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Effects of Buprenorphine Maintenance Dose on μ-Opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers



The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medication's ability to decrease μ-opioid receptor (μOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. We empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. We predicted and confirmed that higher BUP doses would decrease in vivo μOR availability (measured with PET and [11C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (±SEM) whole-brain μOR availability 41±8, 80±2, and 84±2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in μOR availability varied across ROIs (prefrontal cortex, 47% vs amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94–98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5–1, 5–6, and 13–14 ng/ml at 2, 16, and 32 mg, respectively). μOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal μOR occupation, μOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration–effect relationships.

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  1. Bickel WK, Amass L (1995). Buprenorphine treatment of opioid dependence: a review. Exp Clin Psychopharmacol 3: 477–489.

  2. Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988). Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247: 47–53.

  3. Carson RE, Channing MA, Blasberg RG, Dunn BB, Cohen RM, Rice KC et al (1993). Comparison of bolus and infusion methods for receptor quantification: application to [18F] cyclofoxy and positron emission tomography. J Cereb Blood Flow Metab 13: 24–42.

  4. Comer SD, Collins ED, Fischman MW (2001). Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans. Psychopharmacology 154: 28–37.

  5. Cowan A, Lewis JW, Macfarlane IR (1977). Agonist and antagonist properties of buprenorphine: a new antinociceptive agent. Br J Pharmacol 60: 537–545.

  6. Dannals RF, Ravert HT, Frost JJ, Wilson AA, Burns HD, Wagner Jr HN (1985). Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil. Int J Appl Radiat Isot 36: 303–306.

  7. First MB, Spitzer RL, Gibbon M, Williams JBW (1996). Structured Clinical Interview for DSM-IV Axis Disorders—Patient Edition (SCID-I/P, Version 2.0). Biometrics Research Department, NY State Psychiatric Institute: New York.

  8. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ (1995). Statistical parametric maps in functional neuroimaging: A general linear approach. Hum Brain Map 2: 189–210.

  9. Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA et al (1989). Multicompartmental analysis of [11C]carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab 9: 398–409.

  10. Fudala PJ, Jaffe JH, Dax EM, Johnson RE (1990). Use of buprenorphine in the treatment of opioid addiction. II. Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal. Clin Pharmacol Ther 47: 525–534.

  11. Greenwald MK (2002). Heroin craving and drug use in opioid-maintained volunteers: effects of methadone dose variations. Exp Clin Psychopharmacol 10: 39–46.

  12. Greenwald MK, Johanson CE, Schuster CR (1999). Opioid reinforcement in heroin-dependent volunteers during buprenorphine maintenance. Drug Alcohol Depend 56: 191–203.

  13. Greenwald MK, Schuh KJ, Hopper JA, Schuster CR, Johanson CE (2002). Effects of buprenorphine sublingual tablet maintenance on opioid drug-seeking behavior by humans. Psychopharmacology 160: 344–352.

  14. Heel RC, Brogdon RN, Speight TM, Avery GS (1979). Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs 17: 81–110.

  15. Jasinski DR, Pevnick JS, Griffith JD (1978). Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry 35: 501–506.

  16. Jewett DM (2001). A simple synthesis of [11C]carfentanil. Nucl Med Biol 28: 733–734.

  17. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000). A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343: 1290–1297.

  18. Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA, Bigelow GE (1995). A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend 40: 17–25.

  19. Kling MA, Carson RE, Borg L, Zametkin A, Matochik JA, Schluger J et al (2000). Opioid receptor imaging with positron emission tomography and [18F]cyclofoxy in long-term, methadone-treated former heroin addicts. J Pharmacol Exp Ther 295: 1070–1076.

  20. Koeppe RA (1999). Data analysis for PET studies of neuroreceptor modulation. J Nucl Med 5, 287pp.

  21. Kristensen K, Christensen CB, Christrup LL (1995). The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci 56: 45–50.

  22. Kuhlman Jr JJ, Levine B, Johnson RE, Fudala PJ, Cone EJ (1998). Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance, and withdrawal from sublingual buprenorphine. Addiction 93: 549–559.

  23. Lewis JW, Rance MJ, Sanger DJ (1983). The pharmacology and abuse potential of buprenorphine: a new antagonist analgesic. In: Mello NK (ed). Advances in Substance Abuse Vol. 3 JAI Press: Greenwich, 103–154.

  24. Ling W, Charuvastra C, Collins JF, Batki S, Brown Jr LS, Kintaudi P et al (1998). Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 93: 475–486.

  25. Logan J, Fowler JS, Volkow ND, Wang G-J, Ding Y-S, Alexoff DL (1996). Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16: 834–840.

  26. McLellan AT, Luborsky L, Cacciola J, Griffith J, Evans F, Barr HL et al (1985a). New data from the Addiction Severity Index. J Nerv Ment Dis 173: 412–423.

  27. McLellan AT, Luborsky L, O'Brien CP (1985b). Improved diagnostic instrument for substance abuse patients: The Addiction Severity Index. J Nerv Ment Dis 168: 26–33.

  28. Mello NK, Mendelson JH, Kuehnle JC (1982). Buprenorphine effects on human heroin self-administration: an operant analysis. J Pharmacol Exp Ther 223: 30–39.

  29. Mendelson J, Upton RA, Everhart ET, Jacob P, Jones RT (1997). Bioavailability of sublingual buprenorphine. J Clin Pharmacy 37: 31–37.

  30. Meyer CR, Boes JL, Kim B, Bland PH, Zasadny KR, Kison PV et al (1997). Demonstration of accuracy and clinical versatility of mutual information for automatic multimodality image fusion using affine and thin-plate spline warped geometric deformations. Med Image Anal 1: 195–206.

  31. Minoshima S, Berger KL, Lee KS, Mintun MA (1992). An automated method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med 33: 1579–1585.

  32. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984). A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15: 217–227.

  33. Moody DE, Slawson MH, Strain EC, Laycock JD, Spanbauer AC, Foltz RL (2002). A liquid chromatographic-electrospray ionization-tandem mass spectrometric method for determination of buprenorphine, its metabolite, norbuprenorphine, and a coformulant, naloxone, that is suitable for in vivo and in vitro metabolism studies. Anal Biochem 306: 31–39.

  34. Nath RP, Upton RA, Everhart ET, Cheung P, Shwonek P, Jones RT et al (1999). Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol 39: 619–623.

  35. Ohtani M, Kotaki H, Sawada Y, Iga T (1995). Comparative analysis of buprenorphine- and norbuprenorphine-induced analgesic effects based on pharmacokinetic-pharmacodynamic modeling. J Pharmacol Exp Ther 272: 505–510.

  36. Pontani RB, Vadlamani NL, Misra AL (1985). Disposition in the rat of buprenorphine administered parenterally and as a subcutaneous implant. Xenobiotica 15: 287–297.

  37. Rosen MI, Wallace EA, McMahon TJ, Pearsall HR, Woods SW, Price LH et al (1994). Buprenorphine: duration of blockade of effects of intramuscular hydromorphone. Drug Alcohol Depend 35: 141–149.

  38. Schottenfeld RS, Pakes J, Ziedonis D, Kosten TR (1993). Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans. Biol Psychiatry 34: 66–74.

  39. Schuh KJ, Johanson CE (1999). Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend 56: 55–60.

  40. Schuster CR, Greenwald MK, Johanson CE, Heishman SJ (1995). Measurement of drug craving during naloxone-precipitated withdrawal in methadone maintained volunteers. Exp Clin Psychopharmacol 3: 424–431.

  41. Tiffany ST, Fields L, Singleton E, Haertzen C, Henningfield JE (1995, unpublished data). The development of a heroin craving questionnaire.

  42. Titeler M, Lyon RA, Kuhar MJ, Frost JF, Dannals RF, Leonhardt S et al (1989). Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain. Eur J Pharmacol 167: 221–228.

  43. Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995). Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 274: 361–372.

  44. Woods JH, France CP, Winger GD (1992). Behavioral pharmacology of buprenorphine: issues relevant to its potential in treating drug abuse. NIDA Res Monogr 121: 12–27.

  45. Zubieta JK, Greenwald MK, Lombardi U, Woods JH, Kilbourn MR, Jewett DM et al (2000). Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: a preliminary study. Neuropsychopharmacology 23: 326–334.

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USPHS Grants P50 DA00254 and R01 DA10100 from the National Institute on Drug Abuse and a research grant (Joe Young, Sr) from the State of Michigan supported this research.

We thank Dr John Hopper for medical oversight, Ken Bates for recruitment, Ja'Near Mathis for urine testing, Nancy Lockhart, Teresa Woike, and Suzanne Manji for scheduling, and Debra Kish, Rebecca Cohn, and Josh Bueller for data management. We thank the staff of the Neuropsychiatric Research Unit at Wayne State University for blood sample and clinical data collection and observation.

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Correspondence to Mark K Greenwald.

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