Michael C Rowbotham

California Pacific Medical Center Research Institute, San Francisco, California, United States

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Publications (125)712.24 Total impact

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    ABSTRACT: Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at specific mtDNA sites lead to inherited mitochondrial diseases with neurological, sensory, and movement impairments. Here we test the hypothesis that heteroplasmy levels in elderly adults are associated with impaired function resembling mild forms of mitochondrial disease. We examined platelet mtDNA heteroplasmy at 20 disease-causing sites for associations with neurosensory and mobility function among 137 participants from the community-based Health, Aging, and Body Composition Study. Elevated mtDNA heteroplasmy at four mtDNA sites in complex I and tRNA genes was nominally associated with reduced cognition, vision, hearing, and mobility: m.10158T>C with Modified Mini-Mental State Examination score (p = .009); m.11778G>A with contrast sensitivity (p = .02); m.7445A>G with high-frequency hearing (p = .047); and m.5703G>A with 400 m walking speed (p = .007). These results indicate that increased mtDNA heteroplasmy at disease-causing sites is associated with neurosensory and mobility function in older persons. We propose the novel use of mtDNA heteroplasmy as a simple, noninvasive predictor of age-related neurologic, sensory, and movement impairments. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2015; DOI:10.1093/gerona/glv097 · 5.42 Impact Factor
  • Michael C Rowbotham
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    ABSTRACT: BACKGROUND: It is claimed that bispectral index (BIS) and state entropy reflect an identical clinical spectrum, the hypnotic component of anaesthesia. So far, it is not known to what extent different devices display similar index values while processing identical electroencephalogram (EEG) signals. OBJECTIVE: To compare BIS and state entropy during analysis of identical EEG data. Inspection of raw EEG input to detect potential causes of erroneous index calculation. DESIGN: Offline re-analysis of EEG data from a randomised, single-centre controlled trial using the Entropy Module and an Aspect A-2000 monitor. SETTING: Klinikum rechts der Isar, Technische Universität München, Munich. PATIENTS: Forty adult patients undergoing elective surgery under general anaesthesia. INTERVENTIONS: Blocked randomisation of 20 patients per anaesthetic group (sevoflurane/remifentanil or propofol/remifentanil). Isolated forearm technique for differentiation between consciousness and unconsciousness. MAIN OUTCOME MEASURES: Prediction probability (PK) of state entropy to discriminate consciousness from unconsciousness. Correlation and agreement between state entropy and BIS from deep to light hypnosis. Analysis of raw EEG compared with index values that are in conflict with clinical examination, with frequency measures (frequency bands/Spectral Edge Frequency 95) and visual inspection for physiological EEG patterns (e.g. beta or delta arousal), pathophysiological features such as high-frequency signals (electromyogram/high-frequency EEG or eye fluttering/saccades), different types of electro-oculogram or epileptiform EEG and technical artefacts. RESULTS: PK of state entropy was 0.80 and of BIS 0.84; correlation coefficient of state entropy with BIS 0.78. Nine percent BIS and 14% state entropy values disagreed with clinical examination. Highest incidence of disagreement occurred after state transitions, in particular for state entropy after loss of consciousness during sevoflurane anaesthesia. EEG sequences which led to false ‘conscious’ index values often showed high-frequency signals and eye blinks. High-frequency EEG/electromyogram signals were pooled because a separation into EEG and fast electro-oculogram, for example eye fluttering or saccades, on the basis of a single EEG channel may not be very reliable. These signals led to higher Spectral Edge Frequency 95 and ratio of relative beta and gamma band power than EEG signals, indicating adequate unconscious classification. The frequency of other artefacts that were assignable, for example technical artefacts, movement artefacts, was negligible and they were excluded from analysis. CONCLUSION: High-frequency signals and eye blinks may account for index values that falsely indicate consciousness. Compared with BIS, state entropy showed more false classifications of the clinical state at transition between consciousness and unconsciousness.
    Pain 04/2015; 32(5). DOI:10.1097/j.pain.0000000000000189 · 5.21 Impact Factor
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    Faustine L Dufka · Troels Munch · Robert H Dworkin · Michael C Rowbotham
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    ABSTRACT: Evidence-based medicine rests on the assumption that treatment recommendations are robust, free from bias, and include results of all randomized clinical trials. The Repository of Registered Analgesic Clinical Trials search and analysis methodology was applied to create databases of complex regional pain syndrome (CRPS) and central post-stroke pain (CPSP) trials and adapted to create the Repository of Registered Analgesic Device Studies databases for trials of spinal cord stimulation (SCS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). We identified 34 CRPS trials, 18 CPSP trials, 72 trials of SCS, and 92 trials of rTMS/tDCS. Irrespective of time since study completion, 45% of eligible CRPS and CPSP trials and 46% of eligible SCS and rTMS/tDCS trials had available results (peer-reviewed literature, results entered on registry, or gray literature); peer-reviewed publications could be found for 38% and 39%, respectively. Examining almost 1000 trials across a spectrum of painful disorders (fibromyalgia, diabetic painful neuropathy, post-herpetic neuralgia, migraine, CRPS, CPSP) and types of treatment, no single study characteristic consistently predicts unavailability of results. Results availability is higher 12 months after study completion but remains below 60% for peer-reviewed publications. Recommendations to increase results availability include supporting organizations advocating for transparency, enforcing existing results reporting regulations, enabling all primary registries to post results, stating trial registration numbers in all publication abstracts, and reducing barriers to publishing "negative" trials. For all diseases and treatment modalities, evidence-based medicine must rigorously adjust for the sheer magnitude of missing results in formulating treatment recommendations.
    Pain 01/2015; 156(1):72-80. DOI:10.1016/j.pain.0000000000000009 · 5.21 Impact Factor
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    ABSTRACT: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. NeuPSIG of the International Association for the Study of Pain. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Neurology 01/2015; 14(2). DOI:10.1016/S1474-4422(14)70251-0 · 21.90 Impact Factor
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    ABSTRACT: Sample size calculations are used to determine the number of participants required to have sufficiently high power to detect a given treatment effect. In this review, we examined the reporting quality of sample size calculations in 172 publications of double-blind RCTs of non-invasive pharmacologic or interventional (i.e., invasive) pain treatments published in European Journal of Pain, Journal of Pain, and Pain from January 2006 through June 2013. Sixty-five percent of publications reported a sample size calculation but only 38% provided all elements required to replicate the calculated sample size. In publications reporting at least one element, 54% provided a justification for the treatment effect used to calculate sample size, and 24% of studies with continuous outcome variables justified the variability estimate. Publications of clinical pain condition trials reported a sample size calculation more frequently than experimental pain model trials (77% vs. 33%, P < 0.001), but did not differ in the frequency of reporting all required elements. No significant differences in reporting of any or all elements were detected between publications of trials with industry and non-industry sponsorship. Twenty-eight percent included a discrepancy between the reported number of planned and randomized participants. This study suggests that sample size calculation reporting in analgesic trial publications is usually incomplete. Investigators should provide detailed accounts of sample size calculations in publications of clinical trials of pain treatments, which is necessary for reporting transparency and communication of pre-trial design decisions. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
    Journal of Pain 12/2014; 16(3). DOI:10.1016/j.jpain.2014.11.010 · 4.01 Impact Factor
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    ABSTRACT: Peer-reviewed publications of randomized clinical trials (RCTs) are the primary means of disseminating research findings. “Spin” in RCT publications is misrepresentation of statistically non-significant research findings to suggest treatment benefit. Spin can influence the way readers interpret clinical trials and use the information to make decisions about treatments and medical policies. The objective of this study was to determine the frequency with which 4 types of spin were used in publications of analgesic RCTs with non-significant primary analyses in 6 major pain journals. In the 76 articles included in our sample, 28% of the Abstracts and 29% of the main texts emphasized secondary analyses with p-values <0.05; 22% of Abstracts and 29% of texts emphasized treatment benefit based on non-significant primary results; 14% of Abstracts and 18% of texts emphasized within-group improvements over time, rather than primary between-group comparisons; and 13% of Abstracts and 10% of texts interpreted a non-significant difference between groups in a superiority study as comparable effectiveness. When considering the article Conclusion sections, 21% did not mention the non-significant primary result, 22% were presented with no uncertainty or qualification, 30% did not acknowledge that future research was required, and 8% recommended the intervention for clinical use. Perspective This article identifies relatively frequent “spin” in analgesic RCTs. These findings highlight a need for authors, reviewers, and editors to be more cognizant of how analgesic RCT results are presented and attempt to minimize spin in future clinical trial publications.
    Journal of Pain 10/2014; 16(1). DOI:10.1016/j.jpain.2014.10.003 · 4.01 Impact Factor
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    ABSTRACT: The Intention-to-treat (ITT) principle states that all subjects in a randomized clinical trial (RCT) should be analyzed in the group to which they were assigned regardless of compliance with assigned treatment. Analyses performed according to the ITT principle preserve the benefits of randomization and are recommended by regulators and statisticians for analyses of RCTs. The objective of this study was to determine the frequency with which publications of analgesic RCTs in three major pain journals report an ITT analysis and the percentage of the author-declared ITT analyses that include all randomized subjects and thereby fulfill the most common interpretation of the ITT principle. RCTs investigating non-invasive, pharmacologic and interventional (e.g., nerve blocks, implantable pumps, spinal cord stimulators, surgery) treatments for pain, published between January 2006 and June 2013 (n =173), were included. None of the trials using experimental pain models reported an ITT analysis; 47% of trials investigating clinical pain conditions reported an ITT analysis and 5% reported a modified ITT analysis. Of the analyses reported as ITT, 67% reported reasons for excluding subjects from the analysis and 18% of those listing reasons for exclusion did not do so in the Methods section. Such mislabeling can make it difficult to identify traditional ITT analyses for inclusion in meta-analyses. We hope that deficiencies in reporting identified in this study will encourage authors, reviewers, and editors to promote more consistent use of the phrase ITT for more accurate reporting of RCT-based evidence for pain treatments.
    Pain 10/2014; 155(12). DOI:10.1016/j.pain.2014.09.039 · 5.21 Impact Factor
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    Faustine L Dufka · Robert H Dworkin · Michael C Rowbotham
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    ABSTRACT: Transparency in research requires public access to unbiased information prior to trial initiation and openly available results upon study completion. The Repository of Registered Migraine Trials is a global snapshot of registered migraine clinical trials and scorecard of results availability via the peer-reviewed literature, registry databases, and gray literature. The 295 unique clinical trials identified employed 447 investigational agents, with 30% of 154 acute migraine trials and 11% of 141 migraine prophylaxis trials testing combinations of agents. The most frequently studied categories in acute migraine trials were triptans, nonsteroidal anti-inflammatory drugs, antiemetics, calcitonin gene-related peptide antagonists, and acetaminophen. Migraine prophylaxis trials frequently studied anticonvulsants, β-blockers, complementary/alternative therapies, antidepressants, and botulinum toxin. Overall, 237 trials were eligible for a results search. Of 163 trials completed at least 12 months earlier, 57% had peer-reviewed literature results, and registries/gray literature added another 13%. Using logistic regression analysis, studies with a sample size below the median of 141 subjects were significantly less likely to have results, but the dominant factor associated with availability of results was time since study completion. In unadjusted models, trials registered on ClinicalTrials.gov and trials with industry primary sponsorship were significantly more likely to have results. Recently completed trials rarely have publicly available results; 2 years after completion, the peer-reviewed literature contains results for fewer than 60% of completed migraine trials. To avoid bias, evidence-based therapy algorithms should consider factors affecting results availability. As negative trials are less likely to be published, special caution should be exercised before recommending a therapy with a high proportion of missing trial results.
    Neurology 09/2014; 83(15). DOI:10.1212/WNL.0000000000000866 · 8.29 Impact Factor
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    ABSTRACT: Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.
    Pain 05/2014; 155(9). DOI:10.1016/j.pain.2014.05.025 · 5.21 Impact Factor
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    ABSTRACT: The degree of variability in the patient baseline 7-day diary of pain ratings has been hypothesized to have a potential effect on the assay sensitivity of randomized clinical trials of pain therapies. To address this question, we obtained clinical trial data from the Food and Drug Administration (FDA) through the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and harmonized patient level data from 12 clinical trials (4 gabapentin and 8 pregabalin) in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Models were developed using exploratory logistic regression to examine the interaction between available baseline factors and treatment (placebo vs. active-medication) in predicting patient response to therapy (i.e., >30% improvement). Our analysis demonstrated an increased likelihood of response in the placebo-treated group for patients with a higher standard deviation in the baseline 7-day diary without affecting the likelihood of a response in the active-medication treated group, confirming our hypothesis. In addition, there was a small but significant age-by-treatment interaction in the PHN model, and small weight-by-treatment interaction in the DPN model. The patient's sex, baseline pain level, and the study protocol only had an effect on the likelihood of response overall. Our results suggest the possibility that at least in some disease processes excluding patients with a highly variable baseline 7-day diary has the potential to improve the assay sensitivity of these analgesic clinical trials, although reductions of external validity must be considered when increasing the homogeneity of the investigated sample.
    Pain 05/2014; 155(8). DOI:10.1016/j.pain.2014.05.009 · 5.21 Impact Factor
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    ABSTRACT: Eliminating publication bias requires ensuring public awareness of studies and access to results. clinical trial registries provide basic trial information, but access to unbiased trial results is inadequate. nearly all studies of trial registration and results reporting have been limited to the clinicaltrials.gov registry. we analyzed trial registration, registry functionality, cross-registry harmonization, and results reporting on all fifteen primary registries in the who international clinical trials registry platform (ictrp) for post-herpetic neuralgia, painful diabetic neuropathy, and fibromyalgia. a total of 447 unique trials were identified, with 86 trials listed on more than one registry. a comprehensive search algorithm was used to find trial results in the peer-reviewed literature and the grey literature. creating a global database of registered trials and trial results proved surprisingly difficult for several reasons: 1) ictrp does not reliably identify trials listed on multiple registries; manual searches are necessary. 2) searching ictrp yields different results than searching individual registries. 3) outcome measure descriptions for multiply-registered trials vary between registries. 4) registry-publication pairings are often inaccurate or incomplete. 5) grey literature results are not permanent. overall, only 46% of all trials had results available. trials registered on clinicaltrials.gov were significantly more likely to have results (52% vs 18%, p<0.001), partly due to the ability to post results directly to the registry. in addition to the simple remedy of including trial registration numbers on all meeting abstracts and peer-reviewed papers, specific strategies are offered to facilitate identifying multiply-registered studies, and ensuring accurate pairing of results and publications.
    Pain 04/2014; 155(7). DOI:10.1016/j.pain.2014.04.007 · 5.21 Impact Factor
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    ABSTRACT: Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (>1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1-14% of patients following SLNB and in 6-34% following CLND and sensory abnormalities in 0.1-32 and 2-82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to explain persistent pain in 31-66% of patients with SLNB and 82-89% of patients with CLND. Sensory-nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term complications.
    Melanoma research 12/2013; 24(2). DOI:10.1097/CMR.0000000000000041 · 2.28 Impact Factor
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    ABSTRACT: Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
    Pain 11/2013; 154(11):2324-34. DOI:10.1016/j.pain.2013.06.035 · 5.21 Impact Factor
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    ABSTRACT: The National Institutes of Health released the trial registry ClinicalTrials.gov in 2000 to increase public reporting and clinical trial transparency. This systematic review examined whether registered primary outcome specifications (POSs; i.e., definitions, timing, and analytic plans) in analgesic treatment trials correspond with published POSs. Trials with accompanying publications (n=87) were selected from the Repository of Registered Analgesic Clinical Trials (RReACT) database of all postherpetic neuralgia, diabetic peripheral neuropathy, and fibromyalgia clinical trials registered at ClinicalTrials.gov as of 12/1/2011. POSs never matched precisely; discrepancies occurred in 79% of the registry-publication pairs (21% failed to register or publish POs). These percentages did not differ significantly between industry and non-industry sponsored trials. Thirty percent of the trials contained unambiguous POS discrepancies (e.g., omitting a registered primary outcome [PO] from the publication, "demoting" a registered PO to a published secondary outcome), with a statistically significantly higher percentage of non-industry sponsored than industry-sponsored trials containing unambiguous POS discrepancies. POS discrepancies due to ambiguous reporting included vaguely worded PO registration, or failing to report the timing of PO assessment, statistical analysis used for the PO, or method to address missing PO data. At best, POS discrepancies may be attributable to insufficient registry requirements, carelessness (e.g., failing to report PO assessment timing), or difficulty uploading registry information. At worst, discrepancies could indicate investigator impropriety (e.g., registering imprecise POs ["pain"], then publishing whichever pain assessment produced statistically significant results). Improvements in PO registration, as well as journal policies requiring consistency between registered and published PO descriptions, are needed.
    Pain 08/2013; 154(12). DOI:10.1016/j.pain.2013.08.011 · 5.21 Impact Factor
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    European journal of pain (London, England) 08/2013; 17(7). DOI:10.1002/j.1532-2149.2012.00282.x · 2.93 Impact Factor
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    ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients. Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H215O positron emission tomography -- computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRSTMS-NRSplacebo) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded. A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session. Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.
    Molecular Pain 07/2013; 9(1):33. DOI:10.1186/1744-8069-9-33 · 3.65 Impact Factor
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    ABSTRACT: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury. Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds. Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects. Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.
    PLoS ONE 05/2013; 8(5):e64608. DOI:10.1371/journal.pone.0064608 · 3.23 Impact Factor
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    ABSTRACT: Objective: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. Methods: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. Results: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. Conclusions: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.
    Neurology 05/2013; 81(1). DOI:10.1212/WNL.0b013e318297ee69 · 8.29 Impact Factor
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    Mads U Werner · Karin L Petersen · Michael C Rowbotham · Jørgen B Dahl
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    ABSTRACT: Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models. We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models. Within-subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into 'small area' (1(st) quartile [<25%]) and 'large area' (4(th) quartile [>75%]) responders: 56-76% of subjects consistently fell into same 'small-area' or 'large-area' category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models. Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models.
    PLoS ONE 05/2013; 8(5):e62733. DOI:10.1371/journal.pone.0062733 · 3.23 Impact Factor

Publication Stats

7k Citations
712.24 Total Impact Points

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  • 2010–2015
    • California Pacific Medical Center Research Institute
      San Francisco, California, United States
  • 2013
    • University of Washington Seattle
      • Department of Anesthesiology and Pain Medicine
      Seattle, Washington, United States
  • 1989–2012
    • University of California, San Francisco
      • • Department of Psychiatry
      • • Division of Hospital Medicine
      • • Department of Neurology
      San Francisco, California, United States
  • 1996–2011
    • CSU Mentor
      • Department of Neurology
      Long Beach, California, United States
    • University of San Francisco
      San Francisco, California, United States
  • 2008
    • Oregon Health and Science University
      • Comprehensive Pain Center
      Los Angeles, CA, United States
  • 1997–2007
    • California State University
      • Department of Neurology
      Long Beach, California, United States
  • 2004
    • Duke University
      Durham, North Carolina, United States
  • 2002
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2000
    • University of Rochester
      Rochester, New York, United States
    • Beth Israel Medical Center
      • Department of Pain Medicine and Palliative Care
      New York City, New York, United States