Combating opiate dependence: a comparison among the available pharmacological options

Review

2004 © Ashley Publications Ltd ISSN 1465-6566 713

Ashley Publicationswww.ashley-pub.com

1. Overview of opiate dependence

pharmacotherapy

2. Optimal practice

3. The partial opiate-receptor

agonist – buprenorphine

4. α2-Agonist medications:

clonidine and lofexidine

5. Opiate-receptor antagonists:

naltrexone

6. Factors likely to affect choice of

pharmacotherapy

7. Summary and conclusions

8. Expert opinion

9. 5-year view

Monthly Focus: Central & Peripheral Nervous System

Combating opiate dependence: a comparison among the available pharmacological optionsGerardo Gonzalez†, Alison Oliveto & Thomas R Kosten†VA Connecticut Healthcare System, Department of Psychiatry 116A4, 950 Campbell Avenue,

West Haven, CT 06516, USA

Pharmacotherapies for heroin addiction may target opiate withdrawal symp-toms, facilitate initiation of abstinence and/or reduce relapse to heroin useeither by maintenance on an agonist or antagonist agent. Available agentsinclude opioid agonists, partial opioid agonists, opioid antagonists andα2-agonists for use during managed withdrawal and long-term maintenance.Experimental approaches combine α2-agonists with naltrexone to reduce thetime of opiate withdrawal and to accelerate the transition to abstinence.Recently, buprenorphine has been introduced in the US for office-basedmaintenance, with the hope of replicating the success of this treatment inEurope and Australia. Naloxone has been added to buprenorphine in orderto reduce its potential diversion to intravenous use, whilst facilitating theexpansion of treatment. Although comprehensive substance abuse treatmentis not limited to pharmacotherapy, this review will focus on the rationale,indications and limitations of the range of existing medications for detoxifi-cation and relapse prevention treatments. The two major goals of pharmaco-therapy are to relieve the severity of opiate withdrawal symptoms during themanaged withdrawal of the opioid and to prevent relapse to heroin useeither after abstinence initiation or after being stabilised on a long-actingopiate agonist, such as methadone.

Keywords: heroin, opiate, pharmacotherapy

Expert Opin. Pharmacother. (2004) 5(4):713-725

1. Overview of opiate dependence pharmacotherapy

A total of 8 million (0.14%) people worldwide use heroin, with the highest annualprevalence (2%) in South East and South-West Asia [1]. Based on the NationalHousehold Survey [2], the annual prevalence of heroin use in the US has been rela-tively stable at 0.3% since 1998 [3]. In spite of this relatively small number of poten-tial patients compared to other diseases, effective treatment is relatively unavailable.For example, methadone maintenance is available to only ∼ 15% of heroin addictsand most programmes have waiting lists for care. Because of this mismatch betweenprevalence and treatment availability, pharmacotherapy advances are aimed atexpanding the accessibility of long-term treatment. For example, buprenorphinetreatment in an office-based setting should expand available treatment slots andfacilitate general medical care of addicted individuals [4,5].

This review will focus on the rationale, indications and limitations of the range ofexisting medications for detoxification and relapse prevention treatments. The twomajor goals of pharmacotherapy are: relief of opiate withdrawal symptoms; andrelapse prevention either after abstinence initiation or after being stabilised on along-acting opiate agonist, such as methadone.

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Combating opiate dependence: a comparison among the available pharmacological options

714 Expert Opin. Pharmacother. (2004) 5(4)

2. Optimal practice

2.1 Range of pharmacotherapiesFor abstinence initiation, the standard approach uses metha-done substitution for heroin, followed by a gradual taperingin methadone dose. Alternative non-opioid detoxificationagents that have been developed include clonidine and lofexi-dine. Other non-opioid agents, such as benzodiazepines andNSAIDs, are often used to augment the effects of clonidineand lofexidine. The opioid antagonists naltrexone andnalmefene, have also been used during detoxification toshorten the duration of withdrawal symptoms. After success-ful detoxification, naltrexone is commonly used as an orallydelivered maintenance medication. Recently, depot formula-tions of naltrexone have been developed to last for about amonth after injection. Other opioid maintenance medicationsinclude the full opioid agonists, methadone and levo-α-acetyl-methadol (LAAM), and the partial opioid agonist, buprenor-phine. Maintenance on these agonist medications typicallydoes not require an initial detoxification. Office-basedbuprenorphine is the newest addition and promises to expandaccess to treatment.

2.2 Opiate agonist medications2.2.1 Methadone and levo-α-acetylmethadolMethadone is a synthetic, potent µ-opiate-receptor agonist.Methadone is 80% bound to blood proteins and has a longelimination half-life (24 – 36 h) facilitating its use for bothmanaged withdrawal and agonist maintenance [6]. Recently,there have been reports that very high doses of methadone(> 300 mg/day) have been associated with QT-interval prolon-gation [7]. Methadone maintenance dose for substitution ther-apy is usually 60 – 120 mg/day. One study showed thatregardless of methadone dose, there was an average of 10.8 msincrease from baseline to follow-up (p < 0.001) in the QTcinterval among heroin-dependent patients during inductionand stabilisation [8]. However, none of these patients had aclinically significant increase of the QTc interval, which is con-sidered an increase of > 40 ms or over the threshold of 500 ms.

LAAM is a derivative of methadone with a longer elimina-tion half-life and slower onset of action, which provides theadvantage of suppressing opiate withdrawal symptoms for> 72 h. Its long duration of action is likely to be related to twoactive metabolites, 1-α-noracetylmethadol (nor-levoacetyl-methadol) and 1-α-dinor-acetylmethadol (dinor-levoacetyl-methadol). Although oral LAAM is available and currentlyapproved for opiate maintenance, there are concerns about itsassociation with symptomatic cardiac arrhythmias and pro-longation of the QT interval that limit its use [9]. Thus, theuse of LAAM is contraindicated in patients with known orsuspected QT prolongation. Because of this effect, LAAM hasbeen withdrawn from the European market [10] and its pre-scription is limited to patients who have failed maintenancewith methadone in the US [11].

2.2.1.1 Managed withdrawal using methadoneManaged withdrawal using methadone first converts thepatient from heroin to a sufficient methadone dose to relievewithdrawal and then slowly decreases the methadone dose overseveral days or even months. The initial methadone dose istypically 20 mg but larger methadone doses (40 mg over thefirst 24 h) may be required in more severe opiate dependence.Once a stabilising dose has been reached, the methadone doseis tapered. For in-patients, this taper lasts 5 – 10 days as thedose is reduced by ∼ 20% of the starting dose each day. In out-patients, the dose may be more slowly tapered for as long as6 months [12]. Senay et al. [13] compared moderate (reductionsof 10% of initial dose per week) to slow (3% per week) out-patient methadone tapering and found higher drop-out rates,increased illicit opioid use and elevated levels of subjective dis-tress with the 10% decrements and recommended the slowdose-tapering rate. On such a slow regimen, successful detoxi-fication is still only achieved by 40% of out-patients, as meas-ured by completion of detoxification and a withdrawal-freenaloxone challenge test. In contrast, more rapid in-patienttapering (e.g., 10 days) can have an 80% success rate, whichhas led to an interest in these more rapid approaches [12].2.2.1.2 Methadone or levo-α-acetylmethadol maintenanceMethadone or LAAM maintenance substitutes a long-actingopiate for a short-acting opiate, such as heroin, and therebyreduces the fluctuations in opiate receptor stimulation,decreases withdrawal symptoms and through cross-tolerancedecreases the probability of relapse. Cross-tolerance reducesthe euphoric and reinforcing effects of further heroin con-sumption.

Methadone maintenance programmes continue to be themost effective treatment for opiate dependence by decreasingintravenous drug use and HIV infection [14-16]. These pro-grammes also improve social functioning through increasedemployment and decreased criminal activity [17]. Two studiesbefore the emergency of HIV [18,19] and two after [20,21] showdecreased mortality for those patients who continue pro-longed participation in methadone maintenance programmesand Barnett [22] showed an increment of 14,770 additionalyears of life for those clients who participated in prolongedtreatment during the HIV era compared to those who did notreceive treatment.

Pharmacological factors associated with better treatmentoutcomes include an optimal daily dose typically of60 – 100 mg and a slow reduction regimen for well-stabilisedpatients who decide to become abstinent from methadonetherapy. Some patients, whilst being treated for HIV infec-tion, may need doses of > 100 mg/day [23,24]. The length oftime necessary before a patient can be safely transitioned fromlong-term methadone maintenance to complete abstinence isstill a matter of controversy [21].

Oral LAAM is typically administered on a Mon-day–Wednesday–Friday schedule starting at 20 mg withincrements every other day for up to 4 – 6 weeks. Typical

Gonzalez, Oliveto & Kosten

Expert Opin. Pharmacother. (2004) 5(4) 715

weekly maintenance doses range between (50, 50, 70 mg) and(100, 100, 140 mg). Poor treatment retention with LAAMhas been attributed to the prolonged time for LAAM toachieve a steady-state blood level suggesting that more rapidinduction to higher doses might be successful. For example,Judson et al. [25] showed that 51% remained in treatmentwhen using a rapid induction schedule (20, 30, 40, 40 and50 mg) compared to only 23% of those who received a slowerinduction schedule (20, 20, 30, 30, 40, 40, 50, 50, 60, 60,70, 70 and 75 mg). Furthermore, Ling et al. [26] in a ran-domised, double-blind trial, showed that medium (50, 50,70 mg) and high (100, 100, 140 mg) induction doses werewell-tolerated with excellent retention or 83% for either dosegroup. Both studies suggest that most patients tolerate a1-week rapid induction on to medium to high doses and per-haps have improved treatment retention compared to slow,low-dose induction. However, Jones et al. [27] noticed thathigh-dose induction on to 100 mg by day 4 was associatedwith more drop-outs and agonist side effects than a medium-dose induction schedule using LAAM 30, 40 and 50 mg onthe days 2, 3 and 4 of active dosing. During induction, themost serious risk is overdose if patients use other opiates inconjunction with LAAM [28]. During maintenance Eissenberget al. [29] showed no significant differences in retention amongthe different doses but 34% of those assigned to high-doseLAAM (100, 100, 140 mg) were able to achieve 4 consecutiveweeks of opiate-free urines, compared to 14% assigned tomedium (50, 50, 70 mg) or 11% assigned to the low (20, 20,30 mg) doses. Finally, the LAAM withdrawal syndrome ismodest and Judson et al. [30] showed no retention differencesbetween patients getting abrupt and or gradual discontinua-tion from LAAM.

Some limitations of methadone or LAAM maintenanceprogrammes are the limited access to treatment slots and theneed for daily clinic attendance by clients early in treatment.Later in methadone treatment, patients are given take-homemethadone doses, but regulations on those doses still limittreatment capacity and no take-home doses are allowed withLAAM. Limited treatment access may be addressed in twoways. Firstly, less restrictive regulations for methadone pro-grammes may lead to more liberal use of take-home medica-tion. The creation of a new regulatory system based on anaccreditation model (e.g., Commission on Accreditation ofRehabilitation Facilities; CARF) and a shift of the administra-tive responsibility and oversight from the FDA to SubstanceAbuse and Mental Health Services Administration(SAMHSA), may allow such lessening in regulation [31,32].Secondly, methadone maintenance in physician’s offices or‘medical maintenance’ is an alternative format for take-homemethadone doses that has the potential of expanding metha-done maintenance services for those individuals who are psy-chosocially stable [33-35]. Take-home doses have problems,however, including diversion of methadone to the black mar-ket and fatalities due to accidental ingestion by minors.

3. The partial opiate-receptor agonist – buprenorphine

Buprenorphine is a high affinity, partial µ-opioid agonist that isused alone worldwide and used as a combination tablet ofbuprenorphine and naloxone in the US for substitution ther-apy [36,37]. The combination form of buprenorphine was devel-oped to reduce diversion to illicit intravenous use as suchadministration would precipitate severe withdrawal in an opi-ate-dependent individual. However, doses containing up tosublingual naloxone 6 mg with buprenorphine 24 mg can bedelivered sublingually without adverse reactions [38,39].Buprenorphine and its metabolite norbuprenorphine, achievessteady-state concentrations in ∼ 8 – 10 days [40]. As a partialagonist, buprenorphine has minimal risk of overdose from res-piratory depression and higher doses of buprenorphine simplyappear to increase the duration of its effects [41]. Because of itslong action, buprenorphine can be effectively administered inalternate day dosing and as infrequently as three times per week[39,42]. The ceiling effect of buprenorphine on agonist activitymay also limit its abuse liability [43,44] and this agonist ceilingleads to low toxicity even at high intravenous doses [45,46].

3.1 Managed withdrawalGowing et al. [47] reviewed five randomised or quasi-ran-domised, prospective, controlled studies comparing buprenor-phine to other treatments for managing opiate withdrawal andfound that four of five studies showed buprenorphine to besuperior to other pharmacotherapies for opiate detoxification[48-52]. In these studies, heroin-dependent candidates were tran-sitioned on to buprenorphine no sooner than 6 h since theirlast dose of heroin and they generally showed objective signs ofopiate withdrawal. Thus, clinical guidelines suggest that induc-tion on to buprenorphine [38,39,53,54] can start with buprenor-phine 4 mg plus naloxone 1 mg b.i.d. on day 1, buprenorphine8 mg plus naloxone 2 mg on day 2 and then increase the doseto 16/4 or 24/6 mg buprenorphine/naloxone, respectively, oversuccessive days, as clinically indicated.

Some controlled studies have shown that buprenorphinemay be superior to clonidine alone in reducing opiate with-drawal symptoms and successfully attaining opiate abstinence.For example O’Conner et al. [52] compared three out-patientdetoxification protocols (clonidine alone, clonidine and nal-trexone; and buprenorphine) in 162 heroin-dependentpatients using a randomised, double-blind design. Theyshowed that 81% of both the buprenorphine and the cloni-dine plus naltrexone groups were successfully detoxified com-pared to 65% of the clonidine alone group. A second study[49] showed that buprenorphine was more effective than cloni-dine in reducing opiate withdrawal symptoms in 44 opiate-dependent patients. Janiri et al. [50] showed that buprenor-phine significantly reduced withdrawal symptoms more thanclonidine or lefetamine among 39 patients being detoxifiedfrom methadone 10 mg (p < 0.05). Recently, Lintzeris et al.



[55] compared buprenorphine to clonidine for managed with-drawal in 114 heroin-dependent patients using an open-labelrandomised, controlled design that also had an outcome eval-uation at 4 weeks postwithdrawal. The results showed that thegroup treated with buprenorphine had better treatment reten-tion during the managed withdrawal phase (86 versus 57%)and at 4-week follow-up (62 versus 39%), used heroin fewerdays at both evaluation points (2.6 and 8.2 days versus 4.5and 14.6 days) and had less peak withdrawal discomfort (19.9versus 29.7 SOWS scores) relative to the clonidine group.Another study also evaluated buprenorphine to clonidine in a5-day protocol and showed that the buprenorphine-treatedgroup were more likely to successfully complete an out-patient detoxification programme [56]. However, one control-led study of rapid in-patient detoxification in 25 patients didnot show a significant difference between buprenorphine andclonidine [51]. Umbricht et al. [48], in a randomised, placebo-controlled design showed that adding naltrexone on day 2 ofthe buprenorphine taper significantly reduced opiate with-drawal symptoms during days 3 – 5 relative to the buprenor-phine taper alone. This more rapid symptom resolutionsuggests that naltrexone, in combination with buprenorphine,may be useful in reducing withdrawal symptoms and shorten-ing the length of detoxification. In conclusion, buprenor-phine appears useful in managing withdrawal but data on theclinical effectiveness for a longer duration of detoxification(e.g., > 2 weeks) are still limited [57,58].

3.2 Buprenorphine maintenancePatients inducted on to buprenorphine will usually be stabi-lised with sublingual doses of 12 – 16 mg/day. In a multi-centre randomised clinical trial, Ling et al. [59] showed thatpatients maintained on buprenorphine 8 or 16 mg/day duringa 16-week trial were more likely than patients maintained onbuprenorphine 1 mg per day to remain in treatment, increasetheir rate of opiate-free urines and report reduced opiate crav-ing. Other studies evaluating buprenorphine as a maintenanceagent using daily doses from 1.5 to 16 mg [60-62], have shownthat these doses are as efficacious as modest methadone dosesof ∼ 65 mg in treatment retention and suppressing withdrawalsymptoms. In a primary care setting, heroin-dependentpatients without psychiatric or substance-use comorbiditieswere successfully treated with buprenorphine 24 mg on Mon-day and Wednesday and 36 mg on Friday [63]. In a compari-son between different opiate substitution medications(methadone, LAAM and buprenorphine), Johnson et al. [64]

showed that methadone 60 – 100 mg, LAAM 75 – 115 mgand buprenorphine 16 – 32 mg were all effective and superiorto low-dose (20 mg) methadone.

Since 1996, any physician in France could prescribebuprenorphine 2 and 8 mg sublingually for ambulatory main-tenance of opiate-dependent patients. This policy was associ-ated with a decline of heroin use from 74 to 25% during1995 – 1997 and improvements in the social and medical sta-tus of opiate-dependent patients [65-67]. However, intravenous

drug use was reported by 12% of clients taking buprenor-phine compared to only 4% of those taking methadone. Fur-thermore, among all the intravenous poly-drug users(n = 198) sampled, 57% had used buprenorphine intrave-nously at least once during the previous 6 months, whereasamong those patients who were on buprenorphine mainte-nance (n = 112), 71% had used buprenorphine intravenouslyduring the previous 6 months [36]. Finally, deaths are associ-ated with intravenous injection of crushed buprenorphinetablets and concomitant use of mostly benzodiazepines [68-70].The buprenorphine–naloxone tablet in the US was developedto reduce this potential for misuse and death [71].

4. α2-Agonist medications: clonidine and lofexidine

Clonidine and lofexidine, respectively, are α2-adrenergic ago-nists that are commonly used non-opiate medications fordetoxification from opiates in the US and the UK. Activationof the presynaptic α2-receptors inhibits sympathetic outflowand reduces many withdrawal symptoms. Even though hypo-tension is a significant limitation of clonidine, lofexidine(0.2 and 3.2 mg) does not induce hypotension and effectivelyreduces opiate withdrawal symptoms [72-75].

4.1 Managed withdrawalGold et al. [76] initially reported amelioration of opioid with-drawal symptoms by clonidine. In subsequent studies, clonidinewas reported to reduce or eliminate lacrimation, rhinorrhoea,restlessness, muscle pain, joint pain and gastrointestinal symp-toms but lethargy and insomnia persisted [77]. Sedation and diz-ziness, due to orthostatic hypotension were reported as the mostsignificant side effects of clonidine. In the early protocols, cloni-dine 0.1 – 0.2 mg was administered every 4 – 6 h (as needed)for relieving withdrawal discomfort to a maximum of 1.2 mg, astolerated based on orthostatic hypotension or side effects. Thedetoxification lasted 5 – 7 days in heroin dependence and theclonidine dose was tapered during the last few days to avoidrebound hypertension, headaches and the re-emergence ofwithdrawal symptoms. In an early study [77], 80% of metha-done-maintained patients (taking 5 – 40 mg/day), but only36% of heroin-dependent patients were successfully detoxified.Charney et al. [78] replicated the 80% completion rate for cloni-dine-assisted methadone detoxification, but found that with-drawal symptoms of anxiety, restlessness, insomnia and muscleaches were the most resistant to clonidine treatment. An out-patient study comparing a slow methadone taper (at 1 mg dec-rements starting from methadone 20 mg/day) to clonidinedetoxification over 10 – 13 days demonstrated 40% successfulcompletion of detoxification for both treatments [79]. However,the authors noted that clonidine poses minimal risk of diversionto illicit use compared to methadone, it is not a controlled sub-stance and therefore, is more widely available to general physi-cians, and that it shortens the detoxification period from20 days (for the methadone taper) to 10 – 13 days.



Even though clonidine does not induce euphoria [76], it hasweak reinforcing properties in animals [80,81]. Although therehave been case reports of street abuse of clonidine [82], this hasnot become a widespread problem.

Lofexidine, an analogue of clonidine which is also an ago-nist at the α2-noradrenergic receptor, has shown promise as adetoxification agent and has been widely used for opiatedetoxification in Europe. In general, lofexidine is reported tobe equally effective to clonidine but to have fewer side effects[74,83,84]. For example, an Italian study [85] comparing lofexi-dine to clonidine in a 3-day detoxification regimen showedthat lofexidine significantly lowered the levels of withdrawalsymptoms, had fewer mood problems and had less sedationand hypotension than clonidine. This medication is currentlybeing tested for FDA-approval as an opiate detoxificationagent in the US.

5. Opiate-receptor antagonists: naltrexone

Naltrexone is an oral, long acting competitive antagonist atthe µ-opiate receptor. A daily dose of naltrexone 50 mg willblock the pharmacological effects of heroin 25 mg i.v. for aslong as 24 h and increasing the dose extends its duration ofaction to 48 h with 100 mg and 72 h with 150 mg. Naltrex-one is employed to accelerate opiate detoxification by displac-ing opiate agonists and as a maintenance agent for detoxifiedformerly opiate-dependent patients who want to remain opi-oid-free. The major problem with naltrexone maintenance-therapy is poor medication compliance compared to metha-done, whose agonist effects appear to enhance adherence totreatment. Monthly injectable depot naltrexone is being clini-cally tested in Phase III studies and may help surmount thisadherence barrier.

5.1 Managed withdrawal5.1.1 Rapid antagonist blockadeAlthough clonidine alone reduces some of the symptoms ofopiate withdrawal, it does not alter the time course of the with-drawal [86]. Introducing the opioid antagonist, naltrexone, dur-ing clonidine or lofexidine treatment of opiate withdrawal mayshorten the duration of withdrawal to ∼ 3 days withoutincreasing patient discomfort [87]. In rapid antagonist blockade(RAB), induction on to naltrexone may start with naltrexone12.5 mg on day 1, then increasing to 25 mg on day 2 and to50 mg on day 3 [52,88]. The dose of clonidine is typically0.1 – 0.2 mg every 4 h, but is individually determined eachday based on the severity of the withdrawal symptoms. Con-trolled studies comparing naltrexone plus clonidine to cloni-dine alone or to methadone tapering have found that theformer approach was well-tolerated and reduced the with-drawal period whilst improving retention [52,88-90]. An Italianstudy showed equal efficacy for clonidine compared to lofexi-dine when combined with naloxone and naltrexone for a 3-dayrapid detoxification [85]. However, lofexidine had fewer sideeffects, thereby making it more suitable for out-patient

settings. This study also allowed oxazepam, baclofen and keto-profene to be added during the detoxification, whichcomplicates the interpretation of the study. Finally, a laterstudy [48] further showed that stabilising patients on buprenor-phine for as little as 3 days before starting detoxification usingnaltrexone combined with clonidine was a safe interventionthat further shortened the duration of opioid detoxification to1 day, compared to the 3 days required when starting withpatients stabilised on methadone or using heroin.

Vining et al. [91] found that out-patients using RAB withclonidine plus naltrexone had a completion rate of 75% com-pared to 40% for methadone or clonidine alone. Diazepam10 mg b.i.d. on days 1 and 2 was found to be very effective forpersistent restlessness and muscle aches during the RAB. Sim-ilarly, O’Connor et al. [52] in a randomised, double-blind,clinical trial showed that 81% of the group treated with thecombination of naltrexone plus clonidine were detoxified suc-cessfully in comparison with 65% of the participants whoreceived clonidine alone. These findings suggest that naltrex-one is an effective and safe addition to clonidine in the man-agement of opiate withdrawal. The use of opiate antagonistsduring detoxification not only may safely reduce the length ofthe detoxification but also may facilitate greater success instarting these antagonists.

5.1.2 Ultra-rapid antagonist blockadeUltra-rapid antagonist blockade (URAB) using sedatives andanaesthetics, is a recent controversial extension of the cloni-dine–naltrexone combination approach for RAB. URAB wasfirst described in 12 opioid-dependent patients who weregiven naloxone while under general anaesthesia [92]. Loimeret al. [93] reported using barbiturate anaesthesia with metho-hexitone (100 mg i.v. pretreatment, followed by 400 mg i.v.)plus naltrexone (10 mg i.v.) to detoxify patients from opiatesin 48 h. This URAB required intensive medical treatmentincluding intubation and artificial ventilation and because ofthe risks of anaesthesia, its utility and safety has been contro-versial. A critical consideration is that untreated opiate with-drawal is generally not life-threatening and has no seriousmedical complications, while anaesthesia has known medicalrisks and mortality; several deaths related to this interventionhave been reported [94-96].

Subsequent studies of this technique have varied theapproach to sedation or general anaesthesia [96-98]. These stud-ies have generally been small and methodologically limited,have not compared URAB to other methods and have pro-vided little long-term follow-up [97,99]. One telephone follow-up study of detoxified patients found that only 10% continuednaltrexone maintenance therapy for 7 months [100]. Substantialwithdrawal symptoms also persist well beyond detoxification[98,101,102]. The utility of URAB is further limited by theexpense of this procedure, the additional risk associated withgeneral anaesthesia and other safety concerns [97,103,104]. Gen-eral anaesthesia with intubation avoids the significant risk ofvomiting and aspiration, which may occur with sedation but



safety concerns led to the termination of at least one clinicalprogramme providing URAB [105]. Many investigators havesuggested that the procedure should be limited to clinical trialsuntil its safety and efficacy can be further established [106].

Some follow-up data on URAB have been collected. Alba-nese et al. [107] evaluated the 6-month outcome data of 93 menand 27 women treated with ultra-rapid detoxification followedby naltrexone maintenance and an aftercare programme. Allthose enrolled reported to have not relapsed back to opiate useat 6 months, based on urine drug screen, the report of theirsignificant other and/or of their therapist. Hensel & Kox [108]

reported follow-up data from 72 opioid (morphine, codeine,heroin, methadone)-dependent patients detoxified using theultra-rapid method with propofol general anaesthesia and sub-sequently treated with long-term naltrexone maintenance anda supportive psychotherapy programme. After 12 months,49 patients (68%) were abstinent from opiates, 17 hadrelapsed and 6 were lost to follow-up. Both of these follow-upstudies had similar design limitations of being base on an opentrial, which lacked a comparison group and certainly had selec-tion bias. A recent study [109] included the design strength ofcomparison of URAB to an alternative method of 30-day in-patient detoxification and found that URAB was less effective.A total of 81 of 87, 30-day detoxification patients and 82 of139 URAB patients (93 versus 55%) were interviewed by tele-phone 12 – 18 months after programme participation. TheURAB was more expensive and less effective than traditionaltreatment. This study was limited by its retrospective designand non-randomised assignment but does not support anadvantage for URAB.

In conclusion, URAB remains controversial but may be anacceptable treatment to certain otherwise healthy patientsunwilling to interrupt their work or personal schedules for amore comprehensive treatment commitment. It may also pro-vide rapid induction to and maintenance on naltrexone. Nev-ertheless, the risks remain considerable and the long-termoutcomes do not support its relative efficacy over existingtreatments.

5.2 Naltrexone maintenanceNaltrexone maintenance typically involves an initial adminis-tration of 25 or 50 mg followed by one of the following dos-age schedules:

• 50 mg/day• 100 mg on Monday, 100 mg on Wednesday and 150 mg

on Friday• 150 mg on Monday and 200 mg on Thursday

Whereas Marrazzi et al. [110] found that high doses of naltrex-one (200 mg b.i.d.) used to treat eating disorders were notassociated with side effects or laboratory changes in liver func-tion, naltrexone has been associated with hepatotoxicity atdoses of > 200 mg/day. Thus, it is common clinical practice toevaluate liver function tests before starting patients on naltrex-one. Although the pharmacological properties of naltrexone

makes it promising for maintaining long-term abstinence, ithas had limited clinical use.

A meta-analysis of randomised control studies evaluatingnaltrexone, Kirchmayer et al. [111] found insufficient evidenceto evaluate its efficacy for opioid dependence. However,Shufman et al. [112] in a double-blind, controlled design evalu-ated the efficacy of naltrexone in reducing opioid-positiveurines during a 12-week trial found naltrexone to be superiorto placebo. Similarly, in a multi-site controlled trial with ran-dom allocation, Hollister [113] examined 170 opiate-dependentpatients at 9-months follow-up and found that the grouptreated with naltrexone had more opiate-free urines andreduced attrition rates. However, other studies [114-116] did notshow significant differences between treatment groups, prima-rily due to large dropout rates. Finally, Hulse et al. [117] evalu-ated treatment outcome at 6 months for 100 heroin-dependent patients maintained on naltrexone, defining successas a reduction to periodic heroin use or as complete absti-nence. Considering success as a reduction from daily to peri-odic heroin use rather than just complete abstinence, 60% ofthe subjects were still on naltrexone, although only ∼ 50%maintained complete abstinence and the rest had returned toperiodic heroin use, despite of naltrexone’s complete blockadeof heroin reinforcement. Thus, periodic heroin use during nal-trexone maintenance may not prevent successful outcomes inother areas of functioning including remaining in treatment.

In order to improve adherence to naltrexone, depot formula-tions have been developed. These experimental formulationsare composed of slow-release suspensions of microspheresadministered by intramuscular or subcutaneous injections,which can deliver therapeutic doses over a period of up to4 weeks after a single injection [118,119]. Its actions are identicalto those of orally administered naltrexone, which have substan-tial blockade of heroin effects by an antagonist effect on theopioid receptor. Clinical trials of depot naltrexone for opiatedependence are being supported by at least three manufacturers– Alkermes, Biotek and Drug Abuse Sciences and a differentimplantable formulation has been developed in Australia [120].Except for the Australian implant [95], once naltrexone depothas been administered the dose cannot be retrieved, so that thetherapeutic effect of naltrexone cannot be readily reversed dur-ing the month after dosing [119]. A promising recent study [121]

showed > 65% treatment retention with clinical improvementat 1 year follow-up among 156 heroin-dependent patients whowere treated with the subcutaneous implant.

To improve further the success of naltrexone, newapproaches are being developed in order to address the precip-itants of relapse, such as stress. Stress is known to increasedrug craving and risk of relapse to drugs [122-125]. Lofexidine,an α2-adrenergic agonist, has been shown to attenuate stress-induced reinstatement of opiate-seeking behaviour in labora-tory animals [126,127]. Thus, a pilot safety and preliminary effi-cacy study was conducted to evaluate the addition oflofexidine to naltrexone treatment for opiate addiction [128]. Atotal of 25 opiate-dependent individuals were recruited



immediately following opiate detoxification to participate in atwo-phase, 8-week study. In Phase I, upon initiation of nal-trexone 50 mg/day, subjects were randomly assigned to one ofthree dosing schedules in an open-dosing manner with aninduction on to an escalating dose of lofexidine starting at0.8 mg and titrated to a maximum dose of 2.4 mg/day. Opi-ate withdrawal symptoms, side effects, blood pressure andopiate urines were assessed three times weekly. A total of 18 of25 (72%) of subjects completed the 4-week, Phase I and thelofexidine and naltrexone combination was found to be toler-able and without any significant adverse events. In Phase II,subjects were randomised to either remain on lofexidine or betapered to placebo, in a double-blind, placebo-controlledmanner, whilst remaining on naltrexone 350 mg/week. Lofex-idine–naltrexone-treated subjects were significantly morelikely to remain opiate-free, had higher number of days ofcompliance with daily naltrexone and reported lower weeklyopiate craving and perceived stress as compared to naltrexone-placebo subjects. These findings suggest that the lofexi-dine–naltrexone combination is well-tolerated and that thecombined treatment may enhance opiate treatment outcomesby addressing stress related relapse.

6. Factors likely to affect choice of pharmacotherapy

The most important factor affecting choice of pharmacother-apy is the decision to attain and maintain abstinence fromopiates at the initiation of treatment or to use opioid agonistsubstitution therapy. This decision is typically based on sev-eral factors. Firstly, the severity and duration of opiatedependence. For example, patients who have been using opi-ates for < 1 year, particularly if they are adolescents, should beencouraged to undergo managed withdrawal with abstinenceas the treatment goal or to be inducted on to naltrexone main-tenance. Naltrexone can be highly effective if an interventionand support system can be mobilised to insure compliancewith the three times per week dosing. Depot naltrexone mayaddress this adherence challenge more effectively than currentoral formulations of naltrexone. Lofexidine during the firstfew months of naltrexone may be a useful addition in somepatients in order to improve naltrexone adherence. Secondly,long-term substitution therapy may not be immediately avail-able due to lack of treatment slots and long waiting lists andto local regulations that restrict this treatment (e.g., somestates in the US do not allow methadone maintenance).Whereas the availability of office-based buprenorphine inFrance and Australia have addressed successfully this accessissue, in the US there are currently insufficient physicians pre-scribing buprenorphine to adequately address this problem.Finally, patient preference and treatment history are also fac-tors involved in the decision-making process. Recurrent pastfailures at abstinence oriented treatments with or withoutmedication strongly suggest that substitution therapy is

warranted. These patients are best placed directly on to main-tenance treatment with methadone or buprenorphine with agoal of at least 2 years on the medication with urine monitor-ing to ensure a reduction in illicit opiate use. Medication dos-age is critical for the success of these maintenance treatmentsin order to provide reduction in craving and cross-tolerance tothe effects of illicit heroin use.

If naltrexone induction or medication-free treatment isplanned, then management of opiate withdrawal needs con-sideration. Most patients prefer using methadone for a detoxi-fication that will be extended over several weeks but a morerapid detoxification using clonidine or lofexidine is likely tohave greater success at getting the patient started on naltrex-one or in becoming opiate-free. Rapid detoxification usingclonidine with naltrexone can be facilitated by an initial sev-eral days on buprenorphine (Suboxone®) and most patientswelcome this buprenorphine stabilisation, which as with thedetoxification itself, can be done in an out-patient setting.

Adverse effects of opiate agonists or α-adrenergic agonistsas detoxification agents are quite different during the initialdoses, but the break-through of opiate withdrawal symptomscan occur with either approach. The α-adrenergic agonists,such as clonidine, produce sedation and orthostatic hypoten-sion and even with the addition of benzodiazepines, oftenprovide incomplete symptom relief throughout a relativelybrief detoxification where peak symptoms from heroin occurat day 3 and most symptoms subside by day 7. In contrast,modest doses of opiate agonists, such as methadone orbuprenorphine, relieve most all symptoms, including cravingbut as these medication doses are tapered down, opiate with-drawal symptoms emerge. Thus, in a 21 day tapering schedulefor methadone the last 7 days (days 14 – 21) are typicallyunpleasant due to low-level withdrawal symptoms of nausea,diarrhoea, anxiety, insomnia and drug craving.

Adverse effects of maintenance agents also differ substan-tially. Constipation and sedation frequently occur with meth-adone treatment, whereas headache occurs withbuprenorphine treatment in a minority of patients. Ifpatients have very large amounts of opiate consumption (e.g.,methadone > 60 mg/day), then treatment with buprenor-phine may precipitate opiate withdrawal that may last for24 – 48 h. For naltrexone, the typical adverse events resembleopiate withdrawal including nausea, vomiting, diarrhoea,anxiety and drug craving. These adverse effects often clearwithin a few days and lofexidine or clonidine treatment maybe helpful.

Potential efficacy of these treatments in unselected patientsfavours substitution therapy with either methadone orbuprenorphine rather than detoxification and maintenance onnaltrexone. Whether depot naltrexone or sustained lofexidinetreatment may improve the potential efficacy of naltrexone isan interesting question for future research. The induction onto naltrexone is clearly more successful with RAB proceduresthan using either clonidine alone or methadone tapering.



7. Summary and conclusions

The heroin epidemic has been escalating over the last decadebut the development of new pharmacotherapies such asbuprenorphine and rapid clonidine or lofexidine plus naltrex-one detoxification are augmenting the options of the alreadyproven efficacy of methadone. RAB has reduced the cost andimproved the efficacy of induction on to the antagonist, nal-trexone, for maintenance of abstinence. A long-acting depotnaltrexone, requiring only monthly administrations, can alsoimprove adherence with this pharmacologically effective treat-ment. Adding lofexidine to naltrexone during the first fewmonths of treatment may be useful for reducing stress-inducedrelapse and is being assessed in several ongoing clinical trials.

For maintenance treatment the long acting form of metha-done (LAAM) appears to have limited utility due to cardiaccomplications (QT-interval prolongation). However, one ofthe most promising new developments in the US is animprovement in the delivery system for opioid maintenanceusing office-based buprenorphine. In France, this approachhas successfully reduced overdose deaths, improved publichealth related to the transmission of AIDS and hepatitis andreplaced criminal activity with more pro-social activities byformer heroin addicts. Thus, new treatments are available forthis worldwide epidemic of heroin dependence and its associ-ated complications including AIDS.

8. Expert opinion

Most opiate-dependent patients prefer maintenance stabili-sation treatment on methadone or buprenorphine. Metha-done programmes in the US are highly structured and havelimited access relative to demand, however. The relatively

rigid structure of US methadone programmes make themunacceptable to some patients but internationally, metha-done is more readily available in more acceptable office-basedsettings. Buprenorphine plus naloxone (Suboxone) is nowavailable in the US for office-based practice [63,129,130] andthis approach is expected to increase the access to treatmentby transferring stable methadone maintained patients out ofmethadone clinics and opening methadone treatment slotsfor more complex patients, by increasing the number ofuncomplicated heroin-dependent patients treated directlyfrom office-based or primary care settings. However, thisapproach in the US has had a relatively slow start in develop-ing a sufficient number of physicians prescribing the medica-tion. The barriers to suboxone prescribing include a specialcertification requirement through the Drug EnforcementAdministration, as well as uneasiness of psychiatrists and gen-eral practice physicians in treating heroin-dependent individ-uals. The ∼ 10 times higher cost of suboxone compared tomethadone has also been a financial barrier to using subox-one. Nevertheless, suboxone use is expected to expand in theUS, although it is unlikely to be as widespread as buprenor-phine use in Australia or France, where it has had a majorpublic health impact in reducing overdose deaths and variousinfectious diseases related to intravenous drug use [131,132].

The alternative maintenance treatment uses naltrexone, anopiate antagonist and in the future may use nalmefene, a sim-ilar orally effective antagonist [133]. In order to start theseantagonists, the patient must be fully withdrawn from opiate

Box 1. Key issues.

• Maintenance treatment to prevent relapse is preferred to simple detoxification because of the high relapse to opiate abuse without continued treatment

• Maintenance on opioid agonist is most commonly used option in the US using methadone but buprenorphine (Suboxone®) has become available for office-based practice and is hoped to be as successful as it has been in France and Australia

• Detoxification has become more cost-effective using clonidine, particularly in combination with naltrexone precipitation of withdrawal

• Lofexidine availability in the US is expected to improve upon clonidine-assisted withdrawal treatments, as it has in many European countries

• Depot forms of naltrexone are in successful clinical devel-opment and can address adherence problems to compro-mise the efficacy of opiate antagonist treatment

• Stress-induced relapse during naltrexone maintenance may be reduced by sustained treatment of several months with lofexidine after detoxification is completed

Box 2. Information resource guide.

Manufacturer information (Reckitt Benkizer)• http://www.suboxone.com; E-mail: [email protected];

Tel: (800) 444-7599Frequently asked questions from the CSAT website• http://buprenorphine.samhsa.gov/faq.htmlModel Policy Guidelines from the Federation of State Medical Boards• http://buprenorphine.samhsa.gov/model.htmlInformation on Suboxone and Subutex are available from the FDA website• http://www.fda.gov/cder/drug/infop-

age/subutex_suboxone/default.htmThe CSAT buprenorphine website• http://buprenorphine.samhsa.gov/Information on obtaining training to meet the requirements set out in the Drug Addiction Treatment Act of 2000 and the use of Suboxone and Subutex• http://buprenorphine.samhsa.gov/training.htmlInformation on the Drug Addiction Treatment Act of 2000 waiver process• http://buprenor-

phine.samhsa.gov/waiver_qualifications.htmlThe SAMHSA treatment facility locator a list of physicians who have waivers• http://buprenorphine.samhsa.gov/bwns_locator/



dependence. The standard approach has been to place thepatient on a modest dose of methadone (e.g.,20 – 40 mg/day) and then taper down the dose over as little as5 days or as long as several months. This approach has hadlimited success, particularly in getting patients then main-tained on naltrexone. More successful approaches to naltrex-one induction have involved clonidine or lofexidine toattenuate withdrawal symptoms. These medications are oftenaugmented by ancillary medications for sleep, anxiety andgastrointestinal symptoms. The detoxification procedure itselfhas been made more efficient by combining these ameliorat-ing medications with naltrexone to precipitate opiate with-drawal. Using these RAB approaches, patients have beeninducted on to naltrexone within 3 days. Most recently,patients have been first transitioned to buprenorphine2 – 8 mg/day for several days and then given a RAB treatmentthat can be completed within a day. An alternative 1-dayapproach has been URAB using general anaesthesia combinedwith naltrexone precipitation of withdrawal. This costlyURAB approach has had significant medical complicationsand is generally not recommended.

After induction on to naltrexone, adherence can be a seriousproblem in the utility of this treatment. To improve adherenceseveral new depot naltrexone formulations are being developed.These depot formulations last ∼ 1 month after a single injec-tion and have been safe and effective during Phase II and IIIclinical trials. A summary of the key issues in combating opiatedependence can be found in Box 1. Further information onbuprenorphine can be found at the websites listed in Box 2.

9. 5-year view

Over the next 5 years, the expected treatment advances will bein the availability of new agents and the widespread availabil-ity of buprenorphine in the US. Two expected new agents formaintenance and relapse prevention are depot naltrexone andpossibly an alternative oral opiate antagonist – nalmefene.Lofexidine, a new detoxification agent, which has been availa-ble and widely used in Europe for many years, will probablybecome available in the US. Lofexidine may also be useful forsustained treatment of several months after detoxification iscompleted in order to reduce stress-induced relapse duringnaltrexone maintenance. The procedure of URAB appears tobe problematic and may become relatively unavailable, at leastin the US. The option of LAAM use as an agonist mainte-nance agent will probably be limited to methadone mainte-nance failures who do not have prolonged QTc at treatmententry. Finally, the widespread availability of suboxone in theUS should increase access to opiate stabilisation treatmentthrough office-based settings, whereas methadone mainte-nance may also get greater access through office-based settingsfor well-stabilised, successfully treated patients.

Acknowledgements

This work was supported by the National Institute on DrugAbuse Grant 1K23DA14331 (GG), K05-DA00454 (TRK),P50-DA12762, R01-DA05626 and Department of VeteransAffairs, New England MIRECC.

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AffiliationGerardo Gonzalez MD†, Alison Oliveto PhD & Thomas R Kosten MD†Author for correspondenceDepartment of Psychiatry, Division of Substance Abuse, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USATel: +1 203 937 5453;Fax: +1 203 937 3478;E-mail: [email protected]

Combating opiate dependence: a comparison among the available pharmacological options

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