- Email: [email protected]
Ultra-rapid opiate detoxification using deep sedation with oral midazolam: short and long-term results
Drug and Alcohol Dependence 52 (1998) 243 – 250
Ultra-rapid opiate detoxification using deep sedation with oral midazolam: short and long-term results Anne The´re`se Cucchia, Martine Monnat, Jacques Spagnoli, Franc¸ois Ferrero 1, Gilles Bertschy1 * De´partement Uni6ersitaire de Psychiatrie Adulte, Site de Cery, 1008 Prilly-Lausanne, Switzerland Received 5 August 1997; received in revised form 1 May 1998; accepted 19 May 1998
Abstract The present study describes an ultra-rapid opiate detoxification method using direct transition from heroin or methadone to oral naltrexone after deep sedation with oral midazolam in conjunction with ondansetron and clonidine treatment. Twenty patients were detoxified with the method. No serious events occurred, but two out of three patients vomited during the acute phase of deep sedation, which involves some risks. Withdrawal symptoms were still present 24 h after detoxification and 80% of the patients relapsed during a 6-month follow-up. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Opiate detoxification; Midazolam; Naltrexone
1. Introduction Procedures to detoxify heroin addicts using opiate antagonists under general anaesthesia or deep sedation have been published in the recent years by groups in Vienna (Loimer et al., 1989, 1991, 1993) and Seville (Legarda and Gossop, 1994). These first reports were very optimistic and have been confirmed by more recent publications (Bartter and Goobermann, 1996; Brewer et al., 1996; Seoane et al., 1997). The potential advantages of the method are: The acceleration of withdrawal by displacing agonists from opioid receptors allows shorter hospitalization of patients, probably at lower costs. An improvement in the patient’s acceptance of withdrawal during the early phase of the treatment; this improvement comes from better subjective comfort, due to deep sedation and perhaps amnesia. * Corresponding author. Tel.: +41 22 3054766; fax: + 41 22 3054769. 1 Present address: Clinique de Psychiatrie II, Belle-Ide´e, Chemin du Petit-Bel-Air 2, 1225 Cheˆne-Bourg, Switzerland.
The maintenance on the opiate antagonist naltrexone from the very first stage of the treatment: inasmuch as it is used after detoxification, naltrexone may provide a useful protection again relapse. Before, what is labelled now as ultra-rapid opiate detoxification (UROD), various attempts were made to speed up the detoxification process. Given that opiate antagonists can displace opiate agonists from receptor sites, it was appropriate to think that a shortening of withdrawal could be obtained by progressively introducing an opiate antagonist during the very first days of detoxification. The first trials were performed with naloxone alone (Resnick et al., 1977) or in association with symptomatic medications (Kurland and McCabe, 1976; Resnick et al., 1977). As clonidine demonstrated its efficacy to reduce the intensity of opiates withdrawal symptoms (Gold et al., 1978; Charney et al., 1981), some authors used naloxone in combination with clonidine (Riordan and Kleber, 1980; Masini et al., 1981; Kleber, 1996). But it seemed easier to use naltrexone, which can be given orally in association with clonidine (Charney et al., 1982). Then, higher doses of naltrexone were introduced from the first day and
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00100-8
244
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
benzodiazepines, which can also reduce opiate withdrawal symptoms efficiently (Drummond et al., 1989), were added. By doing so, withdrawal could be completed in 4–5 days (Charney et al., 1986) and even 2–3 days (Brewer et al., 1988; Vining et al., 1988). Loimer et al. (1989) went further with naloxone; claiming that precipitation of withdrawal symptoms in rats could soon be followed by attenuation, they wondered whether withdrawal symptoms during detoxification treatment of opiate addicts could be suppressed by continuous administration of naloxone. They gave six opiate addicts 10 mg naloxone under short anaesthesia with methohexitone, followed by repeated doses of 0.4 mg/h naloxone for 72 h. They considered that their results clearly supported their initial hypothesis. In a subsequent work, they reported similarly optimistic results for seven patients on methadone with a slightly different method (Loimer et al., 1991). Patients were no longer anaesthetized but only deeply sedated with intravenous midazolam and woken with flumazenil. After awaking, naltrexone was substituted for naloxone. The same author (Loimer et al., 1993), described another method tested among 20 heroin sniffers or smokers. Midazolam was administered orally (60 mg) in association with clonidine (0.3 mg), which was not used in previous work. They also used ondansetron (5.0 mg), a 5 HT3-antagonist, to diminish vomiting and abdominal cramps which were not mentioned in the previous reports. Opiate antagonists consisted of 4 mg of naloxone administered intranasally as a spray and, 10 min later, naltrexone 50 mg orally. Again, the results were reported as very successful. Legarda and Gossop (1994) reported a yet slightly different method of direct naltrexone transition (without naloxone use) administered to 11 heroin addicted patients. Midazolam and guanfacine (which was substituted for clonidine) were administered intravenously in association to ondansetron (5.0 mg) and loperamide (4 mg, to prevent diarrhoea) orally. The very optimistic results of the pioneer work have been confirmed by recent studies using sedation with phenobarbital alone or in combination with diazepam (Bartter and Goobermann, 1996) or propofol and midazolam (Seoane et al., 1997). The only shadow cast on these enthusiastic data was the publication of a case of impaired oxygen saturation and bradycardia during UROD (San et al., 1995). A naloxone-related change in the permeability of the capillaries in the lung was suggested as the possible source of the problem. In this paper we report on our own experience with UROD, in terms of feasibility and safety, with improvements to simplify the method and make it less invasive: direct transition from agonist to naltrexone without the intermediate use of naloxone and oral administration of midazolam. Given the known limitations on indications for naltrexone among opiate dependent patients (Gon-
zalez and Brogden, 1988), it seemed interesting to examine long-term results of UROD and UROD-induced naltrexone maintenance. Thus, data about a 6-month follow-up are also reported.
2. Method
2.1. General design Twenty patients were withdrawn from opiates with an UROD procedure as described below. Treatment protocol was only partially standardized as some modifications were implemented as we became more experienced. Except for the first patient, clinical and therapeutic data were collected during the first 24 h according to a structured data collection plan. A 6month follow-up was carried on in co-operation with the GP and/or the therapeutic centre to obtain data about clinical evolution.
2.2. Population study Twenty patients were withdrawn from opiates with UROD procedure (12 men, eight women; age range: 18–33). All were opiate dependent for at least 1 year (range 1–15; mean9 S.D.: 6.594.8 years). Seventeen patients followed methadone maintenance treatment (mean methadone dose9 S.D.: 34.89 20.8 mg). Three of them used heroin intermittently, four used it regularly and three patients were heroin-dependent without methadone substitution. Among the seven daily users of heroin, the frequency of heroin intake was once or twice daily (intravenously for the seven patients) for a total estimated daily dose in the range 1–1.5 g. At the time of UROD, no patient had a problem with cocaine and only one patient occasionally took too much alcohol. Two patients intermittently used benzodiazepines and three others were dependent upon these drugs. Seven patients had a job or were in professional training (n= 3). Four patients had a borderline personality with antisocial traits disorders (DSMIII-R). All the patients involved applied specifically for the UROD method as an alternative to the classical method: all had experienced outpatient detoxification and 12 of them had at least one experience of in-patient detoxification (including eight patients who had tried three times). All the candidates were personally examined by a senior psychiatrist (G.B.) to exclude patients with no clear motivation. Some patients were excluded without any direct meeting, but a phone contact with them or their physicians. Not all phone contacts were recorded. We estimate that only about half of them resulted in UROD: two-thirds of the excluded patients were refused on the basis of a phone call, one third after the clinical evaluation.
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
The indications for UROD were detoxifications before admission in a therapeutic community (n = 4), a long lasting stay abroad (n =4) or transition to a naltrexone outpatient treatment (n =12).
2.3. Ultra rapid opiate detoxification procedure Patients were admitted to our hospital at 07:30 h with an empty stomach. In the preceding days a physical examination, an electrocardiogram and laboratory testing (blood count, electrolytes, urea, creatinine, transaminases) were performed. UROD was then initiated by simultaneous oral administration of: clonidine 0.300 mg, midazolam 45–120 mg (the dose was empirically determined taking into account the severity of opiate dependency and the experience of the subject with benzodiazepines; the 45 mg dose was only used for the first patient who was taking only 6 mg methadone per day); ondansetron 8 – 16 mg (the first patient received cisapride and not ondansetron; with experience we have increased the initial dose of ondansetron given the occurrence of vomiting and diarrhoea); loperamide 4–16 mg (for ten patients) or butylscopolamine 20 – 40 mg (for nine patients) to try to reduce diarrhoea and abdominal cramps. Fifteen to forty minutes later, as the patient showed the first signs of sleepiness (it sometimes took more time and additional oral doses of midazolam; the maximum total midazolam for one patient was 240 mg, the mean dose was 136 957 mg), the patient was given naltrexone 50 mg. Thirty to sixty minutes later, the patient entered the most acute phase of the withdrawal for 2 – 4 h. During this and the initiation phase, he was under close supervision by a nurse and a physician. Cardiac activity and oxygen saturation were permanently monitored (if the patient was not very agitated during his sleep). Blood pressure was controlled every half hour. Oxygen therapy by mask, broncho-aspiration and tracheo-intubation material were available in the room (usually used for electroconvulsive therapy) and the physician on duty, although not an anaesthetist, had been trained to use them. Four to five hours after initiation, as the patient become calmer and withdrawal symptoms decreased, he returned to his room. He remained under constant nursing attention until he spontaneously awoke for sufficient time (sometimes between 6 and 10 h after the initiation). When the patient showed excessive global or specific withdrawal symptoms, additional medications were given by mouth. If he awoke during the first acute phase, additional midazolam was delivered (if he was not awake enough for safe oral ingestion, midazolam was replaced by sublingual lorazepam). In case of vomiting or abdominal cramps ondansetron and/or butylscopolamine was administered by intramuscular injection. During the first 24 h, the mean (9S.D.) medication
245
received by the patients were as follows: clonidine 0.529 0.66 mg, benzodiazepines 1189 mg diazepam equivalent (using the equivalences 10 mg diazepam=4.5 mg bromazepam= 1.5 mg lorazepam= 10 mg midazolam) and ondansetron 28912 mg. Patients left hospital 36 h after admission with a prescription for low-dose clonidine and benzodiazepines for 2–3 days and naltrexone 50 mg/day. Five patients remained hospitalized for a longer period, as had been planned before admission. The reasons were: admission to a therapeutic community 3 days later (two cases), admission to benzodiazepine withdrawal program (two cases) and associated depression (one case). The latter three patients, as well as another patient, were personally treated by one of us (G.B.) on an outpatient basis, after discharge. Four patients were admitted in a therapeutic community, four patients left the country for a long stay abroad (range 1–4 months) with a planned follow-up by their GP upon their return. The other eight patients too were personally treated by their general practitioners. All these physicians were experienced in the field of addiction. During the post-discharge period, we were informed on all the patients’ progress either by direct contact or through their doctors or their therapeutic centres. Outpatient ongoing treatment differed according to the settings. It consisted mostly of a 2–3 times a week therapeutic contact for the first weeks and then of a 2–4 times a month contact. Naltrexone intake was not systematically done under supervision.
2.4. First 24 h measures At the times t= 0 (t=0 being initial clonidine and midazolam administration) t= 30, 60, 90, 120, 150, 180, 210, 240 min and then t= 5, 6, 8, 10, 12, 16, 18, 24 h, the following clinical data were collected: blood pressure, pulse rate, patient asleep or awake, withdrawal score using a 13-items symptoms check list rated by a nurse (item present =1 point, absent= 0 point; score range= 0–13) including the following objective items, running eyes, running nose, ‘gooseflesh’, sneezing, agitation, mydriasis, sweating, yawning, myoclonia and the following subjective items, abdominal cramps, backaches, hot and cold flashes and anxiety. Subjective items were not collected if the patient was sleeping. This could lead to moderately higher scores among patients who were awake. The ability to fall or remain asleep during the sedation procedure and the following night depended upon the ability of the procedure to diminish withdrawal symptoms. Such a design increased the sensitivity of the instrument to discriminate between patients who could sleep and those who could not sleep, i.e. situations in which withdrawal symptoms were well controlled and situations in which withdrawal symptoms were not well controlled. Any special incidents (such as vomiting, diarrhoea) were also registered.
246
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
2.5. Six-month follow-up Using contact with the GP and/or therapeutic community staff and, if needed, with the patient, the occurrence or not of a relapse and its timing during the following 6 months were documented.
2.6. Statistical methods Descriptive statistics are used to set forth results. For the evolution of the withdrawal score comparisons are made between one time point and another time point using Wilcoxon matched-pairs signed-ranks test.
2.7. Ethics After four preliminary cases, the project was submitted to and approved by the Ethic Committee of the Faculty of Medicine of Lausanne. After thorough information, patients had to give their written consent.
3. Results
3.1. UROD procedure and 24 h progress No serious adverse event occurred during UROD. One patient showed no signs of withdrawal during the first 4 h. She slept continuously and very quietly for 4 h as no other patient did. She awoke and remained very still for 20 min. Then she began to present a full withdrawal syndrome which required a high dose of lorazepam. Our hypothesis for this delayed withdrawal is that the naltrexone tablet remained stuck somewhere in her oesophagus and that it only reached her stomach when she first awoke after 4 h and sat up in her bed. For patients dependent upon benzodiazepines (n=3) or intermittent users (n = 2) the dose of benzodiazepines during the first 24 h tended to be higher than for the other patients (n =15) (255953 mg of diazepam equivalent versus 1789 89 mg) without being statistically significant. The total withdrawal score curve (Fig. 1) showed a significant clear peak of intensity at 1 h, that is to say 30 – 45 min after naltrexone ingestion (Wilcoxon matched-pairs signed-ranks test: t = + 1 h compared with t=0; P B 0.001). After 1 h, the withdrawal score significantly decreased (t= + 1 h compared with t= + 4 h; PB 0.005), but it remained significantly higher than the base line score (t = 0 as compared with t = +5 h, t = + 12 h, t= + 20 h; P B 0.002). Cardiovascular tolerance was excellent. Figs. 2 and 3, respectively, present 24 h systolic and diastolic blood pressure (BP) curves. Systolic and diastolic BP remained constantly ]80 and 50 mmHg with two exceptions. One patient’s BP dropped to 75/55 mmHg at
Fig. 1. Twenty-four hour total withdrawal score (maximum potential score on the checklist: 13; number of patients n =19; mean 9 S.E.).
t= + 90 min and another patient’s BP dropped to 110/45 mmHg at t= + 20 h. In both cases the BP spontaneously increased after a few minutes without any medical intervention. No problem occurred with oxygen saturation. During the acute phase, patients alternated between long periods of sleep and short periods awake. At each clinical evaluation, the percentage of patients who slept was in the 50–85% range. During sleep, moderate agitation was often present and during periods awake confusion and moderate agitation were also present. Patients were just deeply sedated and even when asleep were able to react to stimulation It is probably because they were not under general anaesthesia that patients had no difficulties in being woken in case of vomiting. However, two out of three vomited and three out of four had diarrhoea during the first critical 4 h, and such problems were still present, although at a lower rate, for the rest of the day (Fig. 4).
Fig. 2. Twenty-four hour systolic blood pressure (number of patients n =19; mean9 S.E.).
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
Fig. 3. Twenty-four hour diastolic blood pressure (number of patients n=19; mean9 S.E.).
No systematic data were collected during the following days. Most patients complained at least of moderate withdrawal symptoms after 24 h and for 3 – 5 days. Digestive symptoms (anorexia, nausea, vomiting, abdominal cramps) and psychic symptoms (anxiety, depression) were often mentioned. One patient with a borderline personality made a serious suicide attempt on the fifth day, using the antidepressant his general practitioner had prescribed the same day.
3.2. Six-month follow-up Fig. 5 shows that the relapse rate reached 80% at the end of the 6 months and that three out of four relapses took place in the first month. We used a very broad definition of relapse. If we use a less restrictive one, distinguishing on the one hand lapses as intermittent heroin intakes with reintroduction of naltrexone maintenance and without resuming daily use or methadone maintenance, and on the other hand, relapses as daily heroin intake and/or resumption of methadone maintenance treatment, the rate of 6-months relapse is lowered to 60%. Nine patients received methadone substitution again.
4. Discussion No serious problem concerning cardio-vascular and respiratory functions occurred during UROD in agreement with previous reports (Loimer et al., 1991, 1993; Legarda and Gossop, 1994). However, vomiting occurred with a high frequency although we used a high dose of ondansetron which is usually considered effective in preventing vomiting (initial dose: 8 – 16 mg; mean dose (9 S.D.) during the first 24 h: 289 12 mg). This finding clearly is in disagreement with other re-
247
ports (Loimer et al., 1993; Legarda and Gossop, 1994). If no broncho-inhalation accident was observed in our deeply sedated patients, it was probably because the sedation was not sufficient. Although relatively high doses of midazolam were used, they hardly counterbalanced the very high level of arousal related to the naltrexone-induced withdrawal state. However, such a high rate of vomiting is not acceptable. We aim to improve the method to reduce vomiting. Stine and Kosten (1992) have suggested that buprenorphine might facilitate the transition from opioid agonists to an antagonist given that buprenorphine is a partial opioid agonist with mixed agonist-antagonist properties. So we are trying to switch UROD candidates from full opiate agonists to buprenorphine one week before UROD. Preliminary results concerning vomiting are very encouraging. General anaesthesia with gastric aspiration is probably another way to solve the problem of vomiting. Withdrawal symptoms appear to be still present 24 h after initiation of naltrexone and to disappear only after 3–5 days, requiring continued clonidine and benzodiazepines adjunctive treatment which brought clear relief to the patients. The lack of quantitative evaluation beyond 24 h is a limitation of our study. Since design of our study was based upon previous reports, we did not anticipate that withdrawal symptoms would continue for several days. However, even relying on patients’ and physicians’ verbal reports, our observations contrast strongly with the other optimistic reports about UROD (Loimer et al., 1991; Legarda and Gossop, 1994), or the report of compressed naltrexone-induced opiate withdrawal syndrome (Farrel and Strang, 1995). Loimer et al. (1991) found that oral administration of 50 mg of naltrexone during and after naloxone administration on the first day and on the following days did not lead to the reappearance of withdrawal symptoms. Using a scale with possible scores ranging from 0 to a maximum of 29, they reported score at 24, 48, 72, 96 and 120 h and the mean values were respectively 1.43, 1.28, 0.86, 0.86, 0.57. Legarda and Gossop (1994) also reported in response to the administration of 50 mg of naltrexone that the morning after detoxification there were no physical signs or subjective symptoms to indicate the presence of opiate withdrawal symptoms. In the Bartter and Goobermann (1996) study, four patients were detoxified by a procedure involving propofol induction, intubation and ventilation: all patients were completely detoxified within 4 h and showed no abstinence symptoms when they were given naltrexone upon waking up. Similarly, Seoane et al. (1997) report at discharge, 24 h after UROD initiation, an almost total absence of withdrawal signs and symptoms: using the same instrument as Loimer et al. (1991) they found a mean 24-h score lower than 1. How can such differences be
248
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
Fig. 4. Percentage of patients with diarrhoea and vomiting during each 4-h interval on the first day.
explained? Given the lack of fundamental difference between the methods, a more realistic observation in our study could be the main reason. An alternative hypothesis is to be considered systematically. As discussed below, naltrexone was not administered under professional supervision after discharge. Since the majority of patients were on methadone, a long-acting opioid, it is possible that without the continued administration post-detox of naltrexone, the opioid still in the body and the brain re-attached to the receptors and further withdrawal would then be precipitated as it gradually came off. Two facts do not support this hypothesis. Firstly, patients who received naltrexone after discharge, under professional supervision, also had persisting withdrawal symptoms. Secondly, all the patients received naltrexone on the second day and withdrawal symptoms were present as well in the hours preceding as in the hours following this naltrexone intake. The relapse rate at 6 months was very high (16 out of 20). The four ‘survivors’ at 6 months were one patient admitted into a therapeutic community (initial number n=4) and three patients switched from a methadone to naltrexone maintenance treatment (initial number n=4). All the patients detoxified before a long stay abroad relapsed in spite of clear recommendations about naltrexone use when they returned home. The relapse rate (80%) is as high as with the usual detoxification method (Gossop et al., 1989), despite naltrexone. It still remains high (60%) even if we discard lapses without complete relapses. Such results lead to less optimism than other reports about UROD (Legarda and Gossop, 1994; Seoane et al., 1997). To our knowledge, it is the first study showing results with a 6-month follow-up. However, the length of the follow-up does not per se explain our
high rate of relapse. If the 6-months relapse rate is 80%, at the first month relapse rate is already 60% compared with 0% in the Legarda and Gossop (1994) report (n = 20) and 7% in the Seoane et al. (1997) study. We do not really think that the difference could be related to differences in patients’ characteristics. Our sample was selected for motivation and did not include street heroin addicts or polydrug abusers with the exception of benzodiazepine-dependent patients. Unstable personality disorders were not very frequent and their presence did not influence the outcomes: the 6-month continuous remission rate among patients with and without borderline personality disorders are, respectively, 25% (n =4) and 19% (n = 16). The high level of side-effects during UROD procedure, particularly vomiting, might have played a role: such an aversive experience with naltrexone at the beginning of detoxification may have led to a negative conditioning about naltrexone compliance. The persistence of withdrawal symptoms for several days may also have negatively contributed to the outcomes. An important difference between our study on the one hand, and the Legarda and Gossop (1994) study and the Seoane et al. (1997) study on the other hand, is that naltrexone was not systematically administered under professional supervision and our patients were not as closely and intensively followed and monitored in the month after discharge as patients in the other studies. Should this difference play a role, future studies would need to focus on the question of the duration of such outpatient intensive care. This point could be of importance as Legarda and Gossop (1994) reported that 0% of their patients relapsed during the month, but that 90% have challenged naltrexone on one occasion.
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
249
Fig. 5. Six-month survival (abstinence) rate after UROD (n =20).
5. Conclusion Our study confirms the feasibility of UROD. No serious negative events occurred but our method is associated with a high rate of vomiting which could be the source of dangerous complications. We are trying to develop a new method to reduce it. Long-term results of our sample tempers the optimism of the available reports. In our opinion UROD is just a technique of detoxification. Its interest is its ability to attract patients reluctant to use classical methods. However, UROD per se could be of no real influence on the very important question of how to help patients to remain on naltrexone maintenance. More long-term studies are needed to explore this question further. Recently, Strang et al. (1997) suggested that this technique should only be used in clinical trials. UROD is probably already too widespread, yet further clinical trials are really needed.
Acknowledgements The authors wish to thank Dr D. Thorin, Department of Anaesthesiology, Lausanne, for his excellent advice and the anaesthesiology training.
References Bartter, T., Goobermann, L.L., 1996. Rapid opiate detoxification. Am. J. Drug Alcohol Abuse 22 (4), 489–495. Brewer, C., Laban, M., Schmulian, C., Kasvikis, Y., Gooberman, L., 1996. Rapid opiate detoxification and naltrexone induction under general anaesthesia and assisted ventilation: experiences with 265 patients in three different centres. Abstracts of the 8th Congress of Association of European Psychiatrists. Eur. Psychiatr. 11 (Suppl. 4), 313S. Brewer, C., Rezae, H., Bailey, C., 1988. Opioid withdrawal and naltrexone induction in 48–72 h with minimal drop-out, using a modification of the naltrexone-clonidine technique. Br. J. Psychiatr. 153, 340 – 343.
Charney, D.S., Sternberg, D.E., Kleber, H.D., Heninger, G.R., Redmond, D.E., 1981. The clinical use of clonidine in abrupt withdrawal from methadone. Arch. Gen. Psychiatr. 38, 1273–1277. Charney, D.S., Riordan, C.A., Kleber, H.D., Murburg, M., 1982. Clonidine and naltrexone. Arch. Gen. Psychiatr. 39, 1327–1332. Charney, D.S., Heninger, G.R., Kleber, H.D., 1986. The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone. Am. J. Psychiatr. 143, 831 – 837. Drummond, D.C., Turkington, D., Rahman, M.Z., Mullin, P.J., Jackson, P., 1989. Chlordiazepoxide vs. methadone in opiate withdrawal: a preliminary double blind trial. Drug Alcohol Depend. 23, 63 – 71. Farrel, M., Strang, J., 1995. Compressed opiate withdrawal syndrome and naltrexone. J. Psychopharmacol. 9 (4), 383 – 385. Gold, M.S., Redmond, D.E., Kleber, H.D., 1978. Clonidine in opiate withdrawal. Lancet 1, 929 – 930. Gonzalez, J.P., Brogden, R.N., 1988. Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 35, 192 – 213. Gossop, M., Green, L., Phillips, G., Bradley, B., 1989. Lapse, relapse and survival among opiate addicts after treatment: a prospective follow-up study. Br. J. Psychiatr. 154, 348 – 353. Kleber, H.D., 1996. Ultra-rapid opioid detoxification using narcotic antagonists. Abstracts of the XXth Collegium Internationale Neuro-Psychopharmacologicum Congress. Eur. Neuropsychopharmacol. 6 (Suppl. 3), 162. Kurland, A.A., McCabe, L., 1976. Rapid detoxification of the narcotic addict with naloxone hydrochloride: a preliminary report. J. Clin. Pharmacol. 16, 66 – 75. Legarda, J.J., Gossop, M., 1994. A 24-h inpatient detoxification treatment for heroin addicts: a preliminary investigation. Drug Alcohol Depend. 35, 91 – 93. Loimer, N., Schmid, R.W., Presslich, O., Lenz, K., 1989. Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addicts during detoxification treatment. J. Psychiat. Res. 23, 81 – 86. Loimer, N., Lenz, K., Schmid, R., Presslich, O., 1991. Technique for greatly shortening the transition from methadone to naltrexone maintenance of patients addicted to opiates. Am. J. Psychiatry 148, 933 – 935. Loimer, N., Hofmann, P., Chaudhry, H., 1993. Ultrashort noninvasive opiate detoxification. Am. J. Psychiatr. 150, 839. Masini, E., Blandina, P., Mannaioni, P.F., Luciani, G., 1981. Clonidine and naloxone for rapid opiate detoxification: comparison between treatments. Clin. Toxicol. 18 (9), 1021 – 1026.
250
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
Resnick, R.B., Kestenbaum, R.S., Washton, A., Poole, D., 1977. Naloxone-precipitated withdrawal: a method for rapid induction onto naltrexone. Clin. Pharmacol. Ther. 1, 409–413. Riordan, C.E., Kleber, H.D., 1980. Rapid opiate detoxification with clonidine and naloxone. Lancet 1, 1079–1080. San, L., Puig, M., Bulbena, A., Farre, M., 1995. High risk of ultrashort non-invasive opiate detoxification. Am. J. Psychiatr. 152, 956. Seoane, A., Carrasco, G., Cabre´, L., Puiggros, A., Hernandes, E., Alvarez, M., Costa, J., Molina, R., Sobrepere, G., 1997. Efficacy and safety of two new methods of rapid intravenous detoxifica-
.
tion in heroin addicts previously treated without success. Br. J. Psychiatr. 171, 340 – 345. Stine, S.M., Kosten, T.R., 1992. Use of drug combinations in treatment of opioid withdrawal. J. Clin. Psychopharmacol. 12, 203– 209. Strang, J., Bearn, J., Gossop, M., 1997. Opiate detoxification under anaesthesia: enthusiasm must be tempered with caution and scientific scrutiny. B. Med. J. 315, 1249 – 1250. Vining, E., Kosten, T.R., Kleber, H.D., 1988. Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers. Br. J. Addict. 83, 567 – 575.
Ultra-rapid opiate detoxification using deep sedation with oral midazolam: short and long-term results Anne The´re`se Cucchia, Martine Monnat, Jacques Spagnoli, Franc¸ois Ferrero 1, Gilles Bertschy1 * De´partement Uni6ersitaire de Psychiatrie Adulte, Site de Cery, 1008 Prilly-Lausanne, Switzerland Received 5 August 1997; received in revised form 1 May 1998; accepted 19 May 1998
Abstract The present study describes an ultra-rapid opiate detoxification method using direct transition from heroin or methadone to oral naltrexone after deep sedation with oral midazolam in conjunction with ondansetron and clonidine treatment. Twenty patients were detoxified with the method. No serious events occurred, but two out of three patients vomited during the acute phase of deep sedation, which involves some risks. Withdrawal symptoms were still present 24 h after detoxification and 80% of the patients relapsed during a 6-month follow-up. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Opiate detoxification; Midazolam; Naltrexone
1. Introduction Procedures to detoxify heroin addicts using opiate antagonists under general anaesthesia or deep sedation have been published in the recent years by groups in Vienna (Loimer et al., 1989, 1991, 1993) and Seville (Legarda and Gossop, 1994). These first reports were very optimistic and have been confirmed by more recent publications (Bartter and Goobermann, 1996; Brewer et al., 1996; Seoane et al., 1997). The potential advantages of the method are: The acceleration of withdrawal by displacing agonists from opioid receptors allows shorter hospitalization of patients, probably at lower costs. An improvement in the patient’s acceptance of withdrawal during the early phase of the treatment; this improvement comes from better subjective comfort, due to deep sedation and perhaps amnesia. * Corresponding author. Tel.: +41 22 3054766; fax: + 41 22 3054769. 1 Present address: Clinique de Psychiatrie II, Belle-Ide´e, Chemin du Petit-Bel-Air 2, 1225 Cheˆne-Bourg, Switzerland.
The maintenance on the opiate antagonist naltrexone from the very first stage of the treatment: inasmuch as it is used after detoxification, naltrexone may provide a useful protection again relapse. Before, what is labelled now as ultra-rapid opiate detoxification (UROD), various attempts were made to speed up the detoxification process. Given that opiate antagonists can displace opiate agonists from receptor sites, it was appropriate to think that a shortening of withdrawal could be obtained by progressively introducing an opiate antagonist during the very first days of detoxification. The first trials were performed with naloxone alone (Resnick et al., 1977) or in association with symptomatic medications (Kurland and McCabe, 1976; Resnick et al., 1977). As clonidine demonstrated its efficacy to reduce the intensity of opiates withdrawal symptoms (Gold et al., 1978; Charney et al., 1981), some authors used naloxone in combination with clonidine (Riordan and Kleber, 1980; Masini et al., 1981; Kleber, 1996). But it seemed easier to use naltrexone, which can be given orally in association with clonidine (Charney et al., 1982). Then, higher doses of naltrexone were introduced from the first day and
0376-8716/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0376-8716(98)00100-8
244
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
benzodiazepines, which can also reduce opiate withdrawal symptoms efficiently (Drummond et al., 1989), were added. By doing so, withdrawal could be completed in 4–5 days (Charney et al., 1986) and even 2–3 days (Brewer et al., 1988; Vining et al., 1988). Loimer et al. (1989) went further with naloxone; claiming that precipitation of withdrawal symptoms in rats could soon be followed by attenuation, they wondered whether withdrawal symptoms during detoxification treatment of opiate addicts could be suppressed by continuous administration of naloxone. They gave six opiate addicts 10 mg naloxone under short anaesthesia with methohexitone, followed by repeated doses of 0.4 mg/h naloxone for 72 h. They considered that their results clearly supported their initial hypothesis. In a subsequent work, they reported similarly optimistic results for seven patients on methadone with a slightly different method (Loimer et al., 1991). Patients were no longer anaesthetized but only deeply sedated with intravenous midazolam and woken with flumazenil. After awaking, naltrexone was substituted for naloxone. The same author (Loimer et al., 1993), described another method tested among 20 heroin sniffers or smokers. Midazolam was administered orally (60 mg) in association with clonidine (0.3 mg), which was not used in previous work. They also used ondansetron (5.0 mg), a 5 HT3-antagonist, to diminish vomiting and abdominal cramps which were not mentioned in the previous reports. Opiate antagonists consisted of 4 mg of naloxone administered intranasally as a spray and, 10 min later, naltrexone 50 mg orally. Again, the results were reported as very successful. Legarda and Gossop (1994) reported a yet slightly different method of direct naltrexone transition (without naloxone use) administered to 11 heroin addicted patients. Midazolam and guanfacine (which was substituted for clonidine) were administered intravenously in association to ondansetron (5.0 mg) and loperamide (4 mg, to prevent diarrhoea) orally. The very optimistic results of the pioneer work have been confirmed by recent studies using sedation with phenobarbital alone or in combination with diazepam (Bartter and Goobermann, 1996) or propofol and midazolam (Seoane et al., 1997). The only shadow cast on these enthusiastic data was the publication of a case of impaired oxygen saturation and bradycardia during UROD (San et al., 1995). A naloxone-related change in the permeability of the capillaries in the lung was suggested as the possible source of the problem. In this paper we report on our own experience with UROD, in terms of feasibility and safety, with improvements to simplify the method and make it less invasive: direct transition from agonist to naltrexone without the intermediate use of naloxone and oral administration of midazolam. Given the known limitations on indications for naltrexone among opiate dependent patients (Gon-
zalez and Brogden, 1988), it seemed interesting to examine long-term results of UROD and UROD-induced naltrexone maintenance. Thus, data about a 6-month follow-up are also reported.
2. Method
2.1. General design Twenty patients were withdrawn from opiates with an UROD procedure as described below. Treatment protocol was only partially standardized as some modifications were implemented as we became more experienced. Except for the first patient, clinical and therapeutic data were collected during the first 24 h according to a structured data collection plan. A 6month follow-up was carried on in co-operation with the GP and/or the therapeutic centre to obtain data about clinical evolution.
2.2. Population study Twenty patients were withdrawn from opiates with UROD procedure (12 men, eight women; age range: 18–33). All were opiate dependent for at least 1 year (range 1–15; mean9 S.D.: 6.594.8 years). Seventeen patients followed methadone maintenance treatment (mean methadone dose9 S.D.: 34.89 20.8 mg). Three of them used heroin intermittently, four used it regularly and three patients were heroin-dependent without methadone substitution. Among the seven daily users of heroin, the frequency of heroin intake was once or twice daily (intravenously for the seven patients) for a total estimated daily dose in the range 1–1.5 g. At the time of UROD, no patient had a problem with cocaine and only one patient occasionally took too much alcohol. Two patients intermittently used benzodiazepines and three others were dependent upon these drugs. Seven patients had a job or were in professional training (n= 3). Four patients had a borderline personality with antisocial traits disorders (DSMIII-R). All the patients involved applied specifically for the UROD method as an alternative to the classical method: all had experienced outpatient detoxification and 12 of them had at least one experience of in-patient detoxification (including eight patients who had tried three times). All the candidates were personally examined by a senior psychiatrist (G.B.) to exclude patients with no clear motivation. Some patients were excluded without any direct meeting, but a phone contact with them or their physicians. Not all phone contacts were recorded. We estimate that only about half of them resulted in UROD: two-thirds of the excluded patients were refused on the basis of a phone call, one third after the clinical evaluation.
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
The indications for UROD were detoxifications before admission in a therapeutic community (n = 4), a long lasting stay abroad (n =4) or transition to a naltrexone outpatient treatment (n =12).
2.3. Ultra rapid opiate detoxification procedure Patients were admitted to our hospital at 07:30 h with an empty stomach. In the preceding days a physical examination, an electrocardiogram and laboratory testing (blood count, electrolytes, urea, creatinine, transaminases) were performed. UROD was then initiated by simultaneous oral administration of: clonidine 0.300 mg, midazolam 45–120 mg (the dose was empirically determined taking into account the severity of opiate dependency and the experience of the subject with benzodiazepines; the 45 mg dose was only used for the first patient who was taking only 6 mg methadone per day); ondansetron 8 – 16 mg (the first patient received cisapride and not ondansetron; with experience we have increased the initial dose of ondansetron given the occurrence of vomiting and diarrhoea); loperamide 4–16 mg (for ten patients) or butylscopolamine 20 – 40 mg (for nine patients) to try to reduce diarrhoea and abdominal cramps. Fifteen to forty minutes later, as the patient showed the first signs of sleepiness (it sometimes took more time and additional oral doses of midazolam; the maximum total midazolam for one patient was 240 mg, the mean dose was 136 957 mg), the patient was given naltrexone 50 mg. Thirty to sixty minutes later, the patient entered the most acute phase of the withdrawal for 2 – 4 h. During this and the initiation phase, he was under close supervision by a nurse and a physician. Cardiac activity and oxygen saturation were permanently monitored (if the patient was not very agitated during his sleep). Blood pressure was controlled every half hour. Oxygen therapy by mask, broncho-aspiration and tracheo-intubation material were available in the room (usually used for electroconvulsive therapy) and the physician on duty, although not an anaesthetist, had been trained to use them. Four to five hours after initiation, as the patient become calmer and withdrawal symptoms decreased, he returned to his room. He remained under constant nursing attention until he spontaneously awoke for sufficient time (sometimes between 6 and 10 h after the initiation). When the patient showed excessive global or specific withdrawal symptoms, additional medications were given by mouth. If he awoke during the first acute phase, additional midazolam was delivered (if he was not awake enough for safe oral ingestion, midazolam was replaced by sublingual lorazepam). In case of vomiting or abdominal cramps ondansetron and/or butylscopolamine was administered by intramuscular injection. During the first 24 h, the mean (9S.D.) medication
245
received by the patients were as follows: clonidine 0.529 0.66 mg, benzodiazepines 1189 mg diazepam equivalent (using the equivalences 10 mg diazepam=4.5 mg bromazepam= 1.5 mg lorazepam= 10 mg midazolam) and ondansetron 28912 mg. Patients left hospital 36 h after admission with a prescription for low-dose clonidine and benzodiazepines for 2–3 days and naltrexone 50 mg/day. Five patients remained hospitalized for a longer period, as had been planned before admission. The reasons were: admission to a therapeutic community 3 days later (two cases), admission to benzodiazepine withdrawal program (two cases) and associated depression (one case). The latter three patients, as well as another patient, were personally treated by one of us (G.B.) on an outpatient basis, after discharge. Four patients were admitted in a therapeutic community, four patients left the country for a long stay abroad (range 1–4 months) with a planned follow-up by their GP upon their return. The other eight patients too were personally treated by their general practitioners. All these physicians were experienced in the field of addiction. During the post-discharge period, we were informed on all the patients’ progress either by direct contact or through their doctors or their therapeutic centres. Outpatient ongoing treatment differed according to the settings. It consisted mostly of a 2–3 times a week therapeutic contact for the first weeks and then of a 2–4 times a month contact. Naltrexone intake was not systematically done under supervision.
2.4. First 24 h measures At the times t= 0 (t=0 being initial clonidine and midazolam administration) t= 30, 60, 90, 120, 150, 180, 210, 240 min and then t= 5, 6, 8, 10, 12, 16, 18, 24 h, the following clinical data were collected: blood pressure, pulse rate, patient asleep or awake, withdrawal score using a 13-items symptoms check list rated by a nurse (item present =1 point, absent= 0 point; score range= 0–13) including the following objective items, running eyes, running nose, ‘gooseflesh’, sneezing, agitation, mydriasis, sweating, yawning, myoclonia and the following subjective items, abdominal cramps, backaches, hot and cold flashes and anxiety. Subjective items were not collected if the patient was sleeping. This could lead to moderately higher scores among patients who were awake. The ability to fall or remain asleep during the sedation procedure and the following night depended upon the ability of the procedure to diminish withdrawal symptoms. Such a design increased the sensitivity of the instrument to discriminate between patients who could sleep and those who could not sleep, i.e. situations in which withdrawal symptoms were well controlled and situations in which withdrawal symptoms were not well controlled. Any special incidents (such as vomiting, diarrhoea) were also registered.
246
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
2.5. Six-month follow-up Using contact with the GP and/or therapeutic community staff and, if needed, with the patient, the occurrence or not of a relapse and its timing during the following 6 months were documented.
2.6. Statistical methods Descriptive statistics are used to set forth results. For the evolution of the withdrawal score comparisons are made between one time point and another time point using Wilcoxon matched-pairs signed-ranks test.
2.7. Ethics After four preliminary cases, the project was submitted to and approved by the Ethic Committee of the Faculty of Medicine of Lausanne. After thorough information, patients had to give their written consent.
3. Results
3.1. UROD procedure and 24 h progress No serious adverse event occurred during UROD. One patient showed no signs of withdrawal during the first 4 h. She slept continuously and very quietly for 4 h as no other patient did. She awoke and remained very still for 20 min. Then she began to present a full withdrawal syndrome which required a high dose of lorazepam. Our hypothesis for this delayed withdrawal is that the naltrexone tablet remained stuck somewhere in her oesophagus and that it only reached her stomach when she first awoke after 4 h and sat up in her bed. For patients dependent upon benzodiazepines (n=3) or intermittent users (n = 2) the dose of benzodiazepines during the first 24 h tended to be higher than for the other patients (n =15) (255953 mg of diazepam equivalent versus 1789 89 mg) without being statistically significant. The total withdrawal score curve (Fig. 1) showed a significant clear peak of intensity at 1 h, that is to say 30 – 45 min after naltrexone ingestion (Wilcoxon matched-pairs signed-ranks test: t = + 1 h compared with t=0; P B 0.001). After 1 h, the withdrawal score significantly decreased (t= + 1 h compared with t= + 4 h; PB 0.005), but it remained significantly higher than the base line score (t = 0 as compared with t = +5 h, t = + 12 h, t= + 20 h; P B 0.002). Cardiovascular tolerance was excellent. Figs. 2 and 3, respectively, present 24 h systolic and diastolic blood pressure (BP) curves. Systolic and diastolic BP remained constantly ]80 and 50 mmHg with two exceptions. One patient’s BP dropped to 75/55 mmHg at
Fig. 1. Twenty-four hour total withdrawal score (maximum potential score on the checklist: 13; number of patients n =19; mean 9 S.E.).
t= + 90 min and another patient’s BP dropped to 110/45 mmHg at t= + 20 h. In both cases the BP spontaneously increased after a few minutes without any medical intervention. No problem occurred with oxygen saturation. During the acute phase, patients alternated between long periods of sleep and short periods awake. At each clinical evaluation, the percentage of patients who slept was in the 50–85% range. During sleep, moderate agitation was often present and during periods awake confusion and moderate agitation were also present. Patients were just deeply sedated and even when asleep were able to react to stimulation It is probably because they were not under general anaesthesia that patients had no difficulties in being woken in case of vomiting. However, two out of three vomited and three out of four had diarrhoea during the first critical 4 h, and such problems were still present, although at a lower rate, for the rest of the day (Fig. 4).
Fig. 2. Twenty-four hour systolic blood pressure (number of patients n =19; mean9 S.E.).
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
Fig. 3. Twenty-four hour diastolic blood pressure (number of patients n=19; mean9 S.E.).
No systematic data were collected during the following days. Most patients complained at least of moderate withdrawal symptoms after 24 h and for 3 – 5 days. Digestive symptoms (anorexia, nausea, vomiting, abdominal cramps) and psychic symptoms (anxiety, depression) were often mentioned. One patient with a borderline personality made a serious suicide attempt on the fifth day, using the antidepressant his general practitioner had prescribed the same day.
3.2. Six-month follow-up Fig. 5 shows that the relapse rate reached 80% at the end of the 6 months and that three out of four relapses took place in the first month. We used a very broad definition of relapse. If we use a less restrictive one, distinguishing on the one hand lapses as intermittent heroin intakes with reintroduction of naltrexone maintenance and without resuming daily use or methadone maintenance, and on the other hand, relapses as daily heroin intake and/or resumption of methadone maintenance treatment, the rate of 6-months relapse is lowered to 60%. Nine patients received methadone substitution again.
4. Discussion No serious problem concerning cardio-vascular and respiratory functions occurred during UROD in agreement with previous reports (Loimer et al., 1991, 1993; Legarda and Gossop, 1994). However, vomiting occurred with a high frequency although we used a high dose of ondansetron which is usually considered effective in preventing vomiting (initial dose: 8 – 16 mg; mean dose (9 S.D.) during the first 24 h: 289 12 mg). This finding clearly is in disagreement with other re-
247
ports (Loimer et al., 1993; Legarda and Gossop, 1994). If no broncho-inhalation accident was observed in our deeply sedated patients, it was probably because the sedation was not sufficient. Although relatively high doses of midazolam were used, they hardly counterbalanced the very high level of arousal related to the naltrexone-induced withdrawal state. However, such a high rate of vomiting is not acceptable. We aim to improve the method to reduce vomiting. Stine and Kosten (1992) have suggested that buprenorphine might facilitate the transition from opioid agonists to an antagonist given that buprenorphine is a partial opioid agonist with mixed agonist-antagonist properties. So we are trying to switch UROD candidates from full opiate agonists to buprenorphine one week before UROD. Preliminary results concerning vomiting are very encouraging. General anaesthesia with gastric aspiration is probably another way to solve the problem of vomiting. Withdrawal symptoms appear to be still present 24 h after initiation of naltrexone and to disappear only after 3–5 days, requiring continued clonidine and benzodiazepines adjunctive treatment which brought clear relief to the patients. The lack of quantitative evaluation beyond 24 h is a limitation of our study. Since design of our study was based upon previous reports, we did not anticipate that withdrawal symptoms would continue for several days. However, even relying on patients’ and physicians’ verbal reports, our observations contrast strongly with the other optimistic reports about UROD (Loimer et al., 1991; Legarda and Gossop, 1994), or the report of compressed naltrexone-induced opiate withdrawal syndrome (Farrel and Strang, 1995). Loimer et al. (1991) found that oral administration of 50 mg of naltrexone during and after naloxone administration on the first day and on the following days did not lead to the reappearance of withdrawal symptoms. Using a scale with possible scores ranging from 0 to a maximum of 29, they reported score at 24, 48, 72, 96 and 120 h and the mean values were respectively 1.43, 1.28, 0.86, 0.86, 0.57. Legarda and Gossop (1994) also reported in response to the administration of 50 mg of naltrexone that the morning after detoxification there were no physical signs or subjective symptoms to indicate the presence of opiate withdrawal symptoms. In the Bartter and Goobermann (1996) study, four patients were detoxified by a procedure involving propofol induction, intubation and ventilation: all patients were completely detoxified within 4 h and showed no abstinence symptoms when they were given naltrexone upon waking up. Similarly, Seoane et al. (1997) report at discharge, 24 h after UROD initiation, an almost total absence of withdrawal signs and symptoms: using the same instrument as Loimer et al. (1991) they found a mean 24-h score lower than 1. How can such differences be
248
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
Fig. 4. Percentage of patients with diarrhoea and vomiting during each 4-h interval on the first day.
explained? Given the lack of fundamental difference between the methods, a more realistic observation in our study could be the main reason. An alternative hypothesis is to be considered systematically. As discussed below, naltrexone was not administered under professional supervision after discharge. Since the majority of patients were on methadone, a long-acting opioid, it is possible that without the continued administration post-detox of naltrexone, the opioid still in the body and the brain re-attached to the receptors and further withdrawal would then be precipitated as it gradually came off. Two facts do not support this hypothesis. Firstly, patients who received naltrexone after discharge, under professional supervision, also had persisting withdrawal symptoms. Secondly, all the patients received naltrexone on the second day and withdrawal symptoms were present as well in the hours preceding as in the hours following this naltrexone intake. The relapse rate at 6 months was very high (16 out of 20). The four ‘survivors’ at 6 months were one patient admitted into a therapeutic community (initial number n=4) and three patients switched from a methadone to naltrexone maintenance treatment (initial number n=4). All the patients detoxified before a long stay abroad relapsed in spite of clear recommendations about naltrexone use when they returned home. The relapse rate (80%) is as high as with the usual detoxification method (Gossop et al., 1989), despite naltrexone. It still remains high (60%) even if we discard lapses without complete relapses. Such results lead to less optimism than other reports about UROD (Legarda and Gossop, 1994; Seoane et al., 1997). To our knowledge, it is the first study showing results with a 6-month follow-up. However, the length of the follow-up does not per se explain our
high rate of relapse. If the 6-months relapse rate is 80%, at the first month relapse rate is already 60% compared with 0% in the Legarda and Gossop (1994) report (n = 20) and 7% in the Seoane et al. (1997) study. We do not really think that the difference could be related to differences in patients’ characteristics. Our sample was selected for motivation and did not include street heroin addicts or polydrug abusers with the exception of benzodiazepine-dependent patients. Unstable personality disorders were not very frequent and their presence did not influence the outcomes: the 6-month continuous remission rate among patients with and without borderline personality disorders are, respectively, 25% (n =4) and 19% (n = 16). The high level of side-effects during UROD procedure, particularly vomiting, might have played a role: such an aversive experience with naltrexone at the beginning of detoxification may have led to a negative conditioning about naltrexone compliance. The persistence of withdrawal symptoms for several days may also have negatively contributed to the outcomes. An important difference between our study on the one hand, and the Legarda and Gossop (1994) study and the Seoane et al. (1997) study on the other hand, is that naltrexone was not systematically administered under professional supervision and our patients were not as closely and intensively followed and monitored in the month after discharge as patients in the other studies. Should this difference play a role, future studies would need to focus on the question of the duration of such outpatient intensive care. This point could be of importance as Legarda and Gossop (1994) reported that 0% of their patients relapsed during the month, but that 90% have challenged naltrexone on one occasion.
A.T. Cucchia et al. / Drug and Alcohol Dependence 52 (1998) 243–250
249
Fig. 5. Six-month survival (abstinence) rate after UROD (n =20).
5. Conclusion Our study confirms the feasibility of UROD. No serious negative events occurred but our method is associated with a high rate of vomiting which could be the source of dangerous complications. We are trying to develop a new method to reduce it. Long-term results of our sample tempers the optimism of the available reports. In our opinion UROD is just a technique of detoxification. Its interest is its ability to attract patients reluctant to use classical methods. However, UROD per se could be of no real influence on the very important question of how to help patients to remain on naltrexone maintenance. More long-term studies are needed to explore this question further. Recently, Strang et al. (1997) suggested that this technique should only be used in clinical trials. UROD is probably already too widespread, yet further clinical trials are really needed.
Acknowledgements The authors wish to thank Dr D. Thorin, Department of Anaesthesiology, Lausanne, for his excellent advice and the anaesthesiology training.
References Bartter, T., Goobermann, L.L., 1996. Rapid opiate detoxification. Am. J. Drug Alcohol Abuse 22 (4), 489–495. Brewer, C., Laban, M., Schmulian, C., Kasvikis, Y., Gooberman, L., 1996. Rapid opiate detoxification and naltrexone induction under general anaesthesia and assisted ventilation: experiences with 265 patients in three different centres. Abstracts of the 8th Congress of Association of European Psychiatrists. Eur. Psychiatr. 11 (Suppl. 4), 313S. Brewer, C., Rezae, H., Bailey, C., 1988. Opioid withdrawal and naltrexone induction in 48–72 h with minimal drop-out, using a modification of the naltrexone-clonidine technique. Br. J. Psychiatr. 153, 340 – 343.
Charney, D.S., Sternberg, D.E., Kleber, H.D., Heninger, G.R., Redmond, D.E., 1981. The clinical use of clonidine in abrupt withdrawal from methadone. Arch. Gen. Psychiatr. 38, 1273–1277. Charney, D.S., Riordan, C.A., Kleber, H.D., Murburg, M., 1982. Clonidine and naltrexone. Arch. Gen. Psychiatr. 39, 1327–1332. Charney, D.S., Heninger, G.R., Kleber, H.D., 1986. The combined use of clonidine and naltrexone as a rapid, safe, and effective treatment of abrupt withdrawal from methadone. Am. J. Psychiatr. 143, 831 – 837. Drummond, D.C., Turkington, D., Rahman, M.Z., Mullin, P.J., Jackson, P., 1989. Chlordiazepoxide vs. methadone in opiate withdrawal: a preliminary double blind trial. Drug Alcohol Depend. 23, 63 – 71. Farrel, M., Strang, J., 1995. Compressed opiate withdrawal syndrome and naltrexone. J. Psychopharmacol. 9 (4), 383 – 385. Gold, M.S., Redmond, D.E., Kleber, H.D., 1978. Clonidine in opiate withdrawal. Lancet 1, 929 – 930. Gonzalez, J.P., Brogden, R.N., 1988. Naltrexone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs 35, 192 – 213. Gossop, M., Green, L., Phillips, G., Bradley, B., 1989. Lapse, relapse and survival among opiate addicts after treatment: a prospective follow-up study. Br. J. Psychiatr. 154, 348 – 353. Kleber, H.D., 1996. Ultra-rapid opioid detoxification using narcotic antagonists. Abstracts of the XXth Collegium Internationale Neuro-Psychopharmacologicum Congress. Eur. Neuropsychopharmacol. 6 (Suppl. 3), 162. Kurland, A.A., McCabe, L., 1976. Rapid detoxification of the narcotic addict with naloxone hydrochloride: a preliminary report. J. Clin. Pharmacol. 16, 66 – 75. Legarda, J.J., Gossop, M., 1994. A 24-h inpatient detoxification treatment for heroin addicts: a preliminary investigation. Drug Alcohol Depend. 35, 91 – 93. Loimer, N., Schmid, R.W., Presslich, O., Lenz, K., 1989. Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addicts during detoxification treatment. J. Psychiat. Res. 23, 81 – 86. Loimer, N., Lenz, K., Schmid, R., Presslich, O., 1991. Technique for greatly shortening the transition from methadone to naltrexone maintenance of patients addicted to opiates. Am. J. Psychiatry 148, 933 – 935. Loimer, N., Hofmann, P., Chaudhry, H., 1993. Ultrashort noninvasive opiate detoxification. Am. J. Psychiatr. 150, 839. Masini, E., Blandina, P., Mannaioni, P.F., Luciani, G., 1981. Clonidine and naloxone for rapid opiate detoxification: comparison between treatments. Clin. Toxicol. 18 (9), 1021 – 1026.
250
A.T. Cucchia et al. / Drug and Alcohol Dependence 243 (1998) 243–250
Resnick, R.B., Kestenbaum, R.S., Washton, A., Poole, D., 1977. Naloxone-precipitated withdrawal: a method for rapid induction onto naltrexone. Clin. Pharmacol. Ther. 1, 409–413. Riordan, C.E., Kleber, H.D., 1980. Rapid opiate detoxification with clonidine and naloxone. Lancet 1, 1079–1080. San, L., Puig, M., Bulbena, A., Farre, M., 1995. High risk of ultrashort non-invasive opiate detoxification. Am. J. Psychiatr. 152, 956. Seoane, A., Carrasco, G., Cabre´, L., Puiggros, A., Hernandes, E., Alvarez, M., Costa, J., Molina, R., Sobrepere, G., 1997. Efficacy and safety of two new methods of rapid intravenous detoxifica-
.
tion in heroin addicts previously treated without success. Br. J. Psychiatr. 171, 340 – 345. Stine, S.M., Kosten, T.R., 1992. Use of drug combinations in treatment of opioid withdrawal. J. Clin. Psychopharmacol. 12, 203– 209. Strang, J., Bearn, J., Gossop, M., 1997. Opiate detoxification under anaesthesia: enthusiasm must be tempered with caution and scientific scrutiny. B. Med. J. 315, 1249 – 1250. Vining, E., Kosten, T.R., Kleber, H.D., 1988. Clinical utility of rapid clonidine-naltrexone detoxification for opioid abusers. Br. J. Addict. 83, 567 – 575.