The journal of pain : official journal of the American Pain Society
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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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The firing rate of low threshold motor units is decreased in constant force contractions during experimental pain. However, as firing rate is a determinant of force, it is unclear how force is maintained. Increased synergist muscle activity may compensate. This was investigated by evaluation of motor unit firing rate in synergist ankle plantar flexor muscles (triceps surae). Single motor unit action potentials were recorded in medial gastrocnemius and soleus muscles with fine wire electrodes in 10 subjects. Gross muscle activity was estimated from surface electromyographic (EMG) recordings. Bolus injections of 5% hypertonic saline were injected into lateral gastrocnemius to induce pain (low intensity, 0.5 mL; high intensity, 1.5 mL). Subjects gently plantar-flexed the ankle to recruit 1 to 4 motor units and performed 3 20-second contractions to this target before, during, and after pain. Firing rate decreased approximately 12% in synergist heads of triceps surae during pain and recovered after pain. Despite reduced firing rate, root-mean-square surface EMG amplitude did not change. The effect of nociceptor stimulation is not restricted to painful muscles but reduces motor unit firing in synergist muscles. Changes in synergist muscles cannot explain the maintenance of muscle force. Maintenance of surface EMG amplitude suggests recruitment of additional motor units. ⋯ This study showed that activity of synergist muscles can be affected by muscle pain. However, the changes in activity of synergist muscles may not compensate for changes in the painful muscle. This finding provides evidence of more widespread effects of pain on muscle control.
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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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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.