The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial Multicenter Study
Lenalidomide for complex regional pain syndrome type 1: lack of efficacy in a phase II randomized study.
Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials. ⋯ This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials.
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Randomized Controlled Trial
Expectancy-induced placebo analgesia in children and the role of magical thinking.
Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6-9 years) who were randomly assigned-stratified for MT and gender-to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children. ⋯ The study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children.
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The purpose of this study was to examine opioid and endocannabinoid mechanisms of exercise-induced hypoalgesia (EIH). Fifty-eight men and women (mean age = 21 years) completed 3 sessions. During the first session, participants were familiarized with the temporal summation of heat pain and pressure pain protocols. In the exercise sessions, following double-blind administration of either an opioid antagonist (50 mg naltrexone) or placebo, participants rated the intensity of heat pulses and indicated their pressure pain thresholds and pressure pain ratings before and after 3 minutes of submaximal isometric exercise. Blood was drawn before and after exercise. Results indicated that circulating concentrations of 2 endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as related lipids oleoylethanolamide, palmitoylethanolamide, N-docosahexaenoylethanolamine, and 2-oleoylglycerol, increased significantly (P < .05) following exercise. Pressure pain thresholds increased significantly (P < .05), whereas pressure pain ratings decreased significantly (P < .05) following exercise. Also, temporal summation ratings were significantly lower (P < .05) following exercise. These changes in pain responses did not differ between the placebo and naltrexone conditions (P > .05). A significant association was found between EIH and docosahexaenoylethanolamine. These results suggest involvement of a nonopioid mechanism in EIH following isometric exercise. ⋯ Currently, the mechanisms responsible for EIH are unknown. This study provides support for a potential endocannabinoid mechanism of EIH following isometric exercise.
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The amygdala contributes to the generation of pain affect, and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study compared the contribution of N-methyl-d-aspartate (NMDA) receptor agonism and antagonism in the CeA to generation of the affective response of rats to an acute noxious stimulus. Vocalizations that occur following a brief tail shock (vocalization afterdischarges) are a validated rodent model of pain affect and were preferentially suppressed, in a dose-dependent manner, by bilateral injection into the CeA of NMDA (.1, .25, .5, or 1 μg/side) or the NMDA receptor antagonist d-(-)-2-amino-5-phosphopentanoic acid (AP5; 1, 2, or 4 μg/side). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of NMDA or AP5 into the CeA. Injection of NMDA, but not AP5, into the CeA increased c-Fos immunoreactivity in the ventrolateral periaqueductal gray, and unilateral injection of the μ-opiate receptor antagonist H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; .25 μg) into ventrolateral periaqueductal gray prevented the antinociception generated by injection of NMDA into the CeA. These findings demonstrate that although NMDA receptor agonism and antagonism in the CeA produce similar suppression of pain behaviors, they do so via different neurobiologic mechanisms. ⋯ The amygdala contributes to production of the emotional dimension of pain. NMDA receptor agonism and antagonism within the CeA suppressed rats' emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders.
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Most clinically used opioids are mu-opioid receptor agonists. Therefore, genetic variation of the OPRM1 gene that encodes the mu-opioid receptor is of great interest for understanding pain management. A polymorphism 118A>G (rs1799971) within the OPRM1 gene results in a missense mutation and affects the function of the receptor. We studied the association between the 118A>G polymorphism and oxycodone analgesia and pain sensitivity in 1,000 women undergoing breast cancer surgery. Preoperatively, experimental cold and heat pain sensitivities were tested. Postoperative pain was assessed at rest and during motion. Intravenous oxycodone analgesia was titrated first by a research nurse and on the ward using a patient-controlled analgesia device. The primary endpoint was the amount of oxycodone needed for the first state of adequate analgesia. For each patient, the 118A>G polymorphism was genotyped using the Sequenom MassARRAY (Sequenom, San Diego, CA). The association between this variant and the pain phenotypes was tested using linear regression. The 118A>G variant was associated significantly with the amount of oxycodone requested for adequate analgesia (P = .003, β = .016). Collectively, oxycodone consumption was highest in individuals having the GG genotype (.16 mg/kg), lowest for those with the AA genotype (.12 mg/kg), and moderate for those having the AG genotype (.13 mg/kg). Furthermore, the G allele was associated with higher postoperative baseline pain ratings (P = .001, β = .44). No evidence of association with other pain phenotypes examined was observed. ⋯ This study demonstrates that the OPRM1 118A>G polymorphism was associated with the amount of oxycodone required in the immediate postoperative period. Although a significant factor for determining oxycodone requirement, the 118A>G polymorphism alone explained less than 1% of the variance. No association was found between 118A>G and experimental pain