The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial Multicenter Study
A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748).
Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained, dose-proportional exposure to gabapentin. This randomized, double-blind, parallel-group, placebo-controlled study evaluated the safety and efficacy of 3 different maintenance doses of oral GEn in subjects with postherpetic neuralgia. Adults with a 24-hour average pain intensity score of ≥4.0 received GEn 1,200 mg, 2,400 mg, 3,600 mg, or placebo for 14 weeks (including a 1-week up-titration, 12-week maintenance, and 1-week taper). The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. The intent-to-treat population consisted of 371 subjects (GEn 1,200 mg = 107, 2,400 mg = 82, 3,600 mg = 87, placebo = 95). With regard to the primary endpoint, all 3 GEn treatment groups demonstrated a statistically significant difference relative to placebo. The adjusted mean change from baseline for the treatment groups ranged from -2.36 to -2.72 versus -1.66 for the placebo group. Exposure-response modeling suggested an ED50 around 1,200 mg/day, which was consistent with historical findings reported for gabapentin. The most commonly reported adverse events were dizziness and somnolence. All studied doses of GEn significantly improved pain associated with postherpetic neuralgia as compared to placebo and were well tolerated. ⋯ GEn provides clinically important pain relief with doses from 1,200 mg to 3,600 mg and is generally well tolerated and efficacious. As an actively transported prodrug of gabapentin, it provides dose-proportional and extended exposure to gabapentin.
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Beliefs surrounding the use of opioids for chronic noncancer pain have vacillated over time. Concerns regarding long-term efficacy and adverse effects of opioids, along with increases in opioid prescribing, have contributed to many political, regulatory, and clinical responses. The present study was designed to (1) develop a reliable and valid measure (Clinicians' Attitudes about Opioids Scale [CAOS]) to assess current and evolving beliefs regarding opioids and opioid use in patients with chronic pain; and (2) survey these beliefs in a nationally representative sample of providers from multiple medical specialties throughout the United States. We developed the questionnaire in 3 phases: (1) focus groups and content development; (2) pilot testing and subsequent revisions; and (3) formal survey (N = 1,535) and assessment of stability (N = 251). The resulting 38-item measure assessed 5 domains: (1) Impediments and Concerns; (2) Perceived Effectiveness; (3) Schedule II versus III Opioids; (4) Medical Education; and (5) Tamper Resistant Formulations. No significant differences were identified among geographical regions; however, several differences were observed among medical specialties. Orthopedists were most troubled by impediments/concerns from long-term opioid use and had the least confidence in opioid efficacy, whereas Pain Medicine specialists and Physical Medicine and Rehabilitation specialists were the most confident in efficacy. ⋯ This article presents the psychometric properties of a new measure of clinicians' beliefs surrounding opioid use for chronic pain. Using this measure, beliefs and behaviors of physicians across medical specialties and geographic regions using a nationally representative sample are presented, updating findings from a similar survey conducted 20 years ago.
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Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. ⋯ This study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.
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Epigenetic regulation of gene expression is a rapidly growing area of research. Considering the longevity and plasticity of neurons, the studies on epigenetic pathways in the nervous system should be of special interest for both epigeneticists and neuroscientists. Activation or inactivation of different epigenetic pathways becomes more pronounced when the cells experience rapid changes in their environment, and such changes can be easily caused by injury and inflammation, resulting in pain perception or distortion of pain perception (eg, hyperalgesia). Therefore, in this regard, the field of pain is at an advantage to study the epigenetic pathways. More importantly, understanding pain from an epigenetics point of view would provide a new paradigm for developing drugs or strategies for pain management. In this review, we introduce basic concepts of epigenetics, including chromatin dynamics, histone modifications, DNA methylation, and RNA-induced gene silencing. In addition, we provide evidence from published studies suggesting wide implication of different epigenetic pathways within pain pathways. ⋯ This article provides a brief overview of epigenetic pathways for gene regulation and highlights their involvement in pain. Our goal is to expose the readers to these concepts so that pain-related phenotypes can be investigated from the epigenetic point of view.
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Vulvodynia (VVD) is a chronic pain disorder wherein women display sensitivity to evoked stimuli at the vulva and/or spontaneous vulvar pain. Our previous work suggests generalized hyperalgesia in this population; however, little is known about central neurobiological factors that may influence pain in VVD. Here we investigated local (vulvar) and remote (thumb) pressure-evoked pain processing in 24 VVD patients compared to 13 age-matched, pain-free healthy controls (HCs). As a positive control we also examined thumb pressure pain in 24 fibromyalgia patients. The VVD and fibromyalgia patients displayed overlapping insular brain activations that were greater than HCs in response to thumb stimulation (P < .005 corrected). Compared to HCs, VVD participants displayed greater levels of activation during thumb stimulation within the insula, dorsal midcingulate, posterior cingulate, and thalamus (P < .005 corrected). Significant differences between VVD subgroups (primary versus secondary and provoked versus unprovoked) were seen within the posterior cingulate with thumb stimulation and within the precuneus region with vulvar stimulation (provoked versus unprovoked only). The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder. Moreover, differing central activity between VVD subgroups suggests heterogeneous pathologies within this diagnosis. ⋯ The presence of augmented brain responses to pressure stimuli remote from the vulva was observed in vulvodynia patients. These findings may guide treatment decisions for better response, as brain mechanisms may be a factor in some VVD patients.