Is buprenorphine-naloxone ready for prime time in the treatment of opioid addiction in managed care?

A casual reader of the article by Kaur et al. in this issue of JMCP might find the results unimpressive for the intervention with buprenorphine-naloxone in 1 large managed care plan.1 Persistence with this intervention therapy to treat patients with a history of prescription opioid use was only 48% at month 1, 27% at month 6, and 20% at month 12. Even for the small proportion of patients persistent on buprenorphinenaloxone, we do not know any clinical outcome measures including the effect on illicit drug use or prescription opiate use not captured in the pharmacy claims system. And, Kaur et al. found no cost savings in total prescription opiate claims when the cost of buprenorphine-naloxone was included in the analysis. Misuse of opioid analgesics is a challenge for every health plan, including a greater number of emergency room visits attributable to opioid analgesic abuse than heroin abuse.2 It is only in the last 8 years that the treatment options for opioid addiction have expanded significantly. For more than 80 years following the 1914 Harrison Narcotic Drug Act, physicians in the United States could not legally prescribe opioid medications for the treatment of opioid dependence. The Harrison Narcotic Drug Act made it illegal for a physician to keep a patient “comfortable by maintaining his customary use.”3 The only exception to this 80-year prohibition was dispensing of methadone in regulated programs.4 On October 17, 2000, the Drug Addiction Treatment Act (DATA) permitted the use of Schedule III, IV, or V narcotics to be used for either detoxification (tapering) or long-term maintenance.5 Buprenorphine had been approved by the U.S. Food and Drug Administration (FDA) 15 years earlier, on December 30, 1985.6 However, the combination therapy with the naloxone was not approved by the FDA for the treatment of opioid dependence until October 8, 2002.7 DATA permitted each physician with a minimum of 8 hours of approved training in treatment and management of opioid addiction or specialty certification to treat no more than 30 patients with buprenorphine-naloxone. In June 2005, federal regulations were relaxed to permit each physician to treat as many as 100 patients. Both buprenorphine alone (Subutex) or in combination with naloxone (Suboxone) are Schedule III controlled substances that require no special waiver for dispensing by pharmacies, but the Substance Abuse and Mental Health Services Administration (SAMHSA) requires physician registration, and SAMHSA maintains a list of physicians by state who are authorized to treat opioid addiction with buprenorphine.8 Buprenorphine is a partial opioid agonist that is administered primarily as an oral sublingual tablet once daily in the dose range of 12 mg to 16 mg. It is appropriate for use only during induction in a clinic setting in which access to opioids can be prevented. In an unsupervised environment in which there is no control over access to illicit opioids, buprenorphine in combination with the opioid antagonist naloxone is preferred. Naloxone is a pure narcotic antagonist that has no agonist effects, and in the presence of opioid agonists causes intense opioid withdrawal symptoms if buprenorphine-naloxone is misused parenterally.7 In 2003, Fudala et al. reported the results of an 8-center trial involving 326 opioid-dependent patients randomized to 16 mg buprenorphine per day in combination with 4 mg of naloxone or 16 mg per day of buprenorphine alone or placebo; this clinical trial was used in the application for FDA approval of buprenorphine-naloxone.9 The proportion of urine samples negative for opiates after 4 weeks of treatment was only 17.8% in the buprenorphine-naloxone group, 20.7% in the buprenorphine only group, and 5.8% in the placebo group (P < 0.001). Clark observed in an accompanying editorial that this study— even its open-label phase—was dissimilar from the real world in which physicians can prescribe up to a 30-day supply of buprenorphine-naloxone.10 Also, the application of the Fudala et al. findings to addiction with prescription opioids is not clear because all of the patients in that study were heroin addicts, with median 7-year duration of use and 2 patients with 35 or more years of heroin use.11 More recently in 2006, Fiellin et al. found 40%-44% of urine samples to be negative for opioids in a 24-week clinical trial of 166 opioid-addicted patients treated with buprenorphine-naloxone in a common dose of 16 mg buprenorphine per day, with some patients dosed up to 24 mg per day if there was ongoing illicit drug use or if the patient reported discomfort.12 The 166 opioidaddicted patients were randomized to 1 of 3 treatment groups: (1) standard medical management and medication dispensing once per week, (2) standard medical management and medication dispensing 3 times per week, and (3) enhanced medical management and medication dispensing 3 times per week. Therefore, the study by Fiellin et al. was primarily a study of the effects of counseling on adherence with buprenorphine-naloxone therapy. Importantly, neither Fudala et al. nor Fiellin et al. studied conditions similar to treatment of opioid-dependent patients enrolled in managed health care plans. Specifically, in addition to the controlled, supervised environment of these 2 studies and the significant behavioral support in the study by Fiellin et al., these studies excluded many patients who would be treated in Is Buprenorphine-Naloxone Ready for Prime Time in the Treatment of Opioid Addiction in Managed Care?