The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial
Dexketoprofen trometamol in the acute treatment of migraine attack: a phase II, randomized, double-blind, crossover, placebo-controlled, dose optimization study.
Migraine is a disabling disease that can significantly affect a person's quality of life. This study assessed the efficacy and tolerability of the 2 doses of dexketoprofen trometamol (DKP) compared to placebo for migraine treatment. Ninety-three patients with at least 1 migraine attack per month in the preceding 6 months were enrolled and randomized to 25 mg DKP, 50 mg DKP, and placebo in a randomized, double-blind, single-center, crossover, placebo-controlled study. Primary endpoint was pain-free episodes 2 hours after drug intake. The presence of accompanying symptoms and adverse effects was also recorded. Seventy-six patients (mean age 40.5 ± 10.9 and 61% female) completed the study. At baseline, mean number of attacks/month was 3.7 ± 1.3, with a mean duration of 15.4 ± 13.5 hours. Prevalence of pain-free episodes after drug intake was significantly reduced by 50 mg DKP vs placebo (33.8 vs 14.7%, P = .0065) whereas the dose of DKP 25 mg was better than placebo but did not reach statistical significance (23 vs 14.7%, P = .1182). Both 25 mg DKP (56.8 vs 25.3%, P = .0002) and 50 mg DKP improved headache relief compared to placebo. Furthermore, both doses of DKP increased the absence of functional disability (25 mg DKP, 39.7 vs 24%, P = .045; and 50 mg DKP, 45.9 vs 24%, P < .0004). Both doses of DKP were effective and well tolerated for acute migraine treatment. ⋯ This article demonstrates the efficacy and tolerability of DKP in the treatment of migraine without and with aura attacks. Its rapid absorption rate with higher maximum plasma concentrations and shorter time to maximum values suggest that this drug is a good option for acute migraine treatment.
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Clinical Trial
Enhancing the placebo response: functional magnetic resonance imaging evidence of memory and semantic processing in placebo analgesia.
Two groups of patients with irritable bowel syndrome rated pain and underwent functional magnetic resonance imaging brain scanning during experimentally induced rectal distension (20 seconds, 7 stimuli). Group 1 was tested under baseline (natural history [NH]) and a verbally induced placebo condition, whereas Group 2 was tested under baseline and standard placebo (no verbal suggestion for pain reduction) and intrarectal lidocaine conditions. As hypothesized, intrarectal lidocaine reduced evoked pain and pain-related brain activity within Group 2. Between-group comparisons showed that adding a verbal suggestion to a placebo condition increased neural activity involved in memory and semantic processing, areas that process the placebo suggestions. These areas, in turn, are likely to influence brain areas involved in emotions and analgesia and consequently the placebo effect. These placebo suggestions also added significant decreases in activity of brain areas that process pain. The test stimulus itself seems to cue these effects and is consistent with previous explanations that somatic focus and sensory feedback reinforce expectations and other factors that mediate placebo analgesic effects. ⋯ Expectations for pain can be verbally manipulated to produce placebo analgesia. Placebo analgesia is accompanied by decreased brain activity related to processing pain and increased brain activity that generates placebo analgesia, including semantic and memory regions. Placebo suggestions may enhance placebo analgesia by engaging a feedback mechanism triggered by the painful stimulus itself and related to brain mechanisms involved in memory and semantic processing.
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Practice Guideline
Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society.
Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence. ⋯ This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.
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Central neuropathic pain (CNP) is a debilitating consequence of central nervous system damage for which current treatments are ineffective. To explore mechanisms underlying CNP, we developed a rat model involving T13/L1 dorsal root avulsion. The resultant dorsal horn damage creates bilateral below-level (L4-L6) mechanical allodynia. This allodynia, termed spinal neuropathic avulsion pain, occurs in the absence of confounding paralysis. To characterize this model, we undertook a series of studies aimed at defining whether spinal neuropathic avulsion pain could be reversed by any of 3 putative glial activation inhibitors, each with distinct mechanisms of action. Indeed, the phosphodiesterase inhibitor propentofylline, the macrophage migration inhibitory factor inhibitor ibudilast, and the toll-like receptor 4 antagonist (+)-naltrexone each reversed below-level allodynia bilaterally. Strikingly, none of these impacted spinal neuropathic avulsion pain upon first administration but required 1 to 2 weeks of daily administration before pain reversal was obtained. Given reversal of CNP by each of these glial modulatory agents, these results suggest that glia contribute to the maintenance of such pain and enduring release of macrophage migration inhibitory factor and endogenous agonists of toll-like receptor 4 is important for sustaining CNP. The markedly delayed efficacy of all 3 glial modulatory drugs may prove instructive for interpretation of apparent drug failures after shorter dosing regimens. ⋯ CNP that develops after trauma is often described by patients as severe and intolerable. Unfortunately, current treatments are not effective. This work suggests that using pharmacologic treatments that target glial cells could be an effective clinical treatment for CNP.
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Peripheral nerve injury (PNI) negatively influences spinal gamma-aminobutyric acid (GABA)ergic networks via a reduction in the neuron-specific potassium-chloride (K(+)-Cl(-)) cotransporter (KCC2). This process has been linked to the emergence of neuropathic allodynia. In vivo pharmacologic and modeling studies show that a loss of KCC2 function results in a decrease in the efficacy of GABAA-mediated spinal inhibition. One potential strategy to mitigate this effect entails inhibition of carbonic anhydrase activity to reduce HCO3(-)-dependent depolarization via GABAA receptors when KCC2 function is compromised. We have tested this hypothesis here. Our results show that, similarly to when KCC2 is pharmacologically blocked, PNI causes a loss of analgesic effect for neurosteroid GABAA allosteric modulators at maximally effective doses in naïve mice in the tail-flick test. Remarkably, inhibition of carbonic anhydrase activity with intrathecal acetazolamide rapidly restores an analgesic effect for these compounds, suggesting an important role of carbonic anhydrase activity in regulating GABAA-mediated analgesia after PNI. Moreover, spinal acetazolamide administration leads to a profound reduction in the mouse formalin pain test, indicating that spinal carbonic anhydrase inhibition produces analgesia when primary afferent activity is driven by chemical mediators. Finally, we demonstrate that systemic administration of acetazolamide to rats with PNI produces an antiallodynic effect by itself and an enhancement of the peak analgesic effect with a change in the shape of the dose-response curve of the α1-sparing benzodiazepine L-838,417. Thus, carbonic anhydrase inhibition mitigates the negative effects of loss of KCC2 function after nerve injury in multiple species and through multiple administration routes resulting in an enhancement of analgesic effects for several GABAA allosteric modulators. We suggest that carbonic anhydrase inhibitors, many of which are clinically available, might be advantageously employed for the treatment of pathologic pain states. ⋯ Using behavioral pharmacology techniques, we show that spinal GABAA-mediated analgesia can be augmented, especially following nerve injury, via inhibition of carbonic anhydrases. Carbonic anhydrase inhibition alone also produces analgesia, suggesting these enzymes might be targeted for the treatment of pain.