The journal of pain : official journal of the American Pain Society
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Previous studies have shown that chemokines might play a role in the pathology of chronic pain. The purpose of this study was to provide an immunohistochemical description of the distribution of CX3CL1 (fractalkine) and its receptor CX3CR1 in the rat spinal cord in a model of inflammatory pain induced by unilateral intraplantar complete Freund's adjuvant (CFA) and in a model of neuropathic pain induced by L5 spinal nerve ligation (modified Chung model or mSNL). In naïve rats, CX3CL1 is found in the cytoplasm of neurons as shown by colocalization of CX3XL1 and NeuN. Similar distribution of CX3CL1 was observed after CFA, whereas after mSNL, CX3CL1 was not only observed in neurons but also found in astrocytes, as shown by colocalization of CX3CL1 and GFAP. Weak immunoreactivity for the CX3CL1 receptor, CX3CR1, was found in microglia in the spinal cord of either naïve rats or rats with inflammation. However, after spinal nerve injury, CX3CR1-LI was upregulated in microglia throughout the dorsal horn. ⋯ This study shows that spinal nerve injury, but not peripheral inflammation, induces the expression of a chemokine, CX3CL1 (fractalkine), in astrocytes and upregulates CX3CR1 in microglia in the spinal cord. This selective regulation of CX3CL1 and its receptor, CX3CR1, suggests that these chemokines may represent new targets for the treatment of neuropathic pain.
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Although epinephrine (EPI) has been suggested to contribute to the pain and hyperalgesia associated with inflammation and nerve injury, there have been very few in vivo electrophysiologic studies of the effects of EPI on nociceptors. We found with the single-unit recording technique that the intradermal administration of EPI resulted in excitation of a group of C fibers and a decrease in the mechanical activation threshold in a non-overlapping group. Unexpectedly, the fibers that were neither excited nor demonstrated a decrease in threshold demonstrated as a group a significant increase in response to sustained suprathreshold mechanical stimuli, an effect not observed in the other 2 groups of C fibers. This identifies a novel response of C-fiber nociceptors to an inflammatory mediator and suggests it is present in a class of C fibers previously considered unresponsive to hyperalgesic inflammatory mediators. ⋯ Our study provides support for the suggestion that EPI, a neuroendocrine stress hormone as well as an inflammatory mediator, might contribute to pain syndromes, especially in the setting of chronic stress.
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Chronic pain patients often report fears that movement will exacerbate their symptoms. The Tampa Scale of Kinesiophobia (TSK) was designed to assess fear of movement. Previous findings with the TSK showed inconsistent factor structures and varied measurement properties. The TSK was completed by a sample of 233 patients with fibromyalgia syndrome who were being evaluated for participation in a rehabilitation program. A principal components analysis initially derived a 5-factor solution. However, the factor structure accounted for less than 50% of the variance, and the internal consistency of the factors was below conventional standards (<0.70). A series of principal components analyses "forcing" different factor structures revealed that the best solution was a single factor solution that contained 4 of the original 17 TSK items, accounting for more than 50% of the variance with adequate internal consistency (alpha =0.71). Inspection of the content of these 4 items, however, suggests that this factor more likely represents catastrophic thinking, rather than fear of movement. Nevertheless, for patients with fibromyalgia syndrome, a 4-item TSK appears to retain the most acceptable factor solution while also maintaining adequate internal consistency. ⋯ Although the TSK is one of the most commonly used measures of fear of movement, the present study using the TSK with a sample of patients with fibromyalgia syndrome suggests that the measurement properties of the TSK are problematic. Recommendations for use of the TSK are provided.
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Randomized Controlled Trial Clinical Trial
Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.
Oxytrex is a novel drug that combines oxycodone with ultralow-dose naltrexone, an opioid antagonist. Ultralow-dose opioid antagonists have been demonstrated to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rodents. This 3-week, Phase II clinical trial assessed safety and analgesic efficacy of Oxytrex in patients with moderate to severe pain from osteoarthritis. Patients with a pain score > or =5 received placebo, oxycodone 4 times a day (qid), Oxytrex qid, or Oxytrex twice a day (bid). All active treatment groups received the same total daily dose and dose escalation of oxycodone starting at 10 and ending at 40 mg/day. Importantly, the Oxytrex bid group received a lower daily dose of naltrexone than Oxytrex qid (0.002 vs 0.004 mg/day). Oxytrex bid produced a 39% reduction in pain intensity, which was significantly greater than that of placebo (P < .001), oxycodone qid (P = .006), and Oxytrex qid (P = .003). Oxytrex bid was also superior to placebo in quality of analgesia (P = .002), duration of pain control each day (P = .05), patients' global assessments (P = .04), and the Western Ontario and MacMaster Universities Osteoarthritis Index total score (P = .03). The incidence of side effects was comparable between active treatments. In this Phase II dose-ranging study, Oxytrex bid demonstrated greater pain relief with a more convenient dosing schedule compared to oxycodone qid. ⋯ Preclinical data have shown ultralow-dose opioid antagonists to enhance and prolong opioid analgesia while reducing analgesic tolerance and physical dependence. Recent molecular pharmacology data show a mechanism of action to be the prevention of aberrant G protein coupling by opioid receptors that underlies opioid tolerance and dependence.
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Temporal summation of deep tissue pain has been suggested to be facilitated in chronic musculoskeletal pain syndromes. This study aimed to test whether temporal summation of mechanical induced pressure pain is (1) more pronounced at short (1 second) interstimulus intervals (ISIs) compared with long ISI (30 seconds), (2) more potent than summation elicited by pure skin stimulation, and (3) attenuated in women compared with men. Twelve age-matched men and 12 women were included. A computer-controlled pressure stimulator with a probe surface of 1 cm2 was used to give 10 stimulations to the tibialis anterior, tibia periosteum, and the first web of the hand. Sequential stimulation at pressure pain threshold intensity was applied with different ISIs (1, 3, 5, 10, and 30 seconds). The pain intensity was assessed on a visual analog scale (VAS) after each individual stimulus. The VAS scores after the 10th stimulation with 1-second ISI were increased (P < .05) by 418% +/- 77%, 378% +/- 89%, and 234% +/- 66% compared with the first stimulation for tibia, tibialis anterior, and web, respectively. Temporal summation of pain was observed for all ISIs in tibialis anterior and tibia, eg, 30-second ISI evoked a VAS increase of 192% +/- 71 % (tibia) and 117% +/- 42% (tibialis anterior) compared with the first stimulation. The VAS score after the 10th web stimulation was smaller (P < .05) than that of the 10th tibialis anterior or tibia stimulation. A regression analysis between stimulation number and VAS score showed that the pain intensity increased progressively (1) more for 1-second ISIs compared with longer ISIs (P < .01) and (2) faster in deep tissue compared with skin (P < .01). No gender difference was observed. The temporal summation might be related to both central and peripheral mechanisms. ⋯ Pain originating in deep tissue influences central pain processing systems more than superficial tissue. This might be of importance in patients with musculoskeletal pain.