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Effects of Milnacipran on Clinical Pain and Hyperalgesia of Patients With Fibromyalgia: Results of a 6-Week Randomized Controlled Trial

      Highlights

      • A 6-week randomized controlled trial of milnacipran or placebo showed significant reduction in clinical fibromyalgia pain.
      • The magnitude of clinical pain reductions was not statistically different between milnacipran and placebo.
      • Mechanical and heat hyperalgesia predicted up to 80% of the variance in clinical fibromyalgia pain.
      • Fibromyalgia patients' hyperalgesia was strongly associated with their clinical pain.

      Abstract

      Milnacipran is a serotonin-norepinephrine reuptake inhibitor that was approved by the U.S. Food and Drug Administration as effective therapy for fibromyalgia (FM) symptoms. However, its analgesic mechanism of action is not well understood. We hypothesized that improvement of mechanical and heat hyperalgesia would be a critical component of overall milnacipran efficacy in FM. We used a novel quantitative sensory testing protocol for assessment of mechanical and heat pain sensitivity that can be used for testing of peripheral and central pain mechanisms and their impact on clinical pain over time. We applied tonic mechanical and heat pain stimuli to 46 patients with FM during a randomized controlled trial with either 50 mg milnacipran (n = 23) or placebo (n = 23) twice daily over 6 weeks. During this trial, mean clinical pain (standard deviation) was evaluated daily, and mechanical and heat pain sensitivity every 2 weeks. At study entry, clinical pain was 5.0 (1.8) and 5.5 (1.8) visual analog scale units for patients with FM randomized to placebo and milnacipran, respectively (P > .05). Over 6 weeks, clinical pain of patients with FM significantly declined by 15%, but this improvement was not statistically different between milnacipran and placebo. However, repeated measures of mechanical and heat pain sensitivity reliably predicted up to 80% of the variance in clinical FM pain at every time point. Clinical pain and mechanical/heat pain sensitivity of patients with FM steadily declined during this trial, but the effects of milnacipran were not found to be superior to placebo. Repeated measures of mechanical/heat hyperalgesia reliably predicted large amounts of the variance in clinical pain across all participants, indicating their relevance for FM pain.

      Perspective

      Although clinical pain and hyperalgesia decreased during this 6-week trial, the efficacy of milnacipran was not superior to placebo. The high correlations between clinical pain and hyperalgesia ratings at every time point seem to emphasize the relevant contributions of mechanical and heat hyperalgesia to clinical FM pain.

      Key words

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      References

        • Arendt-Nielsen L.
        • Henriksson K.G.
        Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition.
        Best Pract Res Clin Rheumatol. 2007; 21: 465-480
        • Barkhuizen A.
        Pharmacologic treatment of fibromyalgia.
        Curr Pain Headache Rep. 2001; 5: 351-358
        • Baron R.
        • Hans G.
        • Dickenson A.H.
        Peripheral input and its importance for central sensitization.
        Ann Neurol. 2013; 74: 630-636
        • Branco J.C.
        • Zachrisson O.
        • Perrot S.
        • Mainguy Y.
        A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia.
        J Rheumatol. 2010; 37: 851-859
        • Braunholtz D.A.
        • Edwards S.J.
        • Lilford R.J.
        Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”.
        J Clin Epidemiol. 2001; 54: 217-224
        • Clauw D.J.
        Fibromyalgia: A clinical review.
        JAMA. 2014; 311: 1547-1555
        • Clauw D.J.
        • Mease P.
        • Palmer R.H.
        • Gendreau R.M.
        • Wang Y.
        Milnacipran for the treatment of fibromyalgia in adults: A 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.
        Clin Ther. 2008; 30: 1988-2004
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences.
        2nd ed. Erlbaum, Hillsdale, NJ1988
      1. European Medicines Agency: European Medicines Agency Comment of Milnacipran. Available at:http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/001034/WC500089875.pdf. 2014. Ref Type: Statute

        • Goldenberg D.L.
        Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain.
        Best Pract Res Clin Rheumatol. 2007; 21: 499-511
        • Greenspan J.D.
        • Slade G.D.
        • Bair E.
        • Dubner R.
        • Fillingim R.B.
        • Ohrbach R.
        • Knott C.
        • Mulkey F.
        • Rothwell R.
        • Maixner W.
        Pain sensitivity risk factors for chronic TMD: Descriptive data and empirically identified domains from the OPPERA case-control study.
        J Pain. 2011; 12: T61-T74
        • Hauser W.
        • Petzke F.
        • Uceyler N.
        • Sommer C.
        Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: A systematic review with meta-analysis.
        Rheumatology. 2010; 50: 532-543
      2. IASP Taxonomy. Available at: http://www.iasp-pain.org/Taxonomy?navItemNumber=576#Hyperalgesia. Accessed June 24, 2015

        • King T.
        • Rao S.
        • Vanderah T.
        • Chen Q.
        • Vardanyan A.
        • Porreca F.
        Differential blockade of nerve injury-induced shift in weight bearing and thermal and tactile hypersensitivity by milnacipran.
        J Pain. 2006; 7: 513-520
        • Kwon M.
        • Altin M.
        • Duenas H.
        • Alev L.
        The role of descending inhibitory pathways on chronic pain modulation and clinical implications.
        Pain Pract. 2013; 20: 10
        • Matsuzawa-Yanagida K.
        • Narita M.
        • Nakajima M.
        • Kuzumaki N.
        • Niikura K.
        • Nozaki H.
        • Takagi T.
        • Tamai E.
        • Hareyama N.
        • Terada M.
        • Yamazaki M.
        • Suzuki T.
        Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites.
        Neuropsychopharm. 2008; 33: 1952-1965
        • Matthey A.
        • Cedraschi C.
        • Piguet V.
        • Besson M.
        • Chabert J.
        • Daali Y.
        • Courvoisier D.
        • Montagne A.
        • Dayer P.
        • Desmeules J.A.
        Dual reuptake inhibitor milnacipran and spinal pain pathways in fibromyalgia patients: A randomized, double-blind, placebo-controlled trial.
        Pain Physician. 2013; 16: E553-E562
        • McCarney R.
        • Warner J.
        • Iliffe S.
        • van Haselen R.
        • Griffin M.
        • Fisher P.
        The Hawthorne Effect: A randomised, controlled trial.
        BMC Med Res Methodol. 2007; 7: 30
        • Mease P.J.
        • Clauw D.J.
        • Gendreau R.M.
        • Rao S.G.
        • Kranzler J.
        • Chen W.
        • Palmer R.H.
        the efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial.
        J Rheumatol. 2009; 36: 398-409
        • Melnikova I.
        Pain market.
        Nat Rev Drug Discov. 2010; 9: 589-590
        • O'Neill S.
        • Manniche C.
        • Graven-Nielsen T.
        • Arendt-Nielsen L.
        Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.
        Eur J Pain. 2007; 11: 415-420
        • Petzke F.
        • Jensen K.B.
        • Kosek E.
        • Choy E.
        • Carville S.
        • Fransson P.
        • Williams S.C.R.
        • Marcus H.
        • Mainguy Y.
        • Ingvar M.
        • Gracely R.H.
        Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia.
        Scand J Pain. 2013; 4: 65-74
        • Price D.D.
        • Bush F.M.
        • Long S.
        • Harkins S.W.
        A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales.
        Pain. 1994; 56: 217-226
        • Price D.D.
        • Dubner R.
        Mechanisms of first and second pain in the peripheral and central nervous systems.
        J Invest Dermatol. 1977; 69: 167-171
        • 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
        • Reichling D.B.
        • Levine J.D.
        Critical role of nociceptor plasticity in chronic pain.
        Trends Neurosci. 2009; 32: 611-618
        • Rolke R.
        • Baron R.
        • Maier C.
        • Tolle T.R.
        • Treede R.D.
        • Beyer A.
        • Binder A.
        • Birbaumer N.
        • Birklein F.
        • Botefur I.C.
        • Braune S.
        • Flor H.
        • Huge V.
        • Klug R.
        • Landwehrmeyer G.B.
        • Magerl W.
        • Maihofner C.
        • Rolko C.
        • Schaub C.
        • Scherens A.
        • Sprenger T.
        • Valet M.
        • Wasserka B.
        Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values.
        Pain. 2006; 123: 231-243
        • Serra J.
        • Collado A.
        • Sola R.
        • Antonelli F.
        • Torres X.
        • Salgueiro M.
        • Quiles C.
        • Bostock H.
        Hyperexcitable C nociceptors in fibromyalgia.
        Ann Neurol. 2014; 75: 196-208
        • Staud R.
        Mechanisms of fibromyalgia pain.
        CNS Spectr. 2009; 14: 4-5
        • Staud R.
        The important role of CNS facilitation and inhibition for chronic pain.
        Int J Clin Rheumtol. 2013; 8: 639-646
        • Staud R.
        • Bovee C.E.
        • Robinson M.E.
        • Price D.D.
        Cutaneous C-fiber abnormalities of fibromyalgia patients are specifically related to temporal summation.
        Pain. 2008; 139: 315-325
        • Staud R.
        • Cannon R.C.
        • Mauderli A.P.
        • Robinson M.E.
        • Price D.D.
        • Vierck C.J.
        Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome.
        Pain. 2003; 102: 87-95
        • Staud R.
        • Price D.D.
        • Fillingim R.B.
        Advanced continuous-contact heat pulse design for efficient temporal summation of second pain (wind-up).
        J Pain. 2006; 7: 575-582
        • Staud R.
        • Robinson M.E.
        • Price D.D.
        Do past pain events systematically impact pain ratings of healthy subjects or fibromyalgia patients?.
        J Pain. 2010; 11: 142-148
        • Staud R.
        • Robinson M.E.
        • Vierck C.J.
        • Cannon R.L.
        • Mauderli A.P.
        • Price D.D.
        Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome.
        Pain. 2003; 105: 215-222
        • Staud R.
        • Robinson M.E.
        • Weyl E.E.
        • Price D.D.
        Pain variability in fibromyalgia is related to activity and rest: role of peripheral tissue impulse input.
        J Pain. 2010; 11: 1376-1383
        • Staud R.
        • Weyl E.E.
        • Bartley E.
        • Price D.D.
        • Robinson M.E.
        Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome.
        Eur J Pain. 2014; 18: 803-812
        • Staud R.
        • Weyl E.E.
        • Price D.D.
        • Robinson M.E.
        Mechanical and heat hyperalgesia highly predict clinical pain intensity in patients with chronic musculoskeletal pain syndromes.
        J Pain. 2012; 13: 725-735
        • Staud R.
        • Weyl E.E.
        • Riley III, J.L.
        • Fillingim R.B.
        Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients.
        PLoS One. 2014; 9: e89086
        • Takeda R.
        • Watanabe Y.
        • Ikeda T.
        • Abe H.
        • Ebihara K.
        • Matsuo H.
        • Nonaka H.
        • Hashiguchi H.
        • Nishimori T.
        • Ishida Y.
        Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model.
        Neurosci Res. 2009; 64: 380-384
        • Treede R.D.
        • Meyer R.A.
        • Raja S.N.
        • Campbell J.N.
        Peripheral and central mechanisms of cutaneous hyperalgesia.
        Prog Neurobiol. 1992; 38: 397-421
        • Uceyler N.
        • Zeller D.
        • Kahn A.K.
        • Kewenig S.
        • Kittel-Schneider S.
        • Schmid A.
        • Casanova-Molla J.
        • Reiners K.
        • Sommer C.
        Small fibre pathology in patients with fibromyalgia syndrome.
        Brain. 2013; 136: 1857-1867
        • Verdu B.
        • Decosterd I.
        • Buclin T.
        • Stiefel F.
        • Berney A.
        Antidepressants for the treatment of chronic pain.
        Drugs. 2008; 68: 2611-2632
        • Verne G.N.
        • Robinson M.E.
        • Price D.D.
        Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome.
        Pain. 2001; 93: 7-14
        • Wade J.B.
        • Dougherty L.M.
        • Archer C.R.
        • Price D.D.
        Assessing the stages of pain processing: A multivariate analytical approach.
        Pain. 1996; 68: 157-167
        • Wolfe F.
        • Smythe H.A.
        • Yunus M.B.
        • Bennett R.M.
        • Bombardier C.
        • Goldenberg D.L.
        • Tugwell P.
        • Campbell S.M.
        • Abeles M.
        • Clark P.
        • Fam A.G.
        • Farber S.J.
        • Fiechtner J.J.
        • Franklin C.M.
        • Gatter R.A.
        • Hamaty D.
        • Lessard J.
        • Lichtbroun A.S.
        • Masi A.T.
        • McCain G.A.
        • Reynolds W.J.
        • Romano T.J.
        • Russell I.J.
        • Sheon R.P.
        The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
        Arthritis Rheumatol. 1990; 33: 160-172
        • Woolf C.J.
        Evidence for a central component of post-injury pain hypersensitivity.
        Nature. 1983; 306: 686-688
        • Woolf C.J.
        An overview of the mechanisms of hyperalgesia.
        Pulm Pharmacol. 1995; 8: 161-167
        • Woolf C.J.
        Central sensitization: Implications for the diagnosis and treatment of pain.
        Pain. 2011; 152: S2-S15
        • Yarnitsky D.
        • Granot M.
        • Granovsky Y.
        Pain modulation profile and pain therapy: Between pro- and antinociception.
        Pain. 2014; 155: 663-665
        • Yarnitsky D.
        • Granot M.
        • Nahman-Averbuch H.
        • Khamaisi M.
        • Granovsky Y.
        Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.
        Pain. 2012; 153: 1193-1198
        • Yarnitsky D.
        • Simone D.A.
        • Dotson R.M.
        • Cline M.A.
        • Ochoa J.L.
        Single C nociceptor responses and psychophysical parameters of evoked pain: Effect of rate of rise of heat stimuli in humans.
        J Physiol. 1992; 450: 581-592
        • 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