Drug Response Profiles to Experimental Pain Are Opioid and Pain Modality Specific

Published:December 13, 2010DOI:


      Given our limited ability to predict analgesic efficacy, further research is needed to understand factors influencing analgesic response patterns. The aim of this study was to better understand the relationship between morphine and butorphanol analgesic efficacy tested against multiple pain modalities within the same individuals. Participants included healthy men (n = 72) and women (n = 67) who underwent thermal, pressure, and ischemic experimental pain testing before and after the double-blind administration of morphine and butorphanol during separate testing sessions. Factor analysis revealed 6 factors with analgesic effects grouped primarily by pain modality and specific to either morphine or butorphanol. Hierarchical cluster analysis of individual factor scores led to 4 distinct drug response profiles. Three groups displayed exceptional analgesic efficacy produced by 1 type of opioid on 1 pain stimulus modality, whereas the fourth drug response profile was characterized by average analgesic efficacy across all pain modalities for both opioids. These findings suggest that opioids with varying efficacy at the μ and κ receptors produce independent effects on unique pain mechanisms and that individual responsiveness for some is dependent on pain mechanism and opioid type, although a subset of the population is moderately responsive to opioids regardless of efficacy of receptor binding or predominant pain mechanism being activated.


      This investigation provides a foundation for understanding patterns of opioid efficacy in varying types of pain. Our findings suggest that opioid response patterns are more complex than originally thought with about half of individuals exhibiting opioid and pain modality specific analgesic response profiles.

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        • Arendt-Nielsen L.
        • Yarnitsky D.
        Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera.
        J Pain. 2009; 10: 556-572
        • Belknap J.K.
        • Noordewier B.
        • Lame M.
        Genetic dissociation of multiple morphine effects among C57BL/6J, DBA/2J and C3H-HEJ inbred mouse strains.
        Physiol Behav. 1989; 46: 69-74
        • Bellgowan P.S.F.
        • Helmstetter F.J.
        The role of mu and kappa opioid receptors within the periaqueductal gray in the expression of conditional hypoalgesia.
        Brain Res. 1998; 791: 83-89
        • Chesler E.J.
        • Ritchie J.
        • Kokayeff A.
        • Lariviere W.R.
        • Wilson S.G.
        • Mogil J.S.
        Genotype-dependence of gabapentin and pregabalin sensitivity: The pharmacogenetic mediation of analgesia is specific to the type of pain being inhibited.
        Pain. 2003; 106: 325-335
        • Coghill R.C.
        • Gracely R.H.
        Validation of combined numerical-analog descriptor scales for rating pain intensity and pain unpleasantness.
        Proc Am Pain Soc. 1996; 15: 86
        • Commiskey S.
        • Fan L.W.
        • Ho I.K.
        • Rockhold R.W.
        • Commiskey S.
        • Fan L.-W.
        • Ho I.K.
        • Rockhold R.W.
        Butorphanol: Effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors.
        J Pharmacol Sci. 2005; 98: 109-116
        • D’Eon J.L.
        • Harris C.A.
        • Ellis J.A.
        Testing factorial validity and gender invariance of the pain catastrophizing scale.
        J Behav Med. 2004; 27: 361-372
        • Danzebrink R.M.
        • Green S.A.
        • Gebhart G.F.
        Spinal mu and delta, but not kappa, opioid-receptor agonists attenuate responses to noxious colorectal distension in the rat.
        Pain. 1995; 63: 39-47
        • Davies P.S.
        • Roth-Roemer S.
        • Coda B.
        Somatic side effects of morphine and hydromorphone during sustained equianalgesia infusions.
        Proc Am Pain Soc. 1997; 16: 120
        • Edwards R.R.
        • Fillingim R.B.
        • Ness T.J.
        Age-related differences in endogenous pain modulation: A comparison of diffuse noxious inhibitory controls in healthy older and younger adults.
        Pain. 2003; 101: 155-165
        • Edwards R.R.
        • Sarlani E.
        • Wesselmann U.
        • Fillingim R.B.
        Quantitative assessment of experimental pain perception: Multiple domains of clinical relevance.
        Pain. 2005; 114: 315-319
        • Elmer G.I.
        • Pieper J.O.
        • Negus S.S.
        • Woods J.H.
        Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests.
        Pain. 1998; 75: 129-140
        • Emmerson P.J.
        • Clark M.J.
        • Mansour A.
        • Akil H.
        • Woods J.H.
        • Medzihradsky F.
        Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor.
        J Pharmacol Exp Ther. 1996; 278: 1121-1127
        • Fabrigar L.R.
        • Wegener D.T.
        • MacCallum R.C.
        • Strahan E.J.
        Evaluating the use of exploratory factor analysis in psychological research.
        Psychol Methods. 1999; 4: 272-299
        • Fillingim R.B.
        • Gear R.W.
        Sex differences in opioid analgesia: Clinical and experimental findings.
        Eur J Pain. 2004; 8: 413-425
        • Fillingim R.B.
        • King C.D.
        • Ribeiro-Dasilva M.C.
        • Rahim-Williams B.
        • Riley III, J.L.
        Sex, gender, and pain: A review of recent clinical and experimental findings.
        J Pain. 2009; 10: 447-485
        • Fillingim R.B.
        • Ness T.J.
        • Glover T.L.
        • Campbell C.M.
        • Hastie B.A.
        • Price D.D.
        • Staud R.
        Morphine responses and experimental pain: Sex differences in side effects and cardiovascular responses but not analgesia.
        J Pain. 2005; 6: 116-124
        • Fillingim R.B.
        • Ness T.J.
        • Glover T.L.
        • Campbell C.M.
        • Price D.D.
        • Staud R.
        Experimental pain models reveal no sex differences in pentazocine analgesia in humans.
        Anesthesiology. 2004; 100: 1263-1270
        • Gallantine E.L.
        • Meert T.F.
        Antinociceptive and adverse effects of mu and kappa opioid receptor agonists: A comparison of morphine and U50488-H.
        Basic Clin Pharmacol Toxicol. 2008; 103: 419-427
        • Gear R.W.
        • Miaskowski C.
        • Gordon N.C.
        • Paul S.M.
        • Heller P.H.
        • Levine J.D.
        Kappa-opioids produce significantly greater analgesia in women than in men.
        Nat Med. 1996; 2: 1248-1250
        • Gear R.W.
        • Miaskowski C.
        • Gordon N.C.
        • Paul S.M.
        • Heller P.H.
        • Levine J.D.
        The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain.
        Pain. 1999; 83: 339-345
        • Kindler L.L.
        • Riley III, J.L.
        • Sibille K.
        • Fillingim R.
        Analgesic responses for morphine and butorphanol are independent and pain modalitiy specific.
        J Pain. 2010; 11: S44
        • Kohn P.M.
        Sensation-seeking, augmenting-reducing, and the strength of the nervous system.
        in: Spence J.T. Izard C.E. Motivation, emotion, and personality. Elsevier, Amsterdam1985: 167-173
        • Koltzenburg M.
        • Pokorny R.
        • Gasser U.E.
        • Richarz U.
        Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine.
        Pain. 2006; 126: 165-174
        • LaCroix-Fralish M.L.
        • Mogil J.S.
        Progress in genetic studies of pain and analgesia.
        Annu Rev Pharmacol Toxicol. 2009; 49: 97-121
        • Lotsch J.
        • Geisslinger G.
        • Tegeder I.
        Genetic modulation of the pharmacological treatment of pain.
        Pharmacol Therap. 2009; 124: 168-184
        • Luginbuhl M.
        • Schnider T.W.
        • Petersen-Felix S.
        • Arendt-Nielsen L.
        • Zbinden A.M.
        Comparison of five experimental pain tests to measure analgesic effects of alfentanil.
        Anesthesiology. 2001; 95: 22-29
        • Maixner W.
        • Gracely R.H.
        • Zuniga J.R.
        • Humphrey C.B.
        • Bloodworth G.R.
        Cardiovascular and sensory responses to forearm ischemia and dynamic hand exercise.
        Am J Physiol. 1990; 259: R1156-R1163
        • Mogil J.S.
        • Kest B.
        • Sadowski B.
        • Belknap J.K.
        Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: Influence of nociceptive assay.
        J Pharmacol Exp Ther. 1996; 276: 532-544
        • Mogil J.S.
        • Marek P.
        • Flodman P.
        • Spence M.A.
        • Sternberg W.F.
        • Kest B.
        • Sadowski B.
        • Liebeskind J.C.
        One or two genetic-loci mediate high opiate analgesia in selectively bred mice.
        Pain. 1995; 60: 125-135
        • Mogil J.S.
        • Wilson S.G.
        • Chesler E.J.
        • Rankin A.L.
        • Nemmani K.V.
        • Lariviere W.R.
        • Groce M.K.
        • Wallace M.R.
        • Kaplan L.
        • Staud R.
        • Ness T.J.
        • Glover T.L.
        • Stankova M.
        • Mayorov A.
        • Hruby V.J.
        • Grisel J.E.
        • Fillingim R.B.
        The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans.
        Proc Nat Acad Sci U S A. 2003; 100: 4867-4872
        • Moore P.A.
        • Duncan G.H.
        • Scott D.S.
        • Gregg J.M.
        • Ghia J.N.
        Submaximal effort tourniquet test: Its use in evaluating experimental and chronic pain.
        Pain. 1979; 6: 375-382
        • Naef M.
        • Curatolo M.
        • Petersen-Felix S.
        • Arendt-Nielsen L.
        • Zbinden A.
        • Brenneisen R.
        The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions.
        Pain. 2003; 105: 79-88
        • Nielsen C.S.
        • Stubhaug A.
        • Price D.D.
        • Vassend O.
        • Czajkowski N.
        • Harris J.R.
        Individual differences in pain sensitivity: Genetic and environmental contributions.
        Pain. 2008; 136: 21-29
        • Pennebaker J.W.
        The Psychology of Physical Symptoms.
        Springer, New York1982
        • Price D.D.
        • Hu J.W.
        • Dubner R.
        • Gracely R.H.
        Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.
        Pain. 1977; 3: 57-68
        • Price D.D.
        • Von der Gruen A.
        • Miller J.
        • Rafii A.
        • Price C.
        A psychophysical analysis of morphine analgesia.
        Pain. 1985; 22: 261-269
        • Pud D.
        • Yarnitsky D.
        • Sprecher E.
        • Rogowski Z.
        • Adler R.
        • Eisenberg E.
        Can personality traits and gender predict the response to morphine? An experimental cold pain study.
        Eur J Pain. 2006; 10: 103-112
        • Reyes-Gibb C.C.
        • Shete S.
        • Rakvag T.
        • Bhat S.V.
        • Skorpen F.
        • Bruera E.
        • Kaasa S.
        • Klepstad P.
        Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene.
        Pain. 2007; 130: 25-30
        • Riley J.L.
        • Hastie B.A.
        • Glover T.L.
        • Fillingim R.B.
        • Staud R.
        • Campbell C.M.
        Cognitive-affective and somatic side effects of morphine and pentazocine: Side-effect profiles in healthy adults.
        Pain Med. 2010; 11: 195-206
        • Rollman G.B.
        • Lautenbacher S.
        Sex differences in musculoskeletal pain.
        Clin J Pain. 2001; 17: 20-24
        • Sindrup S.H.
        • Brosen K.
        The pharmacogenetics of codeine hypoalgesia.
        Pharmacogenetics. 1995; 5: 335-346
        • Staahl C.
        • Christrup L.L.
        • Andersen S.D.
        • Arendt-Nielsen L.
        • Drewes A.M.
        A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model.
        Pain. 2006; 123: 28-36
        • Staahl C.
        • Olesen A.S.
        • Andresen T.
        • Arendt-Nielsen L.
        • Drewes A.M.
        Assessing analgesic actions of opioids by experimental pain models in healthy volunteers: An updated review.
        Br J Clin Pharmacol. 2009; 68: 149-168
        • Sternberg W.F.
        • Bailin D.
        • Grant M.
        • Gracely R.H.
        Competition alters the perception of noxious stimuli in male and female athletes.
        Pain. 1998; 76: 231-238
        • Sullivan M.J.
        • Bishop S.R.
        • Pivik J.
        The Pain Catastrophizing Scale: Development and validation.
        Psychol Assess. 1995; 7: 524-532
        • Vanderburght M.
        • Rasmussen S.E.
        • Arendtnielsen L.
        • Bjerring P.
        Morphine does not affect laser induced warmth and pin prick pain thresholds.
        Acta Anaesthesiol Scand. 1994; 38: 161-164
        • Walsh S.L.
        • Chausmer A.E.
        • Strain E.C.
        • Bigelow G.E.
        Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade.
        Psychopharmacology. 2008; 196: 143-155
        • Watson D.
        • Clark L.A.
        • Tellegen A.
        Development and validation of brief measures of positive and negative affect: The PANAS scales.
        J Pers Soc Psychol. 1988; 54: 1063-1070
        • Wilson S.G.
        • Smith S.B.
        • Chesler E.J.
        • Melton K.A.
        • Haas J.J.
        • Mitton B.
        • Strasburg K.
        • Hubert L.
        • Rodriguez-Zas S.L.
        • Mogil J.S.
        The heritability of antinociception: Common pharmacogenetic mediation of five neurochemically distinct analgesics.
        J Pharmacol Exp Ther. 2003; 304: 547-559
        • Yamada H.
        • Shimoyama N.
        • Sora I.
        • Uhl G.R.
        • Fukuda Y.
        • Moriya H.
        • Shimoyama M.
        Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors.
        Brain Res. 2006; 1083: 61-69
        • Yeomans D.C.
        • Pirec V.
        • Proudfit H.K.
        Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: Behavioral evidence.
        Pain. 1996; 68: 133-140
        • Yeomans D.C.
        • Proudfit H.K.
        Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: Electrophysiological evidence.
        Pain. 1996; 68: 141-150