The journal of pain : official journal of the American Pain Society
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An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hours after CFA injection, whereas a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hours. Thermal hyperalgesia at day 3, but not at 6 hours, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin on peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia. ⋯ This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.
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Randomized Controlled Trial Comparative Study
Effect of morphine and pregabalin compared with diphenhydramine hydrochloride and placebo on hyperalgesia and allodynia induced by intradermal capsaicin in healthy male subjects.
Intradermal (ID) capsaicin injection in humans induces spontaneous pain, flare, primary hyperalgesia, secondary hyperalgesia, and allodynia. Secondary hyperalgesia and allodynia are a reflection of central sensitization. The effect of treatment of single doses of (1) pregabalin, 300 mg single oral dose, and (2) morphine, 10 mg IV, on the area of secondary hyperalgesia induced by ID capsaicin injection was studied by using a randomized, double-blinded, placebo-controlled, 4-period, cross-over design in 20 healthy men. Compared with active placebo diphenhydramine (50 mg oral dose), pregabalin and morphine significantly reduced the area of secondary hyperalgesia over 15 to 240 minutes after capsaicin injection (approximately 25%, P = .002 and approximately 33%, P < .001, respectively). A smaller reduction was observed when pregabalin and morphine were compared with true placebo (approximately 13%, P = .081 and approximately 24%, P = .009, respectively). Diphenhydramine, on the other hand, increased the area of secondary hyperalgesia in comparison with true placebo (approximately 16%, P = .061). The relationship between the baseline area of hyperalgesia and assay sensitivity suggests that establishing minimum entry criteria for the baseline area of hyperalgesia requirement increases the sensitivity of the assay. ⋯ These results suggest that the minimally invasive intradermal capsaicin model, when it is compared with true placebo, can potentially be used for an early assessment of relevant pharmacology of novel analgesic compounds in healthy subjects. This platform may provide a means to rapidly assess new analgesics and enhance dose selection and decision-making during clinical development.
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Randomized Controlled Trial
Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain.
This randomized, double-blind, placebo- and active-controlled, parallel-group study was designed to demonstrate the superiority of oxycodone in combination with naloxone in a prolonged release (PR) formulation over placebo with respect to analgesic efficacy. The active control group was included for sensitivity and safety analyses, and furthermore to compare the analgesic efficacy and bowel function of oxycodone PR/naloxone PR with oxycodone PR alone. The analgesic efficacy was measured as the time from the initial dose of study medication to multiple pain events (ie, inadequate analgesia) in patients with moderate to severe chronic low back pain. The full analysis population consisted of 463 patients. The times to recurrent pain events were significantly longer in the oxycodone PR/naloxone PR group compared with placebo (P < .0001-.0003); oxycodone PR/naloxone PR reduced the risk of pain events by 42% (P < .0001; full analysis population). The appearance of pain events was comparable for oxycodone PR/naloxone PR versus oxycodone PR, confirming that the addition of naloxone PR to oxycodone PR in a combination tablet did not negatively affect analgesic efficacy of the opioid. Furthermore, oxycodone PR/naloxone PR offers benefits in terms of an improvement in bowel function. In a therapeutic area of great unmet need, therefore, the combination tablet of oxycodone PR/naloxone PR offers patients effective analgesia while improving opioid-induced bowel dysfunction. Taken together with the observation that the safety profile of oxycodone PR/naloxone PR is consistent with that expected from other opioid analgesics except opioid-induced constipation, these findings indicate that the addition of naloxone to oxycodone in a PR combination tablet offers improved tolerability. Oxycodone PR/naloxone PR is therefore a promising new treatment approach for the management of chronic pain. ⋯ This study evaluated the analgesic efficacy and safety of the combination of oxycodone PR/naloxone PR in chronic nonmalignant pain. Opioids are often reduced in dosage or even discontinued as a result of impaired bowel function, leading to insufficient pain treatment. Not only does oxycodone PR/naloxone PR demonstrate analgesic efficacy comparable with oxycodone PR, but it also improves opioid-induced bowel dysfunction, and may therefore improve the acceptability of long-term opioid treatment for chronic pain.
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Multicenter Study
Validating PRISM (Pictorial Representation of Illness and Self Measure) as a measure of suffering in chronic non-cancer pain patients.
The Pictorial Representation of Illness and Self Measure (PRISM) is a recently developed tool designed to measure the burden of suffering due to illness in a variety of patient populations. The purpose of the current study was to validate PRISM as a measure of suffering in patients with chronic non-cancer pain. Patients (n = 138) were recruited from 2 hospital pain clinics, where they were participating in a 10-week, mindfulness-based chronic pain management course and during which they completed validated questionnaires to assess their outcomes. Convergent validity was assessed by correlating their PRISM scores with scores on the Short-Form 36v2 quality of life instrument, the Pain Catastrophizing Scale, and the 0 to 10 Numeric Pain Scale. Content validity and test-retest reliability were assessed, and a factor analysis performed to identify relationships among the PRISM domains. PRISM was found to have good reliability and was significantly correlated with many of the subdomains of the other questionnaires. Qualitative data (n = 26) revealed that PRISM was well understood and that there was consistency in interpreting the task. Our data suggest that the PRISM task measures constructs relating to quality of life, pain catastrophizing, and pain intensity and probably measures suffering in patients with chronic non-cancer pain, providing a novel and quick tool for clinicians. ⋯ This study demonstrates the reliability and validity of the PRISM task for measuring the burden of pain in a population of chronic pain sufferers. Clinicians in the field of chronic pain management may find PRISM useful for monitoring the impact of pain management strategies on pain perception and the psychosocial variables that influence suffering.
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Randomized Controlled Trial
Reduction of pain-related fear and disability in post-traumatic neck pain: a replicated single-case experimental study of exposure in vivo.
For patients with acute post-traumatic neck pain (PTNP), pain-related fear has been identified as a potential predictor of chronic disability. If such is the case, fear reduction should enhance the prevention of further pain disability and distress after traumatic neck pain disability. However, exposure-based treatments have not been tested in patients with PTNP. Using a replicated single-case crossover phase design with multiple measurements, this study examined whether the validity of a graded exposure in vivo, as compared with usual graded activity, extends to PTNP. Eight patients who reported substantial pain-related fear were included in the study. Daily changes in pain intensity, pain-related fear, pain catastrophizing, and activity goal achievement were assessed. Before and after each intervention, and at 6-month follow-up, standardized questionnaires of pain-related fear and pain disability were administered, and, to quantify daily physical activity level, patients carried an ambulatory activity monitor. The results showed decreasing levels of self-reported pain-related fear, pain intensity, disability, and improvements in physical activity level only when graded exposure in vivo was introduced, and not in the graded activity condition. The results are discussed in the context of the search for customized treatments for PTNP. ⋯ This is the first study showing that the effects of graded exposure in vivo generalize to patients with chronic PTNP reporting elevated levels of pain-related fear. This could help clinicians to customize treatments for PTNP.