Max Klein - Academia.edu (original) (raw)

Papers by Max Klein

Research paper thumbnail of Undiagnosed Small-Fiber Polyneuropathy - Is it a Component of Gulf-War Illness

Research paper thumbnail of Small-fiber polyneuropathy (SFPN), a common underlying diagnosis in syndromes involving unexplained chronic pain and multi-system symptoms

Molecular Pain, 2014

The Harvard community has made this article openly available. Please share how this access benefi... more The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Oaklander, Anne Louise, Heather Downs, Zeva Daniela Herzog, and Max Klein. 2014. "Small-fiber polyneuropathy (SFPN), a common underlying diagnosis in syndromes involving unexplained chronic pain and multi-system symptoms." Molecular Pain 10 (Suppl 1): O12.

Research paper thumbnail of Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?

Rambam Maimonides medical journal, 2013

The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries... more The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain's surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuro...

Research paper thumbnail of Evidence of Small-Fiber Polyneuropathy in Unexplained, Juvenile-Onset, Widespread Pain Syndromes

PEDIATRICS, 2013

Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and un... more Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and untreatable. Small-fiber polyneuropathy causes widespread pain and multisystem complaints in older adults. Some causes are treatable. Neurodiagnostic skin biopsy, autonomic function testing, and nerve biopsy permit objective diagnosis. WHAT THIS STUDY ADDS: It identifies definite (in 59%) and probable (in 17%) small-fiber polyneuropathy among 41 young patients with otherwise-unexplained, childhood-onset widespread pain. It characterizes this new disease' s clinical features, diagnostic, and treatment options. Some cases appeared immune mediated and responded to immunomodulatory therapies. abstract OBJECTIVE: We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. METHODS: Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. RESULTS: Age at illness onset averaged 12.3 6 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninetyeight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). CONCLUSIONS: More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immunemediated and improved with immunomodulatory therapies.

Research paper thumbnail of Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

PAIN®, 2013

Fibromyalgia is a common, disabling, syndrome that includes chronic widespread pain plus other di... more Fibromyalgia is a common, disabling, syndrome that includes chronic widespread pain plus other diverse symptoms. No specific objective abnormalities have been identified, precluding definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established etiologies, some diagnosable and definitively treatable, e.g., diabetes. To evaluate the hypothesis that some patients labeled with "fibromyalgia" have unrecognized SFPN causing their illness symptoms, we analyzed SFPN-associated symptoms, signs, and pathological and physiological markers in 27 fibromyalgia patients and 30 matched normal controls. Fibromyalgia subjects had to satisfy American College of Rheumatology criteria plus present documented evidence of a physician's actual fibromyalgia diagnosis. Study instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). 41% of skin biopsies from fibromyalgia subjects vs. 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher among fibromyalgia than control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from all 13 fibromyalgia subjects with SFPN-diagnostic skin biopsies provided insights into etiologies. All glucose tolerance tests were normal, but eight subjects had dysimmune markers, 2 had hepatitis C serologies, and one family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as "fibromyalgia" have unrecognized small-fiber polyneuropathy, a distinct disease that can be objectively tested for and sometimes definitively treated.

Research paper thumbnail of Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors

European Journal of …, 2011

Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned an... more Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick-nerve-injury (NNI) to one tibial nerve of outbred Sprague-Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post-traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain-behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham-operated controls were removed 14 days post-surgery for morphometric analysis. PGP9.5 + unmyelinatedfibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood-vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non-hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial bloodvessels. Similar pathological changes have been identified in CRPS-I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralesional nerves might potentially contribute to extraterritorial pain in CRPS.

Research paper thumbnail of Undiagnosed Small Fiber Polyneuropathy: Is it a Component of Gulf War Illness?

The term small-fiber polyneuropathy (SFPN) refers to body-wide dysfunction and degeneration of sm... more The term small-fiber polyneuropathy (SFPN) refers to body-wide dysfunction and degeneration of small-diameter axons that transmit pain and control the body's autonomic functions. The vague, widespread symptoms of SFPN overlap substantially with those of Gulf War Illness (GWI). We propose that there may be a SFPN component to GWI. To identify and apply the best tests to diagnose SFPN in Gulf War-ill veterans, we are recruiting, screening, and testing normal control subjects and patients with definite SFPN to compare the sensitivity and specificity of the best current and potential new tests. We will then apply and compare results the best tests in Gulf War veterans with and without GWI to identify how often this diagnosable and treatable neurological illness is masquerading as GWI. By doing so, we will not only establish the relationship between GWI and SFPN, but will also determine which tests are the most diagnostically useful. This report summarizes progress against Specific Aim I of the basic statement of work.

Research paper thumbnail of Transcranial Magnetic Stimulation (TMS) of the Brain

PAIN, 2015

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked dev... more Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of non-invasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multi-day repetitive TMS (rTMS) can induce long-lasting, potentially therapeutic, brain plasticity. Nearby ferromagnetic or electronic implants are contraindications, and adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. TMS devices are marketed for depression and migraine in the U.S. and for multiple indications elsewhere. Although multiple studies report that high-frequency rTMS of motor cortex reduces neuropathic pain, their quality has been insufficient to support FDA application. Harvard&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters, and improve strategies for sham and double-blinding. Subjects should have common, well-characterized pain conditions amenable to motor-cortex rTMS and samples should be adequately powered. They recommended standardized assessment tools (e.g., NIH&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (e.g. IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion/exclusion criteria, baseline and post-treatment means and standard deviations, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months post-initiation with pre-specified statistical analyses. Multi-group collaborations or registry studies may be needed for pivotal trials.

Research paper thumbnail of Undiagnosed Small-Fiber Polyneuropathy - Is it a Component of Gulf-War Illness

Research paper thumbnail of Small-fiber polyneuropathy (SFPN), a common underlying diagnosis in syndromes involving unexplained chronic pain and multi-system symptoms

Molecular Pain, 2014

The Harvard community has made this article openly available. Please share how this access benefi... more The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Oaklander, Anne Louise, Heather Downs, Zeva Daniela Herzog, and Max Klein. 2014. "Small-fiber polyneuropathy (SFPN), a common underlying diagnosis in syndromes involving unexplained chronic pain and multi-system symptoms." Molecular Pain 10 (Suppl 1): O12.

Research paper thumbnail of Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?

Rambam Maimonides medical journal, 2013

The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries... more The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain's surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuro...

Research paper thumbnail of Evidence of Small-Fiber Polyneuropathy in Unexplained, Juvenile-Onset, Widespread Pain Syndromes

PEDIATRICS, 2013

Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and un... more Acquired widespread pain syndromes of youth are prevalent, disabling, usually unexplained, and untreatable. Small-fiber polyneuropathy causes widespread pain and multisystem complaints in older adults. Some causes are treatable. Neurodiagnostic skin biopsy, autonomic function testing, and nerve biopsy permit objective diagnosis. WHAT THIS STUDY ADDS: It identifies definite (in 59%) and probable (in 17%) small-fiber polyneuropathy among 41 young patients with otherwise-unexplained, childhood-onset widespread pain. It characterizes this new disease' s clinical features, diagnostic, and treatment options. Some cases appeared immune mediated and responded to immunomodulatory therapies. abstract OBJECTIVE: We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. METHODS: Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. RESULTS: Age at illness onset averaged 12.3 6 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninetyeight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). CONCLUSIONS: More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immunemediated and improved with immunomodulatory therapies.

Research paper thumbnail of Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia

PAIN®, 2013

Fibromyalgia is a common, disabling, syndrome that includes chronic widespread pain plus other di... more Fibromyalgia is a common, disabling, syndrome that includes chronic widespread pain plus other diverse symptoms. No specific objective abnormalities have been identified, precluding definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established etiologies, some diagnosable and definitively treatable, e.g., diabetes. To evaluate the hypothesis that some patients labeled with "fibromyalgia" have unrecognized SFPN causing their illness symptoms, we analyzed SFPN-associated symptoms, signs, and pathological and physiological markers in 27 fibromyalgia patients and 30 matched normal controls. Fibromyalgia subjects had to satisfy American College of Rheumatology criteria plus present documented evidence of a physician's actual fibromyalgia diagnosis. Study instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). 41% of skin biopsies from fibromyalgia subjects vs. 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher among fibromyalgia than control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from all 13 fibromyalgia subjects with SFPN-diagnostic skin biopsies provided insights into etiologies. All glucose tolerance tests were normal, but eight subjects had dysimmune markers, 2 had hepatitis C serologies, and one family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as "fibromyalgia" have unrecognized small-fiber polyneuropathy, a distinct disease that can be objectively tested for and sometimes definitively treated.

Research paper thumbnail of Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors

European Journal of …, 2011

Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned an... more Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick-nerve-injury (NNI) to one tibial nerve of outbred Sprague-Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post-traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain-behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham-operated controls were removed 14 days post-surgery for morphometric analysis. PGP9.5 + unmyelinatedfibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood-vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non-hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial bloodvessels. Similar pathological changes have been identified in CRPS-I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralesional nerves might potentially contribute to extraterritorial pain in CRPS.

Research paper thumbnail of Undiagnosed Small Fiber Polyneuropathy: Is it a Component of Gulf War Illness?

The term small-fiber polyneuropathy (SFPN) refers to body-wide dysfunction and degeneration of sm... more The term small-fiber polyneuropathy (SFPN) refers to body-wide dysfunction and degeneration of small-diameter axons that transmit pain and control the body's autonomic functions. The vague, widespread symptoms of SFPN overlap substantially with those of Gulf War Illness (GWI). We propose that there may be a SFPN component to GWI. To identify and apply the best tests to diagnose SFPN in Gulf War-ill veterans, we are recruiting, screening, and testing normal control subjects and patients with definite SFPN to compare the sensitivity and specificity of the best current and potential new tests. We will then apply and compare results the best tests in Gulf War veterans with and without GWI to identify how often this diagnosable and treatable neurological illness is masquerading as GWI. By doing so, we will not only establish the relationship between GWI and SFPN, but will also determine which tests are the most diagnostically useful. This report summarizes progress against Specific Aim I of the basic statement of work.

Research paper thumbnail of Transcranial Magnetic Stimulation (TMS) of the Brain

PAIN, 2015

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked dev... more Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of non-invasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multi-day repetitive TMS (rTMS) can induce long-lasting, potentially therapeutic, brain plasticity. Nearby ferromagnetic or electronic implants are contraindications, and adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. TMS devices are marketed for depression and migraine in the U.S. and for multiple indications elsewhere. Although multiple studies report that high-frequency rTMS of motor cortex reduces neuropathic pain, their quality has been insufficient to support FDA application. Harvard&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters, and improve strategies for sham and double-blinding. Subjects should have common, well-characterized pain conditions amenable to motor-cortex rTMS and samples should be adequately powered. They recommended standardized assessment tools (e.g., NIH&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (e.g. IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion/exclusion criteria, baseline and post-treatment means and standard deviations, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months post-initiation with pre-specified statistical analyses. Multi-group collaborations or registry studies may be needed for pivotal trials.