Susan M. Stine, MD, PhD and Thomas R. Kosten, MD, PhD
CHAPTER OUTLINE
■ OVERVIEW OF PHARMACOLOGIC INTERVENTIONS
■ ABSTINENCE SYNDROMES AND MEDICALLY SUPERVISED WITHDRAWAL
■ LONG-TERM TREATMENTS FOR OPIOID DEPENDENCE
■ SPECIAL ISSUES IN MAINTENANCE TREATMENT
■ SUMMARY
This chapter first provides a brief overview of the main pharmacologic agents for treating opioid dependence. Second, it provides a brief overview of pharmacologic approaches to medically assisted withdrawal, and, finally, this chapter focuses on long-term pharmacologic (maintenance) treatments.
OVERVIEW OF PHARMACOLOGIC INTERVENTIONS
The principal opioid medications used to treat opioid dependence covered in this chapter are the μ-receptor antagonists naloxone and naltrexone, the full agonists methadone and levo-alpha-acetylmethadol (LAAM), the partial agonist buprenorphine, and the nonopioid α2-adrenergic agonists clonidine and lofexidine.
Opioid Antagonists
Naloxone
Naloxone is a short-acting, parenterally administered full opioid antagonist medication used to counter the life-threatening depression of the central nervous and respiratory systems caused by opioid overdose. It is a competitive antagonist with an extremely high affinity for μ-opioid receptors, and its rapid displacement of any opioid agonists and blockade of the μ-opioid receptors often produces rapid onset of withdrawal symptoms. Naloxone also has antagonist action, though with a lower affinity, at κ- and δ-opioid receptors. Naltrexone is structurally similar but has a slightly increased affinity for κ-opioid receptors over naloxone and can be administered orally with a longer duration of action than naloxone.
Naltrexone
Naltrexone hydrochloride is a competitive opioid antagonist and reversibly blocks the effects of opioids. Although naltrexone has few, if any, intrinsic actions besides its opioid-blocking properties (1), it produces some pupillary constriction, by an unknown mechanism (2). The administration of naltrexone is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptoms. Clinical studies indicate that 50 mg of naltrexone hydrochloride will block the pharmacologic effects of 25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that doubling its dose provides blockade for 48 hours, and tripling its dose provides blockade for about 72 hours.
Opioid Full and Partial Agonists
Methadone
Methadone is an orally active, long-acting synthetic opioid that was recognized in the 1960s as having the potential to treat opioid dependence. A clinical pharmacology study demonstrated that increasing doses of methadone affected abstinence signs and symptoms and reduced drug craving. Doses of methadone ranging from 80 to 120 mg/d produced a tolerance to the effects of intravenously administered heroin, hydromorphone, and methadone. The term agonist blockade was coined to describe this phenomenon.
LAAM
LAAM is the α-acetyl congener of methadone. Its principal difference from methadone is its longer half-life and its conversion to the active metabolites norLAAM and dinorLAAM. It is approved by the U.S. Food and Drug Administration (FDA) for opioid maintenance treatment in opioid treatment programs (OTPs) but is no longer marketed owing to low demand in the wake of reports of an association with cardiac arrhythmias (torsade de pointes [TdP]).
Buprenorphine
Buprenorphine is a high-affinity μ-opioid partial agonist and κ-opioid antagonist that the FDA approved as a pharmacotherapy for opioid dependence in October 2002 (3,4). Despite its higher unit-dose cost compared to methadone, buprenorphine has expanded access to opioid dependence treatment owing to its availability in office-based practice. This could reduce the disparity between the number of opioid-dependent individuals and the number of treatment slots available to them and facilitate general medical care of dependent individuals (5–7).
Nonopioid Agonists: α-Adrenergic Agents
Clonidine
Clonidine is a centrally acting α-adrenergic receptor agonist with more affinity for α2 than α1 receptors. It decreases adrenergic neurotransmission from the locus caeruleus through feedback inhibition. The medication is FDA approved for the treatment of hypertension but is used off label for the medical management of opioid withdrawal. Many of the autonomic symptoms of opioid withdrawal result from the loss of opioid suppression of the locus caeruleus system during the abstinence syndrome. The use of clonidine in the management of opioid withdrawal has been hampered by side effects of sedation and hypotension.
Lofexidine
Lofexidine is also a centrally acting α2-adrenergic agonist, which has not yet been approved by the FDA but is used in Europe. It is associated with less of the hypotension that limits the use of clonidine for withdrawal treatment and therefore is currently being studied in clinical trials for the medical management of withdrawal.
ABSTINENCE SYNDROMES AND MEDICALLY SUPERVISED WITHDRAWAL
The opioid abstinence syndrome is characterized by two phases (8): a relatively brief initial phase in which opioid-dependent patients experience acute withdrawal followed by a protracted abstinence (PA) syndrome. Current pharmacotherapeutic strategies are designed to address these two distinct phases, acute withdrawal and protracted withdrawal. The acute withdrawal syndrome lasts from 5 to 14 days and consists of a wide range of symptoms. Symptoms include gastrointestinal distress (such as diarrhea and vomiting), disturbances in thermal regulation, insomnia, muscle pain, joint pain, marked anxiety, tremor, and dysphoria. Although these symptoms generally include no life-threatening complications, the acute withdrawal syndrome causes marked discomfort, often prompting continuation of opioid use, even in the absence of any opioid-associated euphoria. Longer-term, PA symptoms are discussed in this chapter under long-term treatments.
Medically supervised withdrawal is discussed briefly next and in greater detail elsewhere in this text.
Opioid Agonists and Partial Agonists
Opioid-based medically supervised withdrawal is based on the principle of cross-tolerance, in which one opioid is replaced with another that is slowly tapered. Methadone is used because it has a long half-life and can be administered once daily. Withdrawal from heroin is usually managed with initial dosages of methadone in the range of 15 to 30 mg/d (9). Although this dosage is generally adequate to control symptoms in many heroin users over a 24-hour period, additional methadone can be given as required on the basis of clinical findings. However, a simple conversion of short-acting prescription medications into an equivalent dosage of methadone can lead to overdose as the methadone accumulates over the first several days of dosing. Thus, any methadone dose over about 40 mg daily should involve careful and slow dosage increases over at least several days. Various guidelines that are available for conversion from short-acting opioids to methadone typically suggest giving half of the calculated equivalent methadone dose to any patient with a calculated dose of more than 50 mg daily of methadone. In acute medical settings, this starting dosage should be maintained through the 2nd or 3rd day after the peak dose is attained, and then the methadone can be slowly tapered by approximately 10% to 15% per day. Longer-term medically supervised opioid withdrawal using methadone is often available through drug treatment programs. Although a licensed physician can perform supervised methadone withdrawal in an inpatient medical setting when the primary reason for hospital admission is not opioid dependence/use disorder, outpatient withdrawal using methadone must be performed in a federally licensed OTP.
Buprenorphine has been studied as a treatment for opioid withdrawal. Buprenorphine’s slow dissociation from μ-opioid receptors results in a long duration of action (ideal for a maintenance medication) and also has milder withdrawal signs and symptoms on discontinuation than full agonists (10–15), making it particularly useful for medically supervised withdrawal from opioids. An early study randomly assigned 45 heroin-dependent patients to buprenorphine (2-mg sublingual solution) or methadone (30 mg) for 3 weeks, followed by tapering over a 4-week period, and found both approaches to be equivalent (16). Another study that compared a gradual (36-day) to a more rapid (12-day) buprenorphine taper (initially 8 mg) found the gradual approach to be superior (10), but a subsequent much larger study that randomized patients to a 7-day buprenorphine/naloxone taper versus a 28-day taper after 4 weeks of stabilization on buprenorphine/naloxone demonstrated significantly lower rates of opioid-positive urine specimens after the 7-day taper as opposed to the 28-day taper with no differences in 3-month outcomes between the two conditions (17). These findings indicate that in the use of buprenorphine/naloxone to manage opioid withdrawal, there is no advantage to a longer taper period. A study that compared a 3-day course of buprenorphine (3 mg) to a 5-day course of clonidine reported that these approaches were equivalent (11), although another study found that a longer course of buprenorphine (10 days) was superior to clonidine (18). A larger study (19) of 162 heroin-dependent patients withdrawn in a primary care setting randomly assigned the patients to three 8-day treatment protocols: clonidine, combined clonidine and naltrexone, and buprenorphine. Participants in the combined clonidine and naltrexone group and the buprenorphine group were more likely to complete medically supervised withdrawal than the clonidine group, whereas the buprenorphine group experienced less severe withdrawal symptoms than did the other two groups. Another study provided further evidence that step-down medically supervised withdrawal using buprenorphine minimizes withdrawal symptoms, thus reducing the need for concurrent medication (20). The clinical effectiveness of buprenorphine/naloxone and clonidine for medically supervised opioid withdrawal in inpatient and outpatient community treatment programs was investigated in the first studies of the National Institute on Drug Abuse Clinical Trials Network (21). Opioid-dependent individuals seeking short-term treatment were randomly assigned, in a 2:1 ratio favoring buprenorphine/naloxone, to a 13-day medically supervised withdrawal using buprenorphine/naloxone or clonidine. A total of 113 inpatients (77 buprenorphine/naloxone, 36 clonidine) and 231 outpatients (157 buprenorphine/naloxone, 74 clonidine) participated. Primary outcome measures included the proportion of subjects in each condition who both were retained in the study for the entire duration and provided an opioid-free urine sample on the last day. Secondary outcome measures included use of ancillary medications, number of side effects, and withdrawal and craving ratings. A total of 59 of the 77 (77%) inpatients assigned to buprenorphine/naloxone achieved treatment success compared to 8 of the 36 (22%) assigned to clonidine. Forty-six of the 157 (29%) outpatients assigned to buprenorphine/naloxone achieved treatment success, compared to 4 of the 74 (5%) assigned to clonidine. Thus, several studies have supported the benefits of buprenorphine and buprenorphine/ naloxone for medically supervised opioid withdrawal.
The optimum dose of buprenorphine for acute inpatient opioid withdrawal has not been determined. A randomized, double-blind, double-dummy pilot study conducted by Oreskovich et al. (22) compared two buprenorphine sublingualtablet dosing schedules to oral clonidine. Heroin users (n = 30) who met DSM-IV criteria for opioid dependence and achieved a Clinical Opiate Withdrawal Scale (COWS) score of 13 (moderate withdrawal) were randomly assigned to receive higher-dose buprenorphine (HD, 8-8-8-4-2 mg/d on days 1 to 5), lower-dose buprenorphine (LD, 2-4-8-4-2 mg/d on days 1 to 5), or clonidine (C, 0.2-0.3-0.3-0.2-0.1 mg QID on days 1 to 5). COWS scores were obtained four times daily. Twenty-four hours after randomization, the percentages of subjects who achieved suppression of withdrawal, as defined by four consecutive COWS scores less than 12, were C = 11%, LD = 40%, and HD = 60%. COWS scores over the course of 5 days were lower in both LD and HD compared to C. Similar analyses examining scores over time on the Adjective Rating Scale for Withdrawal (ARSW) and on a visual analogue scale (VAS) of opiate craving indicated an overall treatment effect on the VAS accounted for by a significant difference between HD and C but no overall treatment effect on the ARSW. Both HD and LD regimens were found safe and efficacious treatments for supervised opioid withdrawal, but HD demonstrated superiority to C, including a lesser severity of withdrawal symptoms at both doses of buprenorphine and decreased craving at the higher dose. A later meta-analysis (23) compared buprenorphine-assisted opioid withdrawal to other established methods. This study selected randomized controlled trials involving the use of buprenorphine to modify the signs and symptoms of withdrawal in primarily opioid-dependent participants and made a comparison either to a different buprenorphine protocol or to interventions involving reducing doses of methadone, α2-adrenergic agonists, symptomatic medications, or placebo. Twenty-two studies (1,736 participants) were included. The major comparisons were with methadone (5 studies) and clonidine or lofexidine (12 studies). Five studies compared different rates of buprenorphine dose reduction. The authors reported that severity of withdrawal was similar for withdrawal managed with buprenorphine and withdrawal managed with methadone, but withdrawal symptoms may resolve more quickly with buprenorphine. Buprenorphine was reported to be more effective in relieving symptoms of withdrawal than was clonidine or lofexidine, and patients treated with buprenorphine remained in treatment longer and were more likely to complete withdrawal treatment. While no significant difference was observed in the incidence of adverse effects, dropout due to adverse effects may be more likely with clonidine. Overall conclusions were that buprenorphine was more effective than clonidine or lofexidine for the management of opioid withdrawal and may also offer some advantages over methadone in terms of quicker resolution of withdrawal symptoms.
Nonopioid Medication Treatments
The α-adrenergic agents are widely used in medically supervised withdrawal, especially in clinical settings that do not have availability of controlled substances. Nonopioid methods of medically supervised opioid withdrawal have focused primarily on clonidine, an α2-adrenergic agonist. This approach is based on the discovery that one important mechanism underlying opioid withdrawal is noradrenergic hyperactivity (24). Therefore, α2-adrenergic agonists act centrally at the locus coeruleus via presynaptic receptors to moderate the symptoms of noradrenergic hyperactivity during medically supervised opioid withdrawal. Discovery of the capacity of the α2-adrenergic agonist, clonidine, to ameliorate some signs and symptoms of withdrawal led to widespread use of this drug as a nonopioid alternative for managing withdrawal (25) as well as interest in developing other α2-adrenergic agonists for this indication.
Clonidine
Early clinical studies demonstrated that clonidine diminished withdrawal symptoms in patients who were withdrawn from methadone (26,27). Clonidine seems to be most effective in suppressing autonomic signs and symptoms of opioid withdrawal but is less effective for subjective withdrawal symptoms (28). Initial daily doses of up to 1.2 mg per 24 hours in divided doses are commonly suggested. For example, a regimen of 0.1 to 0.2 mg every 4 hours has been used in two clinical trials for heroin withdrawal, with careful monitoring of blood pressure. Because it may be less effective in managing subjective withdrawal symptoms, adjuvant therapy (nonsteroidal anti-inflammatory drugs for myalgia, benzodiazepines for insomnia, medications for diarrhea, and antiemetics) may be needed (19,29). In addition, in a randomized trial that included 55 patients who received clonidine in a primary care setting, 65% of patients underwent successful medically supervised withdrawal (19). In another study that examined predictors of successfully completed supervised withdrawal using clonidine, patients who completed withdrawal were more likely to be heroin smokers (rather than intravenous users) and to have abstained from opioids for a longer time before presenting for treatment (30).
Lofexidine and Other α2-Adrenergic Agonists
The use of clonidine in the management of opioid withdrawal has been hampered by side effects of sedation and hypotension. This in turn has led to the investigation of the effectiveness of other α2-adrenergic agonists—lofexidine, guanfacine, and guanabenz acetate—in the management of opioid withdrawal, the aim being to find a drug that has clonidine’s capacity to ameliorate the signs and symptoms of opioid withdrawal but with fewer side effects.
Lofexidine, a centrally acting α2-adrenergic agonist, has, after clonidine, been the most used and investigated α2-adrenergic treatment for opioid withdrawal, although it has not yet been approved by the FDA. In the United Kingdom, lofexidine has had a product license for treatment of opiate detoxification since 1992, and the extent of use has increased steadily since that time.
Lofexidine treatment is typically initiated at 0.2 mg twice daily, increasing daily by 0.2 to 0.4 mg with a recommended final dose of 2.4 mg/d (31). Doses required to effectively manage withdrawal symptoms, however, vary for each patient depending on the amount, frequency, and duration of opioid used. In a randomized trial that compared lofexidine to methadone in 86 opioid-dependent patients, lofexidine-treated patients had more severe withdrawal symptoms from days 3 to 7 and again on day 10 but had similar symptoms thereafter. Rates of treatment completion did not significantly differ (30). In two randomized, double-blind trials that compared lofexidine with clonidine in patients dependent on methadone (32,33) and another in heroin patients (34), both agents effectively reduced withdrawal symptoms. Patients treated with lofexidine experienced fewer side effects, especially hypotension. Finally, one study suggested that a 5-day lofexidine regimen decreased symptoms of opioid withdrawal more rapidly than did a 10-day regimen (35). A large multicenter randomized clinical efficacy trial comparing lofexidine to placebo for opioid detoxification found substantial efficacy for lofexidine in symptom reduction and patient retention (36). A Cochrane Review (37) examined 24 controlled trials (1,631 participants) comparing α2-adrenergic agonists with reducing doses of methadone, symptomatic medications or placebo, or comparing different α2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. The review selected α2-adrenergic agonists compared to placebo (4 studies), reducing doses of methadone (14 studies), or lofexidine compared to clonidine (3 studies). α2-Adrenergic agonists were found to be more effective than placebo and in increasing treatment completion but had higher rates of adverse effects. For the comparison of α2-adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar or marginally greater with α2-adrenergic agonists, while signs and symptoms of withdrawal occurred and resolved earlier. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone. However, clonidine was associated with more adverse effects than reducing doses of methadone. Clonidine produced outcomes similar to lofexidine. With respect to adverse events, lofexidine did not reduce blood pressure to the same extent as clonidine, but was otherwise similar to clonidine. In another review (38), nine clinical studies of lofexidine (354 patients) were compared to clarify dosing methods and efficacy. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6 to 3.2 mg/d in divided doses for a total of 5 to 18 days. The data support the efficacy of lofexidine in reducing opioid withdrawal symptoms: Lofexidine appeared to be at least as effective as the opioid receptor agonists utilized for medically supervised withdrawal. The authors also point out some withdrawal symptoms, notably insomnia and aching, are not alleviated by α2-agonists. The most common adverse event with lofexidine was insomnia, and hypotension was also reported. Overall, this review of studies comparing clonidine with lofexidine again supported decreased incidence and severity of adverse events with lofexidine.
Medication Combinations, Rapid and Ultrarapid Opioid Detoxification
Because most opioid and nonopioid approaches to medically supervised withdrawal require a prolonged time frame of a week or more, “rapid” and “ultrarapid” opioid withdrawal protocols have been developed (39,40). These “rapid” protocols use an opioid antagonist (e.g., naloxone or naltrexone) to cause an accelerated withdrawal response, with the goal of completing withdrawal in shorter periods from 8 days to as little as 2 or 3 days. In addition to an opioid antagonist, rapid approaches use pharmacotherapies (e.g., clonidine and sedation) to minimize the acute withdrawal symptoms experienced when opioid antagonists are administered. Because withdrawal is completed more quickly, the combination rapid approach has been proposed to have the advantage of minimizing the risk for relapse and allowing patients to enter continued treatment with naltrexone maintenance more rapidly. These methods have not been in widespread use, however. Ultrarapid methods are similar in pharmacologic approach to the rapid method but use general anesthesia and complete the procedure in several hours. This method was not found to be superior in long-term efficacy to the use of buprenorphine or clonidine in a 2006 review and therefore was not deemed to justify the risks of general anesthesia (41). A Cochrane Review in 2010 (42) selected controlled studies of antagonist-induced withdrawal under heavy sedation or anesthesia in opioid-dependent participants compared with other approaches or a different regimen of anesthesia-based antagonist-induced withdrawal. Nine studies (1,109 participants), including eight randomized controlled trials, met the inclusion criteria for the review. Antagonist-induced withdrawal in general was found to be more intense but less prolonged than withdrawal managed with reducing doses of methadone. Importantly, a significantly greater risk of adverse events was found with heavy, compared to light, sedation. Heavy sedation compared to light sedation also did not confer additional benefits in terms of less severe withdrawal or increased rates of beginning naltrexone maintenance treatment. The authors concluded that since the adverse events are potentially life-threatening, the value of antagonist-induced withdrawal under heavy sedation or anesthesia is not supported. They further conclude that the high cost and the use of scarce intensive care resources suggest that anesthesia-based approaches to treatment should not be pursued.
LONG-TERM TREATMENTS FOR OPIOID DEPENDENCE
Dependence and Protracted Abstinence
In patients with a history of opioid dependence, acute withdrawal and medically supervised withdrawal are only the beginning of treatment. Himmelsbach (43), reporting on 21 prisoners dependent on morphine, observed that “physical recovery requires not less than 6 months of total abstinence.” Factors he measured included temperature, sleep, respiration, weight, basal metabolic rate, blood pressure, and hematocrit. The times required for return to baseline ranged from 1 week to about 6 months. Martin and Jasinski (8) reported in a subsequent study that the period of PA persisted for 6 months or more after withdrawal and that it was associated with “altered physiologic function.” They found decreased blood pressure, decreased heart rate and body temperature, miosis, and a decreased sensitivity of the respiratory center to carbon dioxide, beginning about 6 weeks after withdrawal and persisting for 26 to 30 or more weeks. They also found increased sedimentation rates (which persisted for months) and electroencephalograph (EEG) changes. Martin and Jasinski (8) postulated a relationship between the PA syndrome and relapse. Based on similar observations, Dole (44) concluded that “human addicts almost always return to use of narcotics” after medically supervised withdrawal in the hospital. In his paper, Dole reviewed the relative importance of metabolic and conditioned factors in relapse and concluded that the underlying drive is metabolic, arguing that “psychological factors are only triggers for relapse.” In another study, Shi et al. (45) compared PA symptoms between drug-free and methadone-maintained former heroin users after similar lengths of heroin abstinence. Seventy former heroin users were included in one of four groups: in days 15 to 45 of short-term methadone maintenance treatment (MMT), in months 5 to 6 of MMT (long-term MMT), opioid-free for 15 to 45 days after methadone-assisted heroin withdrawal (short-term post-methadone), and opioid-free for 5 to 6 months after methadone-assisted heroin withdrawal (long-term post-methadone). Analysis of PA symptoms during the study allowed the investigators to conclude that long-term methadone maintenance reduces PA symptoms of heroin abstinence and cue-induced craving.
The concept of PA has been controversial (46) but remains a useful model for scientific hypothesis testing and development of new therapeutic approaches (47). Accordingly, Dole (44) recommended MMT, even though “it does establish physical dependence.” Because, as Dole pointed out, methadone continues physical dependence, PA may remain a problem at a later time when medically supervised withdrawal from methadone is undertaken. In addition to biologic considerations, psychosocial concomitants of opioid dependence also necessitate longer, more specialized adjunct treatments for these and additional problems.
Naltrexone Maintenance Treatment
Naltrexone is a long-acting, orally effective, predominantly μ-opioid antagonist that provides complete blockade of μ-opioid receptors when taken at least three times a week for a total weekly dose of about 350 mg (48). Because the reinforcing properties of opioids are completely blocked, naltrexone is theoretically an ideal maintenance agent in the rehabilitation of opioid-dependent patients who can successfully complete withdrawal and maintain abstinence from opioids. However, this optimistic theoretical perspective is contradicted by clinical reality, as reflected in treatment retention rates of only 20% to 30% over 6 months. Multiple factors appear to account for such poor retention (49). Opioid antagonists, unlike methadone, do not provide any opioid effect. Therefore, if antagonists are stopped, there is no immediate reminder in the form of withdrawal. In addition, craving for opioids may continue during naltrexone treatment. A meta-analysis of multiple studies did not provide strong support for naltrexone treatment of opioid dependence (50). Nevertheless, for certain highly motivated subsamples of opioid-dependent patients (such as health care professionals, business executives, or probation referrals) for whom there is an external incentive to comply with naltrexone therapy and to remain opioid abstinent, naltrexone has been very effective (51–54). Improved adherence has also been reported in programs that include psychosocial therapy (55,56), including contingency management (57,58).
Clinically, oral naltrexone is initiated after acute withdrawal from opioids. There should be at least a 5- to 7-day opioid-free period for the short-acting opioids and a 7- to 10-day period for the long-acting agents. This, of course, does not apply to withdrawal treatments using the naltrex-one–clonidine combination. The first dosage of naltrexone is typically preceded by a naloxone challenge test to assure the absence of any precipitated withdrawal symptoms prior to administering naltrexone. The initial dose of naltrex-one used generally is 25 mg on the 1st day, followed by 50 mg daily or an equivalent of 350 mg weekly, divided into three doses (100, 100, and 150 mg). The principal reason for the reduced dose on day 1 is the potential for gastrointestinal side effects, such as nausea and vomiting. This occurs in about 10% of patients taking naltrexone. In most cases, gastrointestinal upset is relatively mild and transient, but, in some cases, it may be so severe as to cause discontinuation of the naltrexone. The most serious (but far less frequent) potential side effect of naltrexone is liver toxicity; however, 50 mg daily has been given safely to opioid-dependent individuals (59). Liver toxicity, in the rare instances it occurs, appears to be limited in extent in that it resolves when naltrexone is discontinued and does not progress to liver failure. The enzyme dihydrodiol dehy-drogenase appears to catalyze the metabolism of naltrexone to the active metabolite, 6-β naltrexol. When administered orally, naltrexone has an average plasma half-life of 4 hours, whereas 6-β naltrexol has an average half-life of 13 hours after oral administration of the parent drug. In summary, though oral naltrexone has not lived up to expectations, for selected, motivated patients who are opioid-dependent, it may represent a very effective form of maintenance pharmacotherapy.
To address the problems of adherence and limited retention associated with oral naltrexone described above, use of extended-release formulations of naltrexone (by implant and by depot injection) was investigated. An extended-release formulation of naltrexone (XR-NTX) injected once monthly (every 4 weeks), found safe and well tolerated by participants in studies of treatment for alcohol dependence (60–62), was approved for this indication by the FDA in 2006. The medication has peak drug concentrations occurring at 2 hours and again at 2 to 3 days, remaining at therapeutic levels through 30 days. The recommended dose of 380 mg of extended-release naltrexone resulted in “minimal and generally mild” adverse events. The most common adverse events associated with XR-NTX in clinical trials were nausea, vomiting, headache, dizziness and injection site reactions, and possible hepatic toxicity. It can also increase sensitivity of opioid receptors, which can increase the potential for overdose if opioids are used following cessation of long-term naltrexone treatment. In preliminary studies of sustained-release naltrexone in opioid-dependent subjects, Comer et al. (63–65) found that 384-mg naltrex-one in a sustained-release depot formulation was able to block the reinforcing, subjective, and physiologic effects of up to 25-mg heroin and provided therapeutic plasma levels for approximately 30 days (63–65). At this dose, naltrexone also resulted in better than 80% retention in treatment at 6 weeks versus 40% for placebo (65). In comparison with the oral formulation, naltrexone implants showed significantly higher rates of abstinence and better treatment outcomes at 12-month follow-up (66–69). Adverse events were minimal and limited to local responses at the implant site (70). A full-scale trial of XR-NTX in opioid-dependent patients was reported by Krupitsky (71,72). This trial was a randomized, placebo-controlled, double-blind trial of XR-NTX conducted in Russia, where agonist therapy is not available (71,72). Participants were first withdrawn from opioids in inpatient settings for less than 30 days to ensure at least 7 days of opioid abstinence. Participants received monthly intramuscular injections of XR-NTX 380 mg (n = 126) or placebo (n = 124) for 4 months with 12 biweekly counseling sessions. The number of weeks of confirmed abstinence (based on rate of opioid-negative urine drug tests and self-report during weeks 5 to 24) was the primary outcome. In the XR-NTX group, 90% were abstinent versus 35% for placebo (p = 0.0002). The XR-NTX participants also had more opioid-free days, greater retention, and reduced craving compared to no change in the placebo group. No XR-NTX participants died, overdosed, or ended participation due to severe adverse events associated with the study protocol. XR-NTX was approved by the FDA in October 2010 for the treatment of opioid dependence based on the above-described trial. Ongoing research will be needed to answer questions of how the effectiveness of XR-NTX compares with methadone and buprenorphine and which patients may differentially respond to this medication. Other implant formulations of depot naltrexone are also being studied; several international implants are reviewed by Krupitsky and Blokhina (72). The most studied is a single-dose Australian naltrexone implant. A double-blind, placebo-controlled, randomized clinical trial showed the effectiveness of this formulation in comparison with oral naltrexone (73).
Methadone Maintenance Treatment
The initial pharmacologic rationale for long-term methadone maintenance was its ability to relieve the PA syndrome and to block heroin euphoria (44,74). However, an equally important benefit of longer-term maintenance has proved to be the opportunity it affords for psychosocial stabilization in the context of symptom relief. Good treatment retention, improved psychosocial adjustment, and reduced criminal activity are among the benefits reported (44,75). No serious side effects are associated with continued methadone use (49) with the exception of hypogonadism in men and risk of QT prolongation and exceedingly rare but potential subsequent progression to TdP (76). Minor side effects, such as constipation, excess sweating, drowsiness, and decreased sexual interest and performance have been noted. In addition, neuroendocrine studies have shown normalization of stress hormone responses and reproductive functioning (both of which are significantly disrupted in heroin users) after several months of stabilization on methadone (77).
A series of large-scale studies have demonstrated that patients maintained on doses of 60 mg or more of methadone a day had better treatment outcomes than those maintained on lower doses and that doses below 60 mg appear to be inadequate for most patients (78–84). In particular, the study by Ball and Ross (81) showed that opioid use was directly related to methadone dose levels and that the effectiveness of methadone was even greater for patients on a 70-mg dose and was still more pronounced for patients on 80 mg a day or more. Another factor mandating higher doses is the current purity of street heroin and potency of prescription opioids: Opioid cross-tolerance implies that the amount of heroin needed to produce euphoria would be prohibitively expensive for someone maintained on a sufficiently high dose of methadone. However, high-purity street heroin can require even higher methadone doses to achieve cross-tolerance (85).
High doses and pure street drugs also may increase the risk of toxicity if patients try to override the cross-tolerance with illicit heroin, as tolerance to respiratory depression may not be as complete as that to euphoria. The functional biologic distinction between these pharmacologic effects in animal and binding studies can perhaps be explained by receptor theory (86). Classic pharmacologic studies have long implied the existence of multiple subtypes of μ-opioid receptors. More recently, a number of variants of the cloned μ-opioid receptor have been described (86). These variants all show the same selectivity for μ-opioids, confirming their classification as μ-opioid receptors. Yet, they differ in their functional activation by opioids as well as in their localization within cells and regions in the brain. These multiple μ-opioid receptors may help explain the range of responses seen clinically among patients for the various opioid drugs. Many diverse factors may, in theory, significantly modify the pharmacologic effectiveness of methadone. Three types of factors that have been shown to significantly modify the metabolic breakdown of methadone in the body, and thus potentially its pharmacologic effectiveness, are the following: (a) chronic diseases, including chronic liver disease, chronic renal disease, and possibly other diseases; (b) medication interactions, including interactions of methadone with rifampin, phenytoin, and carbamazepine in humans and possibly with ethanol and disulfiram, and, also, by inference from animal studies, interactions of methadone with phenobarbital, diazepam, desipramine, and other drugs, as well as with estrogen steroids, cimetidine, and antiviral agents used in the treatment of HIV (87); and (c) altered physiologic states, especially pregnancy. The liver in particular may play a central role in several aspects of methadone disposition, involving not only methadone metabolism and clearance but also storage and subsequent release of unchanged methadone. In a study by Kreek et al. (88), unchanged methadone persisted in the liver for up to 6 weeks, and methadone disposition was significantly altered only in a patient subgroup with moderately severe but compensated cirrhosis. These factors have been reviewed in detail by Kreek (89) and Stine (90). Of the multiple medical problems that result from direct and/or indirect effects of illicit opioid use, chronic liver disease is the most common. For example, 50% to 60% of all heroin-dependent persons entering methadone maintenance have biochemical evidence of chronic liver disease, either secondary to infection (hepatitis B and C) or alcohol-induced liver disease. Chronic liver disease in all its forms has major implications for medication use. For example, opioid medications for treatment of dependence (such as methadone, LAAM, and buprenorphine); medications (such as isoniazid and rifampin) that are prescribed for other prevalent diseases in drug users, such as tuberculosis; as well as some antibiotics (such as trimethoprim– sulfamethoxazole) and some antiretroviral agents (such as atazanavir) may have hepatotoxic effects (89–93). A recent randomized clinical trial (94) comparing buprenorphine treatment with methadone treatment with respect to primary liver transaminase outcome measures reported that there was no clear evidence of liver damage associated with either medication (see START study in the “Comparative Efficacy of Buprenorphine versus Methadone” section below for more detail). Other diseases co-occurring with chronic opioid dependence that can affect maintenance pharmacotherapy are bacterial infections and tuberculosis, particularly drug-resistant and “extrapulmonary” manifestations of tuberculosis in HIV-infected individuals (95–98). Interactions of HIV antiretroviral medications with opioid maintenance treatment may also be problematic. These are discussed further later in this chapter.
The duration of MMT warrants mention. In general, for successful rehabilitation, length of treatment with methadone is best seen in terms of years rather than months. For many patients, 5 to 10 years—or even a lifetime— of methadone maintenance may be required. At about a year of treatment, the pharmacologic component of PA may still present a problem, but ongoing therapeutic support in a context of psychosocial stability may render this problem more manageable. The importance of psychosocial treatment as an adjunct to methadone pharmacotherapy has been emphasized in the field since the Ball and Ross study (81).
From an organizational and public health perspective, early treatment termination, illicit use of nonopioid substances (such as cocaine or alcohol), and diversion of the take-home dose of methadone to the illicit market remain significant issues for most methadone maintenance programs. Although concurrent substance use also is a problem (initially, 20% to 50% of methadone patients use cocaine and 25% to 40% abuse alcohol), several effective treatment interventions have been developed, including behavioral approaches and pharmacologic interventions. Diversion of take-home doses is of concern to every methadone maintenance program, though its impact on illicit opioid use remains small (methadone accounts for about 4% of opioids used on the street).
Levo-Alpha-Acetylmethadol Maintenance Treatment
Initial studies of LAAM were performed in the 1970s. Its duration of action is up to 3 days, which made a three-times-a-week dosing schedule possible. The principal disadvantage of such a long duration of action is the time necessary to reach a steady state and to stabilize the patient at an appropriate comfort level (99,100). The long action of LAAM solved some clinical problems that seemed to undermine the efficacy of methadone in some patients. For example, patients who apparently metabolize methadone quickly, requiring split dosing; patients unable for miscellaneous reasons (e.g., child care needs, employment) to attend daily dispensing clinic; and patients who presented medication diversion risks were able to be successfully treated with LAAM (101). A dose effect of LAAM on illicit opiate use was reported, with the 100/100/140 mg thrice-weekly regimen giving the greatest reduction in opiate use. The FDA issued a boxed warning for LAAM because of postmarketing surveillance reports of QTc prolongation in electrocardiograms (ECGs), with several reports of TdP, a polymorphic life-threatening ventricular arrhythmia. As a result, LAAM was removed from the market in Europe and has been withdrawn by the manufacturer in the United States. Although production has been discontinued by the manufacturer, the medication remains FDA approved, and many physicians feel that it addresses a needed niche (102). The development of buprenorphine, however, has provided an additional option for patients requiring a longer-lasting pharmacotherapy agent.
Buprenorphine Maintenance Treatment
Buprenorphine is a μ-opioid partial agonist that was originally marketed as a parenterally administered analgesic product. Investigators conducting an abuse liability study in human volunteers reported that subcutaneously administered buprenorphine had fewer subjective effects than morphine, a lesser withdrawal syndrome, and an ability to block the subjective responses of up to 120-mg doses of morphine. Subsequent work established that the sublingual route was preferable to oral dosing because of high first-pass effects. The first outpatient treatment study compared 8 mg of sublingual buprenorphine liquid to 20- and 60-mg doses of orally administered methadone in a randomized, double-blind, double-dummy study. Retention and decreased illicit opioid use in the buprenorphine group were superior to the response seen in the group that was receiving 20 mg/d of methadone. A study conducted with a liquid formulation was performed in a multisite trial in which opioid-dependent individuals were randomly assigned to 1, 4, 8, and 16 mg/d of buprenorphine. The comparison was the effects of 1 mg/d versus 8 mg/d on illicit opioid use, retention, and opioid craving. The 8 mg/d dose group had significant reductions in illicit opioid use, reduced craving, and had better retention. Subsequent to the study by Ling et al. (4), it was decided to develop a sublingual tablet and to add naloxone, an opioid antagonist, to one of the formulations. The rationale for adding naloxone was to produce a less abusable, less divertible tablet. The dose ratio of buprenorphine to naloxone was chosen from data gathered in clinical pharmacology studies in opioid-dependent subjects maintained with morphine, methadone, or buprenorphine. In the first study, the subjects maintained on a dosage of 60 mg/d of morphine sulfate were randomly administered one of six medication treatments intravenously in a counterbalanced order: morphine, buprenorphine, buprenorphine/naloxone at 8:1, buprenorphine/naloxone at 4:1, buprenorphine/naloxone at 2:1, and placebo. Subjective measures of positive and negative effects were assessed for the first hour after dosing. The 4:1 ratio was chosen because it produced significant attenuation of buprenorphine’s effects without producing significant withdrawal signs. The 2:1 ratio was aversive because it produced withdrawal on four measures and was the only dose combination for which the subjects would not pay money. A randomized, double-blind comparison of the effects of tablet formulations of 16 mg/d of buprenorphine; 16/4, buprenorphine/naloxone; or placebo was carried out in a multicenter trial. The placebo-controlled portion of the trial lasted 1 month. Subjects in either buprenorphine dose group had reduced opioid use and reduced craving versus the placebo group. Thereafter, all subjects were given open-label buprenorphine/naloxone for 11 months. Other subjects participating at new sites were given 1 year of open-label buprenorphine/naloxone. Most Phase 1 and Phase 2 medication development studies with buprenorphine have been conducted using parenteral and sublingual liquid formulations, and the sublingual liquid has been extensively studied in Phase 3 clinical trials. The buprenorphine sublingual tablet has been available in two forms. One formulation (Subutex) contained only buprenorphine (the “mono” tablet). The second formulation (Suboxone) contained buprenorphine and the opioid antagonist naloxone in a 4:1 ratio, which was designed to discourage illicit diversion and intravenous use. Pharmacokinetic studies have found that the buprenorphine sublingual liquid formulation differs in bioavailability from the sublingual tablet (103–105). The tablet has been shown to produce blood levels that are about 50% to 60% those achieved with the liquid (104). Based on the findings of Compton et al. (106), repeated administration of the tablet achieves about 70% bioequivalence to the solution. The recommended therapeutic dose of buprenorphine/naloxone is 16 mg/4 mg to 24 mg/8 mg. Current available formulations are a buprenorphine/naloxone sublingual film, generic buprenorphine/naloxone sublingual tablets, and generic buprenorphine sublingual tablets. The film was reportedly designed to reduce diversion and is also in response to a concern that the tablet form may appear to be candy to children and result in pediatric emergencies (107). This is hypothesized to have been responsible for ER cases detected by the U.S. Drug Abuse Warning System involving children under 6 years (108). The safety of the film strip has been tested for the Consumer Product Safety Commission, showing that one child out of 50 was able to open two or more of the film pouches (109). The film dissolves more quickly and has similar bioavailability. The film packaging also contains unique identifier information in barcode format, theoretically allowing authorities to track sourcing of diverted supplies. The success of this formulation in achieving safety goals has not yet been demonstrated, however.
Clinical research over the past 15 years has established that buprenorphine formulations are a safe and effective alternative to methadone (16,110–117) and LAAM (118) for opioid agonist maintenance treatment. Treatment with buprenorphine produces significant and substantial improvements over time in psychosocial functioning (119). Buprenorphine also has unique features that permit novel uses, which may alter current strategies for maintenance and medically supervised withdrawal (3). In particular, buprenorphine’s ceiling on agonist activity reduces the danger of overdose and may limit its abuse liability (120,121), and buprenorphine has low toxicity even at high intravenous doses (122,123), thereby increasing the dose range over which it may be administered safely. Buprenorphine appears less likely than methadone to prolong the QT interval on the ECG (124,125). (See section below on QTc prolongation.) Buprenorphine also can produce sufficient tolerance to block the effects of exogenously administered opioids (121,126,127), suggesting that it may help to reduce illicit opioid use. A transdermal formulation and a depot formulation of buprenorphine, though not FDA approved for the treatment of opioid addiction, have been developed that may provide extended relief from opioid withdrawal, reduce required clinic visits, and improve adherence, while having less potential for diversion and abuse (128). In order to enhance effective delivery and to diminish risk of diversion, an implant form of buprenorphine is also in development. This formulation employs a long-term drug delivery system, consisting of a small, solid “rod” made from a mixture of ethylene vinyl acetate and the equivalent of about 80 mg of buprenorphine, released at a measured rate (129,130). The rod is designed to be placed subdermally in the upper arm and removed after 6 months. In a 6-month placebo-controlled trial involving 163 patients randomized 2:1 (implantable buprenorphine/placebo), the study showed that patients assigned to buprenorphine implants, compared with those assigned to placebo, had less illicit opioid use over weeks 1 to 16, 17 to 24, and 1 to 24 (129,130). A later Phase III study of the implant compared with placebo and with buprenorphine/naloxone over a 24-week period has been performed in which the preliminary results confirmed that the implant was noninferior to sublingual buprenorphine/naloxone with respect to urine toxicology and reported opioid use (131). A New Drug Application submitted to the FDA based on these data was rejected in 2013 with the request that additional studies be performed.
Office-Based Treatment
Office-based treatment of opioid dependence with the sub-lingual formulation of buprenorphine/naloxone has been implemented.
Buprenorphine Induction and Stabilization
Buprenorphine can produce withdrawal discomfort among opioid-dependent volunteers under certain conditions, which may be due to more than one mechanism (3,132). Low buprenorphine doses may provide too little agonist effect (i.e., insufficient substitution) relative to the maintenance opioid (such as heroin). In this case, raising the buprenorphine dose may or may not surmount this problem. Put another way, the partial agonist profile of buprenorphine may limit its ability to suppress opioid abstinence signs and symptoms. Alternatively, buprenorphine may directly precipitate withdrawal discomfort, in which case, higher doses could be expected to aggravate the problem. Individuals maintained on the long-acting, full μ-opioid agonist methadone can experience withdrawal symptoms, when given the high-affinity partial μ-agonist buprenorphine, which abruptly reduces the extent of μ-opioid receptor stimulation. This principle has been amply demonstrated in humans: Partial μ-opioid agonists such as nalorphine and butorphanol (133,134) can, in methadone-maintained individuals, abruptly precipitate opioid withdrawal signs and symptoms that are functionally similar to those produced by the antagonist naloxone. Among individuals maintained on shorter-acting μ-opioid agonists such as morphine ( relative to the longer-acting agonist methadone), buprenorphine administered alone did not precipitate a significant opioid withdrawal syndrome provided those individuals have abstained from opioid use long enough to enter a state of early opioid withdrawal (135–138). Bickel and Amass (3) proposed tentative guidelines for inducting opioid-dependent patients onto buprenorphine, which involve considering the amount of opioid used and maintaining a sufficient interval (at least 12 hours) between the last opioid use and the first buprenorphine dose. They recommended that the induction dose of buprenorphine be administered when patients are beginning to experience opioid withdrawal, so that buprenorphine can suppress those symptoms. Clinical experience with administering initial doses of buprenorphine to opioid-dependent patients suggests that an interval of 6 hours probably is sufficient to minimize the risk of precipitated withdrawal.
The general guidelines for beginning opioid treatment medication are published in the CSAT Treatment Improvement Publications (TIPs) 43 (for opioid treatment in OTPs) and 40 (for buprenorphine) (139). After physical assessment to rule out any acute, life-threatening condition, including the presence of sedatives such as benzodiazepines or alcohol (that might have abstinence or intoxication symptoms masked or worsened by buprenorphine treatment), treatment with buprenorphine should begin when there are no signs of opioid intoxication or sedation and some beginning objectively observable signs of opioid withdrawal. Awaiting signs of withdrawal before administering the first dose is especially important for buprenorphine induction because, as described, buprenorphine can precipitate withdrawal in some circumstances (140). Precipitated withdrawal usually is more sudden and can be more severe and uncomfortable than naturally occurring withdrawal. The typical first dose of buprenorphine is 4 mg, and a sublingual tablet should be observed to have dissolved completely under the tongue. After the first dose, TIP 40 recommends that patients should wait in an observation area and be checked 30 to 60 minutes later for acute adverse effects (139). However, as more experience has been gained with this medication, patients are frequently given prescriptions to start treatment in a home setting. Several studies have described evidence for the safety and effectiveness of this approach (141–144). If same-day dosing adjustments must be made, patients should wait 2 to 4 more hours after the additional dosing, for further evaluation when peak effects are achieved. If withdrawal symptoms persist after 2 to 4 hours, the initial dose can be supplemented with up to 4 mg for a maximum 1st day dose of 8 mg of buprenorphine (145). The 1st day’s dose should be followed by dosage increases over subsequent days until withdrawal symptoms are suppressed within about 2 hours after taking the medication and lasting until the next day’s dosing when using once-daily dosing. For most patients undergoing induction, the initial target dose after induction should be 12 to 16 mg of buprenorphine in a 4:1 ratio to naloxone (i.e., 12/3 to 16/4 mg [for buprenorphine/naloxone]). Bringing patients to this target dosage may be achieved over the first 3 days of treatment by doubling the dose each successive day after initial administration. During dose induction, patients may need to visit their OTP or physician’s office daily for dose adjustments and clinical monitoring. Further information and guidelines for buprenorphine induction and use can be found in TIP 40, Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction (139).
Special considerations are needed for patients inducted onto buprenorphine after treatment with or nonmedical use of long half-life full agonist opioid medications such as methadone. Three national evaluations of the buprenorphine–naloxone combination tablet found that direct induction with buprenorphine alone was effective for most people who were opioid addicted. However, buprenorphine tablets without naloxone (often called “monotherapy”) may be used during the first 2 days of induction for patients attempting to transfer from a longer-acting opioid such as sustained-release morphine or methadone (146,147) to avoid any possibility that these patients would experience withdrawal effects from any naloxone absorbed from the combination tablets—an unlikely phenomenon due to the low sublingual absorption of naloxone.
QTc Intervals and Opioid Maintenance Treatment
Drug-induced long QT syndrome occurs with a wide range of medications (148) including methadone and LAAM (described above). A CSAT report on methadone-associated mortality was compiled in 2003 (149). In November 2006, the FDA issued a physician safety alert regarding fatalities and cardiac arrhythmias associated with methadone, which was followed by a boxed warning in the manufacturer’s product labeling (150,151). Also of concern was evidence of a significant knowledge gap among OTP medical staff regarding the risk of QT prolongation and TdP associated with methadone (152). Subsequently, the SAMHSA convened a multidisciplinary expert panel on the cardiac effects of methadone to evaluate the available evidence and formulate recommendations for cardiac safety of patients in OTPs. A report generated by members of this panel (153), which appeared in the January 20, 2009 online issue of the Annals of Internal Medicine (154), recommended five specific precautions:
■ Recommendation 1 (Disclosure): When physicians prescribe methadone, they should inform patients about arrhythmia risk.
■ Recommendation 2 (Clinical History): Physicians should ask patients about any history of structural heart disease, arrhythmia, and syncope.
■ Recommendation 3 (Screening): Physicians should obtain a pretreatment ECG for all patients to measure the QTc interval and then a follow-up ECG within 30 days and annually. If the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures, additional ECG is recommended.
■ Recommendation 4 (Risk Stratification): For patients in whom the QTc interval is between 450 and 500 milliseconds, physicians should discuss the potential risks and benefits of methadone and monitor these patients more frequently. For patients in whom the QTc interval exceeds 500 milliseconds, physicians should consider discontinuing or decreasing the methadone dose, eliminating other contributing factors such as drugs that promote hypokalemia, or using an alternative therapy.
■ Recommendation 5 (Drug Interactions): Physicians should be knowledgeable of interactions between methadone and other drugs that tend to prolong the QT interval or to slow the elimination of methadone.
Although prolongation of the QT interval has served as a surrogate marker for the risk of developing TdP, a potentially lethal ventricular arrhythmia, it is only rarely associated with high daily doses and a prolongation of the QTc interval on an ECG (154–156), and agreement on safe and rational cardiac management of methadone patients has not been achieved. During the review and recommendation processes described above, much debate has been conducted in the scientific literature. For example, after a review of the evidence base on this topic, an expert team in Norway recommended that, instead of being required before methadone treatment, an ECG should be recorded during treatment particularly if there were other risk factors for QTc prolongation present (157). This was largely based on earlier research done by Krantz (158,159). Because of its rarity and expert disagreement about the real-world risks, QTc monitoring via ECGs is not a uniformly accepted standard of care in methadone treatment (160–162). One complicating factor is that scores of medical drugs and psychiatric drugs are known to increase QTc intervals as well (163).
A Norwegian study (164) attempted to estimate the potential impact on mortality from QTc prolongation in a large, national sample of opioid maintenance patients. In that study, 200 patients receiving opioid agonist treatment in Oslo were recruited for a QTc assessment study. The authors also examined the Norwegian register for all patients receiving opioid agonist treatment in Norway (January 1997 to December 2003) as well as the national death certificate register for mortality records of 90 deaths among 2,382 patients with 6,450 total years in treatment. In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone, and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine had QTc results less than 450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. Patient mortality from the Norwegian register, where QTc prolongation could not be excluded as the cause, was 0.06/100 patient-years. The study concludes that the maximum mortality attributable to QTc prolongation and ventricular arrhythmia in opioid maintenance treatment is very low, despite a prevalence of QTc interval above 500 milliseconds of nearly 5% among methadone patients and indications of a dose-dependent relation. The authors did not recommend ECG recording prior to opioid maintenance treatment as a lifesaving, cost-beneficial screening program but suggest a practical approach consisting of a past medical history focused on cardiac symptoms and disorders obtained prior to treatment with methadone. If indicated by the history or in the presence of other known risk factors for QTc prolongation, the drug of choice is primarily buprenorphine. If the patient is started on methadone, an ECG, preferably over 24 hours, should be recorded at this stage. If this reveals QTc prolongation, the patients should be referred for genetic testing if available. The findings of this study concerning buprenorphine are consistent with other reports finding that buprenorphine presents less risk of cardiac conduction problems (124,125,165,166).
The official recommendations by the SAMHSA expert review panel were published in 2011 (167). In that report, routine screening of every patient within 30 days of admission to treatment was not part of the consensus-driven conclusions presented since nine panel participants agreed and four were dissenting (167). The panel did agree that a baseline ECG at the time of admission and within 30 days should be performed on patients with significant risk factors for QT prolongation, including a history of cardiac arrhythmia or prolonged QT interval; symptoms suggestive of arrhythmia, such as episodes of syncope, dizzy spells, palpitations, or seizures; medication history; family history of premature death; or any other historical information suggestive of a possible cardiac arrhythmia. Additional ECGs should be performed annually or whenever the methadone dose exceeds 120 mg/d. The panel also acknowledged that these recommendations were not meant to be a legal standard of care and that clinicians are encouraged to consider these conclusions to the extent that they are practically or financially capable of doing so. This article was published together with two editorial opinions, which present the cases for not adhering rigidly to the recommendations (168) versus the case for adhering closely (169).
In summary, although there are no universally accepted guidelines and views regarding ECG screening are conflicting, methadone clinicians should be aware of the issues and adopt the safest clinical procedures feasible. Buprenorphine, whenever possible, is a choice less likely to present cardiac conduction problems.
Comparative Efficacy of Buprenorphine versus Methadone
The clinical issue of choosing between pharmacotherapy options or matching patients to buprenorphine versus methadone maintenance continues to be an open question that is actively investigated. Early studies offered few head-to-head comparisons, and those available had limited dose comparisons. An important study from Ling et al. (112) in 1996 comparing 225 treatment-seeking opioid-dependent individuals (46 women, 179 men) randomly assigned to either 8 mg/d (sublingual liquid solution) of buprenorphine, 30 mg/d of methadone, or 80 mg/d of methadone maintenance over a 1-year period showed that patients assigned to high-dose methadone maintenance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26-week and 52-week time points. The 8 mg/d of buprenorphine and 30 mg/d of methadone groups had equivalent outcomes. In another early comparison of methadone, buprenorphine, and LAAM by Johnson et al. in 2000 (84), 220 opioid-dependent patients were randomized to LAAM (75 to 115 mg), buprenorphine (16 to 32 mg), and high-dose (60 to 100 mg) or low-dose (20 mg) methadone treatment for 17 weeks. Patients with poor responses to treatment were switched to methadone. Retention was significantly higher for those receiving LAAM, buprenorphine, and high-dose methadone than for those receiving low-dose methadone. With respect to opioid use, the authors concluded that compared with low-dose methadone, LAAM, buprenorphine, and high-dose methadone substantially reduce the use of illicit opioids. A meta-analysis published in 2008 (170) evaluated the effects of buprenorphine maintenance against placebo and methadone maintenance in retaining patients in treatment and in suppressing illicit drug use. The meta-analysis included 24 studies available up to October 2006 (4,497 participants), all randomized clinical trials, all but six double blind. Of these 24 studies, 8 (1,064 participants) were included in the primary meta-analysis. Buprenorphine was found to be statistically significantly superior to placebo medication in retention of patients in treatment at low, medium, and high doses, but only medium- and high-dose buprenorphine suppressed heroin use significantly above placebo. Buprenorphine given in flexible doses was statistically significantly less effective than methadone in retaining patients in treatment but no different in suppression of opioid use for those who remained in treatment. The authors concluded that buprenorphine is an effective intervention for use in the maintenance treatment of opioid dependence, but it is less effective than methadone delivered at adequate dosages. Other, more recent studies have generally had survey and descriptive designs. For example, a study by Ridge et al. (170a) administered a structured interview to 192 patients recruited from 10 addiction treatment services in London and collected data on patient demographics, beliefs, attitudes, and preferences as well as data regarding treatment goals and prescribed medication from interviews with clinical staff. Methadone had a higher preference rating than buprenorphine, and patient preferences and beliefs about opioid agonist medications influenced the odds of being prescribed buprenorphine versus methadone. Buprenorphine was more likely to be prescribed for short-term opioid withdrawal and methadone for maintenance treatment. One head-to-head study of effectiveness in medically assisted withdrawal by Wright et al. (171) (the “LEEDS study”) was an open-label, pragmatic, randomized controlled trial in three prison primary health care departments in the north of England comparing 306 prisoners using illicit opiates who were given daily buprenorphine or methadone in a standard regimen of not more than 20 days. The primary outcome measure was abstinence from illicit opiates at 8 days postwithdrawal, and equal clinical effectiveness was reported. A recent large longitudinal study of opioid-dependent outpatients selected from 10 Italian Public Services for Addiction centers in Naples (Italy) (172) examined the substitution of buprenorphine treatment with the buprenorphine/ naloxone combination and also compared these patients to methadone-maintained patients. In this study, 3,105 (81.5%) were treated with methadone and 707 (18.5%) with buprenorphine. The buprenorphine treatment was switched to buprenorphine/naloxone (4:1), and the patients were followed for about 1 year. The number of patients retained on methadone and buprenorphine/naloxone was found to be similar. However, in patients treated with buprenorphine/naloxone, a significant improvement was reported in social life status, educational level, and toxicologic conditions compared with methadone treatment; but the authors conclude that they cannot exclude a selection bias, that is, patients who were more likely to stabilize their opioid dependence switched to buprenorphine/naloxone. Another dimension of the comparative efficacy of buprenorphine versus methadone is the relative effect each medication has on health indices other than retention and abstinence in opioid dependence treatment. A recent randomized controlled clinical trial compared buprenorphine/ naloxone and methadone with respect to primary liver transaminase outcome measures (93). This study, National Drug Abuse Treatment Clinical Trials Network protocol CTN-0027 (Starting Treatment with Agonist Replacement Therapies [START]), randomized 1,269 opioid-dependent participants at 8 OTP sites to buprenorphine or methadone treatment for 32 weeks. The authors concluded that the study demonstrated no evidence of liver damage during the initial 6 months of treatment with either medication. Changes in transaminase levels did not differ by medication condition, and baseline infection with hepatitis C or B was the only significant predictor of moving from low to high transaminase levels. Methadone participants were retained longer than the buprenorphine participants, but the 24-week retention rates for the buprenorphine group were similar to those seen in prior studies. The authors further comment that because of buprenorphine’s superior safety profile and excellent clinical responses observed in previous studies, this medication could be considered a first-line treatment agent, with methadone reserved for those who do not respond well to buprenorphine.
SPECIAL ISSUES IN MAINTENANCE TREATMENT
Opioid Maintenance Treatment during Pregnancy
Opioid misuse during pregnancy is a serious and growing concern in the United States and around the world and is often associated with a multitude of environmental and medical factors contributing to adverse consequences for both the mother and her infant, including high rates of infection, premature delivery, and low birth weight, which is an important risk factor for later developmental delay (172a,173–180). The pharmacologic management of opioid dependence in pregnant women is a complex clinical problem. The increasing prevalence of nonmedically used analgesics in the general population and women of childbearing age has made the focus on this problem especially urgent. The pattern of increased nonmedical use of opioid analgesics seen in the general population has also been found for pregnant women, with self-reported non-medical use increasing from 51,900 in 1993 to an average of 109,000 in 2002 to 2004 (124). The current literature suggests that children of opioid-dependent women might be at risk for poor outcomes not only because of opioid drug exposure but also because of concomitant alcohol and tobacco exposure and numerous factors related to the care-giving environment (173,181). Treatment options studied include methadone maintenance (182,183), antagonist maintenance (184) (i.e., naltrexone), and medication-assisted withdrawal (185). Methadone maintenance has been the recommended standard of care over no treatment or medication-assisted withdrawal. This recommendation is based on longer durations of maternal drug abstinence, better obstetrical care compliance, avoidance of associated risk behaviors, reductions in fetal illicit drug exposure, and enhanced neonatal outcomes (i.e., heavier birth weight) (182). Methadone is the oldest, most widely used medication prescribed during pregnancy (183), and in comparison to infants from heroin-abusing mothers, infants from methadone-treated mothers have increased fetal growth, reduced fetal mortality, decreased risk of HIV infection, decreased risk of preeclampsia and fetal exposure to rapid and unpredictable cycles of opioid-induced highs and withdrawal, and an increased likelihood of the infant being discharged to his or her parents (178,186). Moreover, for pregnant women under conditions where nonmedication-assisted and methadone treatment were both available, methadone is associated with longer treatment retention (187,188) and less relapse (186). Studies examining the consequences of prenatal methadone exposure on later development have produced inconsistent results (189–196) that could be due to a number of confounding factors and are complicated by significant study attrition (189). One long-term follow-up study of 27 children who had been exposed to methadone in utero found no cognitive impairment in the preschool years (173). Overall, prenatal exposure to methadone provided as a part of comprehensive treatment does not appear to be associated with developmental or cognitive impairments (189).
Nevertheless, methadone use at the usually effective clinical doses during pregnancy may be avoided by some practitioners because of concerns over the associated neonatal abstinence syndrome (NAS). Although newborns of methadone-maintained women may experience opioid withdrawal symptoms, these are readily treated without damaging consequences (189). Generally, 50% to 81% of neonates prenatally exposed to methadone show some signs of NAS (172a,197). In a retrospective review of pregnancies that were maintained on methadone therapy in one hospital (172a), 100 mother/neonate pairs on methadone therapy were identified. Women who received an average methadone dose of greater than 80 mg were similar to women maintained on dosages of ≤80 mg in having infants with similar neonatal abstinence scores, needs for neonatal treatment for withdrawal, and similar duration of withdrawal, when it occurred in the neonate. The authors concluded that maternal methadone dosage does not correlate with neonatal withdrawal; therefore, maternal benefits of effective methadone dosing are not offset by neonatal harm. However, another study addressing maternal maintenance dose found that NAS was related to the mother’s dose of methadone. It reported that opioid-dependent pregnant patients receiving mean methadone doses of 132-mg methadone had less illicit drug use at delivery, but their neonates had no more severe NAS than expectant mothers receiving mean doses of 62 mg of methadone (198). Hence, pregnant women should receive appropriate methadone doses to treat their addiction, but concerns regarding greater NAS severity associated with larger methadone should not be the primary factor in determining dose (199).
Similar to research with methadone, large, definitive randomized controlled trials of buprenorphine in pregnant women have not been conducted. There have been 31 published reports of buprenorphine exposure during pregnancy that were reviewed and summarized by Jones et al. (199). Of note, two small-scale, randomized, double-blind controlled trials were completed using similar methodology to obtain safety and efficacy data comparing methadone and buprenorphine in pregnant women (200–202). In addition, the literature includes 10 prospective studies and 18 reports summarizing case report data. Overall, the studies report approximately 522 neonates prenatally exposed to buprenorphine, with a wide range of therapeutic doses, from 0.4 to 24 mg sublingual tablets per day. Generally, the pregnancies were uneventful, without physical teratogenic effects and with low rates of prematurity, suggesting that buprenorphine is relatively safe and effective in this population. Clearly, conclusions from data on the prenatal exposure to buprenorphine are limited by methodologic challenges (e.g., varied dose ranges, lengths of exposure, care settings). Many published reports omitted information regarding concomitant drug use, including licit drugs of abuse (nicotine, alcohol), prescribed medications (e.g., benzodiazepines, antidepressants), and illicit drugs that could impact the expression of NAS. The most glaring omission is the insufficient detail regarding medication used to treat ensuing NAS as well as the criteria for initiation, maintenance, and weaning of NAS medication. Moreover, the scoring systems used to assess NAS treatment efficacy vary widely across all reports (e.g., Finnegan (203) or modifications of this scale and Lipsitz (203a)) and thus limit the ability to compare studies. Despite significant variability in the instruments and scoring methods used, the literature suggests that buprenorphine exposure is also associated with NAS, half the cases of which require pharmacotherapy. The pregnancy, birth, and NAS outcomes are also confounded by other drug use in 86% of the reports. Although considerable individual variability exists, the NAS timing observed to date has an apparent onset within the first 12 to 48 hours, peaks within approximately 66 to 96 hours, and lasts approximately 120 to 168 hours. The exception to this has been the few infants who were reported to exhibit withdrawal signs for 6 to 10 weeks after delivery. Such a protracted withdrawal syndrome may be due to both the NAS medication and the regimen used to treat withdrawal rather than a direct effect of buprenorphine. To date, only one report has found a correlation between buprenorphine dose and the severity of the NAS (204). Other recent reports (200,202) and one that included a large sample size (205) have reported no correlation.
Although there are hundreds of published papers on methadone treatment of substance-abusing pregnant women and more than 31 published reports documenting perinatal buprenorphine exposure, much of the literature has methodologic limitations. These include the fact that studies are frequently open label, retrospective, of small sample sizes, and lack appropriate controls (e.g., prospective data collection, randomization, blind dosing and data collection, systematic collection of data). The need for a large multisite clinical trial enrolling a diverse sample of pregnant opioid-dependent women in order to conclusively determine each medication’s safety and efficacy was only recently addressed by the Maternal Opioid Treatment: Human Experimental Research study (199,206). This was a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Participants were 18 to 41 years of age, pregnant with estimated gestational age between 6 and 30 weeks, and currently opioid dependent (207) or had a history of opioid dependence and being at risk for relapse (208) and had opioid-positive urine sample results. Buprenorphine without naloxone was selected for this trial to minimize risks of side effects, to obtain scientific information on effects of buprenorphine alone before adding other medications, and to avoid possible maternal and fetal hormonal effects suggested by animal data after naloxone exposure (209,210). A flexible dose range of 2 to 32 mg of buprenorphine estimated to be equivalent to the methadone flexible dosing range of 20 to 140 mg methadone was used based on reported clinical trial data (110–112,209,210). Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference. Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required less morphine (mean dose, 1.1 mg vs. 10.4 mg; p < 0.0091), had a shorter hospital stay (10.0 days vs. 17.5 days, p < 0.0091), and had a shorter duration of treatment for the NAS (4.1 days vs. 9.9 days, p < 0.003125) (p values calculated in accordance with prespecified thresholds for significance). There were no differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events. The authors conclude that buprenorphine is an alternative to methadone for the treatment of opioid dependence during pregnancy. Although there were no differences in rates of NAS among infants exposed to buprenorphine and methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment in pregnancy. However, the authors also caution that clinicians should take into account the possibility of reduced adherence and the ceiling effect of buprenorphine compared with methadone. Although there was no statistically significant difference in retention between buprenorphine-treated and methadone-treated women, the higher rate of treatment discontinuation in the buprenorphine group raises issues of optimal induction onto buprenorphine and retention as an issue for future exploration. Secondary outcomes and exploratory issues have been reported (211).
Interactions of Opioid Maintenance and Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Pharmacotherapy
In response to concerns about HIV and drug injection as a mode of transmission, methadone maintenance has been accorded renewed attention. Prevalence studies in New York City from 1984 to 1985 found that less than 10% of methadone-maintained patients who entered treatment before 1978 were HIV positive, compared to more than half of heroin-dependent patients who were not in treatment (212). Similarly, a prospective study in Philadelphia found an HIV seroconversion rate four times higher in active intravenous heroin users than in patients receiving methadone (213). Other studies documented a dramatically reduced HIV sero-prevalence rate for patients who were successfully maintained on methadone, as compared to active injecting drug users (214–216). Methadone maintenance thus appears to be extremely effective in reducing injection-related risk factors for HIV.
The introduction of new antiretroviral agents and highly active antiretroviral therapy (HAART) created a new therapeutic era for HIV-infected patients but also has introduced new complexities related to potential drug toxicities and interactions. Preclinical studies of antiretroviral medications and opioids indicate that drug interactions may occur as methadone and buprenorphine are both primarily metabolized by hepatic cytochrome CYP 450 3A4 (217,218). A number of antiretroviral medications have been shown in preclinical studies to inhibit or induce the activity of this same enzyme.
Methadone has been associated with several clinically important adverse drug interactions with HIV medications. A study of possible interactions between methadone and zidovudine (azidothymidine, or AZT) has shown that serum levels of methadone are not affected by this drug, but that some patients who receive MMT may show a potentially toxic increase in serum levels of AZT (86). However, the authors caution against making changes in the dose of AZT; instead, they suggest careful clinical monitoring for signs of dose-related AZT toxicity. Another possible complication when an antiretroviral medication that can induce methadone metabolism is discontinued is cardiac arrhythmia due to increased methadone exposure after reversal of methadone metabolism induction leads to increased methadone exposure (153). It has been recommended that after the medication that is inducing CYP 450 3A enzymes is stopped, the methadone dose should be tapered over 1 to 2 weeks to reestablish the previous therapeutic dose of methadone (i.e., that dose on which the patient was stable before starting the HAART regimen) (2). A recent review citing numerous case reports, chart reviews, and pharma-cokinetic studies (219) observed that many HAART drugs compete with methadone for metabolizing enzymes, thus requiring dose changes for methadone during concomitant treatment for HIV.
Buprenorphine has been studied in combination with antiretroviral medications more recently. To date, reductions in buprenorphine concentrations resulting from drug interactions have not been associated with opioid withdrawal. A study examining drug interactions between buprenorphine and the nonnucleoside reverse transcriptase inhibitors efavirenz (EFV) and delavirdine (DLV) (220) found that buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease. They also examined drug interactions between buprenorphine and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). The authors concluded that buprenorphine had no significant effects on the PI area under the curve. Adjustments of doses of buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease (221). Further, a recent review (222) regarding specific interactions between buprenorphine and antiretrovirals found that drug interactions between buprenorphine/naloxone and antiretrovirals are less likely than with methadone.
Though pharmacologically buprenorphine may present fewer medication interaction problems, the outpatient office setting may not be the most therapeutic with respect to medication adherence. OTPs are ideal sites to support adherence to treatment of HIV and other infectious diseases. Resistance to antiretroviral drugs is one of the greatest limitations to effective long-term therapy for HIV infection—a problem alleviated by the development of carefully selected, sequential combination HAART regimens (223). This strategy depends on careful adherence of 90% or greater, in order to maintain efficacy. Drug abuse treatment programs, irrespective of modality, are associated with improved adherence to antiretroviral therapies among drug users (224). Methadone treatment, in particular, has been shown to be associated with HAART adherence and improved HIV treatment outcomes among HIV/HCV coinfected injection drug users (225). It should also be mentioned in this context that a similar situation exists for tuberculosis wherein incomplete chemoprophylaxis and treatment are major causes of the resurgence of this disease, often drug resistant, among drug users. Adherence to and completion of directly observed antituberculosis therapy can be attained by drug users in treatment, even despite ongoing drug misuse (226). A comprehensive review of drug interactions with methadone versus buprenorphine was published in 2009 (227).
In conclusion, opioid maintenance treatment has multiple beneficial effects on clinical status in patients with HIV infection, primarily as a result of improving adherence to treatment and decreasing risky behavior. Both methadone and buprenorphine treatments are compatible with HIV HAART treatment. The complexity of multiple agent antiret-roviral treatment complicates the use of methadone owing to pharmacokinetic interactions, but these can be managed by appropriate dose adjustments. The choice of opioid pharmacotherapy agent should be based on individual clinical needs. Though buprenorphine has fewer clinically significant drug interactions with antiretroviral medications than methadone, some patients may respond better to a full agonist in an OTP. However, if there are no contraindications, patients needing HAART may benefit from a trial of buprenorphine treatment. A trial of buprenorphine may be best managed in an OTP or by physicians who provide HAART treatment and are also qualified to prescribe buprenorphine (228).
Methadone-to-Buprenorphine Transfer
Some patients will be transferred from methadone to buprenorphine for maintenance or medically supervised withdrawal. This clinical decision may be driven by several possible factors. First, there is the unique pharmacology of buprenorphine, leading to its more favorable safety profile and longer duration of action (thus permitting less frequent dosing) relative to methadone (12,229–231). Second, given its status as a novel treatment option (232), buprenorphine may engender less fear of stigma than methadone. Third, owing to its availability in office-based primary care—outside standard OTPs (18,35,233)—buprenorphine is more accessible over a wide geographic area. It also may be more appropriate as an early intervention strategy for those with short dependence histories (e.g., adolescents) or with less physical dependence. However, if a patient is stable on methadone, the advisability of transfer to buprenorphine requires careful scrutiny of the factors motivating the request. Furthermore, transferring patients from a longer-acting agonist such as methadone to buprenorphine without producing significant withdrawal discomfort, attrition, or relapse to drug use has been shown to be more challenging than transfer from a shorter-acting opiate.
Research on transfer from methadone to buprenorphine is limited to small studies, including human laboratory studies, but these results offer some evidence on which to base clinical treatment in both inpatient and outpatient settings. These studies support an important role for agonist maintenance dose and interval between full and partial agonist administration in determining precipitated withdrawal symptoms. Four studies examined the effect of time interval between the last methadone maintenance dose and the initial buprenorphine dose (133,138,234,235). Most subjects were maintained on methadone at 30 mg/d. When buprenorphine was administered, buprenorphine significantly increased opioid withdrawal effects at 2 hours after methadone (234) but not at 20 to 22 hours (133,234), nor at 40 hours (138). Results from another study in which buprenorphine was administered intravenously at about a 20-hour interval (80) also are consistent with these data. Walsh and June (138) systematically addressed whether methadone maintenance dose influences the response to buprenorphine. In that study, one group of volunteers was maintained on 30 mg/d, and a second group was maintained on 60 mg/d. The 60-mg group experienced increased opioid withdrawal symptoms from buprenorphine, whereas the 30-mg group had minimal symptoms. Two additional studies (236,237) also addressed whether buprenorphine dose dependently precipitates opioid withdrawal in methadone-maintained volunteers. In these studies, buprenorphine (five intramuscular active doses from 0.5 to 8 mg) precipitated mild withdrawal at the 2-hour interval, but withdrawal severity was not dose related. Five studies have directly examined a full medication transfer. Kosten and Kleber (236) reported the first outpatient trial of the methadone-to-buprenorphine (using sublingual liquid) transition. In this open-label study, eight heroin-using and eight methadone-maintained (25 mg/d) volunteers were assigned to receive 2 mg (n = 4), 4 mg (n = 2), or 8 mg (n = 2) per day within 24 hours after their last methadone dose in those on methadone. Across the entire sample (n = 16), withdrawal symptoms were not buprenorphine dose dependent and were highest on the first 2 days, but most patients completed the protocol, and later, heroin use was relatively low, with 78% of all samples testing drug-free. In an open-label study, Banys (237) examined the ability of sublingual liquid buprenorphine to suppress opioid withdrawal 26 to 31 hours after discontinuing methadone. Fifteen participants took three low doses of buprenorphine over several hours (0.15 mg, 0.15 mg 1 hour later, then 0.3 mg 2 hours later) to relieve withdrawal signs and symptoms. In six subjects, a low dose of 0.15 to 0.30 mg resulted in the disappearance of subjective and objective withdrawal symptoms within 10 minutes to 2.5 hours. Four others had brief, partial relief of symptoms. Five subjects failed to experience any relief of withdrawal symptoms after a total of 0.6-mg buprenorphine administered over 3 hours. Lukas et al. (238) conducted the first double-blind, double-dummy pilot study of three males—maintained on three different methadone doses (25, 58, and 60 mg/d)—who were switched abruptly to buprenorphine 2 mg/d, subcutaneously with physiologic (including EEG), behavioral, and subjective ratings collected. They found that buprenorphine did not fully substitute for methadone during the transfer. In a within-subject, double-blind, double-dummy procedure with inpatient volunteers, Levin et al. (239) tapered a moderate methadone maintenance dose (60 mg) over a few days (40 mg, 30 mg, 30 mg, then 0 mg) before initiating buprenorphine (4 mg on day 1 followed by 8 mg). Like Kosten and Kleber (236), the protocol of Levin et al. (239) demonstrated some qualified success, in that 79% (15 of 19) of participants who began the dose-taper completed the transfer even though opioid withdrawal symptoms remained elevated, after the first two buprenorphine daily doses (4 mg, then 8 mg). Withdrawal symptoms gradually were suppressed by subsequent daily doses of buprenorphine (8 mg) and returned to baseline during buprenorphine stabilization (8 mg/d). In another small double-blind, double-dummy pilot study (240), five male heroin-dependent outpatient volunteers were transferred from methadone 60 mg (via one intervening 45 mg dose) to the buprenorphine sublingual tablet. Subjective effects and vital signs were collected before the transfer (methadone 60 and 45 mg), on buprenorphine days 1 and 2 (8 mg/d), and on days 7 and 8 (16 mg/d). The 1-day methadone dose-taper did not significantly alter opioid withdrawal, but the protocol used in this pilot study was able to shorten the duration of withdrawal discomfort to about 1 day, relative to the results of Levin et al. (239). These preliminary results suggest that it is feasible to transfer outpatients on methadone 60 mg/d to the buprenorphine 8 mg/d sublingual tablet. The authors suggest that if the first daily transfer dose of buprenorphine does precipitate withdrawal, it may be useful to consider increased subsequent buprenorphine doses to suppress this withdrawal.
More recently, a study by Breen et al. (241) investigated the response of 23 opioid-dependent patients receiving doses of methadone between 30 and 70 mg/d when transferred to buprenorphine at doses between 12 and 16 mg/d. After the last morning dose of methadone, buprenorphine was substituted in doses increasing from 4 mg to a maximum of 16 mg, with adjunctive lofexidine (maximum of 2.4 mg/d). All except two patients successfully completed transfer to buprenorphine. Average stabilization dose of buprenorphine for the sample who completed transfer was 14.0 mg/d (SD, 2.3), and average daily lofexidine dose during transfer was 0.57 mg (SD, 0.39). The high-dose group (50 to 70 mg/d; n = 11) used significantly more lofexidine to complete transfer compared to the intermediate-dose (30 to 49 mg/d; n = 10) group. Higher opioid withdrawal symptoms measured by the Short Opiate Withdrawal Scale (SOWS) were found in the high-dose group during the first and last day of buprenorphine stabilization, but average SOWS scores for the whole of the period of transfer were not significantly different between groups. This study suggested that transfer to buprenorphine is relatively uncomplicated from daily methadone doses of 30 to 70 mg in an inpatient setting and may be facilitated by the use of lofexidine. Glasper et al. (242) conducted a study that showed that transfer from methadone to buprenorphine can safely occur from doses of around 30 mg of methadone. Patients on methadone doses between 30 and 40 mg were randomly assigned to transfer to buprenorphine using a fixed-dose (transfer at 30-mg methadone) or a variable-dose induction (transfer when the methadone dose was sufficiently low to be “uncomfortable”). A third group of patients with methadone doses less than 30 mg were transferred to buprenorphine at their entry methadone dose. Fifty-one patients were inducted into buprenorphine using the same dosing protocol with the first dose of 4-mg buprenor-phine. After stabilization on buprenorphine, patients gradually reduced the buprenorphine dose to 0 mg. Withdrawal severity and drug use were monitored. Severity of withdrawal during transfer to buprenorphine did not significantly differ between the transfer at 30 mg and transfer using the uncomfortable methadone-dosing protocol. Those on doses of less than 30 mg reported significantly less withdrawal discomfort than either of these other two groups during transfer to buprenorphine. All but one patient stabilized on buprenorphine. Thirty-eight of the fifty-one patients inducted into buprenorphine reached 0 mg. Rosado et al. (243) conducted a study to test the acute effects of sublingual buprenorphine/naloxone tablets in volunteers with more physical dependence. The goal was to identify a dose that would precipitate withdrawal. In Phase 1, sublingual buprenorphine/naloxone at four different doses (4/1, 8/2, 16/4, 32 mg/8 mg), intramuscular naloxone (0.2 mg), or placebo was administered to volunteers on 100 mg of oral methadone. Then in Phase 2, they split this buprenorphine/naloxone dose to determine whether withdrawal could be attenuated. The conditions again were methadone, placebo, naloxone, 100% of the buprenorphine/naloxone dose that precipitated withdrawal in Phase 1, and 50% of this dose administered twice during a session. Six subjects did not complete the study. Of the 10 who completed, 3 tolerated up to 32 mg/8 mg of buprenorphine/ naloxone without evidence of precipitated withdrawal. For the seven completing both phases, split doses generally produced less precipitated withdrawal as compared to full doses. The authors concluded that low, repeated doses of buprenorphine/ naloxone (e.g., 2 mg/0.5 mg) may be an effective strategy for safely dosing this medication in persons with higher levels of physical dependence.
In conclusion, a multitude of small clinical studies show that methadone-to-buprenorphine transfer is feasible over a range of starting methadone doses. Owing to variable designs and individual differences among volunteers, a single recommended protocol is not currently available. Recommendations from CSAT (TIP 40) for patients taking methadone are to taper methadone to 30 mg or less per day for 1 week or more before initiating buprenorphine. Induction should not begin until at least 24 hours after the last dose of methadone and should start at 2 mg of the monotherapy formulation. If signs or symptoms of withdrawal are seen after the first dose, a second dose of 2 mg should be administered and repeated, if necessary, to a maximum of 8-mg buprenorphine on day 1. More recently, still in the absence of large clinical trials, the Physician Clinical Support System (PCSS) guidance (PCSS 2006) recommends tapering to 20 or 30 mg of methadone, obtaining a COWS of 15 to quantify withdrawal, and starting buprenorphine at 2 mg, continuing to dose until the patient is comfortable at up to 32 mg on day 1. If withdrawal is precipitated, management with ancillary medications is advised. Discomfort may persist for up to 96 hours, but usually after 3 to 5 days, the patient will be stable and comfortable. Nevertheless, patients on moderate to high doses of methadone (>60 to 100 mg) may not be able to taper without discomfort and a risk of relapse. For these patients, recent data suggest that induction onto buprenorphine/naloxone might still be possible directly from methadone starting with 2/0.5 mg buprenorphine/naloxone tablets.
In addition to clarifying the best strategy for minimizing symptoms during the transfer, larger clinical trials are needed to answer questions concerning short- and long-term clinical outcomes after methadone-to-buprenorphine transfer. A related relevant clinical need is identification of clinical profiles of patients responding differentially to methadone versus buprenorphine (pharmacotherapy treatment matching).
Buprenorphine in Agonist-to-Antagonist Treatment
Buprenorphine has been used in several experimental studies (126,236,244) as a transitional agent between agonists (such as methadone or heroin) and antagonists (such as naloxone or naltrexone). In one study, Kosten and Kleber (236) substituted buprenorphine at 2, 4, and 8 mg for 20 to 30 mg of methadone or heroin for 1 month without precipitating substantial withdrawal symptoms, though buprenorphine may act as an opioid antagonist at doses as low as 8 mg. After 1 month of buprenorphine stabilization, the medication was abruptly discontinued, and a small dose of naltrexone was given 24 hours later. The investigators observed that the transition to buprenorphine generally was well tolerated. The subsequent abrupt discontinuation of buprenorphine was associated with “minimal withdrawal” in the 2- and 4-mg buprenorphine groups, and a low dose of naltrexone (1 mg) did not precipitate withdrawal. However, subjects in the 8-mg group reported a more substantial increase in withdrawal symptoms when buprenorphine was stopped. Because of these properties, Kosten and Kleber examined whether buprenorphine might facilitate the transition from opioid agonists to antagonists in a three-step process: (a) buprenorphine substitution for agonists such as methadone, (b) buprenorphine-induced reduction in physical dependence, and (c) discontinuation of buprenorphine with rapid introduction of naltrexone. In a study testing that hypothesis, Kosten et al. (244) used intravenous naloxone to challenge five opioid-dependent patients who were maintained on 3-mg sublingual buprenorphine. Induction onto naltrexone was attempted in all of those patients who completed 30 days on buprenorphine. Five male opioid-dependent patients maintained on buprenorphine 3 mg sublingually for 1 month as outpatients were abruptly discontinued from buprenorphine by blinded, placebo substitution and enlisted in a placebo-controlled, double-blind challenge with intravenous naloxone at 0.5 mg/kg. The naloxone was given over a 20-minute period using a 10 mg/mL solution. Significant withdrawal symptoms were precipitated. However, 5 hours after this naloxone challenge, withdrawal symptoms were at baseline levels, and oral naltrexone was given at either 12.5 or 25 mg without precipitating further withdrawal symptoms. The authors believed that the withdrawal syndrome was milder for buprenorphine than for pure opioid agonists, “suggesting a partial resetting of the opioid receptors by the antagonist activity of buprenorphine.” In some situations, combination drug treatment may facilitate greater patient acceptance of agonist–antagonist switching. Thus, Fudala et al. (245) have shown that the early use of naltrexone during medically supervised withdrawal in combination with benzodiazepines and clonidine facilitated naltrexone acceptance by patients. Johnson (132), in a study comparing buprenorphine taper alone and buprenorphine with naltrexone, suggested that the combination treatment may reduce the severity of withdrawal symptoms. The use of buprenorphine to stabilize opioid-dependent patients before switching them to naltrexone has the advantage of psychosocial stabilization prior to medically supervised withdrawal. This approach may represent a compromise between acute medically supervised withdrawal and long-term treatment of chronic dependence. The foregoing techniques (clonidine/naltrexone and buprenorphine/naltrexone) may be combined in a clinical protocol that places methadone patients or heroin-dependent patients on buprenorphine for several weeks to stabilize and engage them in the psychosocial aspects of treatment. This could be followed by rapid transition to naltrexone, using clonidine to relieve any withdrawal symptoms caused by stopping the buprenorphine. Such combination approaches are reviewed in Stine and Kosten (246). These generally have been small pilot studies.
SUMMARY
Opioid dependence is unique among substance use disorders in having multiple available pharmacotherapy options for treatment. In addition to full and partial agonist treatments available for medically assisted withdrawal, this treatment remains an area of active research as development of nonopioid medications, especially α2-adrenergic agonists and combination treatments continues. Evidence to date does not support differences in efficacy among these various methods of medically assisted withdrawal but supports the common occurrence of relapse after withdrawal using any method. Therefore, as a chronic relapsing disorder, opioid dependence is primarily treated with long-term pharmaco-therapies. Antagonist maintenance is not widely accepted but may have increased utility with the availability of new depot formulations, another current research question. Full agonist treatments are the most extensively used and researched for efficacy. Although methadone is available only in specialized and licensed OTP settings, buprenorphine is available in medical offices across the United States. Multiple head-to-head studies have shown equivalent efficacy of buprenorphine to moderate doses of methadone. Buprenorphine, however, does appear to possess the advantages of fewer drug interactions and fewer cardiac side effects. Identification of patients who benefit differentially from methadone versus buprenorphine treatments is a topic for active clinical research. Other clinical issues that continue to be studied include updates of nonopioid medication, interactions with various full and partial opioid agonists, uses of combination medications for transitions from full agonists to partial agonists such as buprenorphine or to antagonists such as naltrexone, and using full versus partial opioid agonists in special populations (i.e., pregnant women).
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