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Licensed Unlicensed Requires Authentication Published by De Gruyter April 1, 2013

Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia

F. Petzke, K.B. Jensen, E. Kosek, E. Choy, S. Carville, P. Fransson, S.C.R. Williams, H. Marcus, Y. Mainguy, M. Ingvar and R.H. Gracely



In recent years, the prescription of serotonin-noradrenalin reuptake inhibitors (SNRIs) for treatment of fibromyalgia (FM) has increased with reports of their efficacy. The SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of milnacipran on central pain processing has not been investigated. The primary objective of this study was to assess the effect of milnacipran on sensitivity to pressure-evoked pain in FM. Secondary objectives were to assess the effect of milnacipran on cerebral processing of pressure-evoked pain using fMRI and the tolerability and safety of milnacipran 200 mg/day in FM.


92 patients were randomized to either 13-weeks milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and after treatment using a computer-controlled pressure-pain stimulator. Here, we present the results of several a priori defined statistical analyses.


Milnacipran-treated patients displayed a trend toward lower pressure-pain sensitivity after treatment, compared to placebo, and the difference was greater at higher pain intensities. A single group fMRI analysis of milnacipran-treated patients indicated increased pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala after treatment, compared to before treatment; regions implicated in pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing milnacipran and placebo, before and after treatment, showed that milnacipran-treated patients had greater pain-evoked activity in the precuneus/posterior cingulate cortex after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of milnacipran-treated patients. Patients on milnacipran were more likely to discontinue treatment because of side effects.


Our results provide preliminary indications of increased pain inhibitory responses in milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-pain tolerance after treatment with milnacipran, compared to placebo, especially for higher pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential biomarker for abnormal central pain processing.


The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for chronic pain. Furthermore, our results point toward a potential mechanism for pain normalization in response to milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.

DOI of refers to article:

Mass General Hospital and Harvard Medical School, 2nd Ave. Building 120, Charlestown, MA 02109, USA. Tel.: +1 617 756 7491; fax: +1 617 643 7340

Both these authors contributed equally.

  1. Conflict of interest

    Conflict of interest statement: This study (EudraCT # 2004-004249-16) was financed and performed in collaboration with the pharmaceutical company Pierre Fabre. There are no other conflicts of interest.


This study (EudraCT # 2004-004249-16) was financed and performed in collaboration with the pharmaceutical company Pierre Fabre. There are no other conflicts of interest.


[1] Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 2010;62:600–10.10.1002/acr.20140Search in Google Scholar

[2] Carville SF, Arendt-Nielsen L, Bliddal H, Blotman F, Branco JC, Buskila D, Da Silva JAP, Danneskiold-Samsoe B, Dincer F, Henriksson C, Henriksson KG, Kosek E, Longley K, McCarthy GM, Perrot S, Puszczewicz M, Sarzi-Puttini P, Silman A, Spath M, Choy EH. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis 2008;67:536–41.10.1136/ard.2007.071522Search in Google Scholar

[3] Moret C, Charveron M, Finberg J, Couzinier JMB. Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology 1985;24:1211–9.10.1016/0028-3908(85)90157-1Search in Google Scholar

[4] Vaishnavi S, Nemeroff C, Plott S, Rao S, Kranzler J, Owens M. Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity. Biol Psychiatry 2004;55:320–2.10.1016/j.biopsych.2003.07.006Search in Google Scholar

[5] Nakajima K, Obata H, Iriuchijima N, Saito S. An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat. Pain 2012;153:990–7.10.1016/j.pain.2012.01.029Search in Google Scholar

[6] Kosek E, Ekholm J, Hansson P. Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 1996;68:375–83.10.1016/S0304-3959(96)03188-0Search in Google Scholar

[7] Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 1997;13:189–96.10.1097/00002508-199709000-00003Search in Google Scholar

[8] Mountz J, Bradley L, Modell J, Alexander R, Triana-Alexander M, Aaron L, Stewart K, Alarcon G, Mountz J. Fibromyalgia in women. Abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum 1995;38:926–38.10.1002/art.1780380708Search in Google Scholar

[9] Staud RVCJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001;91:165–75.10.1016/S0304-3959(00)00432-2Search in Google Scholar

[10] Sorensen J, Graven-Nielsen T, Henriksson KG, Bengtsson M, Arendt-Nielsen L. Hyperexcitability in fibromyalgia. J Rheumatol 1998;25:152–5.Search in Google Scholar

[11] Gracely RH, Petzke F, Wolf M, Clauw D. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002;46:1333–43.10.1002/art.10225Search in Google Scholar PubMed

[12] Jensen KB, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SCR, Choy E, Giesecke T, Mainguy Y, Gracely R, Ingvar M. Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain. Pain 2009;144:95–100.10.1016/j.pain.2009.03.018Search in Google Scholar

[13] Jensen KB, Loitoile R, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SCR, Choy E, Mainguy Y, Vitton O, Gracely R, Gollub RL, Ingvar M, Kong J. Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network. Mol Pain 2012;8:32–6.10.1186/1744-8069-8-32Search in Google Scholar

[14] Mainguy Y. Functional magnetic resonance imagery (fMRI) in fibromyalgia and the response to milnacipran. Hum Psychopharmacol: Clin Exp (Suppl) 2009;24:19–23.10.1002/hup.1028Search in Google Scholar

[15] Wolfe F, Smythe H, Yunus M, Bennett R, Bombardier C, Goldenberg D, Tugwell P, Campbell S, Abeles M, Clark P. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–72.10.1002/art.1780330203Search in Google Scholar

[16] Petzke F, Clauw DJ, Ambrose K, Khine A, Gracely RH. Increased pain sensitivity in fibromyalgia: effects of stimulus type and mode of presentation. Pain 2003;105:403–13.10.1016/S0304-3959(03)00204-5Search in Google Scholar

[17] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia - imaging a shared neuronal network. Science 2002;295:1737–40.10.1126/science.1067176Search in Google Scholar PubMed

[18] Brooks J, Tracey I. From nociception to pain perception: imaging the spinal and supraspinal pathway. J Anat 2005;207:19–33.10.1111/j.1469-7580.2005.00428.xSearch in Google Scholar PubMed PubMed Central

[19] Gracely RH, Geisser ME, Giesecke T, Grant MAB, Petzke F, Williams DA, Clauw DJ. Pain catastrophizing and neural responses to pain among persons with Fibromyalgia. Brain 2004;127:835–43.10.1093/brain/awh098Search in Google Scholar PubMed

[20] Ingvar M. Pain and functional imaging. Philos Trans R Soc Lond B: Biol Sci 1999;354:1347–58.10.1098/rstb.1999.0483Search in Google Scholar PubMed PubMed Central

[21] Tracey I. Nociceptive processing in the human brain. Curr Opin Neurobiol 2005;15:478–87.10.1016/j.conb.2005.06.010Search in Google Scholar PubMed

[22] Napadow V, LaCount L, Park K, AsSeine S, Clauw D, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010;62:2545–55.10.1002/art.27497Search in Google Scholar

[23] Derry S, Gill D, Phillips T, Moore RA. Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;3:CD008244.10.1002/14651858.CD008244.pub2Search in Google Scholar

[24] Mease P, Clauw D, Gendreau R, Rao S, Kranzler J, Chen W, Palmer R. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol 2009;36:398–409.10.3899/jrheum.080734Search in Google Scholar

[25] Clauw D, Mease P, Palmer R, Gendreau R, 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;30:1988–2004.10.1016/j.clinthera.2008.11.009Search in Google Scholar

[26] Giesecke T, Williams DA, Harris RE, Cupps TR, Tian X, Tian TX, Gracely RH, Clauw DJ. Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors. Arthritis Rheum 2003;48:2916–22.10.1002/art.11272Search in Google Scholar

[27] Julien N, Goffaux P, Arsenault P, Marchand S. Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 2005;114:295–302.10.1016/j.pain.2004.12.032Search in Google Scholar

[28] Gracely R, Grant M, Giesecke T. Evoked pain measures in fibromyalgia. Best Pract Res Clin Rheumatol 2003;17:593–609.10.1016/S1521-6942(03)00036-6Search in Google Scholar

[29] Legrain V, Iannetti GD, Plaghki L, Mouraux A. The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 2011;93:111–24.10.1016/j.pneurobio.2010.10.005Search in Google Scholar

[30] Geisser ME, Casey KL, Brucksch CB, Ribbens CM, Appleton BB, Crofford LJ. Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing. Pain 2003;102:243–50.10.1016/S0304-3959(02)00417-7Search in Google Scholar

[31] Hsieh J-C, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995;63:225–36.10.1016/0304-3959(95)00048-WSearch in Google Scholar

[32] Niddam D, Chan R-C, Lee S-H, Yeh T-C, Hsieh J-C. Central modulation of pain evoked from myofascial trigger point. Clin J Pain 2007;23:440–8.10.1097/AJP.0b013e318058accbSearch in Google Scholar

[33] Mantini D, Caulo M, Ferretti A, Romani GL, Tartaro A. Noxious somatosensory stimulation affects the default mode of brain function: evidence from functional MR imaging. Radiology 2009;253:797–804.10.1148/radiol.2533090602Search in Google Scholar

[34] Zyloney C, Jensen KB, Gollub RL, LaViolette P, Kaptchuk T, Kong J. Imaging the functional connectivity of the Periaqueductal Gray during verum and sham electroacupuncture treatment. Mol Pain 2010;16:80–4.Search in Google Scholar

[35] Fransson P, Marrelec G. The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: evidence from a partial correlation network analysis. NeuroImage 2008;42:1178–84.10.1016/j.neuroimage.2008.05.059Search in Google Scholar

[36] Hauser W, Wolfe F, Tolle T, Uceyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and metaanalysis. CNS Drugs 2012;26:297–307.10.2165/11598970-000000000-00000Search in Google Scholar

[37] Borsook D, Becerra L, Hargreaves R. A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov 2006;5:411–24.10.1038/nrd2027Search in Google Scholar

[38] Honey G, Bullmore E. Human pharmacological MRI. Trends Pharmacol Sci 2004;25:366–74.10.1016/ in Google Scholar

[39] Tracey I. Prospects for human pharmacological functional magnetic resonance imaging (phMRI). J Clin Pharmacol 2001;21:8S-21S.10.1177/009127001773744125Search in Google Scholar

[40] Abel K, Allin M, Kucharska-Pietura K, David A, Andrew C, Williams S, Brammer M, Phillips M. Ketamine alters neural processing of facial emotion recognition in healthy men: an fMRI study. Neuroreport 2003;14:387–91.10.1097/00001756-200303030-00018Search in Google Scholar

[41] Seifritz E, Bilecen D, Hanggi D, Haselhorst R, Radu E, Wetzel S, Seelig J, Scheffler K. Effect of ethanol on BOLD response to acoustic stimulation: implications for neuropharmacological f MRI. Psychiatry Res 2000;99:1–13.10.1016/S0925-4927(00)00054-8Search in Google Scholar

[42] Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith S, Tracey I. Imaging how attention modulates pain in humans using functional MRI. Brain 2002;125: 310–9.10.1093/brain/awf022Search in Google Scholar PubMed

[43] Honey G, Bullmore E, Soni W, Varatheesan M, Williams S, Sharma T. Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci U S A 1999;96:13432–7.10.1073/pnas.96.23.13432Search in Google Scholar PubMed PubMed Central

[44] Davidson R, Irwin W, Anderle M, Kalin N. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 2003;160:64–75.10.1176/appi.ajp.160.1.64Search in Google Scholar PubMed

Received: 2012-07-10
Revised: 2012-10-11
Accepted: 2012-10-27
Published Online: 2013-04-01
Published in Print: 2013-04-01

© 2012 Scandinavian Association for the Study of Pain