Brief Research Report Low-Frequency Transcranial Magnetic Stimulation in Patients with Fibromyalgia and Major Depressionpme_

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1 PAIN MEDICINE Volume 10 Number Brief Research Report Low-Frequency Transcranial Magnetic Stimulation in Patients with Fibromyalgia and Major Depressionpme_ Blanca Carretero, MD,* Ma José Martín, MD,*, Antonio Juan, MD,* Ma Luz Pradana, PSYD,* Beatriz Martín, PSYD,* Maria Carral, MD,* Teresa Jimeno, MD,* Antonio Pareja, MD,*, Pedro Montoya, PSYD, Iratxe Aguirre, MD,, Joan Salva, MD,, Miguel Roca, MD, Margalida Gili, PSYD, and Mauro Garcia-Toro, MD*, *Hospital Son Llatzer; Hospital Son Dureta; IUNICS, Universitat Illes Balears, Palma de Mallorca, Spain ABSTRACT Objective. To study the efficacy of low-frequency transcranial magnetic stimulation in patients with fibromyalgia and major depression. Design. Twenty-eight patients were randomly assigned to receive 20 sessions of real or sham transcranial magnetic stimulation of the right dorsolateral prefrontal cortex. The main stimulation parameters were 15 trains at 110% of the motor threshold for 60 seconds at a frequency of 1 Hz. Blinded external evaluators administered the fibromyalgia scales (FibroFatigue, Likert pain) and the depression scales (Hamilton Depression Rating Scale, Clinical Global Impression) during the study. Results. Both treatment groups (real and sham) improved their scores in some of the scales (Fibro- Fatigue and Clinical Global Impression), although there were no differences between them. No improvements were observed in the Likert Pain Scale in either of the groups. Conclusion. With the methodology used in this study, patients with fibromyalgia and major depression who received real magnetic stimulation did not present significant differences in symptoms with respect to those who received sham magnetic stimulation. Key Words. Fibromyalgia; Depression; Transcranial Magnetic Stimulation Introduction Repetitive transcranial magnetic stimulation (rtms) involves the minimally painful application of a brief and intense magnetic field capable of penetrating the cranium at specific points in order to stimulate the underlying cerebral cortex. High-frequency rtms (HF-rTMS, greater than 1 Hz) usually activates neurons and increases cerebral perfusion, whereas low-frequency rtms (LFrTMS), 1 Hz or less) does the opposite [1,2]. In most published clinical trials, rtms has proven Reprint requests to: Mauro García-Toro, MD, Servicio de Psiquiatría, Hospital Son Llatzer, C/ Ctra de Manacor, Km 4, Palma de Mallorca, Spain. Tel: ; Fax: ; mgarciat@hsll.es. efficacious in the treatment of major depression, although the optimal stimulation parameters have not been clearly defined. The two options for which there is most evidence of antidepressive efficacy are HF-rTMS applied to the left dorsolateral prefrontal area followed by LF-rTMS applied to the right prefrontal dorsolateral area. In both cases, the magnitude of the effect is usually modest compared with electroconvulsive therapy. Therefore, in addition to trying to improve the technique s therapeutic index, an interesting challenge at present is to establish subgroups of patients with major depression for whom application of rtms could generate better responses [3]. rtms has also been shown to have interesting effects in patients with chronic pain syndromes [4]. American Academy of Pain Medicine /09/$15.00/ doi: /j x

2 LF-rTMS in Fibromyalgia and Depression 749 This coincidence must be probably because of the overlap between the neuronal pathways involved in the perception of pain and those involved in the regulation of emotions [5]. In fact, the coexistence of symptoms of pain and depression in the same patient is extremely common [6], and rtms seems to reduce pain in patients with depression [7]. Fibromyalgia is characterized by generalized chronic pain that the patient experiences in diffuse musculoskeletal locations, although its causes are unknown. Experimental and clinical research have shown that the persons with fibromyalgia present increased sensitivity to pain in several areas of the body, in addition to neuroendocrine abnormalities [8]. Recent data have shown that there are also abnormalities in the cognitive and emotional processing of information related to pain [9]. The pathophysiological mechanisms have yet to be clarified, but it seems that the brain circuits involved in perception of pain could play a role [10]. Many fibromyalgia patients also have depression, which worsens their prognosis [11]. People suffering fibromyalgia have been reported to have major depression with a prevalence between 20% and 80% [12]. The basic principles of treating fibromyalgia are drug therapy, physical exercise, and psychological treatment. At present, in the United States, there are three drugs approved for fibromyalgia: duloxetine, milnacipram, and pregabalin. Different analgesics, anti-inflammatory drugs, and muscle relaxants have been also tried, with disparate results, and no single treatment is likely to offer complete remission of symptoms [8]. For example, antidepressants have proven moderately satisfactory, even in patients with fibromyalgia and no depression, although many patients do not respond or do so only partially [13,14]. Hence, the interest in preliminary studies that propose noninvasive cerebral neurostimulation techniques as a useful treatment option in patients with fibromyalgia is justified [15,16]. One of these studies, a pilot study, used 20 sessions of rtms at 1 Hz on the right dorsolateral prefrontal cortex, leading to improvement in four patients with fibromyalgia and depression [17]. In the present study, our methodology is very similar, although the design is controlled and the sample is larger. Our hypothesis is that LF rtms will re-equilibrate cortical activity in this group of patients with fibromyalgia and major depression, and that this will be translated clinically into improvement of depression and painful symptoms. Methods We carried out a randomized, single-blinded clinical trial with an external evaluator, utilizing a design in which patients and raters (but not the treating physician) were blind to the procedure. The main objective was to evaluate the antidepressive and antalgic efficacy of LF-rTMS as a coadjuvant to pharmacologic treatment in patients with major depression and fibromyalgia. This trial is part of a wider project investigating the usefulness of LF-rTMS in major depression that is being carried out by Hospital Son Llatzer, Hospital Son Dureta, and the University of the Balearic Islands, all in Majorca. The study was approved by the ethics committee of the Balearic Islands. Patients were informed about the objectives of the study and of the possible side effects of the technique before signing the written informed consent. Pharmacologic therapy remained unchanged during the month before the study and during the study. To be included, patients had to be aged over 18 years and fulfill the diagnostic criteria for major depression (Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision) and fibromyalgia (diagnosed by a rheumatologist [Antonio Juan] according to the criteria of the American College of Rheumatology). Furthermore, patients had to follow treatment with antidepressants during the present episode up to the maximum tolerated dose for at least 6 weeks. The study period was 4 weeks. Stimulation sessions were held daily on working days for as many as 20 sessions, with an approximate duration of 30 minutes per session. Follow-up lasted 8 weeks. Investigators who were masked to the intervention made evaluations at weeks 2, 4, and 8. The scales used were the 17-item Hamilton Depression Rating Scale (HDRS), the self-administered Likert Pain Scale, the Clinical Global Impression (CGI) Scale, and the Zachrisson FibroFatigue Scale [18,19]. HDRS has items related to work and activities performance, motor slowness, pain, and energy loss that can be present in patients with fibromyalgia in absence of depression. In patients with major depression, a fall greater than 25% of basal score is clinically meaningful. Likert Scale was graduated between 0 (absence of pain) and 10 (extreme pain) that was evaluated in consideration of pain throughout the body. CGI Scale was scored between 0 (normal, absence of illness) and 7 (extremely ill). The transcranial magnetic stimulation sessions were carried out using a DANTEC TMS equip-

3 750 ment (Dantec Medical, Medtronic Inc., Minneapolis, MN), MagLite model. We used a butterfly coil and each wing was 8.5 cm in diameter. The main stimulation parameters were 20 trains at 110% of motor threshold for 60 seconds at 1 Hz and a 45-second interval between trains. We therefore administered a total of 1,200 pulses at each of the 20 sessions. The stimulation area was the right dorsolateral prefrontal area, 5 cm in front of the specular point that triggered a more selective right-thumb abduction response in the left motor cortex. This is the same stimulation area that was used by Sampson and colleagues in the previously mentioned study [17]. We also think it was a good choice because HF-rTMS had perhaps been worse tolerated than this because of its greater capacity than LF-rTMS to generate discomfort at cranial surface. This is a particular concern in relation to the pain hypersensitivity of patients with fibromyalgia. In the sham sessions, the coil was placed perpendicularly to the cranium at the calculated stimulation point, before being inclined 45 forward on the axis. Thus, the magnetic field did not significantly penetrate the brain, although the patient did hear the sound produced by the apparatus. We explained to the patients that we used two randomly selected methods for applying magnetic fields, and we wanted to know which one was more useful for people in their situation. Unfortunately, we did not systematically collect data on masking effectiveness or patients expectations for improvement. To evaluate the differences between the quantitative variables, we used the t-test for independent and paired samples after confirming that the distribution was normal. Qualitative variables were compared using the chi-square and Fisher exact test. All analyses were carried out with the SPSS statistical package (SPSS Inc., Chicago, IL), version 12.0 for Windows. Results We interviewed 54 preselected patients, of whom 32 met the inclusion criteria. Of these, six did not wish to participate for different reasons. Of the 26 patients who began the study, 14 were randomized to the real LF-rTMS group and 12 to the sham LF-rTMS group (Table 1). The antidepressants taken by the patients were very similar in both groups: dual and selective serotonin reuptake inhibitors. Most patients were taking benzodiazepines in combination 13 in the real LF-rTMS group and eight in the sham group. One patient Table 1 Clinical and demographic data of both groups of patients from each group did not complete the treatment cycle. The data from both these patients were included in the statistical analysis. The statistical analysis did not reveal any differences between the groups for any of the study variables. At the end of the 20-session cycle, the improvement in both groups was statistically significant on the CGI and FibroFatigue, but not on the HDRS or Likert Pain Scale. Decreases in CGI and FibroFatigue Scale scores were less than 25% of basal score, so they could not be considered clinically meaningful. There were no differences between the groups with regard to the decrease on the fibromyalgia and depression scales (Table 1). In the real LF-rTMS group, seven patients reported adverse events. Six of these complained of neck pain and headache associated with the technique, and the remaining patient reported a worsening of the depressive symptoms, although this did not require a change in treatment. As for the 12 patients from the sham group, two complained of neck pain and headache, and a third complained of nausea and increased tiredness. Discussion Real TMS Carretero et al. Sham TMS N Age; years (SD) 47.5 (5.7) 54.9 (4.9) Males 0 2 Prior depressive episodes 13 9 HDRS entry score (SD) 19.4 (5.4) 17.0 (6.3) HDRS 2 weeks (SD) 16.0 (4.1) 11.5 (4.1) HDRS 4 weeks (SD) 15.6 (3.8) 13.2 (4.7) HDRS 8 weeks (SD) 15.1 (4.4) 13.9 (4.6) Likert Pain Scale entry score (SD) 8.7 (1.2) 8.6 (1.9) Likert Pain Scale 4 weeks entry 8.0 (1.3) 6.8 (2.5) score (SD) Likert Pain Scale 8 weeks entry 8.1 (1.0) 7.5 (2.1) score (SD) CGI entry score (SD) 4.5 (0.6) 4.2 (1.0) CGI 2 weeks (SD) 3.9 (0.6) 3.8 (1.5) CGI 4 weeks (SD) 3.6 (0.8)* 3.8 (1.3)* CGI 8 weeks (SD) 3.7 (0.9)* 3.6 (1.0)* Baseline FibroFatigue Scale (SD) 38.3 (5.9) 32.5 (8.5) Baseline FibroFatigue Scale fourth 33.0 (7.7) 28.0 (7.8) week (SD) Baseline FibroFatigue Scale fourth week (SD) 33.9 (6.7)* 29.0 (10.4)* * Statistically significant difference (P < 0.05) compared with baseline value in the t-test for paired samples. CGI = Clinical Global Impression Scale; HDRS = Hamilton Depression Rating Scale; SD = standard deviation; TMS = transcranial magnetic stimulation. The encouraging results with TMS in chronic pain led us to believe that this success could be repeated in patients with fibromyalgia. The few studies published to date seem to point in this

4 LF-rTMS in Fibromyalgia and Depression 751 direction, as do those using another technique, transcranial electric stimulation [20]. The study by Sampson et al. in which four women with fibromyalgia, major depression, and borderline personality disorder reduced both pain and their score on the depression scale suggests that LF-rTMS could improve these clinical conditions in patients who experienced them together [17]. However, our attempt to replicate this study using a similar methodology with a control was not successful. This disparate result could be explained by some of the differences in the stimulation parameters used. In the study by Sampson et al., the patients received 1,600 stimuli with LF-rTMS during each of the 20 sessions, whereas in our study, they received only 1,200. The interval between trains was also greater in our study. Furthermore, all the patients in the Sampson study also had the borderline personality disorder, whereas ours did not. The influence of these differences is difficult to gauge, given the paucity of previous studies in this area. Finally, the patients in the study by Sampson et al. could have had a more severe depressive episode, given their score on the HDRS; however, comparison is not easy, because we used the 17-item HDRS and Sampson used the 28-item HDRS [17]. We must also point to the possible key role of the choice of stimulation area when justifying the results in patients with fibromyalgia. Stimulating the dorsolateral prefrontal cortex has a certain theoretical justification, because the limbic areas involved in processing pain anterior cingulate cortex, which seems to play an important role in the emotional processing of pain are modulated transsynaptically. Furthermore, the right dorsolateral prefrontal cortex has been used successfully in major depression as a stimulation area with LF-rTMS [1,2]. This is the justification for using the dorsolateral prefrontal area in patients with fibromyalgia and major depression, although our study does not support its usefulness. Other studies, in which LF-rTMS has proven useful in treating fibromyalgia pain, stimulated the left motor cortex at a frequency of 10 Hz [20 24]. This stimulation point has also been used satisfactorily with direct electrical stimulation [12]; therefore, it could perhaps be more appropriate for relief of pain in fibromyalgia. Theoretically, differences between right and left hemispheres related to the processing of negative emotions and sympathetic responses to nociceptive stimuli could also favor the left hemisphere to be used as a stimulation site in people with fibromyalgia and major depression. Both in major depression and in fibromyalgia, there are reports of high percentages of responses to placebo. Expectation affects the perception of pain [25] and, logically, LF-rTMS increases patients expectations of improvement. This important placebo effect could be partly responsible for the fact that we did not find significant differences between the two groups. It is also possible that the major depression experienced by patients with fibromyalgia has a different pathophysiological mechanism and that other stimulation areas would be preferable [26,27]. The wide use of benzodiazepines and other potential CNS inhibitory drugs (such as anticonvulsivants) could have confounded the efficacy of rtms. However, there are no significant differences among groups related to use of these drugs (Table 2). Table 2 Psychopharmacological data of both groups of patients Real TMS Sham TMS No. AD type Bzd Others AD type Bzd Others 1 SNRI Yes No SSRI Yes No 2 SSRI Yes No SSRI No No 3 SNRI Yes No SSRI No Pregabalin, topiramate 4 SNRI Yes No SSRI Yes No 5 SSRI Yes No SNRI Yes Quetiapine 6 SSRI Yes No SSRI No Gabapentin 7 SNRI Yes Pregabalin SNRI Yes Pregabalin, topiramate 8 SSRI Yes Pregabalin SNRI Yes No 9 SNRI No Pregabalin TCA No No 10 SNRI Yes No SNRI No Pregabalin 11 SNRI Yes Gabapentin SNRI Yes Pregabalin 12 SSRI Yes Lamotrigine SSRI Yes No 13 SSRI Yes No 14 SNRI Yes Pregabalin AD = antidepressant; Bzd = benzodiazepine; SSRI = selective serotonin reuptake inhibitor; SNRI = dual serotonin and norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; TMS, transcranial magnetic stimulation.

5 752 Finally, our study does have some methodological limitations. First, the sample size is small and probably underpowered to detect differences; and we could not make an estimation of the sample size requirements initially because of the lack of previous similar studies. Second, patients were only evaluated at weeks 2, 4, and 8, and thus, changes in between these periods could not be detected. Next, in terms of the quality of the sham, we carried out the sham stimulation by placing the coil in contact with the cranium at a 45 angle in order to ensure that the sensation experienced by the patient was as similar as possible to that experienced by patients undergoing real stimulation. Although general tolerance was good, the patients mentioned a clearly greater sensation of vibration on the surface of the cranium in the real stimulation than in the sham stimulation. Lastly, our treatment protocol did not include stereotactic measurements to help us locate the stimulation point in a uniform fashion. This might have improved our results. More studies are clearly necessary to clarify the questions raised in this article. Acknowledgments We thank the patients who agreed to participate in the study, as well as the IUNICS Institute and grant SEJ (MICINN-FEDER Funds) for funding the project. References 1 Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 2003;160: Hoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry 2002; 159: Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rtms) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rtms studies. Acta Psychiatr Scand 2007;116: George MS, Nahas Z, Borckardt JJ, et al. Brain stimulation for the treatment of psychiatric disorders. Curr Opin Psychiatry 2007;20: Mountz JM, Bradley LA, Alarcón GS. Abnormal functional activity of the central nervous system in fibromyalgia syndrome. Am J Med Sci 1998;315: Demyttenaere K, Bonnewyn A, Bruffaerts R, et al. Comorbid painful physical symptoms and anxiety: Carretero et al. Prevalence, work loss and help-seeking. J Affect Disord 2008;109: Avery DH, Holtzheimer PE 3rd, Fawaz W, et al. Transcranial magnetic stimulation reduces pain in patients with major depression: A sham-controlled study. J Nerv Ment Dis 2007;195: Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumatol 2007;19: Montoya P, Sitges C, García-Herrera M, et al. Abnormal affective modulation of somatosensory brain processing among patients with fibromyalgia. Psychosom Med 2005;67: Bradley LA, McKendree-Smith NL, Alberts KR, et al. Use of neuroimaging to understand abnormal pain sensitivity in fibromyalgia. Curr Rheumatol Rep 2000;2: Alexander JL, Dennerstein L, Woods NF, et al. Arthralgias, bodily aches and pains and somatic complaints in midlife women: Etiology, pathophysiology and differential diagnosis. Expert Rev Neurother 2007;7:S Fietta P, Fietta P, Manganelli P. Fibromyalgia and psychiatric disorders. Acta Biomed 2007;78: Fregni F, Gimenes R, Valle AC, et al. A randomized, sham-controlled, proof of principle study of treatment of pain in fibromyalgia. Arthritis Rheum 2006;54: Arnold LM. Duloxetine and other antidepressants in the treatment of patients with fibromyalgia. Pain Med 2007;8:S Been G, Ngo TT, Miller SM, Fitzgerald PB. The use of tdcs and CVS as methods of non-invasive brain stimulation. Brain Res Rev 2007;56: Thimineur M, De Ridder D. C2 area neurostimulation: A surgical treatment for fibromyalgia. Pain Med 2007;8: Sampson SM, Rome JD, Rummans TA. Slowfrequency rtms reduces fibromyalgia pain. Pain Med 2006;7: Ramos-Brieva JA, Cordero A. A new validation of the Hamilton Rating Scale for Depression. J Psychiatr Res 1988;22: García-Campayo J, Pascual A, Alda M, et al. The Spanish version of the FibroFatigue Scale: Validation of a questionnaire for the observer s assessment of fibromyalgia and chronic fatigue syndrome. Gen Hosp Psychiatry 2006;28: Fregni F, Freedman S, Pascual-Leone A. Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques. Lancet Neurol 2007;6: Passard A, Attal N, Benadhira R, et al. Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 2007;130: Roizenblatt S, Fregni F, Gimenez R, et al. Sitespecific effects of transcranial direct current stimu-

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