0.5 to 1 mg bid to tid. Prescribe scheduled doses, rather than “as needed.” ACKNOWLEDGMENT The authors wish to thank Jennifer Hong, second-year medical student, Continue the first-line antianxiety agent, and Creighton University School of Medicine, Omaha, NE, for her assistance reiterate to the patient that benzodiazepine ther- in preparing this article for publication. apy will be short-term. continued

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NONDRUG TREATMENTS 7. Gold MS, Miller NS, Stennie K, Populla-Vardi C. Epidemiology of benzodiazepine use and dependence. Psychiatr Annals 1995;25:146-8. Nondrug treatments have been shown to reduce 8. Dumont RL. Abuse of benzodiazepines—the problems and the substance use and control anxiety in some stud- solutions. A report of a Committee of the Institute for Behavior and ies. These include cognitive-behavioral therapy, Health, Inc. Am J Drug Alcohol Abuse 1988;14(suppl 1):1-69. 9. Iguchi MY, Griffiths RR, Bickel WK, et al. Relative abuse liability of motivational enhancement therapy, interperson- benzodiazepines in methadone-maintained populations in three cities. In: Harris LS (ed). Problems of drug dependence, 1988. al therapy, and brief dynamic therapy, among Proceedings of the 50th annual scientific meeting, the Committee others. Their use requires specific training or on Problems of Drug Dependence, Inc. Rockville, MD: U.S. Department of Health and Human Services, Public Health referral to more experienced colleagues. For Service, Alcohol, Drug Abuse, and Mental Health Administration, information on these treatments, consult the National Institute on Drug Abuse, Office of Science, 1989. DHHS publication no. (ADM) 89-1605. Web sites of the National Institute on Drug 10. Longo LP. Non-benzodiazepine pharmacotherapy of anxiety and Abuse and National Institute on Alcohol Abuse in substance abusing patients. Psychiatr Annals 1998;28(3): 142-53. and Alcoholism (see Related resources). 11. Roache JD, Meisch RA. Findings from self-administration research Group and self-help such as on the addiction potential of benzodiazepines. Psychiatr Annals Alcoholics Anonymous or Narcotics Anonymous 1995;25(3):153-7. 12. Zawertailo LA, Busto U, Kaplan HL, Sellers EM. Comparative also have been shown to reduce substance use. abuse liability of , alprazolam, and dextroamphetamine in humans. J Clin Psychopharmacol 1995;15(2):117-24. References 13. Griffiths RR, McLeod DR, Bigelow GE, et al. Comparison of diazepam and oxazepam: preference, liking and extent of abuse. 1. Hales RE, Yudofsky SC. Textbook of clinical psychiatry, 4th ed. J Pharmacol Exp Ther 1984;229(2):501-8. Washington, DC: American Psychiatric Publishing, 2003:318- 19,493,501,1098. 14. Griffiths RR, Wolf B. Relative abuse liability of different benzodi- azepines in drug abusers. J Clin Psychopharmacol 1990;10(4):237-43. 2. Woods JH, Katz JL, Winger G. Use and abuse of benzodiazepines. Issues relevant to prescribing. JAMA 1988;260(23):3476-80. 15. Albeck JH. Withdrawal and detoxification from benzodiazepine dependence: a potential role for clonazepam. J Clin Psychiatry 3. Shaw M, Brabbins C, Ruben S. Misuse of benzodiazepines. Specify 1987;48(suppl):43-9. the formulation when prescribing. BMJ 1994;308(6945):1709. 16. Woods JH, Katz JL, Winger G. Use and abuse of benzodiazepines: 4. Woody GE, O’Brien CP, Greenstein R. Misuse and abuse of issues relevant to prescribing. JAMA 1988;260(23):3476-80. diazepam: an increasingly common medical problem. Int J Addict 1975;10(5):843-8. 17. Maletzky BM, Klotter J. Addiction to diazepam. Int J Addict 1976;II(1):95-115. 5. Pedersen W, Lavik NJ. Adolescents and benzodiazepines: prescribed use, self-medication and intoxication. Acta Psychiatrica Scand 18. Lader M. Short-term versus long-term benzodiazepine therapy. 1991;84:94-8. Curr Med Res Opin 1984(8, suppl 4):120-6. 6. Ruben SM, Morrison CL. Temazepam misuse in a group of 19. Ciraulo DA, Sands BK, Shader RI. Critical review of liability for injecting drug users. Br J Addict 1992;87:1387-92, benzodiazepine abuse among alcoholics. Am J Psychiatry 1988;145(12):1501-6. 20. Berner R. The patient’s perspective. NYS J Med 1991;91(11, suppl):37S-39S. 21. Schatzberg AF. Benzodiazepines: therapeutic, biological and psy- chosocial issues. J Psychiatr Res 1990;24(2):1-2. 22. Lader M. Drug development optimization—benzodiazepines. When substance abusers present Agents Actions 1990;29:59-69. 23. Sellers EM, Marshman JA, Kaplan Hl, et al. Acute and chronic with anxiety, attempt detoxification drug abuse emergencies in metropolitan Toronto. Int J Addict and prescribe non-benzodiazepines. 1981;16(2):283-303. 24. Hamlin M. Guidelines for benzodiazepine prescribing. Br J Hosp If these steps do not work, consider Med 1989;42(1):82. adding short-term, long-acting 25. Piesiur-Strehlow B, Strehlow U, Poser W. Mortality of patients benzodiazepines only for patients dependent on benzodiazepines. Acta Psychiatr Scand 1986;73:330-5. 26. Bendtsen P, Hensing G, McKenzie L, Stardsman AK. Prescribing committed to sobriety, and follow benzodiazepines—a critical incident study of a physician dilemma. precautions carefully. Soc Sci Med 1999;49:459-67. 27. Linnoila MI. Benzodiazepines and alcohol. J Psychiatric Res 1990;24(2, suppl):121-7. 28. Benzodiazepine dependence, toxicity and abuse. A task force report.

Bottom Line Washington, DC: American Psychiatric Association, 1990.

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