, Volume 235, Issue 4, pp 971–981 | Cite as

Characterizing the subjective, observer-rated, and physiological effects of hydromorphone relative to heroin in a human laboratory study

  • Kelly E. Dunn
  • Bruna Brands
  • David C. Marsh
  • George E. Bigelow
Original Investigation



This study compared the effects of the several doses of the opioid agonists heroin and hydromorphone across two routes of administration in humans. The goal was to guide development of human laboratory studies of opioid effects and inform subsequent injection pharmacotherapy trials of hydromorphone-assisted treatment.


A within-subject (N = 16), double-blind, double-dummy, placebo-controlled, evaluation of acute doses of heroin and hydromorphone was completed at four dose levels (placebo, low, medium, high) across two routes of administration (intravenous, subcutaneous) in non-physically dependent, opioid-experienced individuals. Subject and observer ratings, as well as physiological outcomes, were assessed.


Within each route of administration, heroin and hydromorphone produced effects that were qualitatively similar on most variables across the doses examined. All effects were dose-dependent. The drugs produced different effects on VAS ratings of “Feels Like Heroin,” a Heroin Identification Test, observer agonist ratings, and oxygen saturation levels. Drug-dependent differences emerged at the highest doses in all cases. Few significant main effects of Route were identified and their pattern was not uniform. Relative potency calculations across all subject, observer, and physiological outcomes that met analysis criteria revealed similar profiles and resulted in mean heroin:hydromorphone potencies of 3.35:1 and 2.88:1 for the intravenous and subcutaneous routes, respectively, and intravenous:subcutaneous potencies of 0.47:1 and 0.49:1 for heroin and hydromorphone, respectively.


Hydromorphone produced similar subjective and physiological effects as heroin, but was more potent than heroin. The current findings support the use of hydromorphone as a model for heroin in human laboratory and clinical treatment studies, and help identify appropriate hydromorphone dose conversion ratios to produce effects qualitatively similar to heroin.


Opioid Heroin Hydromorphone Potency Heroin-assisted treatment 


Funding information

The study procedures were funded by the Open Society Institute and the Abell Foundation, and the manuscript preparation was funded in the form of salary support from the National Institute on Drug Abuse (NIDA) R01DA03546 (Dunn).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988a) Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247(1):47–53PubMedGoogle Scholar
  2. Bickel WK, Stitzer ML, Liebson IA, Bigelow GE (1988b) Acute physical dependence in man: effects of naloxone after brief morphine exposure. J Pharmacol Exp Ther 244(1):126–132PubMedGoogle Scholar
  3. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL (2011) Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Med 12(4):657–667.; 10.1111/j.1526-4637.2011.01075.x. CrossRefPubMedGoogle Scholar
  4. Blanken P, Hendriks VM, Koeter MW, van Ree JM, van den Brink W (2012) Craving and illicit heroin use among patients in heroin-assisted treatment. Drug Alcohol Depend 120(1-3):74–80. [doi]. CrossRefPubMedGoogle Scholar
  5. Bruneau J, Roy E, Arruda N, Zang G, Jutras-Aswad D (2012) The rising prevalence of prescription opioid injection and its association with hepatitis C incidence among street-drug users. Addiction 107(7):1318–1327.; 10.1111/j.1360-0443.2012.03803.x. CrossRefPubMedGoogle Scholar
  6. Carroll CP, Walsh SL, Bigelow GE, Strain EC, Preston KL (2006) Assessment of agonist and antagonist effects of tramadol in opioid-dependent humans. Exp Clin Psychopharmacol 14(2):109–120. CrossRefPubMedGoogle Scholar
  7. Carter LP, Griffiths RR (2009) Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend 105(Suppl 1):S14–S25. CrossRefPubMedGoogle Scholar
  8. Centers for Disease Control and Prevention (CDC) (2013) Vital signs: overdoses of prescription opioid pain relievers and other drugs among women—United States, 1999-2010. MMWR Morb Mortal Wkly Rep 62:537–542Google Scholar
  9. Chen ZR, Irvine RJ, Somogyi AA, Bochner F (1991) Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 48(22):2165–2171. CrossRefPubMedGoogle Scholar
  10. Compton P, Charuvastra VC, Kintaudi K, Ling W (2000) Pain responses in methadone-maintained opioid abusers. J Pain Symptom Manag 20(4):237–245. CrossRefGoogle Scholar
  11. Compton P, Athanasos P, Elashoff D (2003) Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain 4(9):511–519. CrossRefPubMedGoogle Scholar
  12. Compton WM, Jones CM, Baldwin GT (2016) Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med 374(2):154–163. CrossRefPubMedGoogle Scholar
  13. Demaret I, Quertemont E, Litran G, Magoga C, Deblire C, Dubois N, De Roubaix J, Charlier C, Lemaitre A, Ansseau M (2015) Efficacy of heroin-assisted treatment in Belgium: a randomised controlled trial. Eur Addict Res 21(4):179–187. CrossRefPubMedGoogle Scholar
  14. Duke AN, Correia CJ, Walsh SL, Bigelow GE, Strain EC (2010) Acute effects of intramuscular and sublingual buprenorphine and buprenorphine/naloxone in non-dependent opioid abusers. Psychopharmacology 211(3):303–312. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Duke AN, Bigelow GE, Lanier RK, Strain EC (2011) Discriminative stimulus effects of tramadol in humans. J Pharmacol Exp Ther 338(1):255–262. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Ferri M, Davoli M, Perucci CA (2011) Heroin maintenance for chronic heroin-dependent individuals. Cochrane Database Syst Rev (12):CD003410.
  17. Finney DJ (1964) Statistical method in biological assay, 2nd edn. Charles Griffin & Co. Ltd, LondonGoogle Scholar
  18. Griffiths RR, Troisi JR, Silverman K, Mumford GK (1993) Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans. Behav Pharmacol 4(1):3–13CrossRefPubMedGoogle Scholar
  19. Haasen C, Verthein U, Degkwitz P, Berger J, Krausz M, Naber D (2007) Heroin-assisted treatment for opioid dependence: randomised controlled trial. Br J Psychiatry 191:55–62CrossRefPubMedGoogle Scholar
  20. Havens JR, Lofwall MR, Frost SD, Oser CB, Leukefeld CG, Crosby RA (2013) Individual and network factors associated with prevalent hepatitis C infection among rural Appalachian injection drug users. Am J Public Health 103(1):e44–e52. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1989) Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval. I. Pharmacol Exp Ther 250(2):485–491Google Scholar
  22. Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1990) Acute opioid physical dependence in humans: effect of naloxone at 6 and 24 hours postmorphine. Pharmacol Biochem Behav 36(2):393–399. CrossRefPubMedGoogle Scholar
  23. Karow A, Reimer J, Schafer I, Krausz M, Haasen C, Verthein U (2010) Quality of life under maintenance treatment with heroin versus methadone in patients with opioid dependence. Drug Alcohol Depend 112(3):209–215. CrossRefPubMedGoogle Scholar
  24. Kirby KC, Stitzer ML, Heishman SJ (1990) Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval II. J Pharmacol Exp Ther 255(2):730–737PubMedGoogle Scholar
  25. Overholser BR, Foster DR (2011) Opioid pharmacokinetic drug-drug interactions. Am J Manag Care 17(Suppl 11):S276–S287PubMedGoogle Scholar
  26. Oviedo-Joekes E, Brissette S, Marsh DC, Lauzon P, Guh D, Anis A, Schechter MT (2009) Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med 361(8):777–786. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Oviedo-Joekes E, Guh D, Brissette S, Marsh DC, Nosyk B, Krausz M, Anis A, Schechter MT (2010) Double-blind injectable hydromorphone versus diacetylmorphine for the treatment of opioid dependence: a pilot study. J Subst Abus Treat 38(4):408–411. CrossRefGoogle Scholar
  28. Oviedo-Joekes E, Marsh DC, Guh D, Brissette S, Schechter MT (2011) Potency ratio of hydromorphone and diacetylmorphine in substitution treatment for long-term opioid dependency. J Opioid Manag 7(5):371–376CrossRefPubMedGoogle Scholar
  29. Oviedo-Joekes E, Guh D, Brissette S, Marchand K, MacDonald S, Lock K, Harrison S, Janmohamed A, Anis AH, Krausz M, Marsh DC, Schechter MT (2016) Hydromorphone compared with diacetylmorphine for long-term opioid dependence: a randomized clinical trial. JAMA Psychiatry 73(5):447–455. CrossRefPubMedGoogle Scholar
  30. Parab P, Ritschel W, Coyle D, Gregg R, Denson D (1988) Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects. Biopharm Drug Dispos 9(2):187–199. CrossRefPubMedGoogle Scholar
  31. Paterson S, Cordero R (2006) Comparison of the various opiate alkaloid contaminants and their metabolites found in illicit heroin with 6-monoacetyl morphine as indicators of heroin ingestion. J Anal Toxicol 30(4):267–273. CrossRefPubMedGoogle Scholar
  32. Paterson S, Lintzeris N, Mitchell TB, Cordero R, Nestor L, Strang J (2005) Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence. Addiction 100(12):1832–1839. CrossRefPubMedGoogle Scholar
  33. Perneger TV, Giner F, del Rio M, Mino A (1998) Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments. BMJ 317(7150):13–18. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Preston KL, Bigelow GE (1994) Drug discrimination assessment of agonist-antagonist opioids in humans: a three-choice saline-hydromorphone-butorphanol procedure. J Pharmacol Exp Ther 271(1):48–60PubMedGoogle Scholar
  35. Reisine T, Pasternak GW (1996) Opioid agonists and antagonists. In: Hardman JG, Limbird LE (eds) Goodman and Gilman’s: the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 521–556Google Scholar
  36. Rook EJ, Huitema AD, JMv R, Beijnen JH (2006) Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature. Curr Clin Pharmacol 1(1):109–118. CrossRefPubMedGoogle Scholar
  37. Rudd RA, Paulozzi LJ, Bauer MJ, Burleson RW, Carlson RE, Dao D, Davis JW, Dudek J, Eichler BA, Fernandes JC, Fondario A, Gabella B, Hume B, Huntamer T, Kariisa M, Largo TW, Miles J, Newmyer A, Nitcheva D, Perez BE, Proescholdbell SK, Sabel JC, Skiba J, Slavova S, Stone K, Tharp JM, Wendling T, Wright D, Zehner AM (2014) Increases in heroin overdose deaths – 28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep 63(39):849–854. DOI: mm6339a1 [pii]PubMedPubMedCentralGoogle Scholar
  38. Sigmon SC, Wong CJ, Chausmer AL, Liebson IA, Bigelow GE (2004) Evaluation of an injection depot formulation of buprenorphine: placebo comparison. Addiction 99(11):1439–1449. CrossRefPubMedGoogle Scholar
  39. Stoller KB, Bigelow GE, Walsh SL, Strain EC (2001) Effects of buprenorphine/naloxone in opioid-dependent humans. Psychopharmacology 154(3):230–242. CrossRefPubMedGoogle Scholar
  40. Strain EC, Stoller K, Walsh SL, Bigelow GE (2000) Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology 148(4):374–383. CrossRefPubMedGoogle Scholar
  41. Strassels SA (2009) Economic burden of prescription opioid misuse and abuse. J Manag Care Pharm 15(7):556–562. PubMedGoogle Scholar
  42. Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Behavioral Health Statistics and Quality (2016) 2015 National Survey on Drug Use and Health: detailed tablesGoogle Scholar
  43. Wallenstein SL, Houde RW, Portenoy R, Lapin J, Rogers A, Foley KM (1990) Clinical analgesic assay of repeated and single doses of heroin and hydromorphone. Pain 41(1):5–13. CrossRefPubMedGoogle Scholar
  44. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55(5):569–580. CrossRefPubMedGoogle Scholar
  45. 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(1):361–372PubMedGoogle Scholar
  46. Walsh SL, Nuzzo PA, Lofwall MR, Holtman JR Jr (2008) The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend 98(3):191–202. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Zahari Z, Ismail R (2014) Influence of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Drug Metab Pharmacokinet 29(1):29–43. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Kelly E. Dunn
    • 1
  • Bruna Brands
    • 2
    • 3
    • 4
  • David C. Marsh
    • 5
  • George E. Bigelow
    • 1
  1. 1.Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Health CanadaOttawaCanada
  3. 3.Centre for Addiction and Mental HealthTorontoCanada
  4. 4.University of TorontoTorontoCanada
  5. 5.Northern Ontario School of MedicineSudburyCanada

Personalised recommendations