Susan M. Stine, MD, PhD
Thomas R. Kosten, MD, PhD CHAPTER
49

CHAPTER OUTLINE

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 α_2-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

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