, Volume 189, Issue 3, pp 297–306 | Cite as

Effects associated with double-blind omission of buprenorphine/naloxone over a 98-h period

  • Christopher J. Correia
  • Sharon L. Walsh
  • George E. Bigelow
  • Eric C. StrainEmail author
Original Investigation



Buprenorphine has a long duration of action that allows less than daily dosing for opioid dependence, but pharmacologic characterization of buprenorphine’s duration of effects over multiple days is incomplete.


This study assessed opioid blockade and spontaneous withdrawal effects of buprenorphine/naloxone (B/N) over a 98-h period.

Materials and methods

Residential opioid-dependent volunteers (n = 8) were maintained, in randomized sequence, on each of three different daily sublingual B/N doses (8/2, 16/4, 32/8 mg). After 2 weeks on each maintenance dose, participants underwent challenge sessions on each weekday for 1 week. Challenges consisted of within-session, ascending dose administration of IM hydromorphone (H: 0, 6, and 12 mg). During that week, active B/N dose was given only on Monday; double-blind placebo was administered on the remaining weekdays. Thus, these sessions assessed the extent of both opioid blockade and spontaneous withdrawal at 2, 26, 50, 74, and 98 h after the last active B/N dose.


All three maintenance doses provided substantial but incomplete blockade against opioid agonist effects for 98 h. The extent of blockade diminished steadily but modestly over this time and did not differ as a function of B/N maintenance dose. In general, participants did not report marked spontaneous opioid withdrawal, although mild withdrawal effects were observed as time since the last active B/N dose increased. However, withdrawal did not differ as a function of B/N maintenance dose.


These findings suggest that B/N doses greater than 8/2 mg provide minimal incremental value in terms of opioid blockade and withdrawal suppression.


Buprenorphine Dependence Hydromorphone Naloxone Opioid 



Supported by US Public Health Service Scientist Development Award K02 DA00332 and R01 DA08045 from the National Institute on Drug Abuse.


  1. Amass L, Bickel WK, Higgins ST, Badger GJ (1994) Alternate-day dosing during buprenorphine treatment of opioid dependence. Life Sci 54:1215–1228PubMedCrossRefGoogle Scholar
  2. APA (2000) Diagnostic and statistical manual of mental disorders (text revision), 4th edn. American Psychiatric Association, WashingtonGoogle Scholar
  3. 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 247:47–53PubMedGoogle Scholar
  4. Bickel WK, Amass L, Crean JP, Badger GJ (1999) Buprenorphine dosing every 1, 2, or 3 days in opioid-dependent patients. Psychopharmacology (Berl) 146:111–118CrossRefGoogle Scholar
  5. Boas RA, Villiger JW (1985) Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth 57:192–196PubMedGoogle Scholar
  6. Fraser HF, Van Horn GD, Martin WR, Wolbach AB, Isbell H (1961) Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs, (B) A short-term “direct” addiction test. J Pharmacol Exp Ther 133:371–387PubMedGoogle Scholar
  7. 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 47:525–534PubMedCrossRefGoogle Scholar
  8. Griffiths RR, Bigelow GE, Liebson I (1983) Differential effects of diazepam and pentobarbital on mood and behavior. Arch Gen Psychiatry 40:865–873PubMedGoogle Scholar
  9. Gross A, Jacobs EA, Petry NM, Badger GJ, Bickel WK (2001) Limits to buprenorphine dosing: a comparison between quintuple and sextuple the maintenance dose every 5 days. Drug Alcohol Depend 64:111–116PubMedCrossRefGoogle Scholar
  10. Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J (2000) Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. Drug Alcohol Depend 61:85–94PubMedCrossRefGoogle Scholar
  11. Hill JL, Zacny JP (2000) Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers. Psychopharmacology (Berl) 152:31–39CrossRefGoogle Scholar
  12. Jasinski DR (1977) Assessment of the abuse potentiality of morphine-like drugs (methods used in man). In: Martin WR (ed) Drug addiction I. Springer, Berlin Heidelberg New York, pp 197–258Google Scholar
  13. Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA, Bigelow GE (1995) Buprenorphine treatment of opioid dependence: clinical trial of daily versus alternate-day dosing. Drug Alcohol Depend 40:27–35PubMedCrossRefGoogle Scholar
  14. Johnson RE, Strain EC, Amass L (2003) Buprenorphine: how to use it right. Drug Alcohol Depend 70:S59–S77PubMedCrossRefGoogle Scholar
  15. Kolb L, Himmelsbach CK (1938) Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method of evaluating abstinence syndromes. Am J Psychiatry 94:759–799Google Scholar
  16. Ling W, Wesson DR (2003) Clinical efficacy of buprenorphine: comparisons to methadone and placebo. Drug Alcohol Depend 70:S49–S57PubMedCrossRefGoogle Scholar
  17. McLeod D, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods Instrum 14:463–466Google Scholar
  18. McQuay HJ, Moore RA (1995) Buprenorphine kinetics in humans. In: Cowan A, Lewis JW (eds) Buprenorphine: combatting drug abuse with a unique opioid. Wiley, New York, pp 137–147Google Scholar
  19. Petry NM, Bickel WK, Badger GJ (1999) A comparison of four buprenorphine dosing regimens in the treatment of opioid dependence. Clin Pharmacol Ther 66:306–314PubMedCrossRefGoogle Scholar
  20. Petry NM, Bickel WK, Badger GJ (2001) Examining the limits of the buprenorphine interdosing interval: daily, every-third-day and every-fifth-day dosing regimens. Addiction 96:823–834PubMedCrossRefGoogle Scholar
  21. Reitan RM (1958) Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 8:271–276CrossRefGoogle Scholar
  22. Rosen MI, Wallace EA, McMahon TJ, Pearsall HR, Woods SW, Price LH, Kosten TR (1994) Buprenorphine: duration of blockade of effects of intramuscular hydromorphone. Drug Alcohol Depend 35:141–149PubMedCrossRefGoogle Scholar
  23. Schottenfeld RS, Pakes J, O’Connor P, Chawarski M, Oliveto A, Kosten TR (2000) Thrice-weekly versus daily buprenorphine maintenance. Biol Psychiatry 47:1072–1079PubMedCrossRefGoogle Scholar
  24. Schuh KJ, Walsh SL, Stitzer ML (1999) Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans. Psychopharmacology (Berl) 145:162–174CrossRefGoogle Scholar
  25. Stoller KB, Bigelow GE, Walsh SL, Strain EC (2001) Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology (Berl) 154:230–242CrossRefGoogle Scholar
  26. Strain EC, Preston KL, Liebson IA, Bigelow GE (1992) Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther 261:985–993PubMedGoogle Scholar
  27. Strain EC, Preston KL, Liebson IA, Bigelow GE (1993) Precipitated withdrawal by pentazocine in methadone-maintained volunteers. J Pharmacol Exp Ther 267:624–634PubMedGoogle Scholar
  28. Strain EC, Preston KL, Liebson IA, Bigelow GE (1995) Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone. J Pharmacol Exp Ther 272:628–638PubMedGoogle Scholar
  29. Strain EC, Walsh SL, Preston KL, Liebson IA, Bigelow GE (1997) The effects of buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl) 129:329-338CrossRefGoogle Scholar
  30. Strain EC, Stoller K, Walsh SL, Bigelow GE (2000) Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl) 148:374–383CrossRefGoogle Scholar
  31. Strain EC, Walsh SL, Bigelow GE (2002) Blockade of hydromorphone effects by buprenorphine/naloxone and buprenorphine. Psychopharmacology (Berl) 159:161–166CrossRefGoogle Scholar
  32. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55:569–580PubMedCrossRefGoogle Scholar
  33. Walsh SL, June HL, Schuh KJ, Preston KL, Bigelow GE, Stitzer ML (1995) Effects of buprenorphine and methadone in methadone-maintained subjects. Psychopharmacology (Berl) 119:268–276CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Christopher J. Correia
    • 1
    • 2
  • Sharon L. Walsh
    • 1
    • 3
  • George E. Bigelow
    • 1
  • Eric C. Strain
    • 1
    Email author
  1. 1.Behavioral Pharmacology Research UnitJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Auburn UniversityAuburnUSA
  3. 3.University of KentuckyLexingtonUSA

Personalised recommendations