Opioid agonists

All opioids, including heroin and methadone, are agonists that stimulate opioid receptors. Many opioid agonists are also prescribed for their analgesic properties in pain management, including morphine, codeine, dihydrocodeine, oxycodone, hydrocodone and fentanyl.

Partial agonists

Buprenorphine is a partial agonist at the μ opioid receptor subtype, which means that the system is not fully stimulated even when all the receptors are occupied. This lesser effect is the main contributory mechanism underlying buprenorphine’s better safety profile when taken alone, since the threshold for respiratory depression is not reached even when all the receptors are occupied (Walsh et al., 1994).

As a partial agonist, buprenorphine can also appear to act as an antagonist (and as such may have been described in older literature as a mixed agonist-antagonist). If buprenorphine is given to a person who has taken a full agonist (for example, heroin or methadone), it displaces the full agonist, due to buprenorphine’s higher affinity at the μ opioid receptor, but only partially stimulates these receptors. The difference in activation results in the individual experiencing withdrawal. This can be seen when people convert from their street drug or high-dose methadone to buprenorphine. Therefore a partial agonist behaves like an agonist in the presence of no other agonist; in the presence of high levels of an opioid agonist, it behaves like an antagonist.

Buprenorphine is also an antagonist at the κ receptor and therefore may be less likely to lower mood compared with an agonist.

Tramadol is a more complex drug; its pharmacology is currently not well understood, but it could either be a low-potency μ agonist or a partial agonist. It is more commonly used in the context of pain relief.

Antagonists

An antagonist, such as naltrexone or naloxone, binds to the receptor but does not stimulate it. Naltrexone and naloxone have a high affinity with opioid receptors, such that they will displace existing agonists and prevent further agonists from binding to the receptors. Therefore if an agonist is present stimulating the receptor, for example heroin or methadone, taking naltrexone or naloxone will stop this stimulation, resulting in precipitated (abrupt) withdrawal. For these reasons, naloxone is commonly used in emergency medicine to reverse opioid overdose, while the longer acting naltrexone is prescribed as a maintenance treatment to prevent detoxified service users from relapsing to opioid use.

Tolerance

If opioids are taken repeatedly, their effects are diminished due to the development of tolerance. This means that, in order to achieve the same effect, more of the drug has to be taken. Depending on the effect, tolerance can occur at different rates; for instance, tolerance to euphoria occurs much faster than tolerance to respiratory depression.

Such pharmacological tolerance to opioids is not clearly defined in the literature, but it is likely that it involves changes in opioid receptor availability and function through changes within the cell or effects on other neurotransmitter systems, for example noradrenaline (Maldonado, 1997). In a dependent opioid user, changes in the brain’s circuitry (involving reward, learning and impulse control) also occur. The brain’s opioid system is thought to play a significant role in mediating reward to other drugs of misuse including alcohol and cocaine (Herz, 1997; Van Ree et al., 2000). Tolerance can also vary depending on the context or environment in which the opioid is being taken and can lead to a dose of opioids producing more or less of an effect than expected (Siegel et al., 1982).

Withdrawal

When a person who has become tolerant to the effects of a drug stops taking it, withdrawal symptoms ensue. These may vary in their intensity depending on the level of opioid use as well as other factors such as context and environment. Minimising these symptoms, which emerge within 6–12 hours from short-acting opioids such as heroin and about 24–36 hours after the last dose of methadone or buprenorphine, depending on the dose, is the main aim in any opioid detoxification programme. Although previously divided into psychological and physical symptoms, such a distinction has limited clinical utility given that physical withdrawal can have a large psychological component. Withdrawal can also ensue when an opioid antagonist, such as naloxone or naltrexone is taken; this is called precipitated or abrupt withdrawal. While the withdrawal syndrome for opioids is rarely life-threatening (unlike that for alcohol, due to the potential for seizures and delirium tremens), the discomfort for some people makes it hard to withstand.

Opioid withdrawal consists of a constellation of symptoms, such as pupil dilation, diarrhoea, low mood, irritability, anxiety, insomnia, muscular and abdominal pains, restlessness and ‘craving’. In addition, tachycardia, sweating, runny nose, hair standing on end, shivering, goosebumps (hence the term ‘going cold turkey’) are generally experienced. The latter symptoms are known to be associated with hyperactivity of the noradrenaline system (called a ‘noradrenergic storm’) that occurs to compensate for tolerance at the opioid receptor. This provides the rationale and clinical efficacy for using medication that reduces noradrenergic activity, such as lofexidine or clonidine (alpha₂ adrenergic agonists).

The contribution of changes in the opioid system directly producing withdrawal symptoms is less clear, although increased receptor availability has been shown (Williams, 2007). Gradual reductions of opioid medication should result in the complete absence of, or minimal, withdrawal symptoms. However, medication acting on the noradrenergic system will only ameliorate particular symptoms (see above), necessitating use of other medications to manage all withdrawal symptoms.

The role of the GABA-benzodiazepine receptor is also not certain, but opioids taken over long periods can alter this system (Sivam et al., 1982; Rocha et al., 1993), which may be the basis on which benzodiazepines (such as diazepam and temazepam) are often prescribed during detoxification or used by dependent opioid users when they cannot obtain heroin.

Opioid agonists and partial agonists

The most straightforward pharmacological approach to detoxify a dependent opioid user is by reducing over a period the dose of an opioid substitute medication, for example methadone or buprenorphine. As described above, this should cover all the symptoms of withdrawal. Depending on the substitute medication and starting dose, detoxification can take days to months. For methadone, the most rapid regimes last 7–21 days, while ‘slow tapering’ regimens can last up to 6 months or longer (DH, 1999). Detoxification with buprenorphine is usually faster than with methadone, and can in theory be completed within less than a week, though 14 days to several weeks appears to be typical.

Although it is pharmacologically possible to detoxify directly via tapered doses of heroin (indeed any opioid agonist), this is rarely recommended clinically because the short elimination half-life of heroin results in a particularly acute and intense withdrawal syndrome. Illicit heroin users are normally first stabilised on an opioid substitute prior to starting detoxification.

Opioid antagonists

Opioid antagonists such as naltrexone and naloxone may be used to speed up the process of detoxification. The aim is to flood the brain with an opioid antagonist to remove all agonists and fully occupy the opioid receptors. If given at the start of detoxification, this will lead to abrupt withdrawal for a dependent user with opioids in his or her system, which can be subjectively extremely unpleasant, depending on the amount of agonist present. Sedation or general anaesthesia are likely to be used here, alongside a variety of adjunctive medications, to minimise discomfort. The service user is then generally maintained on naltrexone to prevent relapse. Use of opioid antagonists in this way is often referred to as ultra-rapid or rapid detoxification and is covered in detail in Section 6.5.

Alternatively, to minimise discomfort, naloxone or naltrexone is started after a few days of detoxification and not at full dose, thus shortening and speeding up detoxification while avoiding the requirement for sedation or general anaesthesia. This approach is covered in greater detail also in Section 6.5.

Adjunctive medications

Adjunctive medications are used to ameliorate symptoms of opioid withdrawal, and the term covers a wide number of medications and uses. Those that target the noradrenaline system, including clonidine and lofexidine, alter a brain system known to be involved in mediating a cluster of opioid withdrawal symptoms and signs. Other forms of adjunctive medications are directed at a specific symptom, such as an antispasmodic for gut cramps, or a collection of symptoms, for instance benzodiazepines for anxiolysis and sedation or antipsychotics for agitation or sedation.

Adjunctive medications are often used during detoxification. Their use is particularly important when conducting a detoxification with non-opioid drugs, such as clonidine or lofexidine, since they are not able to cover all withdrawal symptoms. However, the use of adjunctive medications for symptoms, such as for sedation, is also not uncommon during a detoxification using opioid medications (for example, methadone or buprenorphine).

Therefore it is critical when comparing detoxification regimens in the trials reviewed below that the use of adjunctive medication is taken into consideration. This is especially important when comparing opioids (methadone or buprenorphine) with alpha₂ adrenergic agonists (clonidine or lofexidine).

The use of opioid antagonists in addition to other medications is not considered here as a form of adjunctive medication since they do not ameliorate symptoms of withdrawal, although their use can shorten or accelerate detoxification (see above).

Current practice

In the UK, only methadone and buprenorphine are licensed as substitute opioids for the management of opioid dependence. In addition, lofexidine is licensed for symptomatic relief during opioid detoxification. These medications are currently used in the vast majority of opioid detoxifications in the UK. A minority of detoxifications within specialist drug services have involved medications unlicensed for detoxification, including clonidine, naltrexone and dihydrocodeine (Day et al., 2005). Dihydrocodeine has also been used in some primary care and criminal justice settings for opioid detoxification (Wright et al., 2007a).

There appears to be widespread administration of adjunctive medications, most notably benzodiazepines, alongside a ‘core’ medication for the management of opioid withdrawal symptoms, but a review of UK practice has not been conducted to assess how such adjunctive medication is being prescribed.

In addition, there are a number of service users who have attempted unassisted detoxification (Gossop et al., 1991; Noble et al., 2002; Scherbaum et al., 2005; Ison et al., 2006). This is discussed in more detail in Chapter 8.

Abstinence

This refers to evidence for the absence of opioid use at a particular time point (for example, at the end of treatment or at 3-month follow-up). Measures based on urinalysis or other forms of chemical testing were preferred, but self-report measures were not excluded. However, outcomes relating to abstinence, in particular at follow-up, were not widely reported in the trials identified by the evidence search. Although in the majority of studies abstinence was clearly the important long-term goal of detoxification, in some detoxification resulted in the participant being re-established on substitute medication.

Completion of treatment

This is regarded as an important proxy measure of detoxification success. Completion has typically been defined as being retained in treatment up to the final day of its planned duration, ingestion of the final dose of study medication, or reaching the point of zero dose of study medication.

Adverse events

Adverse events are a potentially serious consequence of detoxification and may result in significant negative impact on the individual’s well-being or in the individual being removed from a study (with some requiring medical attention). Significant concerns have been raised over serious adverse events, including death, especially in relation to rapid and ultra-rapid detoxification, and the sedation and anaesthesia procedures involved (Strang et al., 1997a).

Respiratory depression

The following applies to whenever methadone and buprenorphine are being prescribed rather than particularly referring to the process of detoxification.

As a full μ opioid agonist, methadone can result in respiratory depression. Therefore initiation should be undertaken with care (NICE, 2006c). However, some degree of tolerance to its respiratory depressive effects occurs after a period of methadone use. By contrast, buprenorphine, as a partial agonist at the μ opioid receptor, is not associated with significant respiratory depression when taken at therapeutic doses. During detoxification and in early abstinence, it is presumed that any tolerance to respiratory depression is lost, leading to the warning about potential for ‘overdose’ and death from respiratory depression.

However, it is important to remember that for both methadone and buprenorphine, interactions with other respiratory depressants such as alcohol, benzodiazepines and the newer non-benzodiazepine hypnotics (Z-drugs), other sedatives or tricyclic antidepressants may also induce serious respiratory depression (NICE, 2006c). The additive or synergistic effects of such depressant drugs, particularly alcohol or benzodiazepines, may play a contributory role in deaths involving either methadone, buprenorphine or other opioid agonists (White & Irvine, 1999; Corkery et al., 2004; Pirnay et al., 2004). Warning individuals about ‘potential for overdose’ should extend to include concurrent use of respiratory depressant drugs.

Severity of withdrawal

This was generally not reported comprehensively; that is, data were rarely presented for each day over the entire duration of detoxification. The most frequently used scales were the Subjective Opiate Withdrawal Scale and Short Opiate Withdrawal Scale. There was sparse reporting of more protracted withdrawal symptoms that may persist after completion of detoxification. In this analysis, withdrawal scores are presented as: peak (mean maximum score), lowest (mean minimum score), overall (total or mean score over the duration of detoxification) and mean change from baseline (the difference between mean overall score and mean score at baseline). Subjective rather than objective measures of withdrawal were used, as the former were judged by the GDG as more representative of service-user acceptability. In addition, while it is clearly important to use such validated withdrawal scales in trials, the GDG felt that in routine clinical practice these scales should not replace good clinical skills or knowledge, but that consideration could be given to using them to complement good clinical assessment.

Methadone

For comparisons of methadone against other opioid agonists, clonidine or lofexidine, 12 RCTs (BEARN1996; GERRA2000; HOWELLS2002; JIANG1993; KLEBER1985; SALEHI2006; SAN1990; SORENSEN1982; TENNANT1975; TENNANT1978; UMBRICHT2003; WASHTON1980) met the eligibility criteria, providing data on 712 participants. All studies were published in peer-reviewed journals (see Table 3 and Table 4 for further details on study information, critical outcomes and overall quality of evidence). The forest plots and full evidence profiles can be found in Appendix 16 and Appendix 17, respectively.

Table 3

Study information table for trials of methadone for opioid detoxification.

Table 4

Summary evidence table for trials of methadone for opioid detoxification.

Comparisons of methadone against buprenorphine are reviewed separately in the section on buprenorphine below.

Table 4 and Table 5 show studies comparing methadone with an alpha₂ adrenergic agonist. It was found that methadone had a better adverse–event profile, especially in relation to hypotension (versus clonidine), and that it was associated with better completion of detoxification (versus lofexidine). Where described in these trials, additional adjunct medications were typically not used in either treatment arm (clonidine/lofexidine or methadone).

Table 5

Adjunct medications, symptoms and adverse events for opioid detoxification.

Methadone did not differ in efficacy compared with other opioid agonists (propoxyphene napsylate, levo-alpha acetylmethadol [LAAM], tramadol). These are neither licensed nor routinely used in the UK for the treatment of opioid dependence.

Buprenorphine

For comparisons of buprenorphine with methadone, clonidine or lofexidine, 12 RCTs (CHESKIN1994; JANIRI1994; JOHNSON1992; LING2005; LINTZERIS2002; MARSCH2005; NIGAM1993; O’CONNOR1997; PETITJEAN2002; RAISTRICK2005; SEIFERT2002; UMBRICHT2003) met the eligibility criteria, providing data on 653 participants. While the sublingual preparation of buprenorphine was most commonly used, one study (LING2005) used the buprenorphine-naloxone preparation, and in one study all participants received carbamazepine in both the buprenorphine and methadone groups (SEIFERT2002). Most of the included studies were of adults but one study was of adolescents (MARSCH2005). In addition, one cluster-randomised trial (PONIZOVSKY2006) compared buprenorphine with methadone; this study was not included in the meta-analysis. All were published in peer-reviewed journals, with additional unpublished data for one trial provided by the authors (RAISTRICK2005). For further details on study information, critical outcomes and overall quality of evidence see Table 6, Table 7 and Table 8. The forest plots and full evidence profiles can be found in Appendix 16 and Appendix 17, respectively.

Table 6

Study information table for trials of buprenorphine for opioid detoxification.

Table 7

Summary evidence table for trials of buprenorphine for opioid detoxification.

Table 8

Adjunct medications, symptoms and adverse events for buprenorphine detoxification.

Comparisons of buprenorphine with dihydrocodeine are reviewed separately in the section on dihydrocodeine below.

All individual RCTs were included in the meta-analyses (see Table 7). People who underwent buprenorphine detoxification achieved clearly better outcomes on most measures, including completion, abstinence and withdrawal severity, compared with those who used clonidine or lofexidine. Buprenorphine did not differ significantly from methadone on completion rate for detoxification; however, no extractable data were available for abstinence outcomes.

Ponizovsky and colleagues’ (2006) cluster-randomised trial was not included in the meta-analysis and is thus summarised here. Opioid-dependent participants were randomised to receive a 10-day inpatient detoxification using either buprenorphine (n = 100) or clonidine (n = 100) depending on which hospital they attended. The clonidine protocol also included the use of adjunctive medications as indicated (promethazine, dipyrone, trazodone, phenobarbital and antiemetics). Some 90% of the buprenorphine group completed detoxification, compared with only 50% in the clonidine group, a significant difference (RR = 1.80, 95% CI: 1.46 to 2.21). Abstinence outcomes were not reported. This result was consistent with the other buprenorphine trials meta-analysed above.

Dihydrocodeine

Dihydrocodeine is an opioid agonist licensed in the UK for pain relief. It has also been used in a range of UK settings as a substitute medication for opioid dependence both in maintenance and detoxification (Day et al., 2005; Strang et al., 2005; Wright et al., 2007a, b).

Two RCTs (WRIGHT 2007A; SHEARD 2007B) comparing dihydrocodeine with buprenorphine met the eligibility criteria, providing data on 150 participants. Protocols for both studies were published in peer-reviewed journals, with unpublished data for both trials provided by the authors (see Table 9 and Table 10 for further details on study information, critical outcomes and overall quality of evidence). The forest plots and full evidence profiles can be found in Appendix 16 and Appendix 17, respectively.

Table 9

Study information and summary evidence table for trials of dihydrocodeine for opioid detoxification.

Table 10

Adjunct medications, symptoms and adverse events for dihydrocodeine detoxification.

People undergoing dihydrocodeine detoxification were less likely to be abstinent at the end of treatment, and appeared to be no more likely to complete detoxification, than those receiving buprenorphine. There is little justification to recommend the routine use of dihydrocodeine in detoxification.

Alpha₂ adrenergic agonists

The evidence for alpha₂ adrenergic agonists is described in 6.2.7.

Benzodiazepines

Although benzodiazepines are often prescribed as an adjunct during detoxification to treat a range of symptoms such as insomnia, anxiety or agitation, the efficacy of two benzodiazepines compared with an opioid agonist for opioid detoxification has been studied. One study (DRUMMOND1989) compared chlordiazepoxide with methadone and another oxazepam with buprenorphine (SCHNEIDER2000). In the latter study, both groups also received carbamazepine. Both studies had small sample sizes providing data on 51 participants in total.

Evidence from critical outcomes and overall quality of evidence are presented in Table 13. The forest plots and full evidence profiles can be found in Appendix 16 and Appendix 17, respectively. The meta-analysis failed to find a difference between the use of benzodiazepines and opioid agonists for completion of detoxification treatment (see Table 13).

Table 13

Study information and summary evidence table for trials of benzodiazepines for opioid detoxification.

Alternatively, two studies have investigated the use of a benzodiazepine as an adjunct to a reducing methadone regimen. One placebo-controlled crossover study compared diazepam with doxepin, a tricyclic antidepressant, as an adjunct in outpatient methadone detoxification (McCaul et al., 1984). Participants were randomised to receive diazepam (n = 10) or doxepin (n = 13) over the 10-week methadone taper period, and initially received their assigned medication in a range of doses, in a random order. In the final 4 weeks of detoxification, participants could self-administer the assigned medication in an intermediate dose, which could then be titrated. A greater proportion (RR = 6.50; 95% CI 0.90 to 47.19) of the diazepam group (five of ten) completed detoxification in comparison with the doxepin group (1 of 13), who also presented a greater proportion of opioid-positive urines throughout detoxification. However, given the wide scope for within-group variability in dosing schedules, it is not possible to draw any firm conclusions from the above findings.

Preston and colleagues (1984) also conducted a placebo-controlled crossover study, comparing oxazepam and clonidine as adjuncts to methadone detoxification. Six participants were assigned to each group on the basis of baseline characteristics. During each 5-day period for 30 days, participants received their assigned medication (oxazepam 20 mg/day, or clonidine 0.2 mg/day) and placebo capsules, in a random order. Participants then received either capsule of their choice. All participants were tapered from 50 mg methadone to zero over the first 15 days of the study. The authors found that neither clonidine nor oxazepam significantly reduced withdrawal severity relative to their respective placebo control conditions, and likewise self-administration of the active medications had no effect on withdrawal severity.

Carbamazepine

Carbamazepine, an anticonvulsant, can be used to treat alcohol or benzodiazepine withdrawal (Schweizer et al., 1991) and has been studied in cocaine dependence (though not found to be effective; Lima Reisser et al., 2002) as well as being used for a variety of neuropsychiatric conditions. Therefore, the rationale of using it as an adjunct in opioid detoxification is to ascertain whether carbamazepine improved outcome in polydrug users. Two studies have given carbamazepine to all patients when comparing methadone and buprenorphine detoxification (SEIFERT2002) and when comparing oxazepam and clonidine as adjuncts in methadone detoxification (SCHNEIDER2000). However, in neither study was there a group not given carbamazepine, thus it is not possible to deduce if it does improve outcome in polydrug users.

Dosage of methadone

Table 15 summarises study information and evidence from studies comparing high and moderate starting doses. The forest plots and full evidence profiles can be found in Appendix 16 and Appendix 17, respectively.

Table 15

Study information and summary evidence table for trials of methadone dosages in detoxification.

In both studies participants were on methadone and on what may be considered as slow taper regimens, consisting of a 6-month stabilisation phase followed by a detoxification phase of 70 days (STRAIN1999) or 78 days (BANYS1994). It appears that for this type of detoxification regimen, beginning with a high dose of methadone at the stabilisation phase is more effective than a moderate dose and that this continues to affect abstinence during treatment and completion of detoxification.

Duration of methadone taper

Three double-blind RCTs compared different durations of methadone detoxification.

Senay and colleagues (1981) randomised participants to an 84-day methadone taper (n = 37), or a 21-day taper followed by placebo for the remainder of the study period (n = 35). The two groups did not differ in completion rate or abstinence at the end of the active medication period, or abstinence at 1-year follow-up. Sorensen and colleagues (1982) similarly found no significant difference in completion rate for a 21-day methadone taper (n = 15) versus a 42-day methadone taper (n = 18).

Stitzer and colleagues (1984) randomised participants undergoing a 90-day detoxification programme to taper from 60 mg methadone over 70 days (n = 13), or from 30 mg over 28 days (n = 13). There was no significant difference between groups in treatment retention.

In addition, one quasi-experimental study conducted by Gossop and colleagues (1989) in two inpatient detoxification facilities in London compared a 10-day methadone taper (n = 50) against a 21-day methadone taper (n = 82). The 10-day group reported a significantly higher peak withdrawal score on the OWS than the 21-day group (t = 1.79, p < 0.05), although there was no significant difference in the total duration of withdrawal symptoms. The two groups also did not differ in completion rate for detoxification (70.5% for the 10-day group, and 78.8% for the 21-day group; RR = 0.88, 95% CI = 0.71 to 1.09).

Regulation of methadone dosage schedules

There are a variety of ways to manage dosage schedules during methadone detoxification. The effects of providing information to the service user about the dosage schedule, the service user regulating the schedule, and schedules fixed by the clinician (for example, linear and exponential reduction) will be assessed. Three RCTs were identified that compared different ways of managing dosage schedules for methadone detoxification.

In a study lasting 42 days, Dawe and colleagues (1991) randomised participants to a fixed schedule methadone taper (n = 15), or were allowed to regulate their own dosage schedule with the aim of completing detoxification (that is, reaching zero dose) within the study period (n = 24). The fixed group were significantly more likely to complete detoxification (53% versus 17%, χ² = 4.49, p < 0.05), and in a significantly shorter time frame (35 days versus 47 days, t = 1.97, p < 0.05). However, urinalysis suggested no significant difference between groups in illicit opioid use at 6-week follow-up.

Green and Gossop (1988) randomised participants undergoing a 21-day methadone taper to the ‘informed group’ (n = 15), who received detailed information about aspects of the detoxification programme such as dosages and expected symptomatology, and the ‘uninformed group’ (n = 15), who received a routine clinical interview. The informed group were more likely to complete detoxification (46.7% versus 80.0%, χ² = 32.12, p < 0.01), and reported significantly lower withdrawal scores on the final day of detoxification (t = 2.48, p < 0.05) as well as over the 25-day post-detoxification period (F = 3.93, p < 0.05).

Strang and Gossop (1990) randomised participants undergoing a 10-day methadone detoxification programme to a linear (n = 43) or exponential (n = 44) taper schedule. Both groups were equally likely (84%) to complete detoxification but the exponential group reported significantly higher withdrawal severity on the OWS during the acute phase of withdrawal (F = 4.34, p < 0.05).

Dosage and duration of buprenorphine detoxification

The typical duration of detoxification using buprenorphine is between 4 and 8 days. There is one RCT (Assadi et al., 2004) that compared regimens using a high dose of buprenorphine in the first 24 hours only, with a more typical regimen reducing buprenorphine over 5 days. At high doses, buprenorphine may effectively act as an antagonist and hence precipitate withdrawal. Buprenorphine was given intramuscularly; the high dose (12 mg; 6 × 1.5 mg doses) was equivalent to 21.3 mg sublingual and the reducing regimen started at 1.5 mg of intramuscular buprenorphine twice a day. No significant differences in treatment retention, successful detoxification (negative naloxone challenge test) or severity of withdrawal were reported. Adjunctive medications (trazodone and indomethacin) were used more by the high-dose group than when buprenorphine was reduced with equal amounts of the others (diazepam, chlorpromazine and hyoscine).

Dosage schedules for alpha₂ adrenergic agonists

No studies were found comparing different dosage schedules of clonidine or lofexidine, however a variety of regimens were reported in the included studies (see Table 12), with some continuing substitute prescribing for a few days when starting the alpha₂ adrenergic agonist, and in other studies it was stopped at that time. Doses of alpha₂ adrenergic agonists were generally increased over 3 days depending on acceptability and control of withdrawal symptoms, maintained for a period then tapered over approximately 3 days at the end.

Clinical summary

For methadone, a high starting dose (80–100 mg/day) appeared to be superior to a standard starting dose (40–50 mg/day) in abstinence (opioid-negative urinalyses during treatment) and completion outcomes, although it may be argued whether abstinence during treatment is a meaningful outcome in this context, given that a higher methadone dose would be expected to reduce the desire to use additional illicit opioids. Improved completion rates could be the result of participants being better stabilised at the outset on a higher dose.

Regarding the duration of detoxification, neither a long methadone taper (up to 70 days) nor a fairly short programme (14 days) was any better than a standard 21-day taper. Also, keeping service users fully informed about different aspects of detoxification appears to have some effect in improving completion rates and minimising reported withdrawal severity.

There is a lack of data assessing dosage and duration for detoxification using buprenorphine or alpha₂ adrenergic agonists. Therefore it is not yet possible to draw conclusions on these issues at present.

Why this is important

A large variety of adjunctive medications are used for the management of withdrawal symptoms during detoxification, particularly when alpha-2 adrenergic agonists are used. Research is needed to guide decisions on how best to manage withdrawal symptoms with minimal risk of harm to the service user.

Current practice

In the UK, ultra-rapid and rapid detoxification with anaesthesia or sedation are not offered within the NHS but appear to occur in the private sector. They are also available in some parts of Europe (such as Spain, Switzerland and the Netherlands) and Australia (Mattick et al., 2001).

The uses of naltrexone or naloxone to accelerate detoxification appear to be uncommon in specialist drug services in the UK (Day et al., 2005).

Minimal or light sedation

Minimal or light sedation involves the administration of medication in order to deal with anxiety, insomnia or agitation. The defining characteristic of this type of sedation is that the person still appears relatively awake and is able to communicate clearly at all times. Although cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected. This type of sedation is usually not sufficient for a significant procedure or painful intervention to occur. Most studies of ‘conventional’ detoxification in which adjunct sedative medications are prescribed fall under this classification (see Section 6.2).

Moderate sedation

During moderate sedation, a higher level of sedation than minimal or light sedation, the person appears obviously sedated, but importantly can maintain an open airway independently and respond purposefully to stimuli (such as verbal questioning).

Deep sedation (or heavy sedation)

During deep sedation (or heavy sedation), an even higher level of sedation, the person is clearly sedated, may not be easily aroused or respond purposefully to verbal commands, and may only respond minimally to very significant stimuli (such as high levels of pain). A person may experience partial or complete loss of protective reflexes, including the ability to maintain an open airway independently and continuously. He or she may therefore require assistance in maintaining an open airway, and spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

While deep sedation may not equate to general anaesthesia, there is a consensus that its supervision requires the same level of training and skill (The Royal College of Anaesthetists, 2001). If verbal responsiveness is lost, the person requires a level of care identical to that needed for general anaesthesia.

General anaesthesia

Under general anaesthesia a person is unconscious and unresponsive, even in the face of significant stimuli. The ability to maintain ventilatory function independently is often impaired. The person often requires assistance in maintaining an open airway, and positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

Asturian method

One approach, the ‘Asturian method’, has been used at home without direct medical or nursing supervision (Carreno et al., 2002). Service users were requested to take no opioids for 12 hours before the procedure in order to reduce the severity of precipitated withdrawal. They were then moderately sedated using the following medication: 0.45 mg clonidine, 40 mg famotidine, 4 mg loperamide, 22.5 mg midazolam, 12 mg ondansetron and 50 mg clorazepate. After 45 minutes, they were then woken to receive 10 mg metoclopramide and 50 mg naltrexone to precipitate withdrawal. After 1 hour 45 minutes, further symptomatic medication was provided (20 mg hyoscine butylbromide, 0.3 mg clonidine and 10 mg metocopramide). After 24 hours, service users were given a physical examination, medication to manage withdrawal symptoms was provided if needed, and individuals were inducted onto naltrexone maintenance treatment.

Carreno and colleagues (2002) reported a case series of 1,368 service users who had received the Asturian method. This report was primarily descriptive, with limited reporting of outcomes, and involved no comparison group; therefore conclusions drawn on the efficacy of this procedure are limited.

Accelerated detoxification under minimal or light sedation

Adding an opioid antagonist to clonidine, lofexidine or buprenorphine detoxification had no effect on completion rates, but showed a trend for increased withdrawal severity, as might be expected from a process that accelerates withdrawal. Data for abstinence at follow-up were inconsistent, with one study showing a trend favouring an opioid antagonist at 9-month follow-up while another study showed the opposite trend at 6-month follow-up.

Rapid detoxification under moderate sedation

No firm conclusions could be drawn from the limited evidence base concerning the safety and efficacy of this detoxification method. It was apparent however that precipitating withdrawal necessitated the polypharmacy of adjunct medications for managing symptoms; this is likely to carry inherent risks (for example, increased likelihood of medication interactions), particularly if detoxification occurs within a setting with minimal medical supervision (for example, at home).

Ultra-rapid detoxification under general anaesthesia

This is associated with a substantially increased risk of serious adverse events, including complications associated with the anaesthesia (such as aspiration pneumonia, delirium and fever), above what would normally be expected in conventional opioid detoxification under minimal sedation. In addition, the polypharmacy of adjunct medications is likely to carry inherent risks. Although the evidence suggests that ultra-rapid detoxification is a very effective way of initiating individuals onto naltrexone maintenance (compared with detoxification with clonidine) and that it may have better abstinence outcomes at 3- to 6-month follow-up, these benefits are outweighed by the considerable risks.

Clinical summary

In summary, there is a lack of trials assessing the efficacy of acupuncture during detoxification either alone or as an adjunct to other treatments. Therefore there is no established evidence base to support this as an effective method of detoxification.