Journalof SubstanceAbuse Treatment,Vol. 11, No. 4, pp. 319-323, 1994 Copyright0 1994Elsevier Science Ltd Pergamon Printedin the USA. All rightsreserved 0740-5472/94$6.00 + .OO


Treatment of Withdrawal With Substitution and Taper


*Department of Psychiatry, University of Michigan, Ann Arbor, Michigan; tsubstance Abuse Clinic, Department of Veterans Affairs Medical Center, Ann Arbor, Michigan; SChelsea Arbor Treatment Center, Chelsea, Michigan

Abstract- We describe the first case series (n = 6) of using chlordiazepoxide to accomplish a rapid, well-tolerated withdrawal from alprazolam. After abruptly discontinuing alprazolam, we substi- tuted a 50-mg dose of chlordiazepoxide for each I mg of alprazolam (except for one elderly patient where we substituted 25 mg) and gave additional chlordiazepoxide doses (25-50 mg every 4-6 hours) as neededfor the first l-2 days of hospitalization. With this approach, the mean ‘substitution ra- tio" of ChIordiazepoxide to alprazolam was 86 to I. We then tapered chlordiazepoxide by an aver- age of 10% each day over a 7- to Il-day period according to the symptoms manifested and tolerated by individual patients. No or other serious side effects occurred. Incomplete cross- dependence, as described elsewhere in the literature, was not observed. The rapidity and familiar- ity of the method are advantages for inpatient units, but careful titration of dosage, diagnostic clarity, and extended follow-ups are necessary when applying this approach,

Keywords-alprazolam; chlordiazepoxide; ; substance withdrawal; .

INTRODUCTION importance of treating , physicians will likely continue prescribing it in the near future. ALPRAZOLAM IS A MEDICATIONthat is Alprazolam, like other benzodiazepines, has defi- highly effective and well studied for treating panic dis- nite abuse liability (American Psychiatric Association, order (Schweizer, Rickels, Weiss, & Zavodnick, 1993). 1990; Ciraulo & Sarid-Segal, 1991; Juergens, 1991). Panic disorder results in significant disability (Mar- Here, abuse refers to taking alprazolam for its nonmed- kowitz, Weissman, Ouellette, Lish, & Klerman, 1989) ical, euphoric effects despite harmful consequences. and may increase the risk for (Noyes, 1991). The vast majority of treated patients do not abuse ben- Although other therapies are available @elder, 1991), zodiazepines (American Psychiatric Association, 1990; alprazolam often works more quickly and has fewer Woods, Katz, & Winger, 1988). A prior history of sub- side effects and greater patient acceptance (Schweizer stance abuse, abusing other substances such as alco- et al., 1993). Given the benefits of alprazolam and the hol or , and a family history of may all increase the risk for benzodiazepine abuse (Ciraulo

Requests for reprints should be addressed to Kirk J. Brower, MD, & Sarid-Segal, 1991; Woods et al., 1988). University of Michigan Research Center, 400 E. Eisenhower, Apart from its abuse potential, Suite A, Ann Arbor, MI 48104. on alprazolam develops frequently (Fyer et al., 1987;

Received August 2, 1993; Accepted March 8, 1994.

319 320 M. H. Glosser and K. J. Bro wer

Rickels, Schweizer, Weiss, & Zavodnick, 1993). Phys- used adjunctively to facilitate the rate of alprazolam ical dependence refers to the appearance of withdrawal reduction with varying degrees of success. symptoms upon reducing or discontinuing drug use. After a patient on our unit suffered a dur- Physical dependence on alprazolam occurs even with ing alprazolam reduction without substitution, we de- controlled use of therapeutic doses. In studies of grad- veloped a protocol for chlordiazepoxide substitution ual alprazolam discontinuation in panic-disordered and taper. We reasoned that chlordiazepoxide had the patients, 53-63% of them had moderate to severe with- advantage of familiarity on our treatment unit, where drawal symptoms after taking therapeutic doses for we regularly employed it to treat alcohol withdrawal. 3-10 months (Fyer et al., 1987; Rickels et al., 1993). Some evidence suggests that withdrawal from alpra- METHOD zolam may be more difficult than withdrawal from some other benzodiazepines, because of its higher po- Patients tency and shorter duration of action (Noyes, Garvey, Cook, & Suelzer, 1991). Withdrawal symptoms include The sample consisted of consecutively admitted inpa- agitation, , depersonalization and derealization, tients to our chemical dependency unit from 1987 to depression, diaphoresis, difficulty concentrating, diz- 1989 whose primary diagnosis was alprazolam depen- ziness, headaches, increased perceptual acuity for sights dence, and who had a history of withdrawal symptoms and sounds, , light-headedness, loss of appe- upon discontinuation. During this period, we treated tite, malaise, muscular pains, , poor coordina- six patients for alprazolam withdrawal (Table 1). The tion, restlessness, , , and weakness charts of our six patients were retrospectively reviewed (Fyer et al., 1987; Pecknold, Swinson, Kuch, 8~Lewis, for demographics, alprazolam history, diagnoses, and 1988; Rickels et al., 1993). Symptoms may begin within hospital course. 1 day of stopping alprazolam, peak within 3 days to 2 weeks, and generally subside by 2-4 weeks (American Treatment Procedures Psychiatric Association, 1990; Fyer et al., 1987; Peck- nold et al., 1988; Rickels et al., 1993). At worst, seizures, On admission all patients received complete medical, , and can occur during alprazolam psychiatric, substance use, and laboratory evaluations. withdrawal (Browne & Hauge, 1986; Warner, Pea- For treatment of alprazolam withdrawal, a modifica- body, Boutros, & Whiteford, 1990; Zipursky, Baker, tion of our protocol was imple- & Zimmer, 1985), so abrupt or rapid discontinuation mented. Except for one case, we substituted 50 mg without other pharmacological intervention is clearly of chlordiazepoxide for each 1 mg of alprazolam re- contraindicated. ported, and we gave this amount orally as a regular The manufacturer recommends a reduction in al- divided dosage (3-4 times daily). Our exceptional case prazolam of not more than 0.5 mg every 3 days. Al- was an elderly patient (72 years old) for whom we sub- though this recommendation provides a maximal rate, stituted 25 mg of chlordiazepoxide for each 1 mg of many patients do not tolerate a taper this rapid, espe- alprazolam. In addition, we gave each patient supple- cially toward the end of their tapers, and so optimal mental doses of chlordiazepoxide by mouth: 25-50 mg rates of reduction are usually slower. Even if one as- every 4-6 hours as needed to suppress withdrawal sumes the maximal rate, a taper from 6 mg would take symptoms. The next scheduled dose was held if the 36 days. Patients and physicians sometimes desire patient was drowsy. If withdrawal symptoms wors- more rapid techniques, especially in chemical depen- ened on the second day, then we allowed an additional dency treatment settings. 24-hour period of “as-needed” dosing in addition to the Substitution strategies make rapid discontinuation regular dosing. The total 24-hour dosage of chlordi- possible. Typically, alprazolam is discontinued abruptly, azepoxide (regular plus supplemental amounts) needed and a long-acting is substituted to suppress to suppress withdrawal was regarded to be equivalent harmful withdrawal symptoms, after which the latter to the patient’s daily alprazolam dosage. We then de- sedative is tapered completely over l-2 weeks. Pheno- creased chlordiazepoxide at an average rate of 10% per (Juergens & Morse, 1988; Ravi, Maany, Burke, day (range 7.7%-14.3%). The rate of taper was indi- Dhopesh, & Woody, 1990) and the benzodiazepines, vidualized as determined by each patient’s symptom (Albeck, 1987; Patterson, 1990), profile. In sum, we took 1-2 days to establish a sub- (Harrison, Busto, Naranjo, Kaplan, & Sellers, 1984), stitution dose, and then tapered the substituted dose and chlordiazepoxide (Juergens & Morse, 1988), have over the next 7-14 days. all been used this way. Other classes of After the taper was finished, patients were expected such as (Ries, Roy-Byrne, Ward, Neppe, to complete a 2-week program of chemical dependency & Cullison, 1989; Schweizer, Rickels, Case, & Green- rehabilitation. We made follow-up observations dur- blatt, 1991) and (Fyer et al., 1988) have been ing this time. AIprazolam Withdrawal 321

TABLE 1 Medications Used

Alprazolam Duration of Chlordiazepoxide Chlordiazepoxide Dosea Alprazolam Doseb DurationC Substitution Patient (mg/d) (mo) (m9) (days) Ratiod

1 6.0 (12) 4 300 9 50.00 2 4.0 72 350 15 87.50 3 3.0 48 195 15 65.00 4 4.0 72 225 10 56.25 5 2.0 (10) 60 350 9 175.00 6 5.0 48 400 9 80.00 aAlprazolam dosage on admission. For cases 1 and 5, value in parentheses is dose from which outpatient taper began prior to hospitalization. bTotal 24-hr dosage needed to suppress withdrawal symptoms. ‘Total days of chlordiazepoxide administration, including substitution and taper. dChlordiazepoxide dosage in column 4 divided by alprazolam dosage in column 2.

RESULTS four patients were followed for 12, 14, 15, and 48 days, respectively, and received regular discharges. During The mean age of our patients was 44.8 years (range the follow-up periods for the six patients, we observed 23-72), and five patients were female. The primary in- the following symptoms: anxiety (n = 4), insomnia dications for initially prescribing alprazolam were (n = 3), high blood pressure (n = 2), tachycardia panic disorder in five patients (two of whom had ad- (n = l), irritability (n = l), tremor (n = l), deperson- ditional admitting diagnoses of either generalized anx- alization or derealization (n = l), and headache (n = iety or social phobia) and generalized anxiety by itself 1). No panic attacks were observed during the follow- in one patient. Discharge diagnoses included alprazo- up period. No seizures, episodes of delirium, or psy- lam dependence (n = 6), major depression (n = l), chosis occurred in any patient during the entire course mixed personality disorder (n = l), of observation. (n = l), alcohol and dependence (n = l), and Two patients (cases 1 and 3) had residual symptoms bulimia (n = 1). Patients’ daily alprazolam dose at time at the time of discharge. One patient continued to have of admission ranged from 2 to 6 mg (M = 4.0 mg), decreased sleep (~5 hr/night), and the other com- and the duration of use ranged from 4 to 72 months plained of mild anxiety. Both patients had complicating (M = 52.7) (Table 1). For each patient, we calculated psychiatric and medical problems requiring medica- the “substitution ratio” of chlordiazepoxide to alpra- tions (major depression, mixed personality disorder, zolam as the total 24-hour dosage of chlordiazepox- sustained hypertension, coronary artery disease, chronic ide given before tapering, divided by the admission obstructive pulmonary disease, irritable bowel syn- dosage of alprazolam (Table 1). The mean substitution drome, and fibromyositis). We attributed the two pa- ratio was 85.6 (range 50-175). The mean number of tients’ residual symptoms to coexisting diagnoses days on chlordiazepoxide was 11.2 (range 9-15 days), rather than to poorly treated alprazolam withdrawal. and the mean number of days to taper chlordiazepox- ide was 9.5 (range 7-13 days). All patients remained in treatment for the duration of the taper. DISCUSSION Discontinuation symptoms during chlordiazepox- ide administration included anxiety (n = 6), insomnia To our knowledge, this is the first reported case series (n = 4), high blood pressure (n = 4), tachycardia (n = in which chlordiazepoxide was used successfully to 3), irritability (n = 2), tremor (n = 2), depersonaliza- treat inpatients for physical withdrawal from alpra- tion or derealization (n = 2), sweatiness (n = l), and zolam. Early reports cautioned that incomplete cross- aches (n = 2). One was noticed in one pa- dependence between alprazolam and either chlordiaz- tient. After chlordiazepoxide was discontinued, we re- or diazepam might result in seizures and corded follow-up observations for the remainder of delirium (Browne & Hauge, 1986; Kantor, 1986; hospitalization. One patient was admitted for detoxi- Zipursky et al., 1985). None of our patients manifested fication only and was discharged without symptoms seizures, delirium, or psychosis. None of them left 2 days after stopping chlordiazepoxide. Another pa- treatment during the taper, and all of them completed tient was asymptomatic for 5 days but then left against the taper without difficulty. In short, we did not ob- medical advice before completing the rehabilitation serve evidence for a lack of cross-dependence between program because of a relationship conflict. The other alprazolam and chlordiazepoxide in our six patients. 322 M. H. Glosser and K.J. Bro wer

The early reported failures with diazepam (Zipursky two important advantages. First, it allows for individ- et al., 1985) and chlordiazepoxide (Kantor, 1986) may ual differences, and we found a wide range of substi- have resulted from drug interactions, insufficient dos- tution ratios (Table 1). Second, patients do not always ing, or coexisting diagnoses. We are aware of only know or reliably report how much alprazolam and three cases in the literature in which chlordiazepoxide other they are taking. Indeed, our patient was substituted for treating alprazolam withdrawal who suffered a seizure when we attempted reduction (Albeck, 1987; Juergens &Morse, 1988; Kantor, 1986). without chlordiazepoxide substitution later told us she In the case reported by Kantor (1986), a dose of 150 mg took twice the daily dosage that she reported on ad- did suppress withdrawal symptoms from a daily 2-mg mission. Providing nursing staff with the discretion to dose of alprazolam, but the authors were then unable administer “as-needed” doses allows for necessary, up- to taper the chlordiazepoxide because of “severe agi- ward adjustment of dosing in a timely fashion. Doses tation and crippling back spasm.” They eventually were withheld if patients showed signs of toxicity such substituted diazepam and tapered it over 19 weeks. A as drowsiness, , slurred speech, double vision, diagnosis of major depression and concurrent phen- and . Thus, our procedure prevented both elzine administration may have complicated this case. over- and undermedication problems, as we carefully Albeck (1987) substituted 300 mg of chlordiazepoxide titrated the dosage according to individual need. for a daily consumption of lo-35 mg of alprazolam, We were hesitant to employ the higher (50: 1) sub- and the patient remained tremulous with tachycardia, stitution ratio of chlordiazepoxide to alprazolam in our high blood pressure, diaphoresis, vomiting, formica- elderly patient (case l), because the patient’s age raised tion, and headache. This was an insufficient chlordi- concerns about the accumulation of a long-acting med- azepoxide dosage compared with our cases. Eventually, ication (Closser, 1991). Although we conservatively 10 mg of clonazepam was substituted successfully, employed a 25: 1 substitution ratio, our patient ulti- which has two to four times the of alprazo- mately required a 5O:l substitution ratio after we lam (American Psychiatric Association, 1990; Smith included the “as-needed” doses in our calculation (Ta- & Seymour, 1991). Finally, Juergens and Morse (1988) ble 1). Interestingly, we did not find a significant cor- used chlordiazepoxide successfully over a 7-day period relation between age and substitution ratio (rs = in a patient who was taking 8 mg of alprazolam, but -0.43, p = 0.40). they did not report chlordiazepoxide dosage. Our cases were confined to inpatients whose daily One milligram of alprazolam is generally considered alprazolam dosage ranged from 2 to 6 mg. We cannot equivalent to 20 or 25 mg of chlordiazepoxide (Amer- recommend this procedure for outpatients at this time, ican Psychiatric Association, 1990; Smith & Seymour, nor do we know if our substitution ratios apply to pa- 1991). This 20-25 : 1 ratio contrasts with our mean sub- tients taking more than 6 mg of alprazolam daily. In stitution ratio of 86: 1, but it is closer to the 100: 1 ra- the substitution and taper method of Smith and Sey- tio published by Harrison et al. (1984). Nevertheless, mour (1991), a maximum daily dosage of 500 mg of Harrison et al. (1984) recommended substituting di- (the equivalent of about 420 mg of azepam in a loading dose that was 40% of reported chlordiazepoxide) is recommended, regardless of the daily consumption, which amounts to a 40: 1 ratio in sedative amount the patient used. chlordiazepoxide equivalents. Only 1 of 23 patients in Our mean follow-up period (2 weeks) was too short their case series was alprazolam-dependent, and the au- to observe the full course of withdrawal (2-4 weeks) thors did not specify if that case was successfully to determine relapse rates and to rule out completely treated or 1 of the 4 patients who left against medical a recurrent panic disorder in need of further treatment. advice within 6 days (Harrison et al., 1984). Smith and Nevertheless, withdrawal symptoms do peak, and Seymour (1991) observed that their conversion factors alprazolam-related seizures occur, within 2 weeks of (25 : 1 for chlordiazepoxide to alprazolam) might be discontinuation (American Psychiatric Association, low when treating alprazolam withdrawal. We suspect 1990; Warner et al., 1990). Moreover, our immediate that higher ratios are needed when substituting chlor- outcomes were favorable in contrast to previous re- diazepoxide for alprazolam for the purpose of a rapid ports of chlordiazepoxide substitution (Albeck, 1987; taper, because steady-state concentrations of chlordi- Kantor, 1986). Finally, all inpatients require contin- azepoxide are not achieved by the time chlordiazepox- ued monitoring for diagnostic and treatment purposes ide tapering begins (l-2 days after its substitution). following discharge. Another limitation of our retro- Smith and Seymour (1991) argued against “as- spective study was the lack of structured rating scales needed” dosing in order to avoid drug-seeking behav- for withdrawal symptoms, which made it difficult to ior by sedative-dependent patients. One could argue distinguish withdrawal symptoms from symptoms of that the higher ratios required by our patients resulted a recurrent . 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