ORIGINAL STUDY
Transcranial Magnetic Stimulation in the Treatment of Chronic Widespread Pain A Randomized Controlled Study David H. Avery, MD,*† Paul Zarkowski, MD,* Daniel Krashin, MD,*‡ Wang-ku Rho, MD,*§ Chandra Wajdik, BS,* Jutta M. Joesch, PhD,* David R. Haynor, MD,∥ Dedra Buchwald, MD,¶ and Peter Roy-Byrne, MD*† Objective: Our objective was to assess transcranial magnetic stimulation (TMS) in the treatment of chronic widespread pain. Methods: Nineteen participants were randomized into 2 groups: one group receiving active TMS (n = 7) and another group receiving sham stimulation (n = 11) applied to the left dorsolateral prefrontal cortex. During sham stimulation, subjects heard a sound similar to the sound heard by those receiving the active treatment and received an active electrical stimulus to the scalp. The stimulation protocol consisted of 15 sessions completed within a 4-week period. Blind assessments were done at baseline and after each 5 sessions followed by blind assessments at 1 week, 1 month, and 3 months after the last TMS sessions. The primary outcome variable was a pain measure, the Gracely Box Intensity Scale (BIRS). Results: The percentage of subjects who guessed that they were receiving TMS was similar in the 2 groups. Both the TMS group and the sham group showed a statistically significant reduction in the BIRS scores from baseline during the acute phase of treatment and the follow-up phase. However, the TMS and sham groups did not differ in the change in the BIRS scores. Discussion: Although some previous clinical studies and basic science studies of TMS in treating pain are promising, this study found no difference in the analgesic effect of TMS and sham stimulation. Future studies should use a sham condition that attempts to simulate the sound and sensation of the TMS stimulation. Stimulus location and other stimulus parameters should be explored in future studies. Key Words: transcranial magnetic stimulation, chronic widespread pain, fibromyalgia (J ECT 2015;31: 57–66)
From the *Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine; †Psychiatric Medicine Associates; ‡Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA; §Department of Psychiatry of Catholic University of Korea College of Medicine, Seoul, South Korea; ∥Department of Radiology, University of Washington School of Medicine; and ¶Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA. Received for publication January 1, 2014; accepted February 7, 2014. Reprints: David H. Avery, MD, Psychiatric Medicine Associates, 1505 Westlake Ave N, Suite 920, Seattle, WA 98109 (e‐mail: [email protected]). The study was funded by the National Institute for Arthritis, Musculoskeletal and Skin Diseases, R21 AR053963, and the Bipolar Illness Fund. Neuronetics, Inc. loaned the TMS machine to the study. Dr. Avery was a consultant for Neuronetics, Inc. for one day, is a member of the Data and Safety Monitoring Board for Cervel Neurotech, Inc., was on the speakers' bureau for Eli Lilly and Takeda, was a consultant for Takeda, and received a grant from the National Institute of Mental Health. Dr. Roy-Byrne is editor for Journal Watch, Depression and Anxiety, and UpToDate and has stock in Valant Medical Systems. None of the other authors has potential conflicts of interest or financial disclosures to report. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YCT.0000000000000125
C
hronic widespread pain (CWP) is a disorder that affects approximately 4% to 13% of the general population and causes much suffering and disability and has significant economic impact.1 Patients with fibromyalgia (FM) lie at the more severe end of the CWP syndrome and comprise approximately 20% of the CWP population.2 Patients with chronic pain are 3.6 times more likely to be depressed than patients without chronic pain; patients with depression are more 4 times more likely to have chronic pain than nondepressed patients.3 In addition, several treatments for major depression have been found to reduce levels of pain. In meta-analyses of placebo-controlled studies, antidepressants have been found effective for reducing pain in depressed patients and in patients with chronic nonmalignant pain.4 Although some treatments, such as antidepressant treatments, may lessen symptoms, there is a need for improved treatments for this disorder.5,6 Transcranial magnetic stimulation has been shown effective in treating major depressive disorder.7–10 Transcranial magnetic stimulation (TMS) has been used in a variety of pain syndromes with varying degrees of success.11,12 Compared to sham treatment, TMS to the dorsolateral prefrontal cortex was found to have an analgesic effect in patients with major depression.13 However, most previous studies of TMS in pain syndromes used sham conditions that did not sound or feel like the real TMS. The sound and sensation of the real TMS could have unblinded the participants and biased the outcome of the studies; it is important that the TMS condition and the sham condition differ only in the presence or absence of the magnetic stimulation. Previous TMS studies of pain have targeted different brain regions, including the dorsolateral prefrontal cortex and the motor cortex. Chronic widespread pain is associated with altered brain processing of sensory signals in various brain regions.14,15 In functional magnetic resonance imaging (fMRI) studies in which subjects receive a similar pressure on a finger, patients with chronic pain have shown increased activation of several brain regions compared with controls.14 These regions include the anterior cingulate, medial prefrontal gyrus, and the insula. Furthermore, a scale assessing the catastrophizing of the pain correlated significantly with increased activation of the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the medial frontal cortex.16 In patients with FM, the level of depression correlated with fMRI activation of insula and amygdalae when pain was induced by pressure to a finger.14 The clinical pain intensity correlated with fMRI activations of the insula, the contralateral anterior cingulate, and the prefrontal cortex. A review of functional imaging studies of major depression indicates involvement of the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital prefrontal cortex, anterior cingulate, thalamus, and hippocampus.17 In particular, decreased activity in the dorsolateral prefrontal cortex is one of the more common findings in major depression. In addition, changes in the activity of the insula are often associated with recovery from depression.18,19 Transcranial magnetic
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.ectjournal.com
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stimulation to the prefrontal cortex has effects on the dorsolateral, medial, and orbital prefrontal cortex; anterior cingulate cortex; insula; and thalamus.20,21 Thus, there is not only clinical overlap between chronic pain and depression but also neuroanatomical overlap, including alterations in function in several neuroanatomical sites: prefrontal cortex, anterior cingulate, insula, and thalamus. Because of the probable role of the dorsolateral prefrontal cortex in pain and the analgesic effect of TMS to the dorsolateral prefrontal cortex in depressed patients,13 we chose the dorsolateral prefrontal cortex as the site of stimulation. To address the possibility that inadequate blinding confounded previous studies, we compared TMS to the dorsolateral prefrontal cortex with an “active” sham condition; the participants who were randomized to sham heard a sound similar to the sound heard by those receiving the active TMS treatment, received an electrical stimulus, which created a sensation at the site of stimulation on the scalp, but did not receive the magnetic pulses. Our study was designed to determine whether 15 TMS sessions had a greater analgesic effect than 15 sessions of sham TMS in participants with CWP with or without depression.
MATERIALS AND METHODS Overall Design Women with CWP were randomized using urn randomization into one of 2 conditions: (1) TMS at 120% of the estimated prefrontal cortex threshold intensity with high frequency (10 Hz with 4-second trains) to the left dorsolateral prefrontal cortex and (2) sham stimulation. Each participant was to receive 15 sessions with 75 trains per session for a period of 4 weeks. Blind assessments of pain and depression took place before the first session, after the fifth, the 10th, and 15th sessions and 1 week after the 15th session. In a second phase of the study, we assessed the subjects in naturalistic follow-ups 1 month and 3 months after the last session at which time the blind was broken. Nonresponders to sham at the end of the 3-month follow-up were offered 15 TMS sessions and assessed in an open-label manner after the real TMS sessions.
Subjects Subjects were recruited through advertising, through publicity on television, and from a hospital clinic that specializes in the treatment of fibromyalgia. A research coordinator screened potential participants by telephone to determine who were likely to meet entry criteria for the study. If the subjects were considered likely to qualify, they came for the baseline assessment and interview. The subjects were nonpregnant, non–breast-feeding women between 18 and 65 years of age and had CWP as defined by the 1990 American College of Rheumatology guidelines.1 This definition requires musculoskeletal pain for 3 months or more; pain above and below the waist, on both right and left sides, and at 1 axial site (eg, head, neck, spine, or back). The subjects had to have a global pain score of at least 4 on the Pain Intensity Numerical Rating Scale (PI-NRS) before treatment and at least an 8 on the Gracely Box Intensity Scale (BIRS) at screening. They were willing to undergo randomization and regularly come for treatments. Participants were allowed to continue their current medicines as usual at stable doses for 4 weeks before and then during the acute phase of the study. Psychotherapy was allowed if it has been ongoing for 3 months or more before the treatment starts. Potential participants were excluded if the screening history or physical examination revealed the following: (1) a concurrent
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medical condition associated with substantial pain such as diabetic neuropathy, systemic lupus erythematosus, or severe degenerative joint disease or a condition that might increase the risk of seizures from the TMS, (2) a history of a seizure disorder or a first-degree blood relative with a seizure disorder, (3) previous use of TMS, (4) involvement in litigation or compensation related to FM, CWP, or depression, (5) current use of proconvulsant medications such as bupropion, (6) metal in the body that is a contraindication to an MRI or TMS, (7) a history of head injury associated with loss of consciousness, brain surgery, or lithium toxicity, (8) a history of a current or past major psychiatric disorder (other than major depression) including bipolar disorder, schizophrenia, obsessive compulsive disorder, and current substance abuse or dependence, (9) active suicidal intent or plan, (10) severe claustrophobia resulting in an inability to tolerate confinement in the MRI scanner. Patients with a current major depression were not excluded except for those with psychotic features or a major depressive episode that has lasted for 5 years or more. Using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria to define remission, we required that patients have not been in an episode of major depression for at least 2 months within the past 5 years. Initially in the study, patients taking opiates were excluded. However, because of the widespread use of opiates in this population and of difficulty recruiting subjects, a stable dose of opiate was allowed. The University of Washington Human Subjects Committee approved this study, and all patients provided written informed consent before inclusion.
Clinical Assessments and Timing of Assessments At the screening visit, the subject was interviewed by a psychiatrist and had a physical examination, including a neurological examination and a tender point examination,22 basic blood assessment, and urinalysis, including a drug toxicology screen. The subjects had no major medical problems. They were asked to complete questionnaires that assess pain, functional status, depression ratings, fatigue, sleep, and other measures of health. The research coordinator, blind to the randomization, repeated the baseline assessments of pain, functional status, depression, fatigue, and sleep before the first and after the fifth, the 10th, and the 15th TMS sessions as well as 1 week, 1 month, and 3 months after the last TMS treatment except for the Medical Outcomes Study Short Form-36 General Health Survey (SF-36), neuropsychological tests, audiometry, and dolorimetry, which were only done at baseline and 1 week after the 15th TMS session. The tender point examination and laser-evoked potentials were only done at baseline and after the 15th session.
Measures of Pain Gracely Box Intensity Scale (BIRS) and the Gracely Box Unpleasantness Rating Scales (BURS) The BIRS is a reliable, valid, and sensitive measure that has been used in a number of studies of analgesics and studies of changes of pain intensity over time15,16,23–29 and was selected as the primary outcome variable. Each scale is a 20-point scale that has clear anchor points. Patients were classified as responders if they had a 4-point drop or more on the BIRS. To be randomized, subjects were to have had a BIRS score of at least 8.
Pain Intensity Numerical Rating Scale (PI-NRS) The PI-NRS is an 11-point (0–10) simple rating scale for pain that was recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials Committee.30 © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of ECT • Volume 31, Number 1, March 2015
We also categorized patients as responders if they had a 30% or more reduction in pain intensity, based on the Committee’s recommendations. Other measures included the McGill Pain Questionnaire— Short Form,31,32 the Brief Pain Inventory (BPI)—Revised,33 SF-36,34 the Multidimensional Fatigue Inventory,35 and visual analog scales of fatigue, sleep, pain, and overall well-being.
Pain Thresholds Using a Dolorimeter Blinded assessments were made by the research coordinator, measuring sensitivity to pain by using a dolorimeter (pressure gauge) on the thumbnail. The dolorimeter was applied to the thumbnail and then pressure was slowly increased by 1 kg/s up to 12 kg. The subject was asked when she began to sense pain (pain threshold) and when it became intolerable (pain tolerance). We chose the Multiple Random Staircase (MRS) paradigm, in which the dolorimeter is applied only to the right thumb and pressure stimuli are applied in a random fashion.29 We chose the MRS pressure method because the ascending ramp used with other standard methods of assessing pain pressure stimuli may be influenced by participants' distress.
Depression and Neuropsychological Measures The psychiatrist diagnosed patients' conditions according to the DSM-IV criteria. The research coordinator used the Structured Clinical Interview for DSM-IV Disorders—Research Version, version 2.0.36 The research coordinator administered the Hamilton Depression Rating Scale-17 item37 to assess the level of depression. The subjects completed the Beck Depression Inventory.38 The research coordinator who was blind to the randomization conducted neuropsychological testing before the first TMS session and after the 15th TMS session. These cognitive tests included the following: Rey Auditory Verbal Learning Test, Logical Memory (Wechsler Memory Scale), Digit Symbol Test, Digit Span (WAIS-R), the Mini Mental State Examination, Trails A and B, Stroop, and the Controlled Oral Word Association Test (COWAT).39
Transcranial Magnetic Stimulation in Chronic Pain
Magnetic Resonance Imaging After this initial visit, the subjects had a 3-T MRI with vitamin E capsules (which are visible on the MRI) placed over the motor cortex and treatment stimulation site marked on a swim cap. In most previous TMS studies, scalp-cortex distances (SCDs) were assumed to be identical at the prefrontal cortex and the motor cortex. However, these distances may differ, resulting in TMS stimulus not reaching the prefrontal cortex in some patients with SCDs that were greater in the prefrontal cortex than in the motor cortex. To correct for these differences, the neuroradiologist measured the SCD at the site of prefrontal stimulation and the motor cortex using visualization of vitamin E capsules on the MRI. This allowed us to correct for the differences in the SCD and estimate the threshold for stimulating the prefrontal cortex, the corrected MT as we did in our previous study of TMS in major depression.7,13 The MRI also allowed us to screen for intracranial pathology that might be causing the chronic pain/depression or might pose a seizure risk and to verify the determination of the TMS stimulation site.
Randomization At the completion of the baseline assessment, the patients were randomly assigned to either real TMS or sham stimulation using a computerized urn randomization program that uses an adaptive randomization and stratification strategy. The urns included the following41: (1) the presence or absence of major depression, (2) the presence or absence of FM, and (3) the severity of pain (
Transcranial Magnetic Stimulation in the Treatment of Chronic Widespread Pain A Randomized Controlled Study David H. Avery, MD,*† Paul Zarkowski, MD,* Daniel Krashin, MD,*‡ Wang-ku Rho, MD,*§ Chandra Wajdik, BS,* Jutta M. Joesch, PhD,* David R. Haynor, MD,∥ Dedra Buchwald, MD,¶ and Peter Roy-Byrne, MD*† Objective: Our objective was to assess transcranial magnetic stimulation (TMS) in the treatment of chronic widespread pain. Methods: Nineteen participants were randomized into 2 groups: one group receiving active TMS (n = 7) and another group receiving sham stimulation (n = 11) applied to the left dorsolateral prefrontal cortex. During sham stimulation, subjects heard a sound similar to the sound heard by those receiving the active treatment and received an active electrical stimulus to the scalp. The stimulation protocol consisted of 15 sessions completed within a 4-week period. Blind assessments were done at baseline and after each 5 sessions followed by blind assessments at 1 week, 1 month, and 3 months after the last TMS sessions. The primary outcome variable was a pain measure, the Gracely Box Intensity Scale (BIRS). Results: The percentage of subjects who guessed that they were receiving TMS was similar in the 2 groups. Both the TMS group and the sham group showed a statistically significant reduction in the BIRS scores from baseline during the acute phase of treatment and the follow-up phase. However, the TMS and sham groups did not differ in the change in the BIRS scores. Discussion: Although some previous clinical studies and basic science studies of TMS in treating pain are promising, this study found no difference in the analgesic effect of TMS and sham stimulation. Future studies should use a sham condition that attempts to simulate the sound and sensation of the TMS stimulation. Stimulus location and other stimulus parameters should be explored in future studies. Key Words: transcranial magnetic stimulation, chronic widespread pain, fibromyalgia (J ECT 2015;31: 57–66)
From the *Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine; †Psychiatric Medicine Associates; ‡Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA; §Department of Psychiatry of Catholic University of Korea College of Medicine, Seoul, South Korea; ∥Department of Radiology, University of Washington School of Medicine; and ¶Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA. Received for publication January 1, 2014; accepted February 7, 2014. Reprints: David H. Avery, MD, Psychiatric Medicine Associates, 1505 Westlake Ave N, Suite 920, Seattle, WA 98109 (e‐mail: [email protected]). The study was funded by the National Institute for Arthritis, Musculoskeletal and Skin Diseases, R21 AR053963, and the Bipolar Illness Fund. Neuronetics, Inc. loaned the TMS machine to the study. Dr. Avery was a consultant for Neuronetics, Inc. for one day, is a member of the Data and Safety Monitoring Board for Cervel Neurotech, Inc., was on the speakers' bureau for Eli Lilly and Takeda, was a consultant for Takeda, and received a grant from the National Institute of Mental Health. Dr. Roy-Byrne is editor for Journal Watch, Depression and Anxiety, and UpToDate and has stock in Valant Medical Systems. None of the other authors has potential conflicts of interest or financial disclosures to report. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/YCT.0000000000000125
C
hronic widespread pain (CWP) is a disorder that affects approximately 4% to 13% of the general population and causes much suffering and disability and has significant economic impact.1 Patients with fibromyalgia (FM) lie at the more severe end of the CWP syndrome and comprise approximately 20% of the CWP population.2 Patients with chronic pain are 3.6 times more likely to be depressed than patients without chronic pain; patients with depression are more 4 times more likely to have chronic pain than nondepressed patients.3 In addition, several treatments for major depression have been found to reduce levels of pain. In meta-analyses of placebo-controlled studies, antidepressants have been found effective for reducing pain in depressed patients and in patients with chronic nonmalignant pain.4 Although some treatments, such as antidepressant treatments, may lessen symptoms, there is a need for improved treatments for this disorder.5,6 Transcranial magnetic stimulation has been shown effective in treating major depressive disorder.7–10 Transcranial magnetic stimulation (TMS) has been used in a variety of pain syndromes with varying degrees of success.11,12 Compared to sham treatment, TMS to the dorsolateral prefrontal cortex was found to have an analgesic effect in patients with major depression.13 However, most previous studies of TMS in pain syndromes used sham conditions that did not sound or feel like the real TMS. The sound and sensation of the real TMS could have unblinded the participants and biased the outcome of the studies; it is important that the TMS condition and the sham condition differ only in the presence or absence of the magnetic stimulation. Previous TMS studies of pain have targeted different brain regions, including the dorsolateral prefrontal cortex and the motor cortex. Chronic widespread pain is associated with altered brain processing of sensory signals in various brain regions.14,15 In functional magnetic resonance imaging (fMRI) studies in which subjects receive a similar pressure on a finger, patients with chronic pain have shown increased activation of several brain regions compared with controls.14 These regions include the anterior cingulate, medial prefrontal gyrus, and the insula. Furthermore, a scale assessing the catastrophizing of the pain correlated significantly with increased activation of the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the medial frontal cortex.16 In patients with FM, the level of depression correlated with fMRI activation of insula and amygdalae when pain was induced by pressure to a finger.14 The clinical pain intensity correlated with fMRI activations of the insula, the contralateral anterior cingulate, and the prefrontal cortex. A review of functional imaging studies of major depression indicates involvement of the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital prefrontal cortex, anterior cingulate, thalamus, and hippocampus.17 In particular, decreased activity in the dorsolateral prefrontal cortex is one of the more common findings in major depression. In addition, changes in the activity of the insula are often associated with recovery from depression.18,19 Transcranial magnetic
Journal of ECT • Volume 31, Number 1, March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.ectjournal.com
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Journal of ECT • Volume 31, Number 1, March 2015
Avery et al
stimulation to the prefrontal cortex has effects on the dorsolateral, medial, and orbital prefrontal cortex; anterior cingulate cortex; insula; and thalamus.20,21 Thus, there is not only clinical overlap between chronic pain and depression but also neuroanatomical overlap, including alterations in function in several neuroanatomical sites: prefrontal cortex, anterior cingulate, insula, and thalamus. Because of the probable role of the dorsolateral prefrontal cortex in pain and the analgesic effect of TMS to the dorsolateral prefrontal cortex in depressed patients,13 we chose the dorsolateral prefrontal cortex as the site of stimulation. To address the possibility that inadequate blinding confounded previous studies, we compared TMS to the dorsolateral prefrontal cortex with an “active” sham condition; the participants who were randomized to sham heard a sound similar to the sound heard by those receiving the active TMS treatment, received an electrical stimulus, which created a sensation at the site of stimulation on the scalp, but did not receive the magnetic pulses. Our study was designed to determine whether 15 TMS sessions had a greater analgesic effect than 15 sessions of sham TMS in participants with CWP with or without depression.
MATERIALS AND METHODS Overall Design Women with CWP were randomized using urn randomization into one of 2 conditions: (1) TMS at 120% of the estimated prefrontal cortex threshold intensity with high frequency (10 Hz with 4-second trains) to the left dorsolateral prefrontal cortex and (2) sham stimulation. Each participant was to receive 15 sessions with 75 trains per session for a period of 4 weeks. Blind assessments of pain and depression took place before the first session, after the fifth, the 10th, and 15th sessions and 1 week after the 15th session. In a second phase of the study, we assessed the subjects in naturalistic follow-ups 1 month and 3 months after the last session at which time the blind was broken. Nonresponders to sham at the end of the 3-month follow-up were offered 15 TMS sessions and assessed in an open-label manner after the real TMS sessions.
Subjects Subjects were recruited through advertising, through publicity on television, and from a hospital clinic that specializes in the treatment of fibromyalgia. A research coordinator screened potential participants by telephone to determine who were likely to meet entry criteria for the study. If the subjects were considered likely to qualify, they came for the baseline assessment and interview. The subjects were nonpregnant, non–breast-feeding women between 18 and 65 years of age and had CWP as defined by the 1990 American College of Rheumatology guidelines.1 This definition requires musculoskeletal pain for 3 months or more; pain above and below the waist, on both right and left sides, and at 1 axial site (eg, head, neck, spine, or back). The subjects had to have a global pain score of at least 4 on the Pain Intensity Numerical Rating Scale (PI-NRS) before treatment and at least an 8 on the Gracely Box Intensity Scale (BIRS) at screening. They were willing to undergo randomization and regularly come for treatments. Participants were allowed to continue their current medicines as usual at stable doses for 4 weeks before and then during the acute phase of the study. Psychotherapy was allowed if it has been ongoing for 3 months or more before the treatment starts. Potential participants were excluded if the screening history or physical examination revealed the following: (1) a concurrent
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medical condition associated with substantial pain such as diabetic neuropathy, systemic lupus erythematosus, or severe degenerative joint disease or a condition that might increase the risk of seizures from the TMS, (2) a history of a seizure disorder or a first-degree blood relative with a seizure disorder, (3) previous use of TMS, (4) involvement in litigation or compensation related to FM, CWP, or depression, (5) current use of proconvulsant medications such as bupropion, (6) metal in the body that is a contraindication to an MRI or TMS, (7) a history of head injury associated with loss of consciousness, brain surgery, or lithium toxicity, (8) a history of a current or past major psychiatric disorder (other than major depression) including bipolar disorder, schizophrenia, obsessive compulsive disorder, and current substance abuse or dependence, (9) active suicidal intent or plan, (10) severe claustrophobia resulting in an inability to tolerate confinement in the MRI scanner. Patients with a current major depression were not excluded except for those with psychotic features or a major depressive episode that has lasted for 5 years or more. Using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria to define remission, we required that patients have not been in an episode of major depression for at least 2 months within the past 5 years. Initially in the study, patients taking opiates were excluded. However, because of the widespread use of opiates in this population and of difficulty recruiting subjects, a stable dose of opiate was allowed. The University of Washington Human Subjects Committee approved this study, and all patients provided written informed consent before inclusion.
Clinical Assessments and Timing of Assessments At the screening visit, the subject was interviewed by a psychiatrist and had a physical examination, including a neurological examination and a tender point examination,22 basic blood assessment, and urinalysis, including a drug toxicology screen. The subjects had no major medical problems. They were asked to complete questionnaires that assess pain, functional status, depression ratings, fatigue, sleep, and other measures of health. The research coordinator, blind to the randomization, repeated the baseline assessments of pain, functional status, depression, fatigue, and sleep before the first and after the fifth, the 10th, and the 15th TMS sessions as well as 1 week, 1 month, and 3 months after the last TMS treatment except for the Medical Outcomes Study Short Form-36 General Health Survey (SF-36), neuropsychological tests, audiometry, and dolorimetry, which were only done at baseline and 1 week after the 15th TMS session. The tender point examination and laser-evoked potentials were only done at baseline and after the 15th session.
Measures of Pain Gracely Box Intensity Scale (BIRS) and the Gracely Box Unpleasantness Rating Scales (BURS) The BIRS is a reliable, valid, and sensitive measure that has been used in a number of studies of analgesics and studies of changes of pain intensity over time15,16,23–29 and was selected as the primary outcome variable. Each scale is a 20-point scale that has clear anchor points. Patients were classified as responders if they had a 4-point drop or more on the BIRS. To be randomized, subjects were to have had a BIRS score of at least 8.
Pain Intensity Numerical Rating Scale (PI-NRS) The PI-NRS is an 11-point (0–10) simple rating scale for pain that was recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials Committee.30 © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of ECT • Volume 31, Number 1, March 2015
We also categorized patients as responders if they had a 30% or more reduction in pain intensity, based on the Committee’s recommendations. Other measures included the McGill Pain Questionnaire— Short Form,31,32 the Brief Pain Inventory (BPI)—Revised,33 SF-36,34 the Multidimensional Fatigue Inventory,35 and visual analog scales of fatigue, sleep, pain, and overall well-being.
Pain Thresholds Using a Dolorimeter Blinded assessments were made by the research coordinator, measuring sensitivity to pain by using a dolorimeter (pressure gauge) on the thumbnail. The dolorimeter was applied to the thumbnail and then pressure was slowly increased by 1 kg/s up to 12 kg. The subject was asked when she began to sense pain (pain threshold) and when it became intolerable (pain tolerance). We chose the Multiple Random Staircase (MRS) paradigm, in which the dolorimeter is applied only to the right thumb and pressure stimuli are applied in a random fashion.29 We chose the MRS pressure method because the ascending ramp used with other standard methods of assessing pain pressure stimuli may be influenced by participants' distress.
Depression and Neuropsychological Measures The psychiatrist diagnosed patients' conditions according to the DSM-IV criteria. The research coordinator used the Structured Clinical Interview for DSM-IV Disorders—Research Version, version 2.0.36 The research coordinator administered the Hamilton Depression Rating Scale-17 item37 to assess the level of depression. The subjects completed the Beck Depression Inventory.38 The research coordinator who was blind to the randomization conducted neuropsychological testing before the first TMS session and after the 15th TMS session. These cognitive tests included the following: Rey Auditory Verbal Learning Test, Logical Memory (Wechsler Memory Scale), Digit Symbol Test, Digit Span (WAIS-R), the Mini Mental State Examination, Trails A and B, Stroop, and the Controlled Oral Word Association Test (COWAT).39
Transcranial Magnetic Stimulation in Chronic Pain
Magnetic Resonance Imaging After this initial visit, the subjects had a 3-T MRI with vitamin E capsules (which are visible on the MRI) placed over the motor cortex and treatment stimulation site marked on a swim cap. In most previous TMS studies, scalp-cortex distances (SCDs) were assumed to be identical at the prefrontal cortex and the motor cortex. However, these distances may differ, resulting in TMS stimulus not reaching the prefrontal cortex in some patients with SCDs that were greater in the prefrontal cortex than in the motor cortex. To correct for these differences, the neuroradiologist measured the SCD at the site of prefrontal stimulation and the motor cortex using visualization of vitamin E capsules on the MRI. This allowed us to correct for the differences in the SCD and estimate the threshold for stimulating the prefrontal cortex, the corrected MT as we did in our previous study of TMS in major depression.7,13 The MRI also allowed us to screen for intracranial pathology that might be causing the chronic pain/depression or might pose a seizure risk and to verify the determination of the TMS stimulation site.
Randomization At the completion of the baseline assessment, the patients were randomly assigned to either real TMS or sham stimulation using a computerized urn randomization program that uses an adaptive randomization and stratification strategy. The urns included the following41: (1) the presence or absence of major depression, (2) the presence or absence of FM, and (3) the severity of pain (
