The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial
Effects of the N-methyl-D-aspartate receptor on temporal summation of second pain (wind-up) in irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the pathophysiological mechanisms of the pain and hypersensitivity are not well understood. IBS patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting that central hyperalgesic mechanisms may be involved. In the current study, during the wind-up testing session, a series of 6 heat pulses were presented with an interstimulus interval (ISI) of 3 seconds. Following the 1st, 3rd, and 6th thermal stimuli, subjects were asked to rate the late thermal sensation or second pain. IBS patients who demonstrated temporal summation of pain (TSSP) then received dextromethorphan and placebo in a randomized, double-blind, fashion to block wind-up. The results showed: 1) a subset of IBS patients, but not controls, showed TSSP in response to a series of noxious heat pulses; and 2) TSSP was blocked by administration of dextromethorphan, an NMDA receptor antagonist. In summary, these findings further elucidate mechanisms of somatic hypersensitivity in a subset of IBS patients. Our results also support an etiologic basis for abnormal NMDA receptor mechanisms in some IBS patients. Future studies are needed to determine if NMDA receptor antagonists may be used to treat IBS patients. ⋯ This study evaluates temporal summation of second pain in a subset of IBS patients that is blocked by Dextromethorphan, an NMDA receptor antagonist. Theses results could lead to the use of an NMDA receptor antagonist in the treatment of pain in a subset of IBS patients.
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Randomized Controlled Trial Multicenter Study
A randomized, placebo-controlled phase 3 trial (Study SB-767905/012) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain.
Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated. ⋯ These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.
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Randomized Controlled Trial Comparative Study
Reduced analgesic effect of acupuncture-like TENS but not conventional TENS in opioid-treated patients.
Evidence from recent animal studies indicates that the analgesic effect of low-frequency transcutaneous electrical nerve stimulation (TENS) is reduced in opioid-tolerant animals. The aim of the present study was to compare the analgesic effect of conventional (high frequency) and acupuncture-like (low frequency) TENS between a group of opioid-treated patients and a group of opioid-naive patients in order to determine if this cross-tolerance effect is also present in humans. Twenty-three chronic pain patients (11 who took opioids and 12 who did not) participated in the study. Participants were assigned in a randomized crossover design to receive alternately conventional and acupuncture-like TENS. There was a significant reduction in pain during and after conventional TENS when compared to baseline for both the opioid and nonopioid group (P < .01). For acupuncture-like TENS however, the analgesic effect of TENS was only observed in the nonopioid group (P < .01), with opioid-treated patients showing no change in pain scores during and after TENS when compared to baseline (P > .09). The reduced analgesic effect of acupuncture-like TENS in opioid-treated patients is coherent with previous animal studies and suggests that conventional TENS should be preferred in patients taking opioids on a regular basis. ⋯ This study shows that patients taking opioids on a regular basis are less susceptible to benefit from acupuncture-like TENS. This phenomenon is probably attributable to the fact that the analgesia induced by acupuncture-like TENS and opioids are mediated by the same receptors (ie, μ opioid receptors).
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The hot plate is a widely used test to assess nociception. The effect of non-nociceptive factors (weight, sex, activity, habituation, and repeated testing) on hot-plate latency was examined. Comparison of body weight and hot-plate latency revealed a small but significant inverse correlation (light rats had longer latencies). Habituating rats to the test room for 1 hour prior to testing did not decrease hot-plate latency except for female rats tested on days 2 to 4. Hot-plate latency decreased with repeated daily testing, but this was not caused by a decrease in locomotor activity or learning to respond. Activity on the hot plate was consistent across all 4 trials, and prior exposure to a room-temperature plate caused a similar decrease in latency as rats tested repeatedly on the hot plate. Despite this decrease in baseline hot-plate latency, there was no difference in morphine antinociceptive potency. The present study shows that weight, habituation to the test room, and repeated testing can alter baseline hot-plate latency, but these effects are small and have relatively little impact on morphine antinociception. ⋯ This manuscript shows that non-nociceptive factors such as body weight, habituation, and repeated testing can alter hot-plate latency, but these factors do not alter morphine potency. In sum, the hot-plate test is an easy to use and reliable method to assess supraspinally organized nociceptive responses.
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We explored the contribution of median nerve small (Aδ, C)-and large (Aβ)-fiber damage to the severity and topographic distribution of sensory symptoms in carpal tunnel syndrome (CTS) and the timing of fiber damage across CTS stages. We recruited 106 CTS patients. After selection, 49 patients were included. They underwent electrodiagnostic and quantitative sensory testing (QST) study and were asked on the severity of Boston Carpal Tunnel Questionnaire (BCTQ) Symptoms Severity Scale, daytime pain (DP), night pain and paresthesia, on the distribution of hand symptoms, and the presence of proximal symptoms. BCTQ Symptoms Severity Scale and DP severity was significantly correlated with Aδ-fiber damage. Small-fiber QST measures were impaired in electrodiagnostic-negative CTS patients and did not change across CTS neurographic stages. QST findings were not correlated to the topographical distribution of symptoms. Aδ-fiber damage contributes to CTS symptoms and in particular to DP. Night pain and paresthesia might be ascribed to ectopic fiber discharges secondary to median nerve enhanced mechanosensitivity. Small-fiber damage takes place earlier than large fiber. Median nerve fiber involvement does not directly contribute to extraterritorial symptoms spread. Our data may help understanding CTS pathophysiology and explain the well-known discrepancy between CTS symptoms and electrodiagnostic findings. ⋯ We explored the involvement of median nerve small and large fibers in carpal tunnel syndrome (CTS). We found a significant correlation between Aδ-fiber function and CTS symptoms. Small-fiber involvement took place in milder disease stages. These findings could help reconcile the discrepancy between CTS symptoms and electrodiagnostic data.