Advances in the Treatment of Opioid Dependence

AMA. 2010;304(14):1612-1614. doi:10.1001/jama.2010.1496

Illicit drug use is a major cause of morbidity and mortality worldwide. In the United States, the 2009 National Survey on Drug Use and Health documented that 8.7% of individuals older than 12 years reported past month illicit drug use.¹ Illicit opioid use is an important contributor to health problems, including human immunodeficiency virus and hepatitis C infection and overdose-related deaths. While historically heroin has been most commonly abused, nonmedical use of prescription opioid pain relievers is now the dominant form of opioid abuse in the United States. In 2009, more than 5.3 million Americans reported past month prescription opioid abuse¹ and the 2009 Monitoring the Future Study demonstrated that among 12th-graders, 9.7% reported abuse of hydrocodone and 4.9% reported abuse of oxycodone in the past year.² Thus, illicit opioid use is a critical national health issue that requires creative approaches to prevention and treatment.

Opioid dependence is characterized by physical dependence, medical and psychological problems, and social dysfunction. Treatment strategies include counseling and pharmacotherapy. Medications have been particularly effective for treating opioid dependence given the unique effects of opioids on the brain and the availability of medications that can modulate these effects. Opioid agonist treatment has been demonstrated to most effectively decrease craving and drug use and improve health and social outcomes; furthermore, sustained medication maintenance is much more effective than short-term detoxification.³ Methadone maintenance has been the gold standard treatment since it was described by Dole and Nyswander in JAMA in 1965.⁴ Since then, dozens of studies have reaffirmed the effectiveness of methadone although it has not been without controversy, including potential toxicities and the strict regulatory restrictions on its use.⁵ Other agonist medications such as levo-alpha-acetylmethadol (LAAM) and diacetylmorphine (heroin)⁶ have been examined, but none has gained significant acceptance.

The newest medication treatment for opioid dependence is the partial opioid agonist buprenorphine. When used alone, or in combination with naloxone (buprenorphine-naloxone) in a sublingual tablet formulation, buprenorphine improves drug use–related outcomes in a manner similar to methadone⁷ with an improved safety profile. The naloxone component is not significantly absorbed sublingually but is included to block opioid effects if intravenous use is attempted. Buprenorphine was approved by the US Food and Drug Administration (FDA) in 2002 and its use has increased considerably. Along with enhanced safety, buprenorphine has the advantage of being available through prescription by trained generalist and specialty physicians in their offices, thus expanding the availability of maintenance treatment outside the confines of licensed programs.⁸ Subsequent research has expanded knowledge on how⁹ and in whom¹⁰ buprenorphine can be used most effectively.

Despite these advantages, buprenorphine use has been limited by the small (but increasing) number of trained physicians, concerns about diversion, and its high cost relative to methadone. In addition, buprenorphine typically requires daily supervised or self-administration. Thus, particularly in office-based treatment where medication administration is generally unsupervised, effectiveness relies on patient adherence. Efforts to improve adherence have been investigated, including less than daily dosing and electronic compliance monitoring; however, these approaches are seldom used.

Thus, the study of subdermal buprenorphine implants reported by Ling and colleagues¹¹ in this issue of JAMA is an important addition to the literature because this method of medication administration may address limitations of sublingual buprenorphine, in particular adherence and diversion. Patients from 18 addiction treatment centers were randomly assigned to receive buprenorphine or placebo implants and were followed up for 24 weeks. Efforts to blind treatments and assessments were used and meaningful outcomes were selected. Along with the primary outcome of percentage of illicit opioid–negative urine samples, treatment retention, study completion, craving, and withdrawal and dependence severity were assessed. Safety and pharmacokinetic assessments are particularly important when new medication technologies are examined and these were also performed.

The manner in which treatment was provided has important implications regarding study limitations and clinical utility. Both groups received buprenorphine induction with sublingual buprenorphine-naloxone tablets, implant insertion, and up to twice-weekly counseling. In addition, supplemental sublingual buprenorphine-naloxone was provided based on patient-reported withdrawal and craving, and otherwise when requested. Thus, this treatment is not without complexity (eg, the implantation/removal procedures) or resource intensity (eg, specialized counseling). The need to use supplemental medication indicates that risk of diversion is not completely eliminated, especially if its use is unsupervised as is common in practice. Moreover, because this study was performed in treatment centers with specialized counseling and close medication supervision, it provides relatively little information about how implants might be used in office practice.

With these caveats in mind, Ling et al demonstrated that implant buprenorphine was more effective than placebo implants for the primary and major secondary outcomes.¹¹ It is certainly not surprising that buprenorphine implants performed better than placebo implants and one could argue a control group other than placebo should have been used given the established efficacy of buprenorphine. However, attention to patient safety along with the need to carefully assess this new delivery method in a definitive manner, the availability of „rescue“ buprenorphine for all patients, and the 2:1 randomization ratio moderate this concern. Despite the superior urine toxicology results noted with buprenorphine implants, more than 50% of urine samples were positive, suggesting that even the active treatment had significant limitations. This, along with the relatively low buprenorphine plasma levels noted in these patients and the degree to which they required supplemental buprenorphine, suggests that further improvement in the implant delivery system may be warranted. However, the meaning of low drug plasma levels is not entirely clear clinically because effective buprenorphine plasma concentrations are likely to vary considerably between individuals.¹² Ultimately, a direct comparison of implant to sublingual administration that examines pharmacokinetics and drug use is required to better understand the pharmacology and effectiveness of implant buprenorphine and to ensure that effectiveness is not sacrificed for convenience.

The study by Ling et al¹¹ should be viewed in the context of what has been learned about opioid dependence treatment over the past 50 years. While counseling is critical for all substance abuse treatment, opioid dependence is uniquely susceptible to pharmacologic therapy. Patients and their physicians are often tempted to use „quick fix“ detoxification in which short-term medication treatment is provided rather than longer-term maintenance. However, for most opioid-dependent patients there is no quick fix. Detoxification has been conclusively demonstrated to have exceedingly high long-term failure rates¹³ and is not nearly as effective as opioid maintenance.^{3, 10} Extensive research on the effectiveness of methadone maintenance is irrefutable and research on buprenorphine maintenance has followed suit.

The question of where to provide buprenorphine has been the subject of extensive research that has allowed treatment to expand from the maintenance clinic to the physician’s office. Ling et al are addressing the question of how to provide buprenorphine. Intramuscular buprenorphine has been available for many years for pain management and a sublingual liquid formulation was initially used in investigational studies prior to FDA approval for treating opioid dependence. Buprenorphine was subsequently formulated in sublingual tablet forms in combination with naloxone (buprenorphine-naloxone) to discourage diversion. In addition, sublingual film buprenorphine has been developed,¹⁴ a version of which was approved by the FDA in 2010. The use of much longer-acting depot and implant medications has a long history and has demonstrated utility in enhancing adherence in the treatment of conditions such as schizophrenia and as an approach to providing hormonal contraception. A small study of depot injection buprenorphine demonstrated low plasma levels and pharmacologic activity over 6 weeks after one injection.¹⁵ The use of implant buprenorphine in this study suggests that a promising new approach to long-acting buprenorphine administration may be close at hand.

The study by Ling et al¹¹ represents a potentially important step forward in the effort to improve and expand the treatment options for opioid dependence. Further research is needed to assess how this treatment compares with current opioid maintenance treatment prior to the widespread use of implant buprenorphine in clinical practice. If further research suggests that this buprenorphine implant is as good as or better than current treatment approaches, then the study by Ling et al would represent a major advance in the substantial and continued progress that has occurred in the treatment of opioid dependence since methadone maintenance began in the 1960s.

Despite these advances, significant challenges remain. As new and potentially better medications are developed, promoting access to treatment for opioid-dependent patients continues to be a major concern. In addition, physicians must be more knowledgeable about addiction and embrace their responsibility to care for individuals with, or at risk for, substance use disorders so that more patients can be identified and offered treatment. Treatments also need to be carefully designed so that medication effectiveness is maximized and counseling therapies are tailored to meet the needs of individual patients in a cost-effective manner.

Buprenorphine Implants for Treatment of Opioid Dependence

Context Limitations of existing pharmacological treatments for opioid dependence include low adherence, medication diversion, and emergence of withdrawal symptoms.

Objective To determine the efficacy of buprenorphine implants that provide a low, steady level of buprenorphine over 6 months for the treatment of opioid dependence.

Design, Setting, and Participants A randomized, placebo-controlled, 6-month trial conducted at 18 sites in the United States between April 2007 and June 2008. One hundred sixty-three adults, aged 18 to 65 years, diagnosed with opioid dependence. One hundred eight were randomized to receive buprenorphine implants and 55 to receive placebo implants.

Intervention After induction with sublingual buprenorphine-naloxone tablets, patients received either 4 buprenorphine implants (80 mg per implant) or 4 placebo implants. A fifth implant was available if a threshold for rescue use of sublingual buprenorphine-naloxone treatment was exceeded. Standardized individual drug counseling was provided to all patients.

Main Outcome Measure The percentage of urine samples negative for illicit opioids for weeks 1 through 16 and for weeks 17 through 24.

Results The buprenorphine implant group had significantly more urine samples negative for illicit opioids during weeks 1 through 16 (P = .04). Patients with buprenorphine implants had a mean percentage of urine samples that tested negative for illicit opioids across weeks 1 through 16 of 40.4% (95% confidence interval [CI], 34.2%-46.7%) and a median of 40.7%; whereas those in the placebo group had a mean of 28.3% (95% CI, 20.3%-36.3%) and a median of 20.8%. A total of 71 of 108 patients (65.7%) who received buprenorphine implants completed the study vs 17 of 55 (30.9%) who received placebo implants (P < .001). Those who received buprenorphine implants also had fewer clinician-rated (P <.001) and patient-rated (P = .004) withdrawal symptoms, had lower patient ratings of craving (P <.001), and experienced a greater change on clinician global ratings of severity of opioid dependence (P<.001) and on the clinician global ratings of improvement (P < .001) than those who received placebo implants. Minor implant site reactions were the most common adverse events: 61 patients (56.5%) in the buprenorphine group and 29 (52.7%) in the placebo group.

Conclusion Among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples.

Dependence on opioids, in the form of heroin or prescription pain medications, is a significant health concern.^1–3 Methadone maintenance treatment for opioid dependence reduces morbidity, mortality, and the spread of infectious diseases⁴ but is restricted to licensed specialty clinics in the United States, requires frequent clinic visits, and has a risk of mortality with overdose.⁵ These issues have led to increased use of buprenorphine, and numerous studies support the efficacy of sublingually administered buprenorphine.⁶ In the United States, buprenorphine can be prescribed in office-based physician practice.⁷ Because it is a partial agonist, buprenorphine has less risk of overdose than methadone.⁸ However, there are concerns about diversion and nonmedical use of sublingual buprenorphine, even when a buprenorphine-naloxone combination (designed to reduce misuse) is used.^9–11 Poor treatment adherence, resulting in craving and withdrawal symptoms that increase the likelihood of relapse, is also a concern with sublingual buprenorphine.¹²

To address these problems with adherence, diversion, and nonmedical use, an implantable formulation of buprenorphine has been developed. This implant is a polymeric matrix composed of ethylene vinyl acetate and buprenorphine that delivers buprenorphine over 6 months. Following an initial pulse release, a constant and low level of buprenorphine is released, avoiding plasma peaks and troughs observed with sublingual administration. A preliminary open-label phase 2 study reported favorable results with this implant in opioid-dependent patients.¹³

The present study reports results of a phase 3 multicenter, randomized, placebo-controlled investigation of buprenorphine implants for treatment of opioid dependence.

Participants

Patients were recruited for the study from 6 academic, 3 Veterans Affairs, and 9 nonprofit community addiction treatment centers in the United States between April 2007 and June 2008. The study was approved by institutional review boards at each site, and written informed consent was obtained from all participants.

To be eligible for the study, men or nonpregnant women, aged 18 to 65 years, were required to meet Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) diagnosis of current opioid dependence at a screening visit as determined by the Mini International Neuropsychiatric Interview.¹⁴ Exclusion criteria were AIDS, met DSM-IV criteria for current dependence on psychoactive substances other than opioids or nicotine, currently using nonprescribed benzodiazepines, had received medication treatment for opioid dependence within the previous 90 days, or had a current diagnosis of chronic pain that required opioid treatment. Patients were also excluded if they had any of the following: aspartate aminotransferase (AST) levels at least 3 times higher than the upper limit of normal, alanine aminotransferase (ALT) levels at least 3 times the upper limit of normal, total bilirubin levels of at least 1.5 times the upper limit of normal, or creatinine levels at least 1.5 times the upper limit of normal.

Demographics and history were collected by patient self-report based on a list of choices.

Study Intervention and Randomization

Eligible patients entered into an open-label induction phase designed to ensure that buprenorphine could be safely administered. Patients were required to complete induction within 10 days of screening and receive a fixed dose of 12 to 16 mg/d sublingual buprenorphine-naloxone tablets for at least 3 consecutive days immediately before randomization. Patients were excluded from participation if during the induction phase they had reported significant withdrawal symptoms, defined as more than 12 on the Clinical Opiate Withdrawal Scale,¹⁵ or significant cravings for opioids, defined as more than 20 mm on a 100-mm opioid craving visual analog scale (VAS).

At the end of the induction phase, patients were randomized (stratified by sex and site) at a 2:1 ratio to double-blind treatment with either 4 buprenorphine implants (80 mg each) or 4 placebo implants. The 2:1 ratio was used to reduce patient exposure to placebo implants. The implants (26 mm in length x 2.5 mm in diameter) were placed in the subdermal space (2-3 mm below the skin) all at the same time in the inner side of the nondominant arm by a physician who had participated in a 1-day training in implant insertion and removal or who had prior similar experience. No sutures are required for implantation (sutures were used at removal). The physicians who placed and removed the implants were from various medical specialties (eg, family practice, psychiatry, dermatology, obstetrics and gynecology) and had surgical training but did not serve as the site investigator. The implants were removed after 6 months.

After implant placement, patients could receive supplemental sublingual buprenorphine-naloxone tablets, beginning with 4 mg and increasing in 2-mg increments as clinically necessary and tolerated up to 12 to 13 mg, if they experienced significant withdrawal symptoms or significant craving or if they had requested a dose increase that the treating physician judged to be appropriate. The supplemental sublingual buprenorphine-naloxone tablets were administered at the clinic under observation, except for weekends and holidays, for which participants received a maximum of 3 days of dosing to take at home. Patients could receive an additional implant if they required 3 or more days per week of any supplemental sublingual buprenorphine-naloxone tablets for 2 consecutive weeks, or 8 or more days of any supplemental buprenorphine-naloxone tablets over 4 consecutive weeks.

Because the placebo implants had a slightly different appearance than buprenorphine implants, steps were taken to maintain the blind: (1) the physician and staff involved in the implant insertion and removal procedures did not participate in efficacy evaluations or discuss with other study staff any information regarding a patient’s implants, (2) surgical draping prevented patients from viewing the implants during insertion or removal procedures, (3) staff not involved in implant insertion and removal procedures were forbidden from asking those involved in these procedures about the rod’s appearances, (4) each implant was sealed in an opaque, foil-lined pouch that hid the contents from view and was only opened by those involved with the implanting procedures.

All patients received manual-guided individual drug counseling.¹⁶ Sessions were held twice a week during the first 12 weeks and then weekly for the subsequent 12 weeks. If a patient missed 6 consecutive counseling sessions, this was judged to be clinically meaningful nonadherence, causing the patient to be withdrawn from the study. Because experienced drug counselors at each site who were familiar with the drug-counseling treatment model provided services, they received no formal training.

Urine samples were obtained 3 times per week throughout the entire 6-month treatment period. Drug screens were performed by a central laboratory and study staff, and patients remained blind to results. If a patient did not provide 9 consecutive urine samples, they were considered nonadherent and withdrawn (ie, 3 weeks was considered a clinically important interval). Participants could continue in the study regardless of test results. Urine toxicology samples were verified at collection by measurement of urine temperature. Patients provided another sample if a urine sample was outside of a valid temperature range. If the second sample was outside of the temperature range, the sample was designated as missing.

Efficacy Assessments

The primary outcome measure was the percentage of the 48 urine samples that were negative for illicit opioids during the first through 16th week of the trial. This 16-week period was selected because of the interest in examining early-treatment response in the context of this longer-term treatment.

The secondary outcome measure was assessed as the percentages of the 24 urine samples that were negative for illicit opioids during weeks 17 through 24. Additional outcomes measured included the proportion of treatment failures, the proportion of study completers, the patient-report and clinician-report withdrawal scales, a craving scale, and clinician severity and improvement ratings.

Treatment failure was defined as receiving a fifth implant and subsequently requiring 3 or more days per week of supplemental sublingual buprenorphine-naloxone treatment for 2 consecutive weeks or 8 or more days of supplemental sublingual buprenorphine-naloxone treatment over 4 consecutive weeks at any time after the implant dosage increase. Patients who met this definition of treatment failure were withdrawn from the study.

Patient report of withdrawal symptoms was assessed by the Subjective Opiate Withdrawal Scale.¹⁷ Clinician report of withdrawal symptoms was measured with the Clinical Opiate Withdrawal Scale, administered by the investigator or other qualified clinical staff. Craving for opioids was measured using a 100-mm VAS: 0 indicates no cravings; and 100, the maximum craving experienced. All 3 measures were obtained at baseline and at weeks 1, 4, 8, 12, 16, 20, and 24. The clinician-rated Clinical Global Impressions-Severity (CGI-S)¹⁸ (of opioid dependence) and Improvement scales (CGI-I)¹⁸ were obtained at baseline and at weeks 16 and 24 (or end point).

Safety and Pharmacokinetic Assessments

Vital signs, blood and urine laboratory tests (hematology, liver function tests, coagulation, pregnancy test), and electrocardiograms were obtained at regular study visits. The assessment protocol required that study investigators visually inspect the surgical implant location of each participant during each study visit. Levels of plasma buprenorphine were obtained and analyzed from blood samples taken at baseline and monthly thereafter.

Statistical Analyses

Baseline variables were compared across treatment groups using ² for categorical variables and t tests for continuous variables.

The primary analysis was conducted using an intention-to-treat approach that included all randomized patients. The primary statistical analysis specified in the study protocol was a van Elteren Wilcoxon rank sum test,¹⁹ stratified by sex and treatment site, comparing study groups on the distributions of the percentages of urine samples that tested negative for illicit opioids over 16 weeks. Sample size determination was conducted using a 2-sided of .05 and 80% power to detect a shift of 20% (a difference deemed to be clinically relevant) between the placebo and buprenorphine groups on the distributions of the percentage of urine samples negative for illicit opioids over 16 weeks. Approximately 150 patients were required, taking into account the 2:1 randomization scheme, normal distributions without stratification with a common standard deviation of 30% as a conservative powering model, and an attrition rate of approximately 40%.

The denominator for the primary end point was all possible urine samples that could have been collected from implantation through week 16. Missed samples were considered positive for opioids. After a patient was withdrawn from the study, urine samples from the point of withdrawal onward were also considered positive.

A secondary analysis examined the percentage of urine samples over weeks 17 through 24 (using a van Elteren Wilcoxon test stratified for sex and site). Hypothesis testing for the primary analysis and the first secondary analysis was conducted using a fixed-sequence testing procedure. First, the primary hypothesis was tested using a 5% level. Only if the null hypothesis was rejected for the primary analysis did testing proceed to the first secondary analysis. In accordance with this procedure, no adjustment for multiple tests is required and the accepted alternative hypotheses may be claimed significant at the 5% level. An additional van Elteren Wilcoxon rank sum test examined the percentage of urine samples negative for the full 24-week period (72 samples per patient).

The proportions of participants who completed the study (defined as completing 24 weeks) were compared between treatment groups with a Cochran Mantel-Haenszel test, stratified by sex and site. The clinical and subjective withdrawal scales and the craving VAS were analyzed using a mixed-effects repeated-measure analysis of covariance using all available assessments and adjusting for sex, site, and baseline value. A spatial power law correlation structure was specified for these analyses. This covariance structure was used because it is appropriate for modeling data when the measurement time points are continuous (unequally spaced) rather than discrete categories, and the correlations decline as a function of the time difference. The CGI-I and CGI-S were analyzed as categorical variables using a Cochran Mantel-Haenszel test stratified by sex and site.

The incidence of specific adverse events was compared across treatment groups using ² tests. All statistical analyses were performed using SAS software version 8.2 (SAS Institute Inc, Cary, North Carolina).

 

Treatment Exposure

The median number of weeks of exposure to the implants (before they were removed) was 24 (range, 0-43 weeks) for buprenorphine and 16.6 (range, 3-34 weeks) for placebo. Additional implants were received by 20.3% (22 of 108) of those in the buprenorphine group and 58.2% (32 of 55) of those in the placebo group. During weeks 1 through 16, 64 of 108 participants (59%) in the buprenorphine implant group received supplemental sublingual buprenorphine-naloxone tablets for a median of 7.5 days for emergent withdrawal or craving, whereas 50 of the 55 patients in the placebo group (91%) received the buprenorphine-naloxone tablets for a median of 19.5 days. The buprenorphine implant group received a mean dose of 94.1 mg (95% confidence interval [CI], 71.3-117.0 mg) for the weeks 1 through 16 and received an average daily dose of 9.8 mg (95% CI, 8.8-10.8 mg), whereas the placebo group received a mean of 208.3 mg (95% CI, 163.1-253.5 mg) for an average daily dose of 10.4 mg (95% CI, 9.3-11.4 mg). For weeks 17 through 24, 12% (13 of 108) in the buprenorphine implant group received a mean dose of 56.9 mg (95% CI, 29.2-84.6 mg) and an average daily dose of 12.7 mg (95% CI, 10.1-15.2 mg) for a median of 3 days, whereas 20% (11 of 55) in the placebo group received a mean of 175.8 mg (95% CI, 21.0-330.6 mg) and an average daily dose of 12.8 mg (95% CI, 9.8-15.8 mg) for a median of 7 days.

The most frequent reasons for early discontinuation in the buprenorphine implant group were nonadherence with the protocol and being lost to follow-up. In the placebo group, patients most frequently withdrew early because of treatment failure or nonadherence (Figure 1).

Of those who discontinued because of protocol nonadherence, 2 participants in the buprenorphine implant group and 1 in the placebo group missed 6 consecutive counseling sessions and were therefore withdrawn. There was no evidence of unscheduled implant removal or attempted removal.

Efficacy

A mean of 40.4% (95% CI, 34.2%-46.7%; median, 40.7%) of the 48 urine samples taken for each patient in the buprenorphine group during the first 16 weeks of the study tested negative for opiate use vs a mean 28.3% (95% CI, 20.3%-36.3%; median, 20.8%) in the placebo group (P = .04). The distributions of the percentage of 24 urine samples taken from week 17 through 24 that tested negative for opioid use also showed a statistically significant difference (P < .001). For the full 24-week treatment period for a total of 72 urine samples from each patient, the buprenorphine group had a mean 36.6% (95% CI, 30.5%-42.6%; median, 29.9%) of urine samples that tested negative for opioids vs 22.4% (95% CI, 15.3%-29.5%; median, 13.9%) for the placebo group (P = .01).

A mean of 42.9 (44.0%) urine samples were actually provided by patients for weeks 1 through 16 and 17.5 (31.1%) for weeks 17 through 24 for the buprenorphine group vs 31.9 (43.2%) for weeks 1 through 16 and 8.5 (14.1%) for weeks 17 through 24 for the placebo group. Retention in the study is shown in Figure 2.

 

reatment group differences were also evident on additional efficacy measures (Table 2). During weeks 1 through 16, 88 of 108 (81.5%) in the buprenorphine implant group remained in the study vs 28 of 55 (50.9%) in the placebo group (P < .001). A significant difference (P < .001) was also evident in completion rates for the full 24-week study period: 71 of 108 (65.7%), buprenorphine implant group; 17 of 55 (30.9%), placebo group. The buprenorphine implant group had lower scores for clinical (P < .001) and subjective (P = .004) opiate withdrawal and for opioid craving (P < .001) than those in the placebo group across 24 weeks of treatment. At week 24, there were significant differences between the treatment groups on the CGI-S (P <.001) and CGI-I (P < .001) rating scales favoring buprenorphine (Table 2).

 

No patients in the buprenorphine implant group met the definition of treatment failure; 30.9% (17of 55) of placebo patients were classified as treatment failures.

Safety

Ninety-three (86.1%) of those in the buprenorphine implant group had at least 1 adverse event vs 45 (81.8%) of those in the placebo group (Table 3). Implant site adverse events were the most common; these events were normal and expectable consequences of the surgical procedure (not due to difficulties with insertion or removal).

 

mong adverse events not related to implant site, headache and insomnia were the most common in the buprenorphine group. No significant treatment group differences were apparent for adverse events that occurred with 10% or greater frequency (Table 3). No adverse events resulted in discontinuation of treatment in the placebo group. In the buprenorphine group, 3.7% of the patients experienced adverse events for which they were discontinued. These adverse events were implant site pain and infection (2 cases), implant site pain, and elevated liver enzymes. Two patients (1.9%) in the buprenorphine implant group experienced serious adverse events compared with 4 (7.3%) in the placebo group. One patient with a history of pulmonary embolism and chronic obstructive pulmonary disease in the buprenorphine group had a pulmonary embolism and an exacerbation of chronic obstructive pulmonary disease, and these events were judged as possibly related to treatment (because of the effect of opioids on respiratory function). The other patient experienced a burn injury. In the placebo group, 1 patient experienced suicidal ideation, another had pneumonia and cellulitis (related to implant site), another had a relapse of opioid dependence resulting in hospitalization, and another had respiratory failure. The patient with pneumonia and cellulitis was hospitalized for 1 day, during which time an incision and drainage were performed on the infected site, and the patient was treated with intravenous and oral antibiotics.

There were no clinically meaningful changes from baseline in vital signs, physical examinations, or electrocardiograms. No clinically significant changes from baseline were observed in hematology or coagulation values in either group. There was a minor increase in mean ALT and mean AST levels in the buprenorphine group, which was attributable to 1 patient who had significant increases in ALT and AST levels that were likely related to a hepatitis C infection and history of alcohol and drug use.

Pharmacokinetics

Mean (SD) steady state plasma buprenorphine concentrations over weeks 4 through 24 were 941 (832) pg/mL vs 495 (720) pg/mL in the placebo group, and the respective medians were 775 pg/mL (range, 378-8070 pg/mL) vs 237 pg/mL (range, 0-3070 pg/mL). The plasma buprenorphine in the placebo group can be attributed to use of rescue sublingual buprenorphine-naloxone tablets and possibly buprenorphine obtained from outside the study.

his study demonstrated that buprenorphine implants are effective in the treatment of opioid dependence over a 24-week period following implantation. Of particular clinical importance are the favorable urinalysis toxicology results and the good patient retention—with 65.7% of patients who received the active implants completing 24 weeks of treatment without experiencing craving or withdrawal symptoms that necessitated withdrawal from the study. In contrast, a recent study reported a median duration of 40 days for individuals who received sublingual buprenorphine in clinical settings.¹² Available 6-month trials of sublingual buprenorphine have reported retention rates of 35%,²⁰ 38%,²¹ and 35%.²²

The improved retention rate was found in the current study despite the buprenorphine implants resulting in relatively low plasma concentrations of buprenorphine. Given the known pharmacokinetics of buprenorphine,²³ the steady state plasma concentration levels are consistent with a constant buprenorphine release of 1 to 1.3 mg/d from 4 to 5 buprenorphine implants. Results from the prior phase 2 study showed that average plasma concentrations of buprenorphine implants were lower than trough plasma concentrations of sublingual buprenorphine measured in the same patients (prior to implants) and that the initial pulse of buprenorphine in the 24 hours following implant insertion was less than half of peak plasma concentration observed with sublingual buprenorphine prior to implant insertion.¹³ Extrapolating from the low buprenorphine plasma concentrations, it is possible that a higher number of implants would result in greater efficacy. However, no patients in the buprenorphine implant group exceeded the criterion for treatment failure based on the need for sublingual buprenorphine-naloxone tablets. Thus, it appears that 4 or 5 implants are sufficient to control most cravings and withdrawal symptoms.

Minor implant site reactions were common. However, only 1 patient in the placebo group experienced a major implant site reaction (cellulitis). There was no evidence of unscheduled implant removal or attempted removal. Thus, diversion of the buprenorphine implants appears unlikely.

Several limitations of this study are important to consider: (1) All patients received psychosocial counseling in addition to implants. The extent to which the efficacy of the implants is dependent on this ancillary counseling is not known, although this is the standard of care in addiction treatment. (2) Placebo patients had an average buprenorphine plasma concentration that was almost half that of the active implant group due to the need for rescue buprenorphine-naloxone treatment. The use of rescue buprenorphine-naloxone treatment complicates the interpretation of study results, particularly the plasma buprenorphine levels. (3) The current trial was not statistically powered to examine efficacy within subgroups of patients. The number of implants and extent of supplemental sublingual buprenorphine-naloxone treatment may need to vary depending on initial severity of opioid dependence, duration of opioid dependence, or type of opioid. (4) Attrition was high because of the regulatory requirement to include a placebo control.

In summary, this study found that the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks and also across the full 24 weeks.

Pharmacist education in MMT.!, syringes,

Pharmacists have the unique knowledge, skills and responsibilities for assuming an important role in substance abuse prevention education and assistance…  Pharmacists, as health care providers, should be actively involved in reducing the negative effects that substance abuse has on society, health systems and the pharmacy profession.

— American Society of Health-System Pharmacists (2003)

Competency framework

Unless they have taken special training, most pharmacists are unaware of the clinical and practice issues surrounding methadone and their impact on client safety because they have had little or no exposure to them during their undergraduate pharmacy education.

The role of the pharmacist in MMT is unusual and there is no similar model in other therapeutic areas. Daily interactions with clients, along with direct clinical assessments, supervised dose administration and close monitoring do not usually occur in other types of pharmacy care. Pharmacists require a set of key competencies to ensure client safety in methadone maintenance treatment.

The panel recommends that:

15. Pharmacy managers/owners, hospital pharmacy directors and the Ontario College of Pharmacists support and encourage pharmacists providing methadone services to have education in and/or demonstrate knowledge and skills in core competency areas. These areas include:

a. Substance use disorders, including opioid dependence. [IV]

b. The varied models of substance abuse treatment, including harm reduction and its implications for pharmacy. [IV]

c. The impact of attitudes and stigma on client care. [III]

d. Methadone maintenance treatment clinical guidelines and their rationale, particularly with respect to practices to protect client safety, including:

• assessing initial and increased doses for appropriateness
• assessing methadone-dosing histories (for missed doses and irregularities in pattern of pickup) before dispensing a dose of methadone to a client
• ensuring the safe provision of “carries” (take-home doses) to clients
• dealing with intoxicated clients, including understanding the risks of polysubstance abuse. [IV]

Pharmacists need to understand substance use disorders, particularly addiction, and to understand the difference between “use” and “use disorders.” Pharmacists need to be able to identify individuals with substance use disorders and to help motivate them to seek change and treatment. As one of the most accessible health care professionals, the pharmacist can play an important role and refer patients to appropriate services and substance use treatment programs. Many MMT clients have concurrent substance use disorders with substances such as alcohol, benzodiazepines or cocaine. Pharmacists should understand the risks associated with polysubstance use and the risk of toxicity.

Although pharmacists may already be involved in harm reduction, for example, by providing sterile needles and syringes to people who use injection drugs, further involvement could include offering advice to people with substance use problems about health issues and how to minimize health risks. A random survey of 2,017 Canadian pharmacists by Myers et al. (1998) found that while more than 88 per cent of pharmacists were comfortable with the harm reduction role in providing needles and syringes, this comfort did not extend to providing methadone services. This may be due to a misunderstanding of the benefits of methadone maintenance treatment and its role as a harm reduction approach. Educational initiatives need to address such misunderstandings and other negative attitudes or misperceptions that may be held by pharmacists.

Pharmacists must have a good understanding of the critical safety issues associated with methadone. Methadone has a unique pharmacological profile that makes it useful in the treatment of opioid dependence; however, it is different from other opioids and the implications of its long half-life can lead to risks of accumulation contributing to methadone overdose and deaths.

The initiation phase of methadone treatment can be a time of high risk for toxicity and pharmacists’ understanding of dosing recommendations is critical at this stage. Pharmacists need to exercise particular vigilance in monitoring client dosing for appropriateness. For example, where clients have missed several doses (defined as three or more), or fewer (one or two) during periods of methadone dose escalation, pharmacists must understand the concept of loss of tolerance and risks to clients if the usual regular methadone dose is administered (CPSO, 2005).

Pharmacists also have to understand the safety issues associated with “carries.” Having a written carry agreement with the client is one way to help the client understand these issues as well. Pharmacists should be aware of some of the signs that indicate a formerly stable client on a high level of carries is relapsing to instability (e.g., missing observed dosing days, lost carries) (CPSO, 2005).

Pharmacists in Ontario need to be familiar with the CPSO’s most recent Methadone Maintenance Guidelines (2005), the OCP’s Policy for Dispensing Methadone (2006), and CAMH’s Methadone Maintenance: A Pharmacist’s Guide to Treatment (Isaac et al., 2004).

Understanding the risks of polysubstance use and knowing how to deal with intoxicated clients are particularly important core competency areas for pharmacists, with significant safety implications. The pharmacist should have an understanding of the impact that polysubstance use (for example, use of benzodiazepines, alcohol and cocaine) can have on the client taking MMT. Through dialogue and checking for signs of excessive dosing or substance use such as sedation, slurring of speech, smelling of alcohol and unsteady gait, the pharmacist should be able to assess if a client is intoxicated before dosing.

Recommendations from the coroner have highlighted the need for assessing clients for intoxication because deaths have occurred through combination of methadone and other drugs, including alcohol (OCP, 2008).

In an Australian survey (Peterson et al., 2007), pharmacists identified the risk of overdose associated with methadone alone and in combination with other psychoactive drugs as the greatest problematic issue for pharmacists in deciding to provide a methadone service.

In a survey of 148 pharmacists in Australia (Koutroulis et al., 2000), when asked about how they would respond to clients who presented intoxicated for their methadone dose, 44 per cent said they would withhold the dose and inform the client of this. This is the desirable course of action. However, 32 per cent of pharmacists said they would provide the usual dose, 16 per cent would dispense a reduced dose without the client knowing and nine per cent said they would blind the dose with a placebo. Only two per cent of the pharmacists indicated that they would breathalyse an intoxicated client.

Pharmacists who withheld the methadone dose were more likely to inform the prescriber (74 per cent) than pharmacists who dispensed the usual or modified dose. In a focus group, the reasons for dispensing to an intoxicated client were categorized as follows:

• insufficient communication between prescriber and pharmacist
• downplaying the risk of toxicity
• personal beliefs and values
• fear of what the client would do if dose refused
• difficulty in recognizing intoxication and lack of education and training.

Further, Koutroulis et al.’s survey suggested that pharmacists who had more than 10 methadone clients were more likely to provide the usual methadone dose than pharmacists with 10 or fewer clients.

Educational offerings

Many physicians and pharmacists don’t think they see addicts in their practice. The reality is they probably are treating them for other disorders, but the patient just hasn’t been identified as an addict. This also means that dependence treatment needs to become part of regular pharmacy practice as well.

— Open discussion, physicians and pharmacists (Raisch et al., 2005)

The panel recommends that:

16. All pharmacy students receive education on substance abuse, including opioid dependence, its treatment and practical intervention strategies, in their undergraduate curriculum. [IV]

Future pharmacists need to be adequately educated on substance use so that they are prepared upon graduation to care for patients with substance abuse disorders. In particular, opioid dependence and its treatment should be required components in the curriculum. Pharmacists who have had education in this area are likely to feel more comfortable providing pharmaceutical care to this group of clients.

Currently there are two faculties of pharmacy in Ontario, at the University of Toronto and at the University of Waterloo. The Waterloo faculty initiated their program in January 2009; therefore, their plans for curriculum on substance abuse education are still in the development phase.

At Toronto’s Faculty of Pharmacy, pharmacy students receive a rigorous scientific and clinical education over four years but receive little or no education on substance abuse and its treatment. Since the early 1990s, an elective fourth-year problem-based course has been offered (Busto et al., 1994). This course has one 2-hour segment on opioid abuse and treatment. It includes a didactic component, as well as an MMT client interview and discussion of stigma and attitudes. The course is elective and only a small proportion of the fourth-year class has taken this course offering.

Over the last five years enrolment in this elective has increased from 9.7 per cent of the class (13/134 students) in 2003–2004 to 34.2 per cent of the class (79/231 students) in 2008–2009 (personal communication, Dr. B. Sproule, April 29, 2009). Clearly, most future pharmacists have no exposure to substance use, opioid dependence and treatment with methadone.

The lack of specific undergraduate educational activities about substance abuse results in a missed opportunity to positively influence the knowledge, skills and attitudes of future pharmacists in this area.

As the most accessible of all health care professionals, pharmacists have an important role to play to help prevent and treat substance abuse disorders in their clients (Tommasello, 2004). Preparation for this role should begin in the undergraduate pharmacy training.

Experiential learning and other innovative teaching methods, for example, involving real patients (or simulated cases), audiovisual vignettes or other online modules may enhance pharmacy students’ understanding of substance dependence issues and attitudes.

One college of pharmacy in the United States, in addition to a required substance abuse course, offers an elective to illustrate addiction recovery principles. Students taking the elective are asked to give up a habit that is causing them problems for six weeks and they meet weekly to discuss the addiction recovery process. This course has been offered for 15 years and 50 per cent of the substance abuse course students are enrolled (Baldwin, 2008).

From the client consultation interviews

Clients’ need for pharmaceutical care

“I would have liked to know more about methadone before I started. It would have helped me make a better decision. You shouldn’t just tell a sick person ‘this will make you better.’ ” “There has been a lack of care and communication and confusion with my HIV meds. The methadone wasn’t holding me due to medication interactions.” “I felt sick for weeks and didn’t know it was because my dose was too high.”

The panel recommends that:

17. Professional organizations, addiction and mental health agencies and pharmacists’ employers promote the development of, and provide encouragement for all practising pharmacists to participate in, educational events on substance abuse and opioid dependence, including the growing problem of prescription opioid abuse. [III]

Most pharmacists receive little training on opioid dependence and treatment in their undergraduate experience, and it is important that all pharmacists further their knowledge in this area, even if they are not yet providing MMT services. There are indications that abuse and dependence on prescription opioids is increasing in Ontario and Canada. There was an increased number of patients addicted to prescription opioids entering the CAMH methadone maintenance program following the rapid expansion in the availability of MMT in Ontario in the 1990s (Brands et al., 2002; Brands et al., 2000). More recently, the number of individuals seeking detoxification treatment from controlled-release oxycodone at CAMH has also increased significantly (Sproule et al., 2009). In addition, in a cohort study of illicit opioid users, the proportion using prescription opioids increased from the year 2002 to 2005, with regional differences noted across Canada (Fischer et al., 2006). Pharmacists need to increase their knowledge base in prescription opioid addiction, particularly to understand the difference between addiction and physical dependence. Continuing education programs on pain treatment rarely (or inadequately) discuss the issue of opioid abuse and dependence.

A survey in British Columbia of 257 pharmacists (Cohen & McCormick, 2008) found that a slight majority reported training on how to identify signs of prescription drug misuse or abuse. This training was more common in younger pharmacists. The mean amount of training was 13.6 hours. Many pharmacists learned to identify prescription drug misuse through personal experience: they detected multi-doctoring using the provincial PharmaNet prescription drug profile or by recognizing early refills of prescriptions. Most intervened by calling the physician to confirm prescriptions or by confronting the customer directly. The primary reason they gave for not intervening was concern over how the customer might react (i.e., they were afraid that the client would be confrontational or they feared for their own safety). Pharmacists recommended additional training on prescription drug misuse.

Jones et al. (2005) surveyed 42 community pharmacists in Wales and found that at one month after a structured educational evening event there was little maintained change in attitudes. This suggests that changing attitudes is a long-term process. There is a need for reinforcing changes through continuing education.

Practising pharmacists (484) in Florida were surveyed while attending continuing education programs (Lafferty et al., 2006). Of the respondents, 67.5 per cent reported participating in two or fewer hours of addiction/ substance abuse education in pharmacy school and 29.2 per cent said they had received no addiction education. Pharmacists who had more education counselled clients more frequently and felt more confident in dealing with substance abuse clients. Of those surveyed, 53 per cent reported they had never referred a patient to substance abuse treatment in their whole career.

Brooks et al. (2001) conducted a survey in the United States of 556 pharmacists, comparing those who had taken training in addiction treatment to those who had not, and found that those who had taken training would more likely refer clients to community resources and be more involved in working with their chemically dependent clients.

The panel recommends that:

18. The Ontario College of Pharmacists revise the current requirements for pharmacies providing MMT services to mandate earlier training to promote safety. The designated manager and one pharmacist must complete the training within six months of starting to dispense methadone. [IV]

19. CAMH or another approved provider of methadone training develop a brief electronic document (e.g., one page) outlining the key safety features of providing MMT services that can be made available for immediate use by pharmacies initiating MMT services. [IV]

20. CAMH produce an electronic version of its most recent pharmacist’s guide to methadone maintenance treatment that can be purchased online and downloaded immediately so that pharmacies initiating MMT services can access it without delay. [IV]

21. CAMH make the online component of its Opioid Dependence Treatment Course available immediately upon enrolment to pharmacists new to providing MMT services, with the stipulation that these pharmacists attend the workshop component within six months of beginning the course. [IV]

22. CAMH or another approved provider of methadone training monitor and respond to waiting lists for training programs by, for example, offering the training more frequently or by exploring other delivery methods, such as webinars or video conferencing, to help meet the needs of pharmacists in remote areas. [IV]

Since undergraduate training on substance abuse and opioid dependence is lacking, most pharmacists do not have an adequate knowledge base from which to provide MMT services safely.

Having the most essential knowledge and references easily accessible and as early as possible will help facilitate pharmacies starting a methadone service and assist those who are deciding whether to provide MMT.

The online component of the CAMH Opiate Dependence Treatment Interprofessional Education Program would provide a good introduction to providing service, and a brief methadone information sheet would complement this program. The methadone information sheet could include some of the key points in providing MMT service, for example, observing dosing, diluting dose in orange drink, identifying the client, assessing the client for intoxication and informing the prescriber of missed doses.

Having a current version of the CAMH Pharmacist’s Guide available in a downloadable format would enable pharmacists to have this mandatory reference as soon as they need it. The other two references pharmacists dispensing methadone require, the CPSO Methadone Maintenance Guidelines and the OCP Policy for Dispensing Methadone, are currently available electronically.

The panel recommends that:

23. The Ontario College of Pharmacists and providers of methadone training collaborate on ongoing training requirements based on needs identified during the College’s pharmacy inspection process. [IV]

The Ontario College of Pharmacists undertakes regular inspections of community pharmacy practice in the province. Practice issues related to methadone service provision identified during these inspections could be shared with educational service providers for consideration in future training initiatives. This would be an effective mechanism for updating methadone training to reflect current practice issues in the field.

The panel recommends that:

24. CAMH or another approved provider of methadone education deliver methadone training in a manner consistent with interprofessional education principles. [IV]

Since MMT practice is best delivered in a collaborative manner (Health Canada, 2002), a multidisciplinary approach in education will prepare pharmacists to work effectively with other health professionals as a team.

The panel recommends that:

25. The Ontario College of Pharmacists and community colleges providing pharmacy technician training develop core competency requirements for regulated pharmacy technicians providing MMT services. [IV]

Pharmacy technicians are important members of the pharmacy team. They may be involved with preparing and dispensing methadone, and interact with MMT clients in the pharmacy. Core competencies should be developed and educational programs designed to optimize the role of pharmacy technicians in the safe delivery of methadone services. This issue may be particularly important in view of the new regulated status for pharmacy technicians that will be implemented soon in Ontario, where pharmacy technicians will be able to take more responsibility for dispensing.

The panel recommends that:

26. CAMH or another approved provider of methadone education undertake a needs assessment of pharmacists who have participated in the initial MMT training, and then use this information to develop an updated or advanced MMT course for pharmacists. [IV]

27. Professional pharmacy organizations, the Ontario College of Pharmacists, pharmacy managers/owners and hospital pharmacy directors encourage pharmacists to take courses on motivational interviewing, intervention strategies to use with difficult patients, and concurrent disorders, to enhance pharmacists’ skills in dealing with opioid-dependent clients. [IV]

Pharmacists who are already in MMT practice and have taken initial MMT training may wish to update and improve their skills. Since pharmacist training is recommended by the Ontario College of Pharmacists every five years, a new, higher level course would meet the needs of this experienced group of providers. Pharmacists who have taken initial MMT training should be surveyed for their input about topics to include within this higher level course. This advanced training could include, for example, methadone use in pregnancy, in patients with concurrent disorders (e.g., pain, psychiatric disorders, HIV) and in other special populations.

Any interaction with a client has therapeutic potential. Pharmacists using motivational techniques in their interactions with clients may enhance clients’ treatment. The issue of dealing with difficult, demanding clients has been identified by pharmacists as an area in which they would like more training (Cohen & McCormick, 2008). Training in de-escalation techniques to avoid potentially unsafe interactions could help pharmacists achieve greater satisfaction in their practice, as well as improve client outcomes.

The panel recommends that:

28. Drug information service providers ensure that staff is trained on and familiar with common issues in MMT treatment and have a mechanism to refer to experts when necessary. [IV]

Pharmacies must subscribe to a drug information provider service. The staff at the drug information provider should be able to respond to general questions on MMT and substance abuse. To do this they would require training in MMT to understand the patient safety issues and relevant guidelines. For more complex questions, the drug information service should have an arrangement with expert service providers to assist in consultation.

The panel recommends that:

29. Professional pharmacy organizations develop a mechanism in conjunction with the Ontario College of Pharmacists to ensure that pharmacists dispensing methadone are informed in a timely fashion of new educational resources available. [IV]

A timely direct communication via e-mail from the Ontario College of Pharmacists, the Ontario Pharmacists’ Association or another professional pharmacy organization is recommended when any new methadone-related item is posted on the website of either the OCP or the CPSO.

The panel recommends that:

30. Professional pharmacy organizations, CAMH and funding agencies develop a mentorship program to link new methadone service providers with experienced providers. [IV]

31. Professional pharmacy organizations and CAMH promote the CAMH Addiction Clinical Consultation Service to pharmacists providing MMT services. [IV]

The Addiction Clinical Consultation Service (ACCS) is a service provided by CAMH. It is designed to serve health and social service professionals, including pharmacists, who have client-specific questions related to substance abuse. The accs is not designed to deal with health emergencies or immediate or legal issues. The health care worker calls a central phone number and, depending on the question, accs may provide referral to a consultant team member (physician, therapist/counsellor or pharmacist) who will communicate with the health care worker within four hours. Awareness of the service should be promoted to support pharmacists providing methadone services.