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.