Clinical trial NCT01653457: Randomised Controlled Trial of Memantine in Fibromyalgia
Official title: Efficacy of Memantine in the Treatment of Fibromyalgia: a Double-blind Randomized Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Fibromyalgia
Keywords: Fibromyalgia
Magnetic Resonance Spectroscopy
Memantine
electroencephalic cordance
Lead sponsor: Aragon Institute of Health Sciences
Sponsor class: OTHER
First posted: 2012-07-31
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Fibromyalgia (FM) is a chronic rheumatic disease of high prevalence and great clinical impact. However, the treatment for FM has limited efficacy, with an effect size of about 0.5. Recent studies have found raised levels of glutamate in the insula, hippocampus and posterior cingulate cortex regions of the brain. This has led a number of authors to suggest the usefulness of glutamate blocking drugs in the treatment of FM.

Aims: To evaluate the efficacy of memantine in the treatment of pain and other symptoms of FM and to assess its efficacy in reducing brain glutamate levels in patients with FM. Material and methods: Randomized controlled trial, of six months duration (including a dose adjustment period of one month). 60 patients with FM will be recruited for inclusion in the study upon fulfillment of selection criteria, and they will be randomized in two groups: A) Treatment group (n=30), will receive 20 mg of memantine o.d ; B) Control group (n=30) will receive placebo. The main objective is to assess the efficacy of memantine in the treatment of pain (pain threshold, pain perception) and other symptoms in fibromyalgia (cognitive state, health status, state of anxiety and depression, quality of life and perceived improvement. Discussion: There is a need for the development of innovative and more effective alternatives for the treatment of FM. This clinical trial will determine whether memantine can be considered as an option in the treatment of FM patients.


Eligibility criteria: Inclusion Criteria:

1. Male or female aged between 18 and 65 years.
2. Ability to understand Spanish.
3. Diagnosis of fibromyalgia carried out by a rheumatologist according to the American College of rheumatology criteria (ACR1990).
4. Ability to read and understand the Patient Information Sheet
5. Signature of Informed Consent Form.

6 .In the case of women of childbearing age, commitment not to become pregnant during the entire duration of the study.

Exclusion Criteria:

1. Undergoing drug treatment for fibromyalgia. Patients undergoing treatment for fibromyalgia will stop treatment and perform a washout period of one week. During that week the patient may take, if necessary, analgesic such as paracetamol, ibuprofen and other NSAIDS to minimize the influence of medication on brain imaging.
2. Currently taking memantine or having taken memantine during the 2 months prior to recruitment.
3. Another Axis I psychiatric disorder using SCID-I that might hinder adherence to the protocol (e.g.: dementia, alcohol and/or substance abuse/dependence, schizophrenia, chronic delirium, acute depression).
4. Pregnancy or breast-feeding.
5. Hypersensitivity to the active ingredient, memantine, or to the excipients.
6. Medical conditions that require special precautions when administering memantine according to the summary of product characteristics:

   * Epilepsy.
   * Circumstances that may cause high urine pH owing to Proteus urinary infection, renal tubular acidosis or vegetarian diet, recent myocardial infarction, congestive heart disease and uncontrolled arterial hypertension.
7. Clinically significant and active evidence of liver or kidney disease, haematological, respiratory, endocrine or cardiovascular disease or disorders (patients with controlled diabetes and patients with controlled hypertension and complete or incomplete right bundle branch block can be included in the study).
8. Use of prescription drugs that may cause relevant drug interactions with memantine according to the summary of product characteristics: NMDAR antagonists (amantadine, ketamine, dextromethorphan), L-Dopa, dopamine agonists and cholinergic agonists.
9. Use of non-permitted concomitant medication during the week prior to the first evaluation visit or when the patient is expected to require treatment (with at least one of the drugs not permitted during the study): antidepressants (duloxetine, venlafaxine, mirtazapine, bupropion, SSRI, etc.), analgesics (pregabalin, gabapentin, opiates, etc.)

Primary outcomes:
measure: Change from baseline in pain threshold at month 1
timeFrame: Month 1
measure: Change from baseline in pain threshold at month 3
timeFrame: Month 3
measure: Change from baseline in pain threshold at month 6
timeFrame: Month 6
measure: Change from baseline in pain perception at month 1
timeFrame: Month 1
measure: Change from baseline in pain perception at month 3
timeFrame: Month 3
measure: Change from baseline in pain perception at month 6
timeFrame: Month 6
Secondary outcomes:
measure: To assess improvement in cognitive state
timeFrame: Baseline, month 1, month 3 and month 6
measure: To assess improvement in Health Status
timeFrame: Baseline, month 1, month 3 and month 6
measure: To assess Anxiety and depression levels
timeFrame: Baseline, month 1, month 3 and month 6
measure: To assess Quality of life
timeFrame: Baseline, month 1, month 3 and month 6
measure: To assess Clinical Global Impression
timeFrame: Baseline, month 1, month 3 and month 6
measure: Glutamate levels in different brain regions (insula, hippocampus and posterior cingulate cortex).
timeFrame: Baseline, month 6
Other outcomes:
Locations:
city: Zaragoza
country: Spain
facility: Mental Health Unit, Primary Care Center "Torrero".
Study officials:
affiliation: Miguel Servet University Hospital
name: José Javier García Campayo, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Staud R, Vierck CJ, Robinson ME, Price DD. Effects of the N-methyl-D-aspartate receptor antagonist dextromethorphan on temporal summation of pain are similar in fibromyalgia patients and normal control subjects. J Pain. 2005 May;6(5):323-32. doi: 10.1016/j.jpain.2005.01.357.
citation: Graven-Nielsen T, Kendall SA, Henriksson KG, Bengtsson M, Sorensen J, Johnson A, Gerdle B, Arendt-Nielsen L. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000 Apr;85(3):483-491. doi: 10.1016/S0304-3959(99)00308-5.
citation: Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006 Jun;97(6):1611-26. doi: 10.1111/j.1471-4159.2006.03991.x.
citation: Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317-24. doi: 10.1001/jama.291.3.317.
citation: Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006 Jan;63(1):49-54. doi: 10.1001/archneur.63.1.49.
citation: Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg. 2000 Oct;91(4):960-6. doi: 10.1097/00000539-200010000-00036.
citation: Weinbroum AA, Rudick V, Paret G, Ben-Abraham R. The role of dextromethorphan in pain control. Can J Anaesth. 2000 Jun;47(6):585-96. doi: 10.1007/BF03018952.
citation: Sinis N, Birbaumer N, Gustin S, Schwarz A, Bredanger S, Becker ST, Unertl K, Schaller HE, Haerle M. Memantine treatment of complex regional pain syndrome: a preliminary report of six cases. Clin J Pain. 2007 Mar-Apr;23(3):237-43. doi: 10.1097/AJP.0b013e31802f67a7.
citation: Hackworth RJ, Tokarz KA, Fowler IM, Wallace SC, Stedje-Larsen ET. Profound pain reduction after induction of memantine treatment in two patients with severe phantom limb pain. Anesth Analg. 2008 Oct;107(4):1377-9. doi: 10.1213/ane.0b013e31817f90f1.
citation: Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990 Feb;33(2):160-72. doi: 10.1002/art.1780330203.
citation: Gamero Ruiz F, Gabriel Sanchez R, Carbonell Abello J, Tornero Molina J, Sanchez-Magro I. [Pain in Spanish rheumatology outpatient offices: EPIDOR epidemiological study]. Rev Clin Esp. 2005 Apr;205(4):157-63. doi: 10.1157/13074161. Spanish.
citation: Briley M. Drugs to treat fibromyalgia - the transatlantic difference. Curr Opin Investig Drugs. 2010 Jan;11(1):16-8.
citation: Garcia-Campayo J, Magdalena J, Magallon R, Fernandez-Garcia E, Salas M, Andres E. A meta-analysis of the efficacy of fibromyalgia treatment according to level of care. Arthritis Res Ther. 2008;10(4):R81. doi: 10.1186/ar2455. Epub 2008 Jul 15.
citation: Mountz JM, Bradley LA, Modell JG, Alexander RW, Triana-Alexander M, Aaron LA, Stewart KE, Alarcon GS, Mountz JD. 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 Jul;38(7):926-38. doi: 10.1002/art.1780380708.
citation: Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, Pile K. Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum. 2000 Dec;43(12):2823-33. doi: 10.1002/1529-0131(200012)43:123.0.CO;2-E.
citation: Garcia-Campayo J, Sanz-Carrillo C, Baringo T, Ceballos C. SPECT scan in somatization disorder patients: an exploratory study of eleven cases. Aust N Z J Psychiatry. 2001 Jun;35(3):359-63. doi: 10.1046/j.1440-1614.2001.00909.x.
citation: Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009 Oct;60(10):3146-52. doi: 10.1002/art.24849.
citation: Choi DW, Koh JY, Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci. 1988 Jan;8(1):185-96. doi: 10.1523/JNEUROSCI.08-01-00185.1988.
citation: Leuchter AF, Cook IA, Lufkin RB, Dunkin J, Newton TF, Cummings JL, Mackey JK, Walter DO. Cordance: a new method for assessment of cerebral perfusion and metabolism using quantitative electroencephalography. Neuroimage. 1994 Jun;1(3):208-19. doi: 10.1006/nimg.1994.1006.
citation: Leuchter AF, Uijtdehaage SH, Cook IA, O'Hara R, Mandelkern M. Relationship between brain electrical activity and cortical perfusion in normal subjects. Psychiatry Res. 1999 Apr 26;90(2):125-40. doi: 10.1016/s0925-4927(99)00006-2.
citation: Cook IA, Leuchter AF, Morgan ML, Stubbeman W, Siegman B, Abrams M. Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study. J Psychiatr Res. 2005 Sep;39(5):461-6. doi: 10.1016/j.jpsychires.2004.12.002.
citation: Venneman S, Leuchter A, Bartzokis G, Beckson M, Simon SL, Schaefer M, Rawson R, Newton T, Cook IA, Uijtdehaage S, Ling W. Variation in neurophysiological function and evidence of quantitative electroencephalogram discordance: predicting cocaine-dependent treatment attrition. J Neuropsychiatry Clin Neurosci. 2006 Spring;18(2):208-16. doi: 10.1176/jnp.2006.18.2.208.
citation: Hunter AM, Leuchter AF, Morgan ML, Cook IA. Changes in brain function (quantitative EEG cordance) during placebo lead-in and treatment outcomes in clinical trials for major depression. Am J Psychiatry. 2006 Aug;163(8):1426-32. doi: 10.1176/ajp.2006.163.8.1426.
citation: Evans KC, Dougherty DD, Pollack MH, Rauch SL. Using neuroimaging to predict treatment response in mood and anxiety disorders. Ann Clin Psychiatry. 2006 Jan-Mar;18(1):33-42. doi: 10.1080/10401230500464661.
citation: Bares M, Brunovsky M, Kopecek M, Stopkova P, Novak T, Kozeny J, Hoschl C. Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study. J Psychiatr Res. 2007 Apr-Jun;41(3-4):319-25. doi: 10.1016/j.jpsychires.2006.06.005. Epub 2006 Aug 4.
citation: Bares M, Brunovsky M, Kopecek M, Novak T, Stopkova P, Kozeny J, Sos P, Krajca V, Hoschl C. Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder. Eur Psychiatry. 2008 Aug;23(5):350-5. doi: 10.1016/j.eurpsy.2008.03.001. Epub 2008 May 2.
citation: Vargas A, Vargas A, Hernandez-Paz R, Sanchez-Huerta JM, Romero-Ramirez R, Amezcua-Guerra L, Kooh M, Nava A, Pineda C, Rodriguez-Leal G, Martinez-Lavin M. Sphygmomanometry-evoked allodynia--a simple bedside test indicative of fibromyalgia: a multicenter developmental study. J Clin Rheumatol. 2006 Dec;12(6):272-4. doi: 10.1097/01.rhu.0000249770.86652.3b.
citation: Sriwatanakul K, Kelvie W, Lasagna L, Calimlim JF, Weis OF, Mehta G. Studies with different types of visual analog scales for measurement of pain. Clin Pharmacol Ther. 1983 Aug;34(2):234-9. doi: 10.1038/clpt.1983.159.
citation: Lobo A, Saz P, Marcos G, Dia JL, de la Camara C, Ventura T, Morales Asin F, Fernando Pascual L, Montanes JA, Aznar S. [Revalidation and standardization of the cognition mini-exam (first Spanish version of the Mini-Mental Status Examination) in the general geriatric population]. Med Clin (Barc). 1999 Jun 5;112(20):767-74. Spanish.
citation: Klimesch W, Doppelmayr M, Hanslmayr S. Upper alpha ERD and absolute power: their meaning for memory performance. Prog Brain Res. 2006;159:151-65. doi: 10.1016/S0079-6123(06)59010-7.
citation: Rivera J, Gonzalez T. The Fibromyalgia Impact Questionnaire: a validated Spanish version to assess the health status in women with fibromyalgia. Clin Exp Rheumatol. 2004 Sep-Oct;22(5):554-60.