Preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs and 30-day stroke mortality.

OBJECTIVES: To examine whether preadmission use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) influenced 30-day stroke mortality. METHODS: We conducted a nationwide population-based cohort study. Using medical databases, we identified all first-time stroke hospitalizations in Denmark between 2004 and 2012 (n = 100,043) and subsequent mortality. We categorized NSAID use as current (prescription redemption within 60 days before hospital admission), former, and nonuse. Current use was further classified as new or long-term use. Cox regression was used to compute hazard ratios (HRs) of death within 30 days, controlling for potential confounding through multivariable adjustment and propensity score matching. RESULTS: The adjusted HR of death for ischemic stroke was 1.19 (95% confidence interval [CI]: 1.02-1.38) for current users of selective cyclooxygenase (COX)-2 inhibitors compared with nonusers, driven by the effect among new users (1.42, 95% CI: 1.14-1.77). Comparing the different COX-2 inhibitors, the HR was driven by new use of older traditional COX-2 inhibitors (1.42, 95% CI: 1.14-1.78) among which it was 1.53 (95% CI: 1.02-2.28) for etodolac and 1.28 (95% CI: 0.98-1.68) for diclofenac. The propensity score-matched analysis supported the association between older COX-2 inhibitors and ischemic stroke mortality. There was no association for former users. Mortality from intracerebral hemorrhage was not associated with use of nonselective NSAIDs or COX-2 inhibitors. CONCLUSIONS: Preadmission use of COX-2 inhibitors was associated with increased 30-day mortality after ischemic stroke, but not hemorrhagic stroke. Use of nonselective NSAIDs at time of admission was not associated with mortality from ischemic stroke or intracerebral hemorrhage.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.

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.

Safety, tolerability, pharmacokinetics, and effects on human experimental pain of the selective ionotropic glutamate receptor 5 (iGluR5) antagonist LY545694 in healthy volunteers.

The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization.

Persistent postoperative pain and sensory changes following lymph node excision in melanoma patients: a topical review.

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.

Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers.

INTRODUCTION: Heat/capsaicin skin sensitization is a well-characterized human experimental model to induce hyperalgesia and allodynia. Using this model, gabapentin, among other drugs, was shown to significantly reduce cutaneous hyperalgesia compared to placebo. Since the larger thermal probes used in the original studies to produce heat sensitization are now commercially unavailable, we decided to assess whether previous findings could be replicated with a currently available smaller probe (heated area 9 cm(2) versus 12.5-15.7 cm(2)). STUDY DESIGN AND METHODS: After Institutional Review Board approval, 15 adult healthy volunteers participated in two study sessions, scheduled 1 week apart (Part A). In both sessions, subjects were exposed to the heat/capsaicin cutaneous sensitization model. Areas of hypersensitivity to brush stroke and von Frey (VF) filament stimulation were measured at baseline and after rekindling of skin sensitization. Another group of 15 volunteers was exposed to an identical schedule and set of sensitization procedures, but, in each session, received either gabapentin or placebo (Part B). RESULTS: Unlike previous reports, a similar reduction of areas of hyperalgesia was observed in all groups/sessions. Fading of areas of hyperalgesia over time was observed in Part A. In Part B, there was no difference in area reduction after gabapentin compared to placebo. CONCLUSION: When using smaller thermal probes than originally proposed, modifications of other parameters of sensitization and/or rekindling process may be needed to allow the heat/capsaicin sensitization protocol to be used as initially intended. Standardization and validation of experimental pain models is critical to the advancement of translational pain research.

Natural history of herpes zoster: late follow-up of 3.9 years (n=43) and 7.7 years (n=10).

Postherpetic neuralgia (PHN) is a common complication after herpes zoster (HZ). Subjects who completed a longitudinal observational 6-month study (4 visits) of the natural history of HZ were recontacted for 2 additional follow-up visits that included pain and sensory symptom assessment, quantitative sensory testing, capsaicin response test, and 3-mm punch skin biopsies in HZ-affected, mirror-image, and control skin sites. Forty-three subjects (14 with PHN at 6 months) of the original 94 subjects in the cohort were comprehensively assessed at a median 3.9 years after HZ onset (visit 5), and 10 subjects underwent a final assessment at a median 7.7 years after HZ onset (visit 6). At 3.9 years, none of the 29 subjects who had been pain free at 6 months had a recurrence of pain. Only 2 of the 14 subjects with PHN at 6 months still had pain at 3.9 years. One subject with PHN at 6 months was free of symptoms at 3.9 years but had very mild pain at 7.7 years. Sensory function continued on a path toward normalization, but was still abnormal in many subjects, especially those who met criteria for PHN at 6 months. Even at 7.7 years, reinnervation of HZ-affected skin was not apparent.

Healthy volunteers can be phenotyped using cutaneous sensitization pain models.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy.

A length-dependent neuropathy with pain in the feet is a common complication of diabetes (painful diabetic neuropathy). It was hypothesized that pain may arise from sensitized-hyperactive cutaneous nociceptors, and that this abnormal signaling may be reduced by topical administration of the α(2)-adrenergic agonist, clonidine, to the painful area. This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Nociceptor function was measured by determining the painfulness of 0.1% topical capsaicin applied to the pretibial area of each subject for 30minutes during screening. Subjects were then randomized to receive 0.1% topical clonidine gel (n=89) or placebo gel (n=90) applied 3 times a day to their feet for 12weeks. The difference in foot pain at week 12 in relation to baseline, rated on a 0-10 numerical pain rating scale (NPRS), was compared between groups. Baseline NPRS was imputed for missing data for subjects who terminated the study early. The subjects treated with clonidine showed a trend toward decreased foot pain compared to the placebo-treated group (the primary endpoint; P=0.07). In subjects who felt any level of pain to capsaicin, clonidine was superior to placebo (P<0.05). In subjects with a capsaicin pain rating ⩾2 (0-10, NPRS), the mean decrease in foot pain was 2.6 for active compared to 1.4 for placebo (P=0.01). Topical clonidine gel significantly reduces the level of foot pain in painful diabetic neuropathy subjects with functional (and possibly sensitized) nociceptors in the affected skin as revealed by testing with topical capsaicin. Screening for cutaneous nociceptor function may help distinguish candidates for topical therapy for neuropathic pain.

Natural history of sensory function after herpes zoster.

The natural history of sensory function in the first 6months after herpes zoster (HZ) was determined in a cohort of 94 subjects at elevated risk for developing post-herpetic neuralgia (PHN). All four visits included ratings of pain and sensory symptoms, mapping areas of altered sensation and allodynia, and quantitative thermal and mechanical sensory testing. The last three visits included the capsaicin response test. Sensory thresholds in distant control skin were stable. Mirror-image skin was persistently hyperesthetic to warming and mechanical stimuli and hyperalgesic to heat compared to distant control skin. HZ skin showed deficits in all thermal modalities. Sensory recovery was limited and selective. Allodynia area and severity, hyperalgesia to von Frey hair, and cold detection threshold improved, but deficits to warmth and heat pain did not. Capsaicin on HZ skin significantly aggravated pain and allodynia in the majority of subjects at 6-8weeks after HZ onset. At study entry, eventual PHN subjects had significantly more impairment in detecting warmth and cold, a larger area of altered sensation, a larger area of allodynia, and more severe allodynia. The results support the study hypothesis that severity of initial injury predicts PHN, especially impaired cold sensation in HZ skin. The hypothesis that PHN develops because of a failure to recover normal neural function was not supported. Sensory recovery proceeded at the same rate in eventual pain-free and eventual PHN subjects and is not a requirement for pain resolution. Early interventions that reduce neural injury or enhance recovery should be of benefit.

Recommendations for the management of herpes zoster.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization.

In this randomized double-blind placebo-controlled study, the analgesic effect of oral lamotrigine (400 mg) on cutaneous sensitization induced with the heat/capsaicin sensitization model was compared with the effect of oral hydromorphone (8 mg) in healthy volunteers. In a separate session, intravenous remifentanil (0.10 microg.kg(-1).min(-1)) and placebo were administered. This session was used as an additional reference comparator. Outcome measures were the areas of secondary hyperalgesia to brush and von Frey hair stimulation and the painfulness of noxious thermal stimulation in nonsensitized skin. Compared with placebo, both intravenous remifentanil and oral hydromorphone significantly suppressed secondary hyperalgesia and acute thermal nociception. Oral lamotrigine did not reduce secondary hyperalgesia or acute thermal nociception but produced side effects of severity comparable with that of oral hydromorphone. Although lamotrigine is efficacious in the management of some types of chronic neuropathic pain, the lack of effect of this agent on human experimental pain suggests that its analgesic effects depend on nerve injury-associated abnormalities, which cannot be simulated in healthy human volunteers.

The heat/capsaicin sensitization model: a methodologic study.

The heat/capsaicin sensitization model induces cutaneous sensitization by using a combination of heat and topical capsaicin. It has been suggested that the stability and duration of the cutaneous sensitization are due to a synergistic effect between heat and capsaicin. The aim of this study was to evaluate a possible synergistic effect between heat and capsaicin in inducing cutaneous sensitization. Twenty healthy male volunteers completed this random order, 4-session study. Three different stimulation combinations were used to induce cutaneous sensitization: day A, heat and capsaicin; day B, heat alone; day C, capsaicin alone. Combination A was repeated on day D to determine between day reproducibility. Rekindling was performed 3 times at 40-minute intervals to maintain stable areas of secondary hyperalgesia. Brief thermal sensitization (45 degrees C for 3 minutes) was induced at each session. Within and between day reproducibility was calculated. There was no difference between the size of areas of secondary hyperalgesia after stimulation with heat/capsaicin compared to heat and capsaicin stimulation alone. The within day reproducibility was better with heat/capsaicin than with either stimulation alone. There was no synergistic or additive effect between heat and capsaicin in inducing cutaneous sensitization. Rekindling seems to be the important factor in maintaining stable and long-lasting cutaneous sensitization.

Relief of post-herpetic neuralgia by surgical removal of painful skin.

We present a case of longstanding PHN treated by skin excision of the area of greatest pain (11.3 x 26.0 cm(2)). The operation reduced pain, eliminated tactile allodynia, and facilitated greatly reduced medication use over a 1-year follow-up period. Fourteen punch biopsies and 10 strips of skin (each 10 mm long) from the excised painful PHN skin were qualitatively assessed by double-label immunofluorescence using antibodies against protein-gene-product 9.5 (PGP9.5), 200 kDa neurofilament protein (NF), calcitonin gene-related peptide (CGRP) and vanilloid receptor-1 (VR-1). Compared with a punch biopsy from mirror image skin, the pattern of cutaneous innervation in PHN skin was consistently and substantially different. The results may explain the anatomical basis of the capsaicin-response test and have implications for our understanding of clinical mechanisms underlying PHN pain.

Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization.

BACKGROUND: The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers. METHODS: The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin. RESULTS: Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest. CONCLUSION: The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.

Capsaicin evoked pain and allodynia in post-herpetic neuralgia.

The hypothesis that the pain and allodynia associated with post-herpetic neuralgia (PHN) is maintained by a combination of input from preserved primary afferent nociceptors and sensitization of central pain transmitting neurons was examined in 17 subjects with PHN. Pain, allodynia, thermal sensory function, cutaneous innervation, and response to controlled application of 0.075% capsaicin were measured. Compared to mirror-image skin, applying capsaicin on a 9 cm(2) area of PHN skin significantly increased overall PHN pain and allodynia in 11 of 17 subjects. These 'capsaicin responders' were characterized by higher average daily pain, higher allodynia ratings, and relatively preserved sensory function at baseline compared to the non-responders. In three of the 'capsaicin responders' the area of allodynia expanded into previously non-allodynic and non-painful skin that had normal sensory function and cutaneous innervation. These observations support the hypothesis that allodynia in some PHN patients is a form of chronic secondary hyperalgesia maintained by input from intact and possibly 'irritable' primary afferent nociceptors to a sensitized CNS.

Quantitative sensory examination of epidural anaesthesia and analgesia in man: combination of morphine and bupivacaine.

The effect of epidural administration of a combination of low-dose morphine (2 mg) and bupivacaine (25 mg) on somatosensory and motor functions was examined in 13 healthy volunteers. The study design was a double-blind 4-way cross-over in which combined treatment was compared with either drug used alone or placebo. Every 2nd hour for 10 h effects on nociceptive and non-nociceptive somatosensory functions were quantified with 12 psychophysical measures. In addition knee extension strength, reaction time and skin temperature were examined. Epidural bupivacaine had hypoalgesic effect in all nociceptive tests, whereas epidural morphine only demonstrated hypoalgesic properties in nociceptive test with prolonged stimuli. In comparison with bupivacaine alone the combination treatment had a lesser peak effect but a more prolonged hypoalgesic action. In comparison with morphine alone the combination treatment induced a faster onset and demonstrated a modest increase in hypoalgesic effect in a subset of the test, even beyond the duration of bupivacaine when administered alone. Motor function was not attenuated by any of the treatments. Mechanisms of interaction between morphine and bupivacaine as well as their possible clinical implications are discussed.