Treatment of heroin addicts using buprenorphine.

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AM. J. DRUG ALCOHOL ABUSE, 17(2), pp. 119-128 (1991)

Treatment of Heroin Addicts Using Buprenorphine Thomas R. Kosten, MD Charles Morgan, MD Herbert D. Kleber, MD Substance Abuse Treatment Unit Psychiatry Department Connecticut Mental Health Center Yate University School of Medicine New Haven, Connecticut 06579

ABSTRACT Thirty-nine opioiddependent outpatients were treated with the partial agonist buprenorphine at 2 to 6 mg/day for 1 month. Treatment retention was good (72%). and illicit opioid use decreased from 50% overall to 17% for those who remained in treatment. Precipitated withdrawal symptoms were mild and related to dose of buprenorphine. At the end of this month, 28 subjects were abruptly discontinued from buprenorphine and given the antagonist naltrexone. Withdrawal symptoms from buprenorphine were quite mild, and naltrexone was initiated in 20 patients (51 % of total or 71 % of those 28 completing 30 days on buprenorphine), but only 4 patients (10%overall) were successfully maintained on naltrexone for at least 2 weeks.

INTRODUCTION Pharmacologic treatment strategies for heroin addiction currently employ two general approaches: detoxification followed by drug-free abstinence or maintenance on an opioid antagonist; and maintenance treatment with an opioid agonist [l-51. Since agonist maintenance with methadone usually has the goal of eventual detoxification to a drug-free state, transition from methadone or heroin to either drug-free or antagonist treatment is a clinically important treatment strategy. Transition to antagonists, such as naltrexone, has been clinically difficult using

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the current detoxification techniques of either methadone dosage tapering or clonidine substitution [ 1 , 2, 41. Naltrexone introduction needs to be delayed to allow for an adequate opioid-free interval, during which physical dependence will be lost, in order to avoid precipitating withdrawal [5, 61. Typically, 10 to 14 days must intervene between the last opioid agonist dose and the first naltrexone dose in order to avoid precipitating withdrawal [5]. To decrease this long opioid-free period, during which relapse to drug abuse is likely, we have explored the early introduction of opioid antagonists [7-91. While pure antagonists like naltrexone precipitate substantial withdrawal even at very low doses [6-91, another strategy is to introduce a partial opioid agonist that could precipitate mild withdrawal, while at the same time minimizing these symptoms by its agonist activity. This strategy has not been feasible with previously available partial agonists such as pentazocine, cyclazocine, butorphanol, or nalorphine, since they precipitate significant withdrawal in morphine-dependent patients and may cause psychosis in some patients [lo-141. However, the partial agonist, buprenorphine, showed therapeutic promise because of early work indicating that it did not precipitate significant withdrawal in methadone- or morphine-dependent patients [ 16-20]. Furthermore, chronic administration of buprenophine produced minimal withdrawal symptoms when it was stopped [20, 211. Because of these properties, we examined whether buprenorphine might facilitate the transition from opioid agonists to antagonists in a three-step process: 1) buprenorphine substitution for the agonists methadone or heroin, 2) buprenorphine stabilization for 30 days, and 3) abrupt discontinuation of buprenorphine with rapid introduction of naltrexone.

METHODS A. Subjects and Ratings Thirty-nine opioid dependent patients (by DSM 111-R criteria) were entered into a month-long outpatient protocol. The patients included 30 males and 9 females who had a mean age of 30 (k SEM 1) years. Twelve patients came from methadone maintenance at a dose of 25 mg/day, and the other 27 patients were using street heroin. The 12 patients leaving methadone maintenance were all being administratively detoxified for noncompliance with treatment. When they had been tapered down to 25 mg of methadone, it was held at this dosage for 2 weeks, and buprenorphine was offered as an alternative to the usual detoxification of continued tapering of methadone dosage. For those using heroin, opioid addiction


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was confirmed using urine toxicology and challenge with naloxone at 0.8 mg intramuscularly [4, 221. To qualify for inclusion these heroin users had both to meet DSM 111-R criteria for opioid dependence and to attain a withdrawal score above 35 on our cIinician rated scale within 15 minutes of naloxone injection [4, 19, 201. The outpatient withdrawal rating scale includes 24 items with 0-3 point severity ratings and has a score range of 0 to 72. An item score of 3 indicates “severe” withdrawal, and total scores less than 20 indicate minimal withdrawal. The scale includes the following 24 items: loss of appetite, sweating, difficulty sleeping, chills, hot flashes, restlessness, low energy, irritability, stomach cramps, nausea, vomiting, feeling ‘‘blah,” diarrhea, joint pains, muscle pains, tremor, drowsy, runny nose, tearing, craving, yawning, dry mouth, sneezing, and palpitation. Because several scale items were not relevant to a 15-minute period during acute withdrawal (e.g., difficulty sleeping, low energy, loss of appetite), three additional items were assessed for acute withdrawal: dilated pupils, piloerection, and a systolic blood pressure rise of at least 10 mmHg. During this 30-day outpatient trial, withdrawal symptoms were rated daily by a clinician, and urine toxicologies were obtained twice weekly on a randomized schedule. Breath analysis for alcohol was done as clinically indicated by a history of alcoholism (n = 3, see Results) or by intoxication at the time of administering the daily medication.

B. Study Design Patients starting buprenorphine treatment were discontinued from either methadone maintenance or street heroin, and within 24 hours of their last dose were started on sublingualbuprenorphine at 2 mg. After the first 2 days, patients were assigned to fixed dosages of buprenorphine as follows: 2 mg (n = 16), 3 mg (n = 14), 4 mg (n = 6), 6 mg (n = 3). The number of methadone and heroin patients were equivalently distributed across buprenorphine doses with the 2-mg group having 5 methadone and 11 heroin patients, the 3-mg group having 4 methadone and 10 heroin, the 4-mg group having 2 methadone and 4 heroin, and the 6-mg group having 1 methadone and 2 heroin. This was an open trial with single daily dosing 7 days a week for 30 days, following which the buprenorphine was stopped. Naltrexone was given 24 hours after the last buprenorphine dose and was started at 1 mg orally followed by 6, 12.5, 25, and 50 mg on successive days. In the majority of patients we used this low dose gradual induction onto naltrexone because of fears of precipitating severe withdrawal from buprenorphine by the naltrexone. However, minimal withdrawal was precipitated, and in order to assess acutely the full buprenorphine withdrawal syndrome, the last

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5 patients who completed a month of buprenorphine received high dose naloxone (0.5 mg/kg intravenously) before starting naltrexone [23, 241.


RESULTS During the 30-day outpatient protocol, patients showed good retention and reduced illicit opioid use. Out of the 39 entrants, 28 patients (72%)came in daily and completed this protocol. The mean stay was 25 (SD = 8) days, and retention was similar for patients coming from either street heroin (74% retention) or methadone (66% retention). Most patients had mild withdrawal symptoms when started on buprenorphine, but this declined over the first 2 weeks on buprenorphine. The mean score on the 72-point scale was 18 (SD = 15) at Day 2 and had declined to 11 (SD = 9) by Day 14 and to 9 (SD = 8) by Day 20. Although 3 of 11 dropouts were unrelated to illicit drug abuse (e.g., unexpected job transfer), the percentage of illicit opioid urines was greater among the 11 who dropped out (56 % ) than among those who remained in treatment (27 %) (t = 2.6, P < .02), and there was an inverse correlation between days in treatment and percentage of illicit urines ( r = - .34, P < .03) (higher rate of illicit urines with fewer days in treatment). Illicit opioid use declined from 50%of urines in Week 1 (33% for the patients completing treatment) to 17% in Week 4 for those completing 30 days of buprenorphine, and for the dropouts illicit opioid use remained at 50% of urines through Week 3, and both dropouts in Week 4 were using illicit opioids. Illicit opioid usage was not related to dosage of buprenorphine, however, as shown in Table 1. Abuse of other drugs was also relatively common among these patients. Alcohol was regularly used (more than 20 out of the last 30 days before starting this study) by 9 patients (23%), and 3 (8%) reported being intoxicated more than 2 days over the same 30 day period. These 3 patients also met DSM III-Rcriteria for alcoholism. Benzodiazepine use during the month before the study was reported by 8 patients (20%),but only 2 used the drugs more than once ( 5 % ) . None met DSM 111-R criteria for sedative dependence. Cocaine abuse was quite common among these patients, with 20 (51%) reporting any use over the month before this study, and 14 (35%) meeting DSM III-R criteria for cocaine dependence. Half of the 12 post-methadone patients had cocaine positive urine toxicologies during the month before this study. While abuse of alcohol or benzodiazepines did not change during this study, illicit cocaine use was dramatically reduced, as described elsewhere [25, 261. Overall success among the 39 patients, as also shown in Table 1, was 5 1% (n = 20) for taking at least one 6-mg dose of naltrexone, but only 10% (n = 4)


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Table 1. Sample Characteristics and Global Outcome by Maintenance Dose of Buprenorphine ( n = 39)a ~~

~

Buprenorphine dose 2 mg

3 mg

4, 6 mg

Sample size

16

14

9 ( 6 , 3)

Males (%)

69

19

89

77

Age (years f SD)

31 (7)

29 (6)

31 (7)

30 (7)

Post-methadone (X)

31

30

33

31

Outcomes: Stay 30 days (56) Opiate use (X) Take naltrexone (96) Naltrexone > 2 weeks (96)

63 37 50 6

70 27 50 22

89 43 56 0

12 34 51 10


Characteristic

All 39

aNo differences were statistically significant.

for naltrexone maintenance beyond 2 weeks. Among those 28 patients who completed 30 days on buprenorphine as outpatients, 71 9% (20/28) took at least one 6-mg dose of naltrexone. An interesting observation among the 5 patients given the high dose naloxone (0.5 mg/kg) was that 2 were given naltrexone at maintenance doses (50 mg, rather than the usual induction starting with 1 mg of naltrexone) the day after the naloxone without precipitating opioid withdrawal ~31. Demographic comparisons and overall outcome for the various maintenance dosages of buprenorphine are shown in Table 1. While the initial 2 weeks on buprenorphine appeared to be affected by dosage, as described below, overall outcome showed little effect of dosage. None of the outcomes, including retention for 30 days, percentage of urines positive for illicit opioid use, taking at least one dose of naltrexone, and being maintained on naltrexone for at least 2 weeks, was significantly different among the dosage groups. The relationship of withdrawal symptoms to previous types of addiction (heroin vs methadone) (DRUG TYPE)and to maintenance doses of buprenorphine (DOSE) during the course of the trial was examined by first comparing maximum withdrawal symptoms across the four doses. Maximum withdrawal was significantly associated with dose (F = 6.1; df = 3,38; P < .002):2 mg, 16 (SD = 11); 3 mg, 34 (SD = 15); 4 mg 29 (SD = 9); 6 mg, 18 (SD = 8). The 3 and 4 mg groups significantly differed from the 2-mg group in their levels of maximum


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withdrawal, but the 6-mg group did not differ from the 2 or 4 mg groups, probably due to its small sample size and relatively large standard deviation. Using repeated measures analyses of variance on withdrawal ratings from Days 2, 5, 8, 11, 14, 17,20,23,26, and 29, withdrawal symptoms for the three buprenorphine DOSE groups were quite similar beyond Week 2, but significant time by DOSE effects were found up to day 14 (F = 5.4; df = 10,165; P < .OOOl). The 2-mg group showed very little symptom change over the first 2 weeks, while the 3 and 4 mg groups showed significant declines in symptoms, as shown in Fig. 1. The 6-mg group showed a pattern very similar to the 2-mg group, but the small number of subjects makes this finding uncertain.There was also a significant time by DRUG TYPE effect (F = 2.7; df = 5,165; P < .02), as shown in Fig. 2. Withdrawal symptoms remained elevated through Day 8 for the methadone patients, while these symptoms steadily declined for the heroin patients.

DISCUSSION This study showed that heroin addicts or methadone maintained patients can be transferred onto the partial opioid agonist buprenorphine for a l-month outpatient program with good retention and a reduction in illicit opioid use. The retention rate of 72 % at 1 month compares favorably to either naltrexone or methadone maintenance in our clinical programs. The l-month retention in our methadone program, which treats over 500 patients per year, was 75 % last year, while naltrexone retention was 50% at 1 month. This naltrexone retention is comparable to national statistics from a number of treatment sites that have reported outcome since 1973 [5]. Illicit opioid use showed a substantial decline, as expected from the known pharmacology of buprenorphine. However, the other drugs commonly abused by these patients-alcohol, benzodiazepines, and cocaine-generally showed little change from baseline levels of abuse. Cocaine was a notable exception to this pattern and showed a marked reduction in abuse [25, 261. For the first 2 weeks of taking buprenorphine, some patients had mild to moderate withdrawal symptoms, but these symptoms may respond to alterations in initial dosing, since they were related to both dose of buprenorphine and type of previous opioid dependence (e.g., post-methadone versus heroin). The postmethadone patients had mild withdrawal symptoms for about 3 days longer than the post-heroin patients’ symptoms (Days 5 to 8 ), but for both types of patients this initial withdrawal was dose related. Withdrawal symptoms at initiation of buprenorphine treatment were fewest with the lowest dose (2 mg), and at the higher doses a pattern of declining withdrawal symptoms was shown over the

TREATMENT OF HEROIN ADDICTS USING BUPRENORF'HINE

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30

z

25

0


c

*

u)

20

-

15

4

2 U

10

6

0

5

5

5

0 2

5

8

11

14

Days on Buprenorphine Fig. 1. Plot of opioid withdrawal symptoms over first 14 days for patients maintained on buprenorphine at 2 mg (open circles) (n = 16). 3 mg (filled circles) (n = 14), 4 mg (gray squares) (n = 6) or 6 tug (open squares) (n = 3). The mean scores kSEM are plotted.

30 25

1

Methadone

-r

0

; 20 *

C

u)

-

15

E

10

z

5

0

U 5

Heroin

0 2

5

8

11

14

Days on Buprenorphine Fig.2. Plot of opioid withdrawal symptom over first 14 days for patients coming from either methadone maintenance (lilled circles) (n = 12) or street heroin (opencircles) (n = 27) and maintained on buprenorphine at doses of 2 to 6 mg daily. The mean scores *SEM are plotted.


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first 2 weeks of treatment. Beyond 2 weeks, no differences were evident among the four doses, and dosing may be quite similar to that with methadone maintenance in which wide individual variations are common during maintenance treatment [27]. Overall, based on the good retention, minimal initial withdrawal, and limited illicit drug use,buprenorphineclearly holds promise as a treatment agent for opioid addicts. We were surprised that dose was not associated with any outcomes except initial withdrawal symptoms, since we expected differences in rate of illicit opioid use and in response to rapid naltrexone induction. We had expected some decreased illicit opioid use among the higher dose patients, because previous experimental inpatient work had found that at higher doses, subjects stopped self-administering heroin [17, 191. Several factors may have contributed to our inability to find a dose-response relationship between buprenorphine and illicit opioid use. Two factors in the design were the use of an outpatient setting and nonblinded dosing, which both increase uncontrolled influences on illicit drug use of various types. We also used relatively lower buprenorphine doses than did MeUo and Mendelson [17, 191 who had found decreases with parenteral doses of 4 and 8 mg daily. Sublingual dosing, as we used it, appears to yield only half the blood levels of the parenteral route, suggesting that 8 to 16 mg may have been needed to more closely replicate this previous study and show a substantial dose effect [18, 20, 211. In a previous paper we presented some pilot findings including patients given 8 mg sublingually,but these two patients showed no substantive reduction in opioid abuse beyond that of the patients treated with 2 mg daily [28]. This lack of a dosage effect in our studies contrasts not only with the inpatient experiments of Mello and Mendelson, but also with a small (n = 5 ) outpatient study by Bickel et al. using a “within subjects” design and sublingual dosages ranging from 2 to 16 mg [29]. Thus, further outpatient examination of dosage effects using double blinded procedures is indicated. As regards discontinuation of buprenorphine, although successful induction onto naltrexone appeared to have little relationship to buprenorphine dose, this study supports previous work indicating that buprenorphine withdrawal may be substantially less severe than withdrawal from pure agonists such as methadone [ 11-17]. Since a major problem with methadone maintenance treatment for opioid abuse has been the continuation of substantial withdrawal symptoms following attainment of a drug-free state, buprenorphine may offer a method for minimizing the withdrawal symptoms that follow detoxification from maintenance treatment [ l , 301. An important part of our approach was an abrupt discontinuation rather than a gradual tapering of the buprenorphine, because even with abrupt discontinuation, the long action of buprenorphine may facilitate its leaving the



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body gradually, resulting in a mild withdrawal syndrome [20]. The problems with outpatient dosage tapering of buprenorphine were indicated in a study by Bickel et al. [31] in which buprenorphine dosage was gradually tapered over 3 weeks, and illicit drug use steadily increased along with mounting withdrawal symptoms. Tapering the dose may have in fact prolonged the withdrawal syndrome, and more rapid detoxifications are usually more successful for naltrexone induction [5-91. In summary, stabilization on buprenorphine from methadone or heroin dependence by using doses as low as 2 mg sublingually has been reasonably successful, as has been abrupt discontinuationof buprenorphine. Most (71 %) of the patients completing the month on outpatient buprenorphine took at least one 6-mg dose of naltrexone without experiencingwithdrawal (the other 29% refused naltrexone), and this induction process may be further improved by starting with a high dose naloxone challenge before naltrexone induction. Continuation on naltrexone raises separate issues not solved by this technique.

ACKNOWLEDGMENTS Support was provided by the National Institute on Drug Abuse Career Scientist Development Award K02-DA00112 to TRK and Center Grant P5O-DA04060. We thank the nursing staff of the Outpatient Services of the Substance Abuse Treatment Unit.

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Implosive therapy treatment of heroin addicts during methadone detoxification.

Prediction of successful response to multimodality treatment among heroin addicts.

Contingency contracting with heroin addicts.

Sleep quality in heroin addicts under methadone maintenance treatment.

Inflammatory response in heroin addicts undergoing methadone maintenance treatment.

Moods and biorhythms of heroin addicts.

Career dynamics of female heroin addicts.

Manifest psychological needs of heroin addicts.

Plasma cholesterol and triglycerides in heroin addicts.

Cocaine abuse among heroin addicts in Spain.

Plasma gamma-glutamyl transpeptidase in heroin addicts.

Smooth muscle antibody in heroin addicts.

naloxone in buprenorphine-maintained heroin users.

Follow-up of a representative sample of heroin addicts.

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Problems of adjustment reported among a group of heroin addicts.

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