Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of d

http://www.immpact.org/static/publications/Turk%20et%20al.,%202003.pdf

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations.

Interpreting the Clinical Importance of Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT Recommendations

Summary Background 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 E valuation (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. Methods 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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 fi xed-eff ects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment eff ects. Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009). T rial 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, fi nal 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 fi ndings permitted a strong recommendation for use and proposal as fi rst-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. Interpretation 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 effi cacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profi ling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.

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Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

http://www.immpact.org/static/publications/Dworkin%20et%20al.,%202005.pdf

Topical Review and RecommendationsCore outcome measures for chronic pain clinical trials: IMMPACT recommendations

Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes.

Neuropathic pain Redefinition and a grading system for clinical and research purposes

In a longitudinal observational study of 94 patients (39M:55F, mean age 69) at elevated risk for developing post herpetic neuralgia (PHN), the natural history of pain during the first 6 months after herpes zoster (HZ) rash onset was determined. Pain severity and impact were rated using pain-VAS, SF-MPQ, and MPI. Applying a definition of PHN of average daily pain >0/100 on the pain VAS during the last 48 h, 30 subjects had PHN at 6 months. These 30 subjects reported more pain and a higher SF-MPQ score (p  0/100 at 6 months after rash onset appears to substantially overestimate the number of HZ patients negatively impacted by ongoing pain and disability.

/pdf/natural-history-of-pain-following-herpes-zoster-1aba9jhk43.pdf

Natural History of Pain Following Herpes Zoster

We analyzed retrospectively pain relief from an intravenous lidocaine infusion (5 mg/kg/hr for 60 to 90 minutes) in 111 patients with chronic nonmalignant pain. Patients with peripheral nervous system (PNS) injury reported substantially more pain relief than those with central nervous system (CNS) injury or with pain of unknown etiology. These findings suggest that (1) the pathophysiology of chronic pain due to PNS injury is different from that due to CNS injury and idiopathic pain, and that (2) pain due to PNS damage may be suppressible by local anesthetic antiarrhythmic agents.

Response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury

a Pain Research and Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK b Department of Occupational and Social Medicine, University of Göttingen, Waldweg 37 B, D-37073 Göttingen, Germany c The UK Cochrane Centre, NHS R&D Programme, Summertown Pavilion, Middle Way, Oxford OX2 7LG, UK d Pain Clinic/Regional Centre of Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway e Pain Clinic, Department of Anaesthesiology, Helsinki University Central Hospital, PO Box 140, 00029 HUS, Finland f CPMC Research Institute, San Francisco, CA, USA

Clinical effectiveness: an approach to clinical trial design more relevant to clinical practice, acknowledging the importance of individual differences.

We report the results of a single session, non-blinded, trial of topical application of 10% lidocaine in gel form to the painful skin of 11 patients with well established post-herpetic neuralgia (PHN). Pain decreased as measured by 100 mm VAS pain scale and 100 mm VAS pain relief scale in both trigeminal and thoracic PHN patients.

Topical lidocaine reduces pain in post-herpetic neuralgia.

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6 months. In contrast, cutaneous innervation showed no recovery at all by 6 months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.

Michael C. Rowbotham

Papers

Natural History of Pain Following Herpes Zoster

Response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury

Clinical effectiveness: an approach to clinical trial design more relevant to clinical practice, acknowledging the importance of individual differences.

Topical lidocaine reduces pain in post-herpetic neuralgia.

Natural history of cutaneous innervation following herpes zoster.