24-Hour opiate detoxification and antagonist induction at home-the 'Asturian method': a report on 1368 procedures

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1 Addiction Biology (2002) 7, RESEARCH ARTICLE 24-Hour opiate detoxification and antagonist induction at home-the 'Asturian method': a report on 1368 procedures J. E. CARREÑO,1 J. BOBES,3 c. BREWER,4 c. E. ALVAREZ,l, G. I. SAN NARCISO,1 M. T. BASCARÁN2 & J. SÁNCHEZ DEL RÍ03 lclínica Médico Psicológica Asturias (CMPA), Gijón, Asturias, 2Psychiatry Department, Faculty o/ Medicine, Ovíedo Uníversity, Asturias, 3Detoxijication Unit, Hospital Central o/ Asturias, Oviedo, Spain and 4The Staple/ord Centre, London, UK Abstract The technique 01 domiciliar y rapid opiate detoxification (ROD) developed in Asturias since 1994 enables patients dependent on heroin and/or methadone (or other opiates) to start antagonist maintenance with a /ull dose 01 naltrexone (50 mg) and largely recover from the acute opiate withdrawal syndrome in a lew hours at home without direct medical or nursing involvement. Detailed inlormation on 1368 procedures is presented but in Asturias, over 3000 procedures have been completed to date without any deaths or serious medical or psychiatric complications. ~ also describe some recent modifications to the procedure involving the use 01 octreotide as an antidiarrhoeal and the insertion 01subcutaneous naltrexone implants to prevent early relapse. Rather than domiciliar y ROD, we think the procedure is more usefully conceptualized as domiciliar y rapid antagonist induction (RAI), because treatment with well-supervised naltrexone is known to be ejjective in reducing relapse rates. Now that controlled studies uniformly describe greatly increased rates 01 transler to naltrexone meaintenance treatment lollowing RAI, compared with conventional slower withdrawal and naltrexone induction procedures, it is important that the salety, acceptability and simplicity 01 this 'Asturian' RAI/ROD technique become more widely known. Introduction Since the mid-1970s, it has been possible to accelerate considerably the process of opiate detoxification and naltrexone induction. Blachly et al. 1 and Resnick et al. 2 were able to transfer patients from methadone to naltrexone in 24 hours using repeated naloxone injections and moderate sedation with benzodiazepines. Using clonidine and light sedation, Charney et al.3 routinely achieved successful naltrexone induction in 4-5 days with an in-patient protocol. Loimer et al. 4 and Brewer et al. 5 were the first to use anaesthesia and generous oral sedation, respectively, to make the process more acceptable and less uncomfortable. Oral naltrexone has been shown in several controlled studies to reduce both early and later relapse after opiate detoxification, provided it is given under supervision.6-8 In this respect, it has some similarities with supervised disulfiram Correspondence to: Dr Colin Brewer, The Stapleford Centre, 25a Eccleston Street, London SWIW 9NP, UK. Tel: ; fax: ; cb@stap-cen.demon.co.uk Received for publication 8th March Accepted 20th September ISSN printlissn online/02/ Society for the Study of Addietion to Alcohol and Other Drugs DOI: / Carfax Publishing, Taylor & Francis Ltd

2 244 J. E. Carreño et al. treatment.9,1q Conversely, the immediate relapse rate following conventional detoxification is often at least 50%. It is becoming increasingly apparent that leaving a gap between the process of detoxification and initiating naltrexone provides opportunities for relapse of which many patients unfortunately avail themselves. 11ROD is not only a technique for making opiate withdrawal quicker, less unpleasant and therefore less unattractive; it is also a technique for transferring patients quickly, seamlessly and effectively from regular opiate agonist intake to regular opiate antagonist intake. AlI ROD techniques involve the administration of an opiate antagonist to precipitate acute withdrawal by displacing opiates from opiate receptors throughout the body.12 The resultant withdrawal syndrome is generally more intense but much shorter than that observed after the abrupt discontinuation of opiates and the symptoms can be ameliorated or prevented by various drugs. These include: alpha-2 adrenergic agonists such as clonidine or lofexidine to control the adrenergic hyperactivity, anti-emetics such as metoclopramide or ondansetron, drugs to reduce intestinal peristalsis such as atropinics or octreotide, drugs to reduce gastric secretion and acidity such as H2 or proton pump inhibitors, nonopiate analgesics to control pain during or after the acute phase of withdrawal and sedatives or anaesthetic agents to reduce anxiety, agitation and awareness or to achieve total unconsciousness or amnesia.12 While residual withdrawal symptoms, as Himmelsbach reported in 1942, may persist for several days or even weeks or months,13 there is general agreement that with ROD, the worst is usually over within a few hours. Today so many different ROD protocols have been suggested 14 that the choice of treatment has itself become a problem. In 1997, Carreño et al. 15suggested that for an opiate detoxification technique to be considered as both 'rapid' and acceptable, treatment should last no longer than 24 hours; a complete dos e of antagonist (typically naltrexone 50 mg) should be administered, and adequate control of withdrawal symptoms should be achieved. Despite the obvious advantages of making withdrawal shorter and less unpleasant, there have been concerns about the safety of ROD procedures following a small number of high-profile deaths and exaggerated claims of effectiveness and painlessness.16 Several ROD procedures are currentiy employed in various countries and there is little agreement about the best technique or the indications. Important issues include: whether anaesthesia is preferable to sedation? What sort of sedation? What additional anti-withdrawal medications are needed? Is it better to carry out the treatment as an inpatient or outpatient? The purpose of this paper is to describe one particular protocol; to show that despite anxieties about the saftey of ROD, this procedure can be safely carried out in the patients' own homes without direct medical or nursing involvement; and to evaluate effectiveness in the sense of continuing NTX treatment. We also discuss the financial and therapeutic implications for opiate withdrawal programmes. Material and methods This is a descriptive, open-iabel study in which, after screening and baseline assessments, patients start a detoxification and naltrexone induetion programme. The main part of this study involves 1368 outpatients from the two participating centres, the detoxification outpatient unit of the Central Hospital of Asturias, Oviedo and the Clinica Médico Psicológica Asturias, Gijón between January 1994 and January The hospital detoxification unit is situated in the Central Hospital, which belongs to the Spanish National Health Servíce. The Clínica Médico Psicológica Asturias is a private entity. ExactIy the same procedure was used in both centres. Fifteen and 25%, respectively, of the detoxifications performed in the region are carried out in these two establishments. Patients had a choice of detoxification methods, the usual alternative being a day inpatient methadone reduction programme using clonidine and some sedation. During the same period, approximately 3500 patients chose the alternative programme. Patients who were accepted for treatment had to comply with ICD-10 criteria for opiate dependence, to be 18 years or over and to give informed consent. We did not exclude patients with mild non-dependent abuse of alcohol, benzodiazepines or cocaine. We accepted patients who had taken regularly up to 2 g of heroin per day (or other opiate equivalent). Those patients who had the procedure immediately after having failed to complete a more classical detoxification were not included. During the study period, 1414

3 24-Hour opiate detoxifieation and antagonist induction at home 245 Table l. Medication protocol Time First dose Baseline Second dose 45 rninutes Third dose 1 hour 45 minutes Drug Callrnedication oral) Clonidine 0.450rng Famotidine 40 rng Loperamide 4 rng Midazolarn 22.5 rng Ondansetron 12rng Clorazepate 50 rng Metoc1opramide 10 rng Naltrexone 50 rng Hyoscine butylbromide 20 rng Clonidine rng Metoc1oprarnide 10 rng patients requested RAI and 46 were rejeeted because of various contraindications: pregnancy 8.7%; pulmonary disease 52.2%; arrythmia or conduction disorder 17.4%; angina 4.3%; duodenal ulcer 4.3%; epilepsy 2.2%; lack of suitable family support 10.9%. The exclusion rate was therefore 3.25%. Treatment regimen Initial eonsultation The initial consultation included a semi-structured interview (including the responsible carer) confirmation of the patient's claimed drug use by urinalysis, physical examination, ECG and standard haematology/biochemistry tests. It also included a detailed explanation of the procedure to the patient and responsible family member, discussion of risks and potential problems, confirming telephone contacts and obtaining written consent. The medication decribed in Table 1 was then given to the carerothe same doses were used for all patients. All drugs are taken orally, with the exception of oetreotide, recently added to the protocol as an antidiarrhoeal (see below). Treatment is then (or the following day, if the first consultation took place in the evening, for example) initiated in the patient's home under the supervision of the carer, who maintains close telephone contact with the medical team involved. Deseription o/ a typieal proeedure Patients were advised to take no opiates for 12 hours before the procedure. The rationale was Psychiatric condition Family/social Legal situation Other substances Alcohol Employment Medical condition 0-1 No problems 2-3 Slight trouble 4-5 Moderate problems 6-7 severe problems 1 o Figure 1. Europ AS! based analysis of data obtained N = 800 (information as from September 1996).

4 246 J. E. Carreño et al. that this might reduce the severity of the precipitated withdrawal, but failure to follow this advice was not a reason for abandoning treatment. Similarly, patients were advised to minimize the use of other classes of drug, including alcohol. After swallowing the ondansetron, clonidine, midazolam, cworazepate, famotidine and loperamide, most patients are asleep after 30 minutes but are easily wakened to swallow the naltrexone and metoclopramide at 45 minutes. They then go back to sleep for about 30 minutes before the naltrexone-precipitated withdrawal starts. The range and intensity of withdrawal symptoms are shown in Fig. 1. The most visible manifestation is restlessness, which ranges from occasional movements during sleep to attempts to walk around the room. Patients are often confused and incoherent,17,18 but are generally able to indicate a desire to defaecate or pass urine and can usually walk with assistance. This stage is usually handled without much difficulty by the carers. Confusion and restlessness typically abate after 4-6 hours and nearly all patients are well enough to attend the clinic the next day for a further dos e of naltrexone and assessment (see below). Second consultation (24 hours later) Physical examination (further medication given if withdrawal symtoms persist). Completion of Gold's Scale and EuropASI (European adaptation of the fifth American edition of the Addiction Severity Index).19 Start of naltrexone maintenance programme with additional psychosocial therapy as indicated. Third consultation (96 hours later) Continuation of the naltrexone maintenance programme. Results Demographic data Eighty-two per cent of the 1368 were maleo Average age was 26.2 years; 62% were single. Thirty-one per cent were in regular employment and 51 % were unemployed. Seventy-two per cent had only basic education. Eighty-seven per cent used heroin only, 8% used methadone only, 5% used both. Average duration of habit was 4.9 years. Average time since last relapse was 9 months. Of the heroin users, 69% smoked it; 65% used between 0.25 and 0.5 g daily, 28% used g daily, 7% used > 1 g. Seventy-six per cent had previously been in treatment, with an average of four episodes. The results of the EuropASI are given in Fig. l. Since the object of treatment is not simply to accelerate the detoxification process but also to initiate naltrexone maintenance treatment, one simple and practical measure of effectiveness is the proportion of patients who returned for at least a second dose of naltrexone within 24 hours. Only three patients failed to do so. Effectiveness by this criterion was therefore 99.8%. Patients reported the following withdrawal symptoms: vomiting 172 (12.6%), diarrhoea 201 (14.7%), abdominal cramps 73 (5.3%) delirium 2 (0.1 %) and side effects of medication: hypotension 36 (2.6%), bradycardia 12 (0.9%), extrapyramidal syndrome five (0.4%). Twenty-four patients (1.8%) were admitted to hospital for rehydration. There were no cases of hypersedation or respiratory depression. Rating with Gold's Modified Scale indicated only a moderate degree of withdrawal discomfort overall at 24 hours (see Fig. 2). Discussion This study shows that it is possible for a full (50 mg) dose of naltrexone to be given to large numbers of typical opiate-dependent patients, who had generally taken their usual dose of opiate (heroin and/or methadone) within the previous 24 hours, without deaths or serious complications. Family members with only minimal instruction were able to manage the resultant acute antagonist-precipitated withdrawal in all but 1.75% of these patients. Although 24 patients were taken to hospital, most needed only advice and reassurance and none of them required more than a brief admission for rehydration. The introduction of octreotide (see below) should make this complication even more rare. It also makes the protocol similar to that described by Bell et al., 18who also used comparatively light oral sedation and reported no serious complications in 30 cases. Since ours is by far the largest reported series of patients receiving RODIRAI, the results indicate that this protocol has a low risk of significant adverse events. Including the subjects of this study, a total of more than 3000 patients have been treated in Asturias with this technique (as ofsummer 2001) without significant complications.

5 24-Hour opiate detoxifieadon and antagonist induetion at home 247 Anxiety Yawning Sweating Lachrymation Rhinorrhea Mydriasis Piloerection Tremors Shivering Muscle aches Insomnia Hypertension Temperature :::::::J :::::J Restlessness Respiratory depression Agitation E~~~~~~~~~~~~~~~~~~=:J E==:::J ~~~~~~~~~~~~~===:J Nausea Vomiting Tachycardia Diarrhoea Spontaneous ejaculation I I O Figure 2. Evaluation o/ withdrawal symptoms (Gold's rnodified scale) The total cost ofthis domiciliary RAI ( pesetas = approximately D40, 240 or USS230 (including medication, medical examinations and laboratory tests) is quite low. It compares favourably with typical published costs for outpatient detoxification, especially if one considers the cost per suceessful detoxification, as Gossop & Strang2 have pointed out. While a small number of deaths and serious complications have been reported in association with ROD/RAI procedures, nearly all have followed the administration of general anaesthesia or much larger doses of oral or parenteral benzodiazepines than are required with this protocol. Most of the deaths involved patients treated by organizations which have been criticized for their excessive commercialization of ROD procedures using anaesthesia.16 Significantly, one of them (the CITA organization) has consistently denied that any deaths or serious complications have occurred)21 even though at least two have been documented22,23 and an independent follow-up study of CITA patients included the information that one had a cardiac arrest shortly after extubation which responded to treatment.24 Treatment in an intensive care unit with intravenous access provides close monitoring and precise control of medications. Theoretically, this should reduce the risk of complications and ensure a rapid and skilled response to any complications that do occur. In praetice, it seems that invasive procedures such as nasogastric or endotracheal intubation, and the use of propofol or midazolam in high rather than low doses, may sometimes cause problems as well as alleviating them.25 For example, high doses of propofol or midazolam avoid the problem of restlessness or inadequate sedation but may be associated with respiratory complications in a few cases. However, techniques using intravenous sedation or anaesthesia/intubation in RODIRAI may be essential for patients with high sedative tolerance and certain medical or physical conditions requiring additional medication or an absence of restlessness. Maksoud (personal communication) has had no deaths or significant complications in over 5000 procedures using anaesthesia with thiopentone. At any rate our study clearly refutes the claim made by Javier Alvarez et al.26 that domiciliary techniques are too dangerous for routine use. The basic Asturian protocol evidently controls agitation and unease in most patients. Some studies have used antipsychotic drugs as well as benzodiazepines.27 However, these drugs do not necessarily provide adequate levels of amnesia or sedation, have prolonged actions and can be cardiotoxic. Oral midazolam is well absorbed, amnesiogenic and short-acting. Unlike neuroleptics, it also has a specific antagonist (flumazenil) in the event of overdosage. In Britain, it was thought inadvisable for medico-political reasons28-34 to ofier this treatment as a domiciliary procedure. Other faetors also influenced the decision to treat patients in an

6 248 J E. Carreño et al. inpatient setting. First, simple but apparently highly effective naltrexone implants had become available35-37and virtuaily abolished relapse during the crucial and vulnerable first month after RAl. For comparison, relapse occurred in 20% of an earlier cohort of 229 Asturian patients during the first month.29 Inserting a naltrexone implant during the procedure required a hospital setting. Secondly, although most Asturian patients reported adequate levels of symptom relief or amnesia for the acute precipitated withdrawal symptoms (as the increasing number of requests for this technique indicates) it may not be adquate in patients who were tolerant of benzodiazepines even if they were not dependent on them. Inpatient treatment for 24 hours means that additional doses of midazolam can be given in such cases, if necessary, before or after the administration of naltrexone. Further doses of octreotide, clonidine, antiemetics and analgesics can also be given in the minority of patients who report significant levels of distress on waking after 6-8 hours. Given that relapse is common in abstinence-based treatments and that many patients wiil need help to withdraw from opiates again at some stage after undergoing ROD/RAl, ensuring adequate relief or amnesia may minimize the proportion who report that they would not undergo such procedures again, or recommend them.18,30,31 Thirdly, following its initial use at the Stapleford Centre in ,32 experience in several centres (e.g. BeIl et al. 1999;18 Ali et al ) supported the impression that adding octreotide to the protocol greatly reduced the incidence of vomiting and diarrhoea. However, this drug has to be administered bys.c. (or Lv.) injection. In 110 Stapleford patients, the inclusion of 200 flg of octreotide in the premedication reduced the incidence of diarrhoea in the first 6 hours to 4% compared with the 15-65% reported in protocols of similar techniques not using octreotide, including the basic Asturian protocol as mentioned earlier. In Asturias, the protocol has therefore been modified since January 1999, to include 200 flgof octreotide S.C. 1 hour before the first oral dose. It is administered either at the clinic or by suitably instructed family members, depending on geographic and other factors. It replaces the opioid loperamide which, although used in several other ROD/RAl protocols, is probably largely or completely blocked by naltrexone. However, none of the 1368 patients in the main part of this study received octreotide. The results show that the combination of antiwithdrawal medication used in the basic protocol enabled most patients to get through the acute precipitated withdrawal with relatively modest levels of discomfort. However, vomiting was not controlled in ail cases and, like diarrhoea, it can be distressing for both patients and carers. BeIl et al. 18 found thal: ondansetron alone did not prevent vomiting and felt that octreotide was 'probably the most important' anti-emetic. Ali et al.33 reported that 64% of patients undergoing ROD but not receiving octreotide had vomiting andlor diarrhoea, against only 8% in the group receiving octreotide (p < 0.001) Should we conceptualize these procedures as rapid opiate detoxijication or as rapid antagonist induction (RAI)? The emphasis in several previous studies on rapid detoxijication (and the exaggerated and dishonest claims for 'painless' detoxification made by some providers) have diverted attention from the ability of ROD techniques to facilitate the induction of treatment with supervised or implanted naltrexone (or other antagonists existing or being developed). We therefore believe that the procedure should be conceptualized and referred to as rapid antagonist induction (RAl) instead of, or as weil as, ROn. Currie34 and Currie et al. 31 take a very similar view, but suggest the phrases 'rapid induction of opiate receptor blockade' (RIORB) or 'rapid induction onto naltrexone' (RION). We think the former acronym is cumbersome, while the latter ignores the fact that other antagonists such as chlornaltrexamine or nalmefene may be used, or are already being used, in place of naltrexone. For initiating antagonist treatment, naltrexone has obvious practical advantages over naloxone, which is short-acting and needs to be given by injection. Naltrexone is clearly the most appropriate of currently available antagonists for domiciliary treatment. However, there is evidence from some of the earliest studies2 and from very recent ones34,35 that repeated incremental naloxone injections may facilitate transfer to fuil doses of naltrexone after a few hours. In some protocols, nalmefene is used as the initiating antagonist. It has a slightly longer half-life than naltrexone and may be more potent.

7 24-Hour opiate detoxijication and antagonist induction at home 249 As regards the ideal dosage of naltrexone, obviously this must be at least sufficient to guarantee total blockade, normally regarded as 50 mg. Although an increased dose has sometimes been suggested36,37we do not consider this necessary, given that the majority of procedures using antagonists include a second dos e after 24 hours; Le. while the initial dose is still effective. Some studies conclude that increased doses do not seem to reduce the duration of treatment or reduce withdrawal intensity.38 However, McDonald et al.39 found that naltrexone absorbtion during ROD under anaesthesia was unexpectedly variable and negatively correlated with withdrawal symptoms 24 hours later. Another important question is whether ROD/ RAI should be reserved only for heroin addicts or whether it can be used for withdrawal from methadone or other long-acting synthetic opiates such as Laevo alpha acetyl methadone or buprenorphine. Methadone may cause more severe withdrawal symptoms than heroin in conventional procedures40,41 but RAI seems to equalize the withdrawal symptomatology.3,15,42,43currie et al.31 found no differences in acute withdrawal symptoms and only minor and short-lived differences in residual withdrawal symptoms for patients who had been taking methadone compared with patients withdrawing from heroin. However, it is particularly important that antagonist activity should be maintained for several days given the longer-iasting effects of these synthetic opioids, which could still be present in plasma and lead to rapid reoccupation of opiate receptors if naltrexone were discontinued after the first dose. The possible superiority of buprenorphine for RAI procedures remains to be confirmed. Like several other researchers, Currie et al. 31 found no correlation between severity or duration of withdrawal symptoms and the patient's normal daily opiate/opioid dose. However, their results supported a widely held belief that the time elapsed since the last opiate dose relates inversely to withdrawal severity. Studies providing data on post-detoxification monitoringi5,43-45 of both drug-free treatment as well as maintenence programmes with antagonists, reveal that retention in follow-up treatment depends on the type of treatment itself, but not on the initial method of detoxification. However, it is becoming increasingly clear that patients who undergo an RAI procedure are significantly more likely to start an antagonist maintenance programmei5,42,43 than those who have received a more conventional withdrawal and induction. The emphasis, therefore, in the treatment described here, should be on rapid antagonist induction rather than rapid opiate detoxification. References 1. Blachly P, Casey D, Marcel L et al. Rapid detoxification from heroin and methadone using naloxone. A model for study of the treatrnent of the opiate abstinence sindrome. In: Senay E, Shorty V, Alkesne H, editors. Development in the field of drug abuse. Cambridge, MA: Schenkman Publishing Co.; 1975, pp Resnick RB, Kestenbaum RS, Washton A, Poole D. Naloxone-precipitated withdrawal: a method for rapid induetion onto naltrexone. Clin Pharmacol Ther 1977;21: Charney DS, Riordan CE, Kleber HD et al. Clonidine and naltrexone: a safe, effective and rapid treatrnent of abrupt withdrawal from methadone therapy. Arch Gen Psychiatry 1982;39: Loimer N, Schmid R, Presslich O, Lenz K. Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addiets during detoxification treatrnent. J. Psychiatr Res 1988;23: Brewer C, Rezae H, Bailey C. Opioid withdrawal and naltrexone induetion hours using a modification of the naltrexone-c1onidine technique. Br J Psychiatry 1988;153: Gerra G, Marcato A, Caccavari R. Clonidine and opiate receptor antagonists in the treatrnent of heroin addiction. J Subst Abuse Treat 1995;12: Chan KY. The Singapore naltrexone communitybased projeet for heroin addiets compared with drugfree cornmunity-based program: the first cohort. J Clin Forens Med 1996;3: Cornish JW, Metzger D, Woody GE et al. Naltrexone pharmacotherapy for opioid dependent federal probationers J Subst Abuse Treat 1997; 14: 9. Chick J, Gough K, Wojciech F et al. Disulfiram treatrnent of alcoholismo Br J Psychiatry 1992; 161: Brewer C, Meyers R, Johnsen J. Does disulfiram help to prevent relapse in alcohol abuse? CNS Drugs 2000;14: Laheij RlF, Krabbe PFM, De Jong CAJ. Rapid heroin detoxification under general anaesthesia. JAMA 2000;283: Brewer C. Ultra-rapid, antagonist-precipitated opiate detoxification under general anaesthesia or sedation. Addiet BioI1997;2; Himmelsbach CK. Clinical studies of drug addiction, physical dependence, withdrawal and recovery. Arch Int Med 1942;69: Alvarez FJ, Del Rio MC. Desintoxicaciones ultracortas: del triunfo de la farmacología a la innova-

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