Addiction B iolog y (1997) 2, 291 ± 302

BE ST C LINICA L PR AC T IC E

Ultra-rapid, antagonist-precipitated opiate detoxi® cation under general anaesthesia or sedation COLIN BR EWER The Stapleford Centre, London, UK

Abstract Ultra-rapid opiate with drawal precipitated by na loxone or naltrexone during genera l anaesth esia or var ying degrees of sedation, usua lly with the addition of alpha-2 adrenerg ic agonists, is an increasingly popular tech nique . A s with anaesth esia or e Œective analgesia for dentistr y or obstetr ics, it can be justi® ed on general hum ane pr inciples. It also simpli® es and speeds the transition to treatm ent prog ramm es involv ing naltrex one . This paper review s its developm ent and the cur rent range of tech niques, includ ing the use of octreoti de to prevent diarrhoea. The prospect of avoiding or shortening the worst discom forts of with drawal may encoura ge more opiate addicts to attem pt detoxi® cation and opiate-free m anagem ent, includ ing patients who have been successfully rehabilitated on long-ter m m eth adone m aintena nce treatm ent (M M T). Despite good m otivation and preparation, a signi® cant m inor ity of M M T patients consistently fail to com plete conventional with drawal programm es beca use of increa sing physical discom fort. It is emphasized that there is usua lly m ore to the treatment of opiate depend ence than with drawal.

Introdu ction As with alcohol, a signi® cant proportion of those dependent on opiates do not ® nd abstaining for a week or two particularly di cult and m ay be withdrawn, voluntarily or involuntarily, without much physical or psychological discomfort. Animal studies show that the severity of withdrawal symptoms is, at least in part, genetically determined (Suzuki et al. , 1987) The same is probably true of humans and withdrawal severity bears little relationship to daily opiate dose (Kosten, Jacobsen & Kosten, 1989). Although psychosocial factors are also important, biological predisposition to severe withdrawal symptoms probably accounts for a signi® cant proportion

of the patients, often around 25% , who fail to complete conventional inpatient opiate withdrawal programmes and the m uch higher proportion (comm only up to 80% ) who fail outpatient withdrawal (Gossop, John & Green, 1987a). In any case, even for patients who complain of psychological rather than physical discomfort, psychological distress can still be very unpleasant. They may be deterred from seeking treatment because of their fear or previous experience of discomfort. Detoxi® cation fear aŒects up to a third of those wishing to become opiate-free (Milby et al. , 1986; Raczynski et al., 1988). Similar considerations deter some people from having dental ® llings or extractions despite very poor

Correspondence to: Colin Brewer MB, M RC S, MRC Psych, M edical Director, T he Stapleford Centre, 25a Eccleston Street, Belgravia, London SW 1W 9N P, UK . Received for publication 21st May 1996. Accepted 19th February 1997. 1355 ± 6215/97/030291 ± 12 € Society for the Study of Addiction to Alcohol and Other Drugs

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dental health. In such cases, intravenous (i.v.) sedation or general anaesthesia is usually oŒered, thus enabling us to treat those who would otherwise be untreatable (Brewer, 1996). In the past, heavy sedation was sometimes used to cover abrupt opiate withdrawal but it had to be m aintained for at least 3 or 4 days until the withdrawal symptoms were well past their peak (Brewer, 1967; Macleod, 1897). Such prolonged sedation could be hazardous, especially in the pre-antibiotic and pre-intensive care era (M acleod, 1899). The technique was largely abandoned, as were several other brie¯ y fashionable treatments (Kleber & Riordan, 1984). For both humane and practical reasons, there has been renewed and increasing interest in the last 20 years in developing methods of opiate detoxi® cation which make the process shorter and less unpleasant and therefore less frightening to those considering withdrawal. The production of eŒective opiate antagonists in the 1960s was an important development. Competitive antagonists have a high a nity for opiate receptors. If given in su cient dosage, they displace opiates from the receptors. They usually have little obvious eŒect in those who are not opiate dependent (although transient dysphoria, nausea and diarrhoea are not uncommon) but in opiate-dependent subjects they precipitate an acute withdrawal syndrome. They do not remove recently ingested opiates from the blood and tissues but block their pharmacological activity. These opiates are excreted in the normal way. As with several other agonist± receptor interactions, regular opiate administration causes down-regulation of opiate receptors. Opiate antagonists reverse this process, probably in a dose-related fashion. If a short-acting antagonist such as naloxone (half-life about 30 minutes) is given in a single and relatively small dose of 0.4 ± 0.8 mg by intramuscular injection, withdrawal symptoms appear in 10 ± 20 minutes and disappear in about 1 hour. The opiate receptors, and hence the underlying opiate dependence, remain essentially unchanged. This is the basis of the naloxone challenge for con® rming opiate dependenceÐ for example, to establish eligibility for methadone m aintenance treatment. However, if adequate opiate receptor blockade is maintained for more than an hour or two, adaptation and upregulation of the receptors occur progressively (Vining et al., 1988) and they become increasingly similar to the receptors of non-opiate

dependent subjects. Indeed, animal studies suggest that regular antagonist administration can cause an up-regulation of opiate receptors and an increase in receptor numbers even in opiate-naive animals. (M arley et al., 1995; Yoburn, Kosten & Kleber, 1995). After 4 ± 6 hours of total blockade, the precipitated withdrawal symptoms will have largely abated. However, although this shortens the withdrawal syndrome, it makes it more intense. Tornabene (1974) described the accidental precipitation of withdrawal in opiate addicts who had inadvertently consumed naltrexone. The symptoms were extremely severe but not life-threatening. Resnick et al. (1977) used repeated injections of naloxone to precipitate and accelerate the withdrawal process. The withdrawal symptoms were ameliorated by m oderate doses of benzodiazepine (BDZ) sedatives. When the alpha-2 adrenergic agonist clonidine was found to attenuate at least some opiate withdrawal symptoms (Gold, Redmond & Kleber, 1978) it was naturally used in addition to BDZs to alleviate precipitated withdrawal and in the early 1980s, researchers began to use the much longer acting naltrexone instead of, or as well as, naloxone to precipitate withdrawal (Charney, Riordan & Kleber, 1982). Abrupt withdrawal using clonidine alone (or other alpha-2 agonists, principally lofexidine) has been quite widely used but does not greatly reduce the discomfort compared with simple methadone reduction (Washton & Resnick, 1980; Shubert et al. 1984). The addition of naltrexone to a clonidine regime signi® cantly shortens the duration of withdrawal from heroin and other short-acting opiates and appears to be superior to clonidine-only withdrawal (O’ Connor et al., 1995). Furtherm ore, withdrawal from methadone becomes equally rapid (Kleber & Kosten, 1984; Charney, Henninger & Kleber, 1986). However, although the technique does not always require admission to hospital (Vining et al. 1988; O’ C onnor et al., 1995), the level of discomfort is too much for some patients to tolerate. The dose of clonidine should be enough to reduce pretreatment pulse and blood pressure, although not below 80 /50 mm Hg. Up to 2.4 m g of clonidine may be given in 24 hours. Adding larger doses of oral sedation to clonidine and naltrexone reduces the discomfort (Brewer, Rezae & Bailey, 1988; Senft, 1991; O’ C onnor et al. , 1995). It enables most patients to transfer to full doses of naltrexone and be

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discharged within 24 hours (Brewer & M athew, 1989; Brewer, 1989a; Cuccia et al. , 1996). Unfortunately, some patients are rem arkably di cult to sedate adequately with oral BDZs, even with the addition of phenothiazines or chlormethiazole. Compared with anaesthetic drugs, oral sedatives are long-acting and cumulative. The concept of `conscious sedation’ implies that patients are awake or can always be easily roused and will respond to simple commands but the distinction between conscious sedation and something nearer light anaesthesia is not always easy to maintain. The BDZ antagonist ¯ umazenil would presumably be useful if sedation became excessive. Hangover eŒects from sedation m ay persist for several days, although prolonged sedation is not always unwelcome to patients experiencing residual withdrawal symptoms. Patients already dependent on BDZs or alcohol may require very high sedative doses. Despite BDZ sedation, severe restlessness is common in precipitated withdrawal. Even if the patient has a su cient dose of BDZs to be amnesic for the procedure, the restlessness can be a major nursing problem, especially if it is accompanied by diarrhoea and vomiting. Some physicians who encountered these problems simply abandoned the technique, or restricted it to patients with relatively mild withdrawal symptoms. Others, however, asked themselves whether it would be possible to use general anaesthesia instead of oral sedation, since the restlessness generally disappears after a few hours. Working at the University of Vienna’ s Department of Psychiatry, Loimer et al. (1988) discovered that most of the acute withdrawal symptoms, including restlessness, normally precipitated by i.v. naloxone, could indeed be completely suppressed if the naloxone was given during a general anaesthetic with thiopentone and subsequently continued as an infusion for 48 hours. The use of short-acting anaesthetic agents minimized hangover eŒects. Since large doses of antagonists could be given, up-regulation of opiate receptors occurred m ore quickly. Withdrawal signs were therefore relatively mild after waking from anaesthesia a few hours later, although subjective symptoms were sometimes more persistent. This m ultidisciplinary team, drawing on psychiatry, intensive care medicine, pharm acology and psychology, opened a new era in the technology of opiate withdrawal. The rapid establishment of complete opiate

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receptor blockade with naloxone also meant that patients could be started immediately on full doses of the long-acting oral opiate antagonist naltrexone. However, at that time naltrexone was not available in Austria. Because of its long halflife, methadone could have reversed the opiate receptor blockade for up to 4 days after the last methadone dose unless i.v. naloxone was continued throughout that period. Accordingly, the ® rst patients were transferred to and withdrawn from the shorter-acting m orphine (400 ± 600 mg /day) rather than methadone, so that blockade with naloxone did not have to be continued for m ore than 48 hours. Since these original descriptions, some m odi® cations of the technique have emerged and the main purpose of this paper is to review them. It draws on personal experience with nearly 2000 naltrexone-assisted rapid detoxi® cations from heroin and methadone since 1985. M ost have been done under oral sedation (Brewer et al. , 1988; Brewer, 1989a; Brewer & M athew, 1989; Brewer, 1993). In the past 8 years, I have detoxi® ed about 140 patients with naloxone- and naltrexone-precipitated withdrawal under various general anaesthetics (Brewer, 1989b), most of them since 1995. A detailed description of the techniques used in this group is being published separately. (Brewer et al. , 1997). This experience made me speculate that: `Perhaps in the future, withdrawal from opiates will not be the primary responsibility of psychiatrists and psychiatric nurses’ (Brewer, 1993).

T he original techniq ue: thiopenton e or m ethohexitone an d i.v. nalox on e (Loimer et al. , 1988a, b, 1989, 1990; Presslich et al., 1989) Anaesthesia was induced and maintained with intravenous thiopentone or methohexitone and the patient was intubated after receiving succinyl choline. Naloxone 10 mg i.v. was given as a bolus and continued at 0.4 ± 0.8 mg /hour. Patients were allowed to wake from anaesthesia between 30 minutes and 3 ± 4 hours later and were generally ambulant by the following day. The naloxone infusion was discontinued after 48 hours. If necessary, sedation could be maintained with oral or intravenous benzodiazepines. M ost patients felt reasonably comfortable by the second day but were generally encouraged to stay in hospital for up to a week.

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Prem edication with clonidine, an aesthesia with propofo l, naltrexone via nasog astric tube (Brewer, 1989b) In 1989, I described a modi® cation of the basic Vienna technique (with anaesthetic assistance from Dr R. Simons) using propofol for anaesthesia, together with clonidine (i.v.) for prem edication, as in the standard clonidine± naltrexone regimen. After an initial i.v. naloxone bolus, naltrexoneÐ initially 12.5 mgÐ was administered during the procedure by nasogastric tube to maintain blockade during and after anaesthesia.

i.v. S edation with m idazolam , i.v. nalox on e, reversal of sedation w ith ¯ um azenil, transfer to naltrexon e after 2 ± 3 hou rs (Loimer et al., 1991a) Subsequently, instead of methohexitone, Loimer and colleagues used intravenous midazolam and the patients were transferred, after a few hours on a naloxone infusion, to oral naltrexone. Whereas previous patients had been maintained on oral morphine for at least a few days before withdrawal, this group were withdrawn from methadone (average dose 72.8 mg /day, range 40 ± 120 mg). Nevertheless, they were still generally ambulant 24 hours later.

M idazolam , ondanse tron, naltrexone an d intra-n as al naloxon e (Loimer, HoŒm ann & Chaudhry, 1993) Loimer et al. m odi® ed their technique for use in Third World Countries to minimize the need for syringes, intravenous infusions, anaesthesia and skilled personnel. Oral midazolam was used for simplicity. Naloxone was e ciently absorbed from an intranasal spray. However, before sedation took eŒect, the patient swallowed 50 mg of naltrexone. Ondansetron was intended to prevent the vomiting which frequently occurs when naltrexone is swallowed in full doses by people who are still pharm acologically opiate-dependent.

Oral n altrexon e, ondans etron, loperam ide, guan facine, sedation w ith i.v. m idazo lam , reversal of sedation w ith ¯ um azenil (Legarda & Gossop, 1994) Rather unusually for what is essentially an anaesthetic and pharm acological paper, both the authors are psychologists. As described by them,

the technique incorporates features of all the previously reported precipitated withdrawal procedures. Loperamide, an opioid, is used as an antidiarrhoeal agent, in which role it is almost certainly ineŒective since it is completely blocked by naltrexone (see below). Guanfacine is an alpha-2 agonist; i.v. sedation is maintained for about 4 hours. Endotracheal intubation is not used, despite the risk of vomiting from naltrexone swallowed just before the induction of sedation.

R ecent developm ents: as sisted ven tilation , propofol, volatile anae sthetics, bupren or phin e Since 1995, in collaboration with physicians in three other countries, a number of m odi® cations have been exam ined, chie¯ y the use of assisted ventilation. Propofol remains the usual anaesthetic agent but we have also used iso¯ urane with a closed circuit apparatus (Brewer et al. , 1997). This perm its equally rapid recovery from anaesthesia at a m uch reduced cost in anaesthetic agents. Although assisted ventilation reduces the consumption of propofol (an expensive drug), some of the saving is oŒset by equipment costs. Assisted ventilation is certainly not essential. Another way of reducing the consumption of propofol is the `ketamine sandwich’ technique. Ketamine is relatively inexpensive and is a potent analgesic. It is thought to act via NMDA receptors and is not blocked by opiate antagonists (Maurset et al. , 1989). After induction of anaesthesia with propofol, ketamine, in a total dose not exceeding 10 mg /kg, is administered and reduces the dose of propofol needed for maintenance of anaesthesia by about 40% . The ketamine infusion is stopped at least an hour before extubation with an appropriate increase in propofol dosage. This interval allows the ketamine to be largely eliminated before anaesthesia wears oŒ, thus preventing potentially distressing emergence phenomena. These are, in any case, generally prevented by prem edication with benzodiazepines. Since ketamine is also eŒective as an induction agent even when given by the intramuscular route, it can be used to facilitate the insertion of a central venous line in the signi® cant number of patients who lack accessible peripheral veins. Gooberman uses i.v. nalmefene, a new, longeracting parenteral opiate antagonist, before administering a total of 200 m g of naltrexone via naso-

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gastric tube. Like Gooberman & Kasvikis, we continue to give an initial i.v. naloxone infusion followed by naltrexone administered via nasogastric tube. Our rationale is that if any alarming physiological disturbances were to occur shortly after precipitating withdrawal, the short half-life of naloxone would make it easier to terminate the procedure and reverse the blockade. It re¯ ects our cautious approach to a relatively novel procedure and may well be unnecessary. In Israel, Kutz & Reznik ( personal comm unication) use i.v. conscious sedation with midazolam (occasionally propofol) without intubation. However, patients are transferred to the m ixed opiate agonist± antagonist buprenorphine (sublingually) at least 36 hours before treatment. Like Kosten et al. (1990) they ® nd that withdrawal symptoms are less severe and resolve m ore rapidly compared with patients detoxifying from pure opiate agonists. Discharge is usually possible after 8 hours. Sedation is m aintained at a level which enables patients to swallow naltrexone so that neither nasogastric nor endotracheal tubes are necessary. However, buprenorphine can precipitate withdrawal symptoms in heroin- or m ethadonedependent patients. About 20% of patients do not tolerate the change and drop out before treatment. It is possible that, like a naloxone challenge, this technique simply identi® es patients who have particularly severe withdrawal symptoms and who then exclude themselves from treatment. If so, this may still be a useful variation since it could considerably reduce the need for anaesthesia and may enable many patients to be treated m ore economically and perhaps with fewer potential hazards. The Spanish± Israeli CITA organization and its parent company ATT Technologies BV, with which Legarda has been associated, uses propofol, alpha-2 agonists and nasogastric naltrexone with endotracheal intubation but without assisted ventilation. This is clearly an advance on the procedure described by Legarda & Gossop (1994) but C ITA /ATT have published their current m ethods solely in the form of an international patent application (PCT /ES94 /100108), even though their 1994 paper indicates that they did not start using the procedure until October 1992 (Brewer, 1997). Working in Cairo, the toxicologist Abdel M aksoud ( personal communication) uses naloxoneprecipitated withdrawal under 4 ± 6 hours of thiopentone anaesthesia with clonidine and assisted

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ventilation, followed by oral naltrexone. He has also used propofol and volatile anaesthetics but feels that the residual sedative eŒect of thiopentone is actually an advantage in alleviating residual withdrawal symptoms. His patients usually go home after about 20 hours but occasionally need to stay for a second or even a third day. An important development in post-discharge management is the use of naltrexone implants. These can be easily inserted during the period of anaesthesia needed for detoxi® cation, or subsequently under local analgesia. Current experimental m odels appear to give eŒective blood levels of naltrexone for at least 5 weeks (Gooberman, personal communication). They m ay improve treatment retention rates especially during the first few weeks after detoxi® cation when dropout is particularly likely to occur.

D escription of a typical pro cedure Patients on methadone m aintenance take their normal m ethadone dose the previous day or even the same day if the procedure takes place in the afternoon. If employed, they can continue working until the time of admission. After standard pre-anaesthetic assessment, food restriction and preparation, including premedication with clonidine and gastric acid suppressants such as cimetidine or omeprazole, i.v. access is secured, monitoring is established and anaesthesia induced with propofol. As with the standard clonidine± naltrexone techniques, clonidine is given before and during the procedure in doses su cient to reduce the pulse and blood pressure to below pre-treatment levels. Octreotide, and prophylactic anti-emetics are given i.v. A urinary catheter is inserted but rem oved before waking. Central venous lines are used only if peripheral venous access is di cult or impossible. Following the administration of muscle relaxants (if used) and the insertion of endotracheal and nasogastric tubes, i.v. naloxone 2 mg is given. There is often little visible response but piloerection is sometimes seen. Monitoring includes constant EC G, respiration, pulse, BP, SaO 2 and end-tidal CO 2 . Pulse and blood pressure (BP) are generally unchanged but transient, moderate tachycardia and raised BP sometimes occur, usually responsive to further doses of clonidine. In the absence of an adverse response to the naloxone challenge (which has not been reported during detoxi® cation under anaesthesia), nal-

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trexone 25 ± 50 mg, crushed and suspended in 20 ml of water, is given through the nasogastric tube. Further naltrexone doses are given an hour later. Sometimes, piloerection and sweating are seen only at this stage after a negative response to naloxone but minimal responses are common. Muscle relaxation, if used, is maintained at a level which usually permits slight movements. Without relaxants, these movementsÐ the typical myoclonic twitching or `kicking’ of opiate withdrawalÐ may be more apparent but are rarely troublesome. After 4 ± 6 hours, m uscle relaxation is reversed if it has not already worn oŒ and anaesthesia is lightened. Further doses of anti-emetics and octreotide are given as necessary. Following extubation, appropriate doses of sedatives and clonidine are given i.v., or orally if nausea is not a problem. Tachypnoea, a classic opiate withdrawal symptom, m ay persist for a few hours after waking.

Practical consideratio ns dur ing the ® rst 24 ± 48 h our s Diar rhoea Although the use of opiate antagonists in withdrawal greatly speeds up the disappearance of both objective and subjective withdrawal manifestations (Loimer et al., 1990; Loimer, Linzmayer & Grunberger, 1991b) some signs and symptoms appear to improve m ore rapidly than others. Sweating and piloerection tend to disappear early. They also respond well to alphaadrenergic agonists such as clonidine. In contrast, diarrhoea is sometimes profuse and persistent. Furthermore, it is often refractory since opiates almost certainly have no eŒect in patients receiving opiate antagonists. At the very least, it means that medical and nursing staŒ should prepare themselves for the possibility of large-scale incontinence in an environment where contamination is particularly unwelcome. Pre-anaesthetic bowel preparation is often advised. Octreotide has been used successfully to treat several varieties of resistant diarrhoea (Cello et al. , 1991; Shulkes & Wilson, 1994) and is also used in palliative care to reduce both gastric and intestinal secretions (Khoo, Riley & Waxman, 1992; Mercadante et al., 1993). In our experience, it appears to be highly eŒective in the diarrhoea of precipitated withdrawal and since using it rou-

tinely, we do not now use bowel preparation before anaesthesia. It also reduces gastric secretions which are often profuse in this procedure (Brewer et al. , 1997); 100 ± 200 mcg by subcutaneous injection or slow i.v. infusion is usually su cient, although some patients need more. It can be repeated 12-hourly as necessary, even after discharge from hospital. Toxicity appears to be very low, especially in short-term use.

Vom iting Nausea and vomiting are common in ordinary acute opiate withdrawal. Anti-emetic drugs will abort or prevent vomiting in m ost cases, but few drugs are universally eŒective and I have seen patients with persistent vomiting after waking from anaesthesia which was resistant to high doses of metoclopramide, butyrophenones or phenothiazines and ondansetron, although it rarely lasts more than a few hours. However, M aksoud ( personal communication) reports one patient who had persistent vomiting which abated only after several days.

Seizures Seizures are not a feature even of precipitated opiate withdrawal and the EEG shows no signi® cant change (Brewer, 1989a); there is little change in regional cerebral blood ¯ ow, either (van Dyck et al. 1994). However, concurrent pharmacological dependence on BDZs, other tranquillizers or alcohol is not uncommon. After precipitated opiate withdrawal, these other dependencies may need to be managed separately by m aintenance or gradual withdrawal, in the case of tranquillizers, or by BDZ substitution and more rapid withdrawal in the case of alcohol. Reversing midazolam sedation with ¯ umazenil could precipitate seizures in a BDZ-dependent patient (Gri ths et al., 1993) although BDZ antagonists m ight some day make possible an analogous technique of precipitated BDZ withdrawal. Like opiate antagonists, BDZ antagonists appear to reverse the down-regulation of GABABDZ receptors in BDZ dependence (Gerra et al., 1993; Gerra et al. , 1996).

Anx iety and oth er psychiatric symptom s High levels of anxiety are common during withdrawal and are at least partly a pharmacological

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rebound phenomenon, as with alcohol. In most patients having precipitated withdrawal, they settle within the ® rst 24 hours but, as with diarrhoea, they m ay persist for several days. The anxiety can be di cult to manage with good nursing and reassurance alone and may require, as well as alpha-2 agonists, generousÐ if shorttermÐ treatment with tranquillizers, however undesirable this may be from a theoretical standpoint. Insomnia m ay persist and can be very demoralizing. It sometimes fails to respond to large doses of BDZ hypnotics, even when they are reinforced with sedative neuroleptics. In such cases, chlormethiazole or even barbiturates may be necessary for short periods. Psychotic or delirious states are not normally a feature of opiate withdrawal but can occur (Fishbain et al. , 1988) and when withdrawal is precipitated by antagonists delirium may be prominent, though it is usually short-lived (Tornabene, 1974; Brewer, 1989a; Senft, 1991; O’ Connor et al. , 1995). Transient minor visual disturbances are also common. Several patients have told me that objects looked blue or purple. Although after precipitated withdrawalÐ whether m anaged by sedation or anaesthesiaÐ many patients are ® t to return home after 24 ± 48 hours (Brewer et al. , 1988; Brewer, 1989a; Legarda & Gossop, 1994), a variety of behavioural disturbances may cause problems during the ® rst week, in particular.

Pain Typical opiate withdrawal pain, aŒecting the lower back and legs particularly, is common on waking but usually improves quickly. Clonidine and non-opiate analgesics, especially non-steroidal anti-in¯ ammatory agents, generally su ce. In `therapeutic addicts’ Ð patients who become addicted following prescribed opiate use for chronic or recurrent painful conditionsÐ postwithdrawal pain may sometimes be very di cult to manage with conventional non-opiate analgesics. An infusion of ketamine at doses well below anaesthetic levels is generally eŒective. It has been successfully used in conditions ranging from pain after dental extraction to post-herpetic neuralgia and palliative care without usually provoking the hallucinatory emergence phenomena common at higher doses. The concurrent use of BDZs further reduces their incidence (Luczak, Dickenson & Kotlinska-Lemieszek, 1995).

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S peed of recover y Using a 20-item four-point withdrawal rating scale developed by Bradley et al. (1987), a group of 25 patients treated in Athens were rated on admission before precipitated withdrawal under anaesthesia and again the following day before discharge. The overall rating was slightly but not signi® cantly worse after rapid opiate detoxi® cation under anaesthesia (RODA) ( paired T-tests pre- vs. post- 5 8.5 vs. 12.5, t 5 1.5). However, on symptom by symptom comparison (Wilcoxon matched pairs) diarrhoea (Z 5 2.8, p < 0.005) feeling cold (Z 5 2.4, p < 0.01) and hot and cold ¯ ushes (Z 5 2.6, p < 0.01) were signi® cantly worse. Neither age of patient, duration of opiate use nor usual opiate dose correlated with symptom severity (Pearson correlation) (Brewer et al. , 1997). Despite the upregulating eŒect of antagonists on opiate receptors previously mentioned, clinical experience suggests that there are some individuals in whom, despite regular naltrexone, receptor normalization occurs slowly and may be incomplete. If this is so, it is presumably a mirrorimage of the ® nding that some patients can take opiates for long periods with little or no pharmacological dependence.

An aesthetic im plication s Since aspiration of vomit is one of the major hazards of anaesthesia and perhaps especially in this situation, it seems wise to treat anaesthesia during precipitated withdrawal in much the same way as obstetric anaesthesia. Thus it is sensible to reduce gastric acid production before anaesthesia with drugs such as cimetidine or omeprazole. W ithout muscle relaxants, deep anaesthesia may be necesssary to prevent a visible motor reaction to the initial dose of naloxone or naltrexone. Endotrachaeal intubation is probably m andatory although a laryngeal mask might be acceptable. Paralysis with assisted ventilation has a number of theoretical and practical advantages. First, it completely prevents vomiting and the motor restlessness which can persist for a few hours during light anaesthesia or sedation. It also ensures adequate oxygenation. However, there is one important caveat. In the state of hyper-arousal and autonomic overactivity which m ay accompany precipitated withdrawal, the tolerance of patients to doses of sedatives which would normally render them unconscious can be remarkable. In our ® rst assisted ventilation case in 1989, despite

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the m aintenance of anaesthesia with what appeared to be adequate doses of propofol, the patient was intermittently aware during the last few hours of ventilation, although she did not ® nd it very distressing and would undergo the procedure again. With the much shorter period of controlled ventilation now generally used, the risk of awareness is probably much less. In any case, complete paralysis is both unnecessary and undesirable. M onitoring by peripheral nerve stimulation should help to maintain muscle relaxation at the appropriate level.

C om plications If complications occur, the intensive monitoring and nursing techniques which this procedure requires, and the constant presence of resuscitation experts, surely provide the best environment for detecting and m anaging them. No deaths or serious complications during the acute phase were reported by the Vienna group. A patient treated at a CITA clinic in London died in hospital a few hours after waking from anaesthesia but full details are not yet available. One death, apparently soon after extubation, is reported from the USA. The anaesthetist had not used the technique previously (Hodgin, 1997). Another patient died several hours after returning home but post-mortem examination revealed no obvious cause. Many heroin addicts also use cocaine, which is a known cause of sudden death. Cocaine use may be particularly likely after detoxi® cation if heroin use is prevented by naltrexone. Interestingly, no deaths or serious complications occurred in the few reported cases of inadvertent naltrexone ingestion by opiate addicts. Heavy oral sedation is not problem-free, whether used for withdrawal or for general psychiatric indications. One death has been reported, occurring over 12 hours after acute withdrawal symptoms had abated (Brewer, 1993). San et al. (1995) reported hypoxia and bradycardia occurring in a patient having a planned precipitated opiate detoxi® cation under oral sedation with midazolam. He was intubated but no aspiration of vomit occurred and he recovered rapidly.

General cons iderations Complications must be seen in perspective. Two years after its introduction in 1986, 66 midazolam-related deaths had been reported in the US.

M ost were in elderly patients undergoing endoscopy, in which: `cardiac or respiratory depression may go unnoticed for some time. In addition, the endoscopist may be unfamiliar with techniques of cardiorespiratory support if such measures become necessary’ (Editorial, 1988). It is sometimes said (Farrell, 1994) that because death from uncomplicated opiate withdrawal is virtually unknown, it is not justi® able to introduce the potential hazards of anaesthesia. However, in a generally young patient group, the relatively slight hazards of modern anaesthesia (without, in this case, the added risks of a surgical procedure) must be set against the frequent and sometimes lethal complications of continuing opiate abuse, especially if it involves injecting. It could equally be said that because nobody dies from bad teeth, an unshapely nose or the pain of childbirth, it is unjusti® able to oŒer general anaesthesia or epidural analgesia for the management of these conditions, since disasters occasionally occur. Provided that the risks are small and adequately explained, people are surely entitled to take them (Brewer, 1996). Punitive attitudes to drug addicts apparently make some health professionals feel that they do not `deserve’ good symptom relief, or even that an unpleasant withdrawal will `teach them a lesson’. Humane practitioners often have to contend with the `no pain, no gain’ attitudes and generally antipharmacological ethos of Twelve-Step personnel (Mathew, Georgi & Nagy, 1994; Brewer, 1997). I have even heard normally kindly people argue that withdrawal should not be made too easy lest addicts `abuse’ it (Brewer, 1995, 1996). Rapid withdrawal and early discharge mean that, compared with conventional withdrawal programmes, m any more patients can be treated during a given period and without large numbers of nursing hours. Unconscious patients cannot manipulate nursing and medical staŒor sabotage their own or others’ withdrawal by smuggling opiates into the ward. By the time they wake up, they have already received naltrexone which makes it impossible for them to relapse as soon as they leave hospital, as happens typically in around 50% of patients discharged from conventional withdrawal programm es (Gossop et al., 1987b). Post-withdrawal m anag em ent This is not the place for a detailed discussion. After opiate detoxi® cation followed by naltrexone

Opiate detoxi® cation und er general anaesthesia

treatment, as with alcoholic patients taking disul® ram, (Azrin et al., 1982) some patients do well with little or no professional assistance but help is often needed if the transition from pharm acological and psychological dependence to an opiatefree state is to be lastingly successful. Patients and their families sometimes have unrealistic expectations of this treatment, as with other `high tech’ procedures, and it is important to prepare them for problems. Randomized or matched control groups are particularly important in postwithdrawal follow-up studies because so m any variables aŒect the outcome, especially the patient’ s social characteristics and circumstances. After ultra-rapid detoxi® cation, patients can be managed with the same range of approaches that are used after conventional detoxi® cation. However, since they are already taking naltrexone to consolidate the withdrawal process, it makes sense to continue it as part of the treatment programm e, since it has been shown in controlled studies to reduce relapse rates and to increase follow-up attendance rates (Tilly et al., 1991; Shufman et al. , 1994; Gerra et al. , 1995; Chan, 1996). Indeed, the earliest detoxi® cation techniques were conceived, in part, as a way of facilitating the transition from heroin or methadone to naltrexone (Resnick et al., 1977). With naltrexone as with disul® ram , supervised administration improves the outcome (Azrin et al., 1982; Brewer, 1990; Tilley et al. , 1991; Gerra et al., 1995). It is bad practice simply to detoxify patients without oŒering follow-up treatment, which should be tailored to the individual’ s needs and circumstances, even though not all will accept the oŒer.

E Œectiveness studies No randomised studies have compared precipitated withdrawal under anaesthesia or sedation with conventional withdrawal techniques. Apart from the fact that it facilitates transfer to naltrexone maintenance with its demonstrable advantages, I do not think it can be claimed that patients having precipitated withdrawal show, in general, better long-term results than comparable patients who complete conventional inpatient withdrawal program mes. However, it seems likely that a signi® cant proportion of patients who would fail (or have repeatedly failed) to complete conventional withdrawal will succeed with the help of anaesthesia or sedation. For example, in the long-term Swedish methadone m aintenance

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detoxi® cation study, as well as the 34% of patients who relapsed and returned to methadone maintenance, 16% of the patients did not even manage to become methadone-free, even though withdrawal was entirely voluntary (Eklund et al., 1994). This is one important reason for putting these techniques on the therapeutic menu. Another important reason is that, at the dawn of the 21st century, people should not have to suŒer withdrawal symptoms lasting several days which are often unpleasant and sometimes extrem ely unpleasant, if they can be largely avoided or greatly shortened for an acceptable risk.

Abstinence rates dur in g follow -up No really long-term results have been published. In a consecutive group of 30 patients detoxi® ed in Cairo at least 4 months previously (range 4± 8 months), only ® ve patients had not been regularly followed-up, usually because of living or working abroad. Regular urine tests were done in the remaining 25 cases. Only one out of the 25 had relapsed to opiate use, although in 4 cases, urines were positive for cannabis (Brewer et al. , 1997). This very high `success rate’ Ð 76% even if all patients lost to follow-up are assumed to have relapsedÐ probably re¯ ects both the rigorous selection of well-motivated patients and the suitability of closely knit Egyptian family structures for treatment involving fam ily-supervised naltrexone. In contrast, Cuccia et al. (1996) reported, from Lausanne, a 60% drop-out after 1 m onth and 80% after 6 m onths in 20 patients. Withdrawal is always a step into the unknown, especially for patients who have not been opiatefree for m any years. In the case of patients on methadone maintenance, Dole (1973) pointed out that `Each withdrawal is an experiment with the life of a patient’ . A prolonged abstinence syndrome sometimes occurs in which symptoms such as insomnia, lethargy, depression, diarrhoea, restlessness and arthralgia may persist for weeks or months. Noting that `Such patients show an illde® ned but real malaise’ , Dole (1965) speculated that `repeated exposure to large doses of narcotics . . . m ay cause an irreversible change in some biochemical processes’ . Recent research (M utti et al. , 1992) suggests that he was right. Unfortunately, despite good motivation and intensive post-withdrawal support, some patients will ® nd being opiate-free impossible to tolerate.

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In such casesÐ and the study of Eklund et al. (1994) shows that they are not rareÐ initiating or resuming m ethadone maintenance must be considered. Simon, an anaesthetist, argues rather glibly that `naltrexone is a better treatment for heroin addiction than methadone’ (Simon, 1996). In contrast, Dole (1965) notes that `Success . . . must be measured by what people do [and] by their capacity to enjoy the small pleasures of life and meet the larger responsibilities. Treatm ent m ust be directed to the patient and not be distorted by a narrow preoccupation with the chem ical agents of addiction . . . Rehabilitation rather than withdrawal of the drug is the ® rst target . . . the ideal is social and pharmacological cure but if a choice m ust be m ade, rehabilitation should come ® rst ’ [my italics].

Acknow ledgem ents I am grateful to my anaesthetic colleagues, Drs R. Simons, J. M athias, M . Laban, C. Schm ulian, R. Laishley, B. Bracey and J. Williams; to Dr L. Gooberman; to Dr N. Loimer and Dr R. Schmid of the University of Vienna; to Dr A. Lerner and Dr D. Telias of the Israel M inistry of Health; to Dr G. JeŒery of Cornell University Medical centre, Dr Y. Kasvikis of Athens and Dr Nabil Maksoud of Cairo University, for their advice in the preparation of this paper.

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