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Rapid and Ultrarapid Opioid Detoxification Techniques
Patrick G. O'Connor, MD, MPH;
Thomas R. Kosten, MD
JAMA. 1998;279:229-234.
ABSTRACT
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Objective.— To review the scientific literature on the effectiveness of rapid opioid detoxification (RD) (opioid withdrawal precipitated by naloxone hydrochloride or naltrexone) and ultrarapid opioid detoxification (URD) (opioid withdrawal precipitated by naloxone or naltrexone under anesthesia or heavy sedation) techniques.
Data Sources.— The MEDLINE database was searched from 1966 through 1997 using the indexing terms naloxone, naltrexone, substance dependence, and substance withdrawal syndrome. Additional data sources included bibliographies of papers identified on MEDLINE and bibliographies in textbooks on substance abuse.
Study Selection.— Inclusion criteria were studies of RD or URD, pharmacologic protocols specified, and clinical outcomes specified and reported. Exclusion criteria were unpublished data, data not in peer-reviewed journals, abstract-only publications, and review articles.
Data Extraction.— The methodologic characteristics of studies were extracted by the authors and summarized according to key components of research design concerning subject characteristics, therapy allocation, and outcomes assessed.
Data Synthesis.— A qualitative analysis was performed on the 12 studies of RD and the 9 studies of URD identified in our search. The RD studies enrolled 641 subjects (range for individual studies, 1-162): 7 were inpatient studies, and the protocols varied considerably, as did the outcomes assessed. Three RD studies included a control group, 2 used a randomized design, and 3 reported outcomes beyond 12 days. The URD studies enrolled 424 subjects (range for individual studies, 6-300): all were inpatient studies, the detoxification and anesthesia protocols varied, 3 included a control group, 2 used a randomized design, and 2 reported outcomes for URD beyond 7 days.
Conclusions.— The existing literature on RD and URD is limited in terms of the number of subjects evaluated, the variation in protocols studied, lack of randomized design and use of control groups, and the short-term nature of the outcomes reported. Further research is needed using more rigorous research methods, longer-term outcomes, and comparisons with other methods of treatment for opioid dependence.
INTRODUCTION
OPIOID DEPENDENCE is characterized by a withdrawal syndrome that occurs when opioid agonists are discontinued or opioid antagonists are administered in individuals who are opioid dependent.1-2 Managing withdrawal is a critical first step in initiating many patients who are opioid dependent into treatment.3-4 Traditional medical management of opioid withdrawal (eg, detoxification) involves the substitution of a long-acting opioid (eg, methadone) for shorter-acting opioids (eg, heroin) and gradual tapering.1, 5
Nonopioid approaches to opioid detoxification, such as clonidine hydrochloride, have been developed over the past several years.6-7 In addition, a rapid opioid detoxification (RD) technique has been developed, which is designed to shorten detoxification by precipitating withdrawal through the administration of opioid antagonists such as naloxone hydrochloride or naltrexone.8-9 This approach is thought to have the advantage of getting patients through detoxification rapidly to minimize the risk of relapse, and initiating treatment more quickly with naltrexone maintenance combined with suitable psychosocial interventions.10 Ultrarapid opioid detoxification (URD) represents a variant of this technique in which patients undergo opioid antagonist–precipitated withdrawal while under general anesthesia or heavy sedation.11-12
Interest in RD and URD has increased with the recent rise in heroin use in the United States13 and the resulting need to expand available treatment options, and find more cost-effective approaches to substance-abuse treatment. Although it is difficult to estimate the extent of their clinical use, these techniques are becoming increasingly available in response to rising demand for opioid-dependence treatment services.12 For example, in the United States there has been a rapid proliferation of programs offering URD, with some programs charging up to $7500 per treatment.12 However, it is important to carefully assess the evidence for the efficacy of both RD and URD so that clinicians and program administrators considering their implementation can assess their role among the available treatment options for opioid dependence, and to identify remaining questions for further investigation. We performed a review and assessment of the scientific literature on RD and URD to address these issues.
METHODS
A comprehensive review of the scientific literature was performed to identify studies of RD (opioid withdrawal precipitated with naloxone or naltrexone in awake individuals) and URD (opioid withdrawal precipitated under general anesthesia or sedation). We utilized a protocol for identifying relevant literature adapted from that described for performing a meta-analysis of clinical trials.14
Literature Search Strategies
A MEDLINE search identified papers published from 1966 through 1997 under the medical subject heading (MeSH) terms naloxone, naltrexone, substance dependence, and substance withdrawal syndrome. Inclusion criteria were studies of RD or URD, pharmacologic protocols specified, and clinical outcomes specified. Exclusion criteria were unpublished data, data not published in peer-reviewed journals, abstract-only publications, and review articles. Bibliographies of papers and related textbooks were also searched.
Evaluation Criteria
An analysis of methodologic characteristics was adapted from that described for evaluating articles on therapy.15-16 Separate qualitative analyses of RD and URD studies focused on 3 components of research design: subject characteristics (number entered, clinical characteristics, and treatment setting), therapy used, and outcomes assessed.17 Studies were also assessed based on the use of control groups (present vs not present), allocation of therapy (randomized vs not randomized), blinding techniques (double blind, single blind, not blind), and the completeness of subject follow-up (all subjects accounted for vs not accounted for).15, 17 The outcomes were characterized by the primary clinical outcome(s) reported (eg, the author's definition of successful detoxification), the length of follow-up, and secondary outcomes including adverse effects.
RESULTS
Our search identified 12 RD and 9 URD studies.
Studies of Rapid Detoxification
Overall Research Design
The 12 RD studies enrolled a total of 641 subjects: 478 received RD and 163 served as controls (nonrapid detoxification or placebo) (Table 1).7-9,18-26 Enrollment ranged from 120 to 162 subjects.26 Most studies (8) enrolled primarily heroin users, although 3 enrolled methadone-maintained patients.7-9 The clinical features of subjects were not specified in 1 study.19 Most studies (7) were performed in inpatient settings—typically psychiatric facilities with specialized substance abuse services.7-9,19-20,22 Three studies examined outpatients in substance abuse treatment settings.21, 23, 25 More recently, RD was evaluated in an outpatient primary care clinic that was affiliated with a substance abuse treatment program.24, 26
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Table 1.—Overall Research Design Features of Studies of Rapid Detoxification
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Medication protocols varied across studies. All protocols except one8 included clonidine along with an opioid antagonist (naloxone or naltrexone) (Table 1). Five studies used naloxone in a total of 118 patients (58 of which were in the study by Gerra et al)8, 18-20,25 at a dose of 0.2 to 1.2 mg administered in daily or repeated doses. Resnick et al8 administered naltrexone on day 1 (up to 50 mg in divided doses) after several doses of naloxone. Charney et al9 used only naltrexone in low doses (1 to 10 mg every 4 hours) prior to administration of a full dose (50 mg) on day 5. In subsequent studies, the initial dose of naltrexone was increased to as much as 12.5 mg on day 1,23-24,26 with a full dose as early as day 3.23-26 Similarly, the dose of clonidine varied across studies. One study added buprenorphine hydrochloride to reduce the severity of withdrawal symptoms associated with naltrexone.26 Finally, many studies reported using a variety of adjuvant medications to ameliorate withdrawal symptoms, including antiemetics (eg, prochlorperazine), sleep inducers (eg, benzodiazepines), and analgesics (eg, ibuprofen).
The outcomes assessed varied across studies. Most studies evaluated withdrawal symptoms and/or vital signs and "completion" and/or "duration" of detoxification. Completion generally referred to some measure of compliance with the protocol, which typically lasted 5 or more days. Only 3 studies7, 23, 25 included outcome data beyond acute detoxification.
Methodologic Characteristics
Most studies (9) were prospective, observational studies performed without a control group, (Table 2).7-9,18-23 However, 3 studies did include a control group, including clonidine in 3 studies24-26 and placebo in 1 study.25 Two studies used randomized treatment assignment.25-26 In 1 study, however, the method of randomization was not described and the subjects were not equally distributed among the 4 treatment groups (the sample sizes were 33, 42, 58, and 19, respectively), which were randomized.25 Only 3 studies included blinding techniques where research nurses,7, 9 or investigators and patients,26 were blind to protocol assignment.
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Table 2.—Methodologic Characteristics of Studies of Rapid Opioid Detoxification
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All studies reported complete outcome data or, if incomplete, indicated that subjects "dropped out" (Table 2). Most studies (9) reported outcomes only for the "acute" detoxification period with a range of 1 to 12 days. Three studies provided longer-term follow-up data ranging from 1 month to 1 year.7, 23, 25
Studies of Ultrarapid Detoxification
Overall Research Design
Seven of the 9 URD studies were from the same group of investigators11, 27-32 (Table 3). The other studies were from investigators from England33 and Spain.34 One study34 enrolled the majority (300 subjects) of the 424 subjects enrolled in the studies of URD identified in our search. All subjects were treated in inpatient settings.
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Table 3.—Overall Research Design Features of Studies of Ultrarapid Detoxification*
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Eight studies used naloxone,11, 27-32 and 4 (including 3 of those that also used naloxone) used naltrexone (Table 3).29, 31, 33-34 The naloxone dose varied from 2 to 10 mg by intravenous bolus and approximately 0.4 to 0.8 mg/h by infusion. In the study in which naltrexone was the lone opioid antagonist used, 50 mg was administered prior to sedation with midazolam.33 The methods of sedation or general anesthesia varied across studies. The medications employed included methohexitone, thiopentone sodium, and midazolam, and their doses varied. Five studies used general anesthesia that included intubation and mechanical ventilation,11, 27-28,30, 32 and 4 used sedation generally without intubation.29, 31, 33-34
Concerning outcomes, most studies focused on withdrawal signs and/or symptoms (Table 3). Other outcomes of interest included urine toxicology, abstinence, hemodynamic parameters, plasma drug levels, and completion of detoxification and complications. Two studies33-34 evaluated subject outcome following detoxification (maintenance with naltrexone).
Methodologic Characteristics
Only 3 studies of URD included a control group (Table 4).28, 30, 34 In Lorimer et al,28 18 patients were randomized (9 to each group) to receive either 10 mg of intravenous naloxone or placebo. In a later study,30 15 patients undergoing URD were compared with 29 controls detoxified with methadone over approximately 20 days. In the largest study of URD,34 the 300 subjects were given a standardized protocol of clonidine, naloxone, and naltrexone, and were randomized to either light or deep sedation (150 to each method of sedation). Thus the authors were comparing 2 forms of sedation within a URD protocol and no control group was included as an alternative to URD. All studies reported complete results for all subjects (Table 4). Most studies reported short-term outcomes (eg, 6 hours to 7 days). However, 133 reported continuation of naltrexone maintenance for 30 days and another34 reported abstinence (according to self report and urine tests) for 1 month.
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Table 4.—Methodologic Characteristics of Studies of Ultrarapid Opioid Detoxification
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COMMENT
This paper provides a qualitative assessment of research on RD and URD to inform clinicians about their relative effectiveness as reported in the literature. The variability of the patients and techniques and the small number of subjects studied prohibit pooling of data to provide a more quantitative assessment of effectiveness.17 When considering the use of these techniques, clinicians need to be aware of the methodologic limitations of this research as well as specific limitations of each technique.
Most studies examined and enrolled a small number of subjects whose clinical spectrum varied, as did the treatment settings and medication protocols. Only 4 of 12 RD studies and 1 of the URD studies enrolled more than 50 subjects. All but 2 of the URD studies enrolled 20 or fewer subjects. Although all subjects were opioid dependent, the clinical spectrum of subjects varied across (and within) studies. In addition to opiate addiction and heroin abuse, subjects included patients in methadone maintenance programs7, 9, 29 and a patient dependent on prescription narcotics.20 Most studies were inpatient studies, although 3 of the more recent RD studies were performed in outpatient substance abuse treatment settings,21, 23, 25 and 224, 26 were performed in a primary care setting. The proposed use of RD in outpatient and primary care might increase access to these services, although this requires more extensive evaluation in a variety of outpatient settings before it can be recommended routinely. Ultrarapid detoxification does not lend itself to any setting that cannot support general anesthesia or sedation. The medication protocols varied considerably across studies. For example, naloxone was used in some studies, naltrexone in others, and the dosage schedules varied considerably. Some studies described the use of adjuvant medications, including benzodiazepines, to manage withdrawal symptoms that may have affected protocol outcomes. The variable clinical spectrum of subjects, variability in treatment settings, intensiveness of services required in some protocols, and variations in protocols in these generally small studies raise uncertainty about the generalizability of their results.
Since detoxification represents only a first step in the process of substance abuse treatment and relapse rates following detoxification without follow-up treatment are extremely high,35-36 a major concern regarding these studies is the generally short duration of subject follow-up reported. Among these 21 studies, only 423, 25, 33-34 provided follow-up beyond detoxification, and the amount of detail provided was minimal. Among the RD studies, Vining et al23 reported that 9 (53%) of 17 remained in a naltrexone maintenance program for 1 month and Gerra et al25 reported that 125 (82%) of 152 did not drop out by 3 months and provided additional outcomes for up to 6 months. Among the URD studies, only Legarda et al33 provided outcomes beyond detoxification: "In the follow-up 30 days . . . all (11) subjects were still taking naltrexone . . . (and) all but two . . . challenged naltrexone on one occasion." In addition, Seoane et al34 reported that "279 patients (93%) remained abstinent after 1 month follow up" although details of how this was assessed were not provided. The remaining 17 studies focused only on withdrawal symptoms and/or completion of detoxification over a brief time frame (eg, 6 hours to 12 days). A recent study of patients who had previously undergone URD reported a mean compliance with maintenance naltrexone of 3.8 months in patients who had relapsed, and 5.9 months in those who had not relapsed, although this study relied on a telephone follow-up survey for outcome data.37 Thus, longer-term treatment outcomes are needed to provide a more complete assessment of the role of these protocols in the management of opioid dependence. These outcomes should include a detailed assessment of postdetoxification outcomes such as rates of drug use assessed by urine toxicology, rates of medication compliance, clinic attendance, and level of social functioning.
An additional limitation of studies on RD and URD is the lack of control groups in most studies—without which direct comparisons of the effectiveness of these new techniques to more traditional detoxification approaches (eg, methadone taper) is not possible. Only 3 of the RD and 2 of the URD studies included controls that allowed direct comparisons to methods other than RD or URD, including clonidine,24-25,38 methadone,30 and placebo.25, 28 Only 2 of these studies randomly assigned patients to the treatments under study.26, 28 The study that included a methadone-taper control group provided no outcomes beyond the detoxification period in this study.30 However, if getting patients detoxified and into a naltrexone maintenance program in a brief period is a treatment goal, as it was in most of these studies, comparisons of these new techniques with clonidine,24-25,38 or placebo,25 will be of interest as well. In addition, a critical component of longer-term success at ensuring a drug-free outcome is the engagement of the patient in sustained treatment. In the approximately 10% to 20% of unselected persons with opioid dependency who might benefit most from outpatient naltrexone treatment,39 an important question is whether a more prolonged detoxification using alternative techniques (a methadone taper or clonidine) might allow more time for engagement in the therapeutic alliance with the clinician and treatment program or, alternatively, whether the intensity of these newer RD and URD techniques may lead to better long-term outcomes. The general lack of suitable control groups and randomization of treatment assignment in most studies of RD and URD makes it difficult to answer this question definitively.
A major debate regarding URD concerns the risks (morbidity and mortality) and cost of general anesthesia.12 Although the overall risks of general anesthesia are significant in unselected patients (eg, a perioperative mortality rate in which anesthesia was thought to be a contributing factor to mortality of 1 of 1185 to 1 of 6789),40 mortality and morbidity are likely to be much lower in the young, ambulatory population who typically undergo this procedure.41 However, there are few data on the impact of opioid dependence and the comorbid problems commonly seen in this population (eg, human immunodeficiency syndrome or cocaine use) on anesthesia risk. Three relevant case reports included 1 description of respiratory distress that required prolonged intubation in a patient undergoing an ultrashort detoxification42 that was similar to a published protocol,31 and 2 reports that a high dose of naloxone administered under general anesthesia may be associated with cardiovascular morbidity.43-44 Heavy sedation without intubation also carries the potential risk of vomiting with aspiration and sedative overdose. General anesthesia and the need for expensive medical facilities, anesthesia equipment, and nursing staff also contribute to the potentially high cost of URD, which may range from $2500 to $7500 per patient.12 Cost alone may severely limit the applicability of this procedure, especially if it is not covered by medical insurance. These potential risks and costs need to be assessed in individual patients and be balanced against the potential benefits that this procedure may offer.
Despite the limitations of the available literature, clinicians need to consider the role of RD and URD in the spectrum of opioid dependence treatment approaches. An initial consideration among the available options for treating opioid dependence is whether a patient seeking treatment should be offered detoxification-initiated treatment (followed by naltrexone maintenance or drug-free treatment) or opioid-maintenance treatment (eg, methadone or leuomethadyl acetate hydrochloride [LAAM]. Opioid maintenance may be the treatment of choice for many patients, especially those with high levels of dependence, daily users, those with unstable social environments, those who have failed detoxification-initiated treatments on multiple occasions, and those who prefer agonist treatment.45-47 However, naltrexone maintenance treatment conducted with an appropriate level of psychosocial treatment has been shown to be effective for selected populations of opioid-dependent individuals, particularly those who are highly motivated, who are socially stable, and who report relatively low levels of opioid use.47-49 In addition, this approach might be a suitable alternative for patients who do not qualify for, or desire, opioid maintenance treatment, and those for whom maintenance treatment is not otherwise available. Among detoxification approaches, RD and URD may be suitable for selected patients who have failed, or do not desire standard detoxification treatment, or those who desire an expedited detoxification for family or social reasons (eg, employment). Thus, detoxification followed by naltrexone maintenance can have a role for selected patients, while rapid approaches may be well suited to those who fail other standard approaches.39, 48-49
Studies of RD and URD raise the prospect of interesting new approaches to opioid detoxification, although methodologic limitations may limit their generalizability to widespread clinical application. More research on safety, clinical effectiveness, and costs is needed with suitable control groups and long-term treatment outcomes obtained from methodologically rigorous clinical trials. In addition, the subpopulation of patients for whom these approaches may be suitable needs to be further identified. Further assessment of the risks associated with general anesthesia as it is applied in URD is needed. This approach may have limited applicability due to its potentially high cost and the availability of other approaches that do not require general anesthesia.
AUTHOR INFORMATION
The authors would like to thank Brian J. McGrath, MD, for his comments and suggestions.
Reprints: Patrick G. O'Connor, MD, MPH, Yale University School of Medicine, Primary Care Center, 333 Cedar St, New Haven, CT 05620.
From the Departments of Medicine (Dr O'Connor) and Psychiatry (Dr Kosten), Yale University School of Medicine, New Haven, Conn.
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