Hyperalgesia in Heroin Dependent Patients and the Effects of Opioid Substitution Therapy


      Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia. This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults, randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or BUP) stabilization (4–8 weeks), and chronic administration (12–18 weeks), at trough (just prior to dosing) and peak (3 hours after dosing) plasma levels. Collection of the control group’s pain responses occurred twice during a single session, 3 hours apart. Baseline comparisons indicate that heroin-dependent individuals demonstrate significantly shorter latencies to threshold and tolerance for cold-pressor pain than the control group. Across pain stimuli and time points, little change in pain responses was found over time, the exception being cold pressor pain tolerance, for which hyperalgesia significantly increased at trough METH/BUP levels in both groups as they stabilized in treatment. We conclude that heroin-dependent individuals are hyperalgesic, and that once stabilized in treatment, are not different in pain responses regardless of treatment agent. The effects of nonpharmacologic therapy and previous heroin use may explain increased hyperalgesia found with treatment.


      To better understand the clinical phenomenon of opioid-induced hyperalgesia, this article describes experimental pain responses of heroin-dependent participants both prior to and over the course of maintenance therapy with methadone or buprenorphine. Hyperalgesia is present with illicit and treatment opioid use, and does not appear to appreciably improve over the course of treatment.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Alford D.P.
        • Compton P.
        • Samet J.H.
        Acute pain management for patients receiving maintenance methadone or buprenorphine therapy.
        Ann Intern Med. 2006; 17: 127-134
        • Angst M.S.
        • Clark J.D.
        Opioid-induced hyperalgesia; A qualitative systematic review.
        Anesthesiology. 2006; 104: 570-587
        • Athanasos P.
        • Smith C.S.
        • White J.M.
        • Somogyi A.A.
        • Bochner F.
        • Ling W.
        Methadone maintenance patients are cross tolerant to the antinociceptive effects of very high plasma morphine concentrations.
        Pain. 2006; 120: 267-275
        • Beck A.T.
        • Steer R.A.
        • Ball R.
        • Ranieri W.
        Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients.
        J Pers Assess. 1996; 67: 588-597
        • Birklein F.
        • Depmeier C.
        • Rolke R.
        • Hansen C.
        • Rautenstrauss B.
        • Prawitt D.
        • Magerl W.
        A family-based investigation of cold pain tolerance.
        Pain. 2008; 138: 111-118
        • Célèrier E.
        • Rivat C.
        • Jun Y.
        • Laulin J.P.
        • Larcher A.
        • Reynier P.
        • Simonnet G.
        Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine.
        Anesthesiology. 2000; 92: 465-472
        • Chang G.
        • Chen L.
        • Mao J.
        Opioid tolerance and hyperalgesia.
        Med Clin North Am. 2007; 91: 199-211
        • Chu L.F.
        • Angst M.S.
        • Clark D.
        Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations.
        Clin J Pain. 2008; 24: 79-96
        • Colpaert F.C.
        Mechanisms of opioid-induced pain and antinociceptive tolerance: Signal transduction.
        Pain. 2002; 95: 287-288
        • Compton M.A.
        Cold-pressor pain tolerance in opiate and cocaine abusers: Correlates of drug type and use status.
        J Pain Symptom Manage. 1994; 9: 462-473
        • Compton P.
        • Charuvastra V.C.
        • Kintaudi K.
        • Ling W.
        Pain responses in methadone-maintained opioid abusers.
        J Pain Symptom Manage. 2000; 20: 237-245
        • Compton P.
        • Charuvastra V.C.
        • Ling W.
        Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent.
        Drug Alcohol Depend. 2001; 63: 139-146
        • Dinnerstein A.J.
        • Blitz B.
        • Lowenthal M.
        Effects of aspirin on detection and tolerance of electric shock.
        J Appl Physiol. 1965; 20: 1052-1055
        • Doverty M.
        • White J.M.
        • Somogyi A.A.
        • Bochner F.
        • Ali R.
        • Ling W.
        Hyperalgesic responses in methadone maintenance patients.
        Pain. 2001; 90: 91-96
        • Doverty M.
        • Somogyi A.A.
        • White J.M.
        • Bochner F.
        • Beare C.H.
        • Menelaou A.
        • Ling W.
        Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine.
        Pain. 2001; 93: 155-163
        • Eckhardt K.
        • Li S.
        • Ammon S.
        • Schanzle G.
        • Mikus G.
        • Eichelbaum M.
        Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.
        Pain. 1998; 76: 27-33
        • Fishbain D.A.
        • Cole B.
        • Lewis J.E.
        • Gao J.
        • Rosomoff R.S.
        Do opioids induce hyperalgesia in humans? An evidence-based structured review.
        Pain Med. 2009; 10: 829-839
        • Hay J.L.
        • White J.M.
        • Bochner F.
        • Somogyi A.A.
        • Semple T.J.
        Rounsefell: Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients.
        J Pain. 2009; 10: 316-322
        • Ho A.
        • Dole V.P.
        Pain perception in drug-free and in methadone-maintained human ex-addicts.
        Proc Soc Exp Biol Med. 1979; 162: 392-395
        • Koppert W.
        • Schmelz M.
        The impact of opioid-induced hyperalgesia for postoperative pain.
        Best Pract Res Clin Anaesthesiol. 2007; 21: 65-83
        • Lee M.
        • Silverman S.M.
        • Hansen H.
        • Patel V.B.
        • Manchikanti L.
        A comprehensive review of opioid-induced hyperalgesia.
        Pain Physician. 2011; 14: 145-161
        • Li X.
        • Angst M.S.
        • Clark J.D.
        A murine model of opioid-induced hyperalgesia.
        Brain Res Mol Brain Res. 2001; 86: 56-62
        • Liebmann P.M.
        • Lehofer M.
        • Moser M.
        • Hoehn-Saric R.
        • Legl T.
        • Pernhaupt G.
        • Schauenstein K.
        Persistent analgesia in former opiate addicts is resistant to blockade of endogenous opioids.
        Biol Psychiatry. 1997; 42: 962-964
        • Mattick R.P.
        • Breen C.
        • Kimber J.
        • Davoli M.
        Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence.
        Cochrane Database Syst Rev. 2009; 8: CD002209
        • Mattick R.P.
        • Kimber J.
        • Breen C.
        • Davoli M.
        Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.
        Cochrane Database Syst Rev. 2008; 16: CD002207
        • McLellan A.T.
        • Luborsky L.
        • O’Brien C.P.
        • Woody G.E.
        An improved diagnostic instrument for substance abuse patients: The Addiction Severity Index.
        J Nervous Mental Dis. 1980; 168: 26-33
        • Newshan G.
        Pain management in the addicted patient: Practical considerations.
        Nurs Outlook. 2000; 48: 81-85
        • Nielsen C.S.
        • Staud R.
        • Price D.D.J.
        Individual differences in pain sensitivity: Measurement, causation, and consequences.
        Pain. 2009; 10: 231-237
        • Peles E.
        • Schreiber S.
        • Gordon J.
        • Adelson M.
        Significantly higher methadone dose for methadone maintenance treatment (MMT) patients with chronic pain.
        Pain. 2005; 113: 340-346
        • Peles E.
        • Schreiber S.
        • Hetzroni T.
        • Adelson M.
        • Defrin R.
        The differential effect of methadone dose and of chronic pain on pain perception of former heroin addicts receiving methadone maintenance treatment.
        J Pain. 2011; 12: 41-50
        • Potter J.S.
        • Prather K.
        • Weiss R.D.
        Physical pain and associated clinical characteristics in treatment-seeking patients in four substance use disorder treatment modalities.
        Am J Addict. 2008; 17: 121-125
        • Prosser J.M.
        • Steinfeld M.
        • Cohen L.J.
        • Derbyshire S.
        • Eisenberg D.P.
        • Cruciani R.A.
        • Galynker II,
        Abnormal heat and pain perception in remitted heroin dependence months after detoxification from methadone-maintenance.
        Drug Alcohol Depend. 2008; 95: 237-244
        • Pud D.
        • Cohen D.
        • Lawental E.
        • Eisenberg E.
        Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects.
        Drug Alcohol Depend. 2006; 82: 218-223
        • Rosenblum A.
        • Joseph H.
        • Fong C.
        • Kipnis S.
        • Cleland C.
        • Portenoy R.K.
        Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities.
        JAMA. 2003; 289: 2370-2378
        • Ruscheweyh R.
        • Stumpenhorst F.
        • Knecht S.
        • Marziniak M.
        Comparison of the cold pressor test and contact thermode-delivered cold stimuli for the assessment of cold pain sensitivity.
        J Pain. 2010; 11: 728-736
        • Scimeca M.M.
        • Savage S.R.
        • Portenoy R.
        • Lowinson J.
        Treatment of pain in methadone-maintained patients.
        Mt Sinai J Med. 2000; 67: 412-422
        • Soyka M.
        • Kranzler H.R.
        • van den Brink W.
        • Krystal J.
        • Möller H.J.
        • Kasper S.
        The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence.
        World J Biol Psychiatry. 2011; 12: 160-187
        • Spielberger C.D.
        • Gorssuch R.L.
        • Lushene P.R.
        • Vagg P.R.
        • Jacobs G.A.
        Manual for the State-Trait Anxiety Inventory.
        Consulting Psychologists Press, Inc., Menlo Park, CA1983
        • Tursky B.
        • Watson P.D.
        • O’Connell D.N.
        Concentric shock electrode for pain stimulation.
        Psychophysiology. 1965; 1: 296-298
        • Wolff B.B.
        • Kantor T.G.
        • Jarvik M.E.
        • Laska E.
        Response of experimental pain to analgesic drugs. II. Codeine and placebo.
        Clin Pharmacol Ther. 1966; 7: 323-331