Psychopharmacology (2002) 160:344–352 DOI 10.1007/s00213-001-0975-0 Abstract Rationale: Buprenorphine can decrease opioid self-administration by humans and animals, but its abili- ty to decrease drug-seeking behavior and craving (i.e. motivational measures) among outpatient volunteers us- ing clinically relevant dosing schedules has not been ex- tensively studied. Objectives: We investigated whether daily versus alternating-day administration of high ver- sus low buprenorphine doses influenced choice of, and operant responding for, hydromorphone versus money. Methods: Fourteen heroin-dependent outpatients were maintained under four buprenorphine sublingual tablet (double blind) dose conditions using a within-subject, randomized crossover design. All participants received, for 2 weeks each, buprenorphine doses of 2 mg daily, 4 mg/placebo on alternating days, 16 mg daily, and 32 mg/placebo on alternating days. In each laboratory test session, participants chose between money ($2/choice) and drug (1/8 of total hydromorphone, 4 or 24 mg IM in different sessions) alternatives using an eight-trial non-independent progressive ratio schedule (FR 100, 200,...12,800). The drug dose and money amount earned was delivered after the end of the 2.5-h work period. Results: Hydromorphone 24 mg was more reinforcing than 4 mg. Higher versus lower average bu- prenorphine doses (regardless of daily versus alternate- day schedule) significantly decreased hydromorphone 24 mg choice and increased money choice. Baseline her- oin craving questionnaire scores predicted drug choice, and craving scores were significantly decreased by high- dose buprenorphine. Conclusions: High-dose buprenor- phine attenuated opioid drug-seeking behavior, heroin craving self-reports and increased sensitivity to alterna- tive reinforcement. These beneficial effects were re- tained when high-dose buprenorphine was administered on alternate days. Keywords Buprenorphine · Heroin · Progressive ratio · Self-administration · Drug-seeking · Opioid dependence Introduction Buprenorphine (BUP) is a mu-opioid partial agonist be- ing developed as a treatment for opioid dependence (Lewis et al. 1983; Bickel and Amass 1995). Due to its lower intrinsic activity relative to full mu agonists, BUP produces limited respiratory depression even after ad- ministration of high doses (Walsh et al. 1994; Kishioka et al. 2000) that occupy virtually all brain mu-opioid re- ceptors (Zubieta et al. 2000). On the other hand, because buprenorphine has high affinity for opioid receptors (Hambrook and Rance 1976; Sadee et al. 1982; Lewis et al. 1983), moderately high BUP doses can block subjec- tive and physiological effects of mu-opioids for more than 1 day (Jasinski et al. 1978; Rosen et al. 1994; Schuh et al. 1999). Consistent with this human laboratory evi- dence, BUP has been shown to retain its efficacy using less-than-daily dosing schedules in several clinical trials (Fudala et al. 1990; Amass et al. 1994, 1998, 2000; Johnson et al. 1995b; Bickel et al. 1999; Petry et al. 1999). Buprenorphine has been shown to decrease opioid self-administration by primates (Mello et al. 1983; Winger and Woods 1996; Mello and Negus 1998; Briscoe et al. 2000), and human inpatient (Mello and Mendelson 1980; Mello et al. 1982), and outpatient vol- unteers (Johnson et al. 1995a). Comer et al. (2001) showed that BUP 16 versus 8 mg daily sublingual tablet doses decreased progressive ratio breakpoint values for intravenous heroin, but this BUP dose effect was only significant for one of three heroin doses (12.5 mg but not 6.25 mg or 25 mg). The inability of BUP 16 mg consis- M.K. Greenwald ( ✉ ) · J.A. Hopper · C.R. Schuster C.-E. Johanson Addiction Research Institute, Wayne State University School of Medicine, 2761 E. Jefferson, Detroit, MI 48207, USA e-mail: mgreen@med.wayne.edu Tel.: +1-313-9933965, Fax: +1-313-9931372 K.J. Schuh Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA ORIGINAL INVESTIGATION Mark K. Greenwald · Kory J. Schuh John A. Hopper · Charles R. Schuster Chris-Ellyn Johanson Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans Received: 15 May 2001 / Accepted: 6 November 2001 / Published online: 31 January 2002 © Springer-Verlag 2002