The journal of pain : official journal of the American Pain Society
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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
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-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain.
The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients 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 who experienced ≥ 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. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia. ⋯ Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.
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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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Randomized Controlled Trial Comparative Study
A randomized trial of 2 prescription strategies for opioid treatment of chronic nonmalignant pain.
The use of opioid medications for treating chronic noncancer pain is growing; however, there is a lack of good evidence regarding their long-term effectiveness, association with substance abuse, and proper prescribing guidelines. The current study directly compares for the first time in a randomized trial the effectiveness of a conservative, hold the line (Stable Dose) prescribing strategy for opioid medications with a more liberal dose escalation (Escalating Dose) approach. This 2-arm, parallel, randomized pragmatic clinical trial followed 135 patients referred to a specialty pain clinic at a Veterans Affairs Hospital for 12 months (94% male and 74% with musculoskeletal pain). Primary outcomes included monthly or quarterly evaluations of pain severity, pain relief from medications, pain-related functional disability, and opioid misuse behaviors. All subjects received identical pain treatment except for the application of treatment group specific strategies for opioid prescriptions. No group differences were found for primary outcomes of usual pain or functional disability although the Escalating Dose group did show a small but significantly larger increase in self-rated pain relief from medications. About 27% of patients were discharged over the course of the study due to opioid misuse/noncompliance, but there were no group differences in rate of opioid misuse. ⋯ The results of this study demonstrate that even in carefully selected patients there is a significant risk of problematic opioid misuse. Although in general there were no statistically significant differences in the primary outcomes between groups, the escalating dose strategy did lead to small improvements in self-reported acute relief from medications without an increase in opioid misuse, compared to the stable dose strategy.