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Buprenorphine-Induced Changes in Mu-Opioid Receptor Availability in Male Heroin-Dependent Volunteers: A Preliminary Study Jon-Kar Zubieta, M.D., Ph.D., Mark K. Greenwald, Ph.D., Umberto Lombardi, M.D., James H. Woods, Ph.D., Michael R. Kilbourn, Ph.D., Douglas M. Jewett, Robert A. Koeppe, Ph.D., Charles R. Schuster, Ph.D., and Chris-Ellyn Johanson, Ph.D. A principle of opioid pharmacotherapy is that high dependent reductions in ␮OR availability, 36–50% at 2 mg medication doses should occupy fractionally more opioid and 79–95% at 16 mg relative to placebo. Heroin abusers receptors that mediate heroin effects. In this preliminary also had greater ␮OR binding potential in the inferofrontal study we examined in vivo ␮ opioid receptor (␮OR) cortex and anterior cingulate regions during placebo, binding in three healthy opioid-dependent volunteers compared to matched controls. Further studies are during maintenance on 2 and 16 mg sublingual warranted to examine the relationship of ␮OR availability buprenorphine (BUP) liquid, and after detoxification (0 mg) with BUP therapeutic actions, and the clinical implications under double-blind, placebo-controlled conditions, and once of increased ␮OR binding during withdrawal. in matched controls. Binding measures were obtained with [Neuropsychopharmacology 23:326–334, 2000] the ␮OR-selective radioligand [11C]carfentanil (CFN) and © 2000 American College of Neuropsychopharmacology. PET 4 hrs after BUP administration. BUP induced dose- Published by Elsevier Science Inc. All rights reserved. KEY WORDS: Buprenorphine; Positron emission toxicity, treat overdoses) but a primary goal is to atten- tomography; Opiates; Opiate dependence; Mu opioid uate the subjective, behavioral, or physiological effects receptors; Carfentanil of the drug of abuse. Buprenorphine is a high affinity, Medications for the treatment of substance abuse may mu opioid partial agonist, with kappa antagonist action be developed for a variety of purposes (e.g., ameliorate (Cowan et al. 1977; Heel et al. 1979; Lewis et al. 1983). This compound is being evaluated as an alternative to methadone maintenance and detoxification in the treat- From the Mental Health Research Institute and Departments of ment of opioid dependence (Bickel and Amass 1995). Psychiatry, Internal Medicine (Division of Nuclear Medicine) ␮ (MRK, DMJ, RAK), and Neurosciences (J-KZ, UL, MRK, DMJ) and Buprenorphine’s mu receptor ( OR) agonist actions Department of Pharmacology (JHW), University of Michigan, Ann could reduce opiate craving and prevent withdrawal, Arbor, MI; and the Research Division on Substance Abuse, Depart- thus improving compliance with treatment compared ment of Psychiatry and Behavioral Neurosciences (MKG, CRS, C- EJ), Wayne State University, Detroit, MI. to conventional opiate receptor antagonists (e.g., nal- Address correspondence to: Jon-Kar Zubieta, M.D., Ph.D., The trexone). At the same time, its partial efficacy and high University of Michigan, Neuroscience Building, 1103 E. Huron affinity at ␮OR’s provide long lasting functional antago- Street, Ann Arbor, MI 48104–1687. Received September 8, 1999; revised February 21, 2000; accepted nism, making it an effective means of blocking the ef- March 3, 2000. fects of abused opiates. This unique combination of NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 3 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. All rights reserved. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00110-X NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 3 Buprenorphine and Mu Receptor 327 pharmacological properties confers potential advan- fects (Kling et al. 1997). However, this study was con- tages, including enhanced safety over existing medica- ducted utilizing [18F]cyclofoxy, which is a non-selective tions for treating opioid abuse (Lange et al. 1990). ␮OR and kappa receptor marker (Carson et al. 1993), Buprenorphine sublingual (SL) liquid has been and therefore the receptor availability measure calcu- shown to decrease heroin self-administration in single- lated does not refer to one but two receptor sites. Since dose human laboratory studies (Mello and Mendelson methadone has much higher affinity for mu than for 1980; Mello et al. 1981, 1982); the dose-dependency of kappa receptor sites (Kristensen et al. 1995), the use of a its effects on reinforcement has been less well character- non-selective radiotracer would underestimate changes ized. In a clinical study, Johnson et al. (1995) compared in ␮OR availability. Also, the study assumed that the short-term efficacy of placebo, 2 and 8 mg/day bu- healthy subjects and methadone-maintained partici- prenorphine in a parallel group, randomized design pants had similar regional ␮OR binding concentrations, during a two-week initial maintenance period. In this which may not be the case. Similar studies have not study, active doses were more effective than placebo in been conducted with partial opioid agonists, such as decreasing heroin use, however, there were no differ- buprenorphine, or with receptor-selective radiotracers. ences in therapeutic efficacy between 2 and 8 mg. Schot- In this study we present preliminary data on the in tenfeld et al. (1993) used a within-subject study design vivo availability of ␮OR’s after treatment with SL bu- in which heroin-dependent outpatients received as- prenorphine 2 mg, 16 mg, and after detoxification on 0 cending/descending maintenance doses of buprenor- mg, under double-blind conditions. Mu opioid receptor phine ranging from 2 to 16 mg/day. Sixteen milligrams binding was examined in three otherwise healthy opioid- produced significant decreases in opioid-positive urine dependent volunteers and in age-matched controls with samples, relative to lower doses. Thus, available data PET and the selective ␮OR radiotracer [11C]carfentanil. suggest that, relative to placebo, buprenorphine doses ranging from 2 to 8 mg are equally capable of decreas- ing opioid use, whereas doses of 16 mg have greater ef- METHODS ficacy. This may suggest that the effect of buprenor- Participant Recruiting and Selection phine in decreasing opiate self-administration may not be dose-dependent, at least in lower dose ranges. In The Institutional Review Boards of Wayne State Uni- fact, in a recently completed laboratory study in heroin- versity and the University of Michigan approved all dependent volunteers, maintenance doses of 2, 4, and 8 procedures and experimental protocols. Three opioid- mg buprenorphine showed equal efficacy in decreasing dependent volunteers and three age-matched non- the reinforcing effects of hydromorphone (Greenwald dependent healthy volunteers between the ages of 20 et al. 1999). and 50 were recruited through newspaper advertise- On the other hand, laboratory studies have demon- ments. All volunteers provided written informed con- strated that SL buprenorphine blocks many of the sub- sent and were paid for their participation. Opioid- jective effects of hydromorphone, a full mu opioid ago- dependent volunteers were not seeking treatment and nist, in a dose-dependent manner. For instance, Bickel willing to participate in a short-term study involving et al. (1988) showed that maintenance on buprenor- buprenorphine maintenance and detoxification. phine (2, 4, 8, 16 mg) produced dose-related decreases A structured interview (SCID-IV) (First et al. 1996) in subjective effects to cumulative hydromorphone (0, was administered by an experienced, masters’ level 6, 18 mg subcutaneous) challenges. Rosen et al. (1994) psychologist, to all volunteers (SCID-IV patient version also found that maintenance on buprenorphine 12 mg in the case of heroin-dependent volunteers, SCID-IV (relative to 2 and 6 mg) significantly blocked the subjec- non-patient version for healthy control subjects) to rule tive effects produced by hydromorphone relative to out the presence of psychiatric illnesses and diagnose maintenance on 2 and 6 mg. opioid dependency. Severity of opioid dependence was A central principle of pharmacotherapy of opiate de- determined using the Addiction Severity Index (McLel- pendence is that the clinical efficacy of medications is lan et al. 1985a,b). Volunteers were included who were directly related to their occupancy of brain opioid re- otherwise healthy, and had no present or past history of ceptors. Positron emission tomography (PET) and ra- psychiatric illnesses, except for nicotine dependence, diotracers that label opioid receptors have become acute medical or neurological illnesses. Volunteers who available to examine this hypothesis. A single prelimi- met DSM-IV criteria for antisocial personality disorder nary report has shown that participants who were sta- were also excluded. bilized on methadone (30–90 mg/day) and abstinent from heroin had 22–35% lower opioid receptor avail- Drug Preparation ability than healthy controls, 22 hours after the last dose. These data suggest that relatively low degrees of Opioid-dependent participants were maintained on as- occupancy are needed to induce clinically significant ef- cending, then descending sublingual (SL) buprenor- 328 J.-K. Zubieta et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 23, NO. 3 phine (BUP) doses over a six-week period. The liquid box/talkative, rush, friendly) and 16 items are related formulation (1 ml ped-pods; National Institute on Drug to withdrawal symptoms (yawning, restless, watery Abuse) was used to administer BUP. These contained eyes, runny nose, sick to stomach, irritable, tense/jit- BUP

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