Determination of the Effective Dose of Pregabalin on Human Experimental Pain Using the Sequential Up-Down Method

  • Waylan Wong
    Department of Anesthesiology, Cedars Sinai Medical Center, Los Angeles, California
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  • Mark S. Wallace
    Address reprint requests to Mark S. Wallace, MD, University of California, Department of Anesthesiology, UCSD Thornton Hospital, 9300 Campus Point Dr, #7651, La Jolla, CA 92037.
    Division of Pain Medicine, Department of Anesthesiology, University of California, San Diego, La Jolla, California
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Published:November 21, 2013DOI:


      The intradermal capsaicin pain model has been used to evaluate analgesic effects of a variety of drugs. Using the sequential up-down method, we examined the analgesic effects of pregabalin on intradermal capsaicin pain. Using a double-blind, placebo-controlled, crossover study, healthy adult men were randomized to oral pregabalin or placebo on the first visit and returned for the opposite treatment after a washout period. Dosing was set by the Dixon sequential up-down method; that is, a greater or less than 30% reduction in capsaicin pain decreased or increased the dose, respectively, by a fixed interval for the next subject. The median effective dose (ED50) was derived once 7 changes in dose direction occurred. Secondary outcome measures included secondary hyperalgesia and tactile and thermal allodynia, and their respective areas (cm2). Thirteen subjects were required to derive the pregabalin ED50: 252 mg (95% confidence interval 194, 310 mg). Most common side effects were drowsiness (46%), euphoria (31%), and dizziness (7%). Those with ≥30% pain reduction as compared to placebo also had similar reductions in secondary outcome measures. The intradermal capsaicin pain model can be used to efficiently derive the pregabalin ED50, but well-powered dose-response curve studies are needed for comparison and validation.


      Using the Dixon sequential up-down method, the ED50 of pregabalin on intradermal capsaicin induced pain was successfully calculated (252 mg) using only 13 subjects.

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        • Arnold L.
        • Russell I.
        • Dir iE, Duan W.
        • Young J.J.
        • Sharma U.
        • Martin S.
        • Barrett J.
        • Haig G.S.-E.J.
        A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia.
        J Pain. 2008; 9: 792-805
        • Baad-Hansen L.
        • Poulsen H.F.
        • Jensen H.M.
        • Svensson P.
        Lack of sex differences in modulation of experimental intraoral pain by diffuse noxious inhibitory controls (DNIC).
        Pain. 2005; 116: 359-365
        • Breivik H.
        • Borchgrevink P.
        • Allen S.
        • Rosseland L.
        • Romundstad L.
        • Hals E.
        • Kvarstein G.
        • Stubhaug A.
        Assessment of pain.
        Br J Anaesth. 2008; 101: 17-24
        • Caterina M.J.
        • Schumacher M.
        • Tominaga M.
        • Rosen T.A.
        • Levine J.D.
        • Julius D.
        The capsaicin receptor: A heat-activated ion channel in the pain pathway.
        Nature. 1997; 389: 816-824
        • Dixon W.
        Staircase bioassay: The up-and-down method.
        Neurosci Biobehav Rev. 1991; 15: 47-50
        • Dworkin R.
        • Corbin A.
        • Young J.J.
        • Sharma U.
        • Lamoreaux W.
        • Bockbrader H.
        • Garofalo E.
        • Poole R.
        Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial.
        Neurology. 2003; 60: 1274-1283
        • Freedman B.M.
        • O'Hara E.
        Pregabalin has opioid-sparing effects following augmentation mammaplasty.
        Aesthet Surg J. 2008; 28: 421-424
        • Gazerani P.
        • Andersen O.K.
        • Arendt-Nielsen L.
        A human experimental capsaicin model for trigeminal sensitization: Gender-specific differences.
        Pain. 2005; 118: 155-163
        • Gottrup H.
        • Juhl G.
        • Kristensen A.D.
        • Lai R.
        • Chizh B.A.
        • Brown J.
        • Bach F.W.
        • Jensen T.S.
        Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia.
        Anesthesiology. 2004; 101: 1400-1408
        • Jensen M.T.
        • Petersen K.L.
        Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers.
        J Pain. 2006; 7: 211-217
        • LaMotte R.H.
        • Lundberg L.E.
        • Torebjork E.
        Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin.
        J Physiol. 1992; 448: 749-764
        • Lee Y.Y.
        • Ngan Kee W.D.
        • Fong S.Y.
        • Liu J.T.
        • Gin T.
        The median effective dose of bupivacaine, levobupivacaine, and ropivacaine after intrathecal injection in lower limb surgery.
        Anesth Analg. 2009; 109: 1331-1334
        • Lichtman A.
        The up-and-down method substantially reduces the number of animals required to determine antinociceptive ED50 values.
        J Pharmacol Toxicol Methods. 1998; 40: 81-85
        • Modir J.
        • Wallace M.
        Human experimental pain models 3: Heat/capsaicin sensitization and intradermal capsaicin models.
        Methods Mol Biol. 2010; 617: 169-174
        • Sabatowski R.
        • Galvez R.
        • Cherry D.
        • Jacquot F.
        • Vincent E.
        • Maisonobe P.
        • Versavel M.
        • 1008-045 Study Group
        Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: Results of a randomised, placebo-controlled clinical trial.
        Pain. 2004; 109: 26-35
        • Szallasi A.
        • Blumberg P.
        Vanilloid (capsaicin) receptors and mechanisms.
        Pharmacol Rev. 1999; 51: 159-211
        • van Elstraete A.
        • Tirault M.
        • Lebrun T.
        • Sandefo I.
        • Bernard J.
        • Polin B.
        • Vally P.
        • Mazoit J.
        The median effective dose of preemptive gabapentin on postoperative morphine consumption after posterior lumbar spinal fusion.
        Anesth Analg. 2008; 106: 305-308
        • van Seventer R.
        • Feister H.
        • Young J.
        • Stoker M.
        • Versavel M.
        • Rigaudy L.
        Efficacy and tolerability of twice daily gabapentin for treating pain and related sleep interference in post herpetic neuralgia: A 13 week randomized trial.
        Curr Med Res Opin. 2006; 22: 375-384
        • Wallace M.
        • Ridgeway B.
        • Leung A.
        • Schulteis G.
        • Yaksh T.
        Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: Effects upon acute thresholds and capsaicin-evoked hyperpathia.
        J Clin Pharmacol. 2002; 42: 70-80
        • Wallace M.
        • Schulteis G.
        Effect of chronic oral gabapentin on capsaicin-induced pain and hyperalgesia: A double-blind, placebo-controlled, crossover study.
        Clin J Pain. 2008; 24: 544-549
        • Wallace M.
        • Schulteis G.
        • Atkinson H.
        • Wolfson T.
        • Lazzaretto D.
        • Bentley H.
        • Gouaux B.
        • Abramson I.
        Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers.
        Anesthesiology. 2007; 107: 785-796
        • Wallace M.S.
        • Abrams D.I.
        • Yaksh T.L.
        Concentration-effect relations for intravenous lidocaine infusions in human volunteers: Effect on acute sensory thresholds and capsaicin-evoked hyperpathia.
        Anesthesiology. 1997; 86: 1262-1272
        • Wallace M.S.
        • Grubbs D.
        Effects of oral desipramine on capsaicin induced hyperalgesia.
        Anesth Analg. 2002; 95: 973-978
        • Wang H.
        • Bolognese J.
        • Calder N.
        • Baxendale J.
        • Kehler A.
        • Cummings C.
        • Connell J.
        • Herman G.
        Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects.
        J Pain. 2008; 9: 1088-1095
        • Zheng Z.
        • Gibson S.
        • Khalil Z.
        • Helme R.
        • McMeeken J.
        Age-related differences in the time course of capsaicin-induced hyperalgesia.
        Pain. 2000; 85: 51-58