The journal of pain : official journal of the American Pain Society
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Persistent inflammation promotes internalization of synaptic GluR2-containing, Ca(2+)-impermeable AMPA receptors (AMPARs) and insertion of GluR1-containing, Ca(2+)-permeable AMPARs at extrasynaptic sites in dorsal horn neurons. Previously we have shown that internalization of synaptic GluR2-containing AMPARs requires activation of spinal cord protein kinase C alpha (PKCα), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are unclear. Here, using antisense (AS) oligodeoxynucleotides (ODN) that specifically knock down PKCα, we found that a decrease in dorsal horn PKCα expression prevents complete Freund's adjuvant (CFA)-induced increase in functional expression of extrasynaptic Ca(2+)-permeable AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord. Augmented AMPA-induced currents and associated [Ca(2+)](i) transients were abolished, and the current rectification 1 day post-CFA was reversed. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those that exhibited strong adaptation. Finally, dorsal horn PKCα knockdown produced an antinociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain, indicating a role for PKCα in persistent inflammatory pain maintenance. Our results indicate that inflammation-induced trafficking of extrasynaptic Ca(2+)-permeable AMPARs in tonically firing SG neurons depends on PKCα, and that this PKCα-dependent trafficking may contribute to persistent inflammatory pain maintenance. ⋯ This study shows that PKCα knockdown blocks inflammation-induced upregulation of extrasynaptic Ca(2+)-permeable AMPARs in dorsal horn neurons and produces an antinociceptive effect during the maintenance period of inflammatory pain. These findings have potential implications for use of PKCα gene-silencing therapy to prevent and/or treat persistent inflammatory pain.
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Review Meta Analysis
The effects of graded motor imagery and its components on chronic pain: a systematic review and meta-analysis.
Graded motor imagery (GMI) is becoming increasingly used in the treatment of chronic pain conditions. The objective of this systematic review was to synthesize all evidence concerning the effects of GMI and its constituent components on chronic pain. Systematic searches were conducted in 10 electronic databases. All randomized controlled trials (RCTs) of GMI, left/right judgment training, motor imagery, and mirror therapy used as a treatment for chronic pain were included. Methodological quality was assessed using the Cochrane risk of bias tool. Six RCTs met our inclusion criteria, and the methodological quality was generally low. No effect was seen for left/right judgment training, and conflicting results were found for motor imagery used as stand-alone techniques, but positive effects were observed for both mirror therapy and GMI. A meta-analysis of GMI versus usual physiotherapy care favored GMI in reducing pain (2 studies, n = 63; effect size, 1.06 [95% confidence interval, .41, 1.71]; heterogeneity, I(2) = 15%). Our results suggest that GMI and mirror therapy alone may be effective, although this conclusion is based on limited evidence. Further rigorous studies are needed to investigate the effects of GMI and its components on a wider chronic pain population. ⋯ This systematic review synthesizes the evidence for GMI and its constituent components on chronic pain. This review may assist clinicians in making evidence-based decisions on managing patients with chronic pain conditions.
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Randomized Controlled Trial
Postoperative subcutaneous instillation of low-dose ketorolac but not hydromorphone reduces wound exudate concentrations of interleukin-6 and interleukin-10 and improves analgesia following cesarean delivery.
The objectives of this study were to test the effects of low-dose ketorolac and hydromorphone added to continuous local anesthetic wound instillation on surgical-site inflammatory mediators, postoperative pain, and opioid consumption. Sixty healthy women undergoing cesarean delivery were enrolled in this randomized, double-blinded study. Patients were randomized to receive a subcutaneous wound instillation of bupivacaine .5% at 10 mg/hour (active control), bupivacaine .5% with ketorolac .6 mg/hour, or bupivacaine .5% with hydromorphone .04 mg/hour for 48 hours postcesarean. Wound exudate was sampled at 4, 24, and 48 hours postcesarean and assayed for interleukins IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-12, tumor necrosis factor (TNF-α), interferon (INF-γ), and granulocyte-macrophage colony stimulating factor (GM-CSF). The addition of ketorolac to bupivacaine significantly decreased IL-6 (P = .012) and IL-10 (P = .005) compared to plain bupivacaine. Ketorolac, but not hydromorphone, was associated with a decrease in pain (P = .018) and analgesic use (P = .020) following cesarean delivery. Our results are compatible with the view that significant analgesics effects are mediated through local modulation of inflammatory events. Low-dose ketorolac administered into surgical wounds exert significant anti-inflammatory and analgesic effects and may be a valuable analgesic alternative to systemic nonsteroidal anti-inflammatories (NSAIDs) but with potentially fewer side effects. ⋯ This article demonstrates that low-dose ketorolac administered into wounds modulates local inflammatory events, decreases postoperative pain, and reduces opioid consumption. These results suggest that administration of NSAIDs into surgical wounds may be an analgesic alternative to higher systemic dosing of NSAIDs.
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Randomized Controlled Trial Multicenter Study
A randomized, placebo-controlled study of the impact of the 7-day buprenorphine transdermal system on health-related quality of life in opioid-naïve patients with moderate-to-severe chronic low back pain.
This study evaluated the impact of treatment with Buprenorphine Transdermal System (BTDS) on the health-related quality of life for patients with moderate-to-severe chronic low back pain (CLBP), and the correspondence between quality of life and pain. A multicenter, enriched, double-blind (DB), placebo-controlled, randomized trial evaluated BTDS 10 and 20 μg/hour for treatment of opioid-naïve patients with moderate-to-severe CLBP. The SF-36v2 survey, which measures 8 domains of quality of life, was administered at screening and following an open-label run-in period with BTDS and at weeks 4, 8, and 12 of the DB phase. Post hoc analyses compared SF-36v2 scores between BTDS and placebo groups during the DB phase. Condition burden was examined through comparisons with a U.S. general population sample. Correlations examined the correspondence between quality of life and pain measures. BTDS produced larger improvements than placebo at 12 weeks in all quality-of-life domains (Ps < .05). Treatment group differences in both physical and mental quality of life emerged by 4 weeks. Patients' pretreatment quality of life was worse than that in the general population (Ps < .05); only BTDS treatment eliminated deficits in pain, social functioning, and role limitations due to emotional health. Improvements in quality of life were moderately associated with pain reduction. These data suggest that moderate-to-severe CLBP patients receiving BTDS exhibited better quality of life than patients receiving placebo. ⋯ This post hoc analysis suggests that patients with moderate-to-severe CLBP treated with BTDS exhibit better health-related quality of life than those using placebo within 4 weeks of treatment, and were more likely to exhibit clinically meaningful improvements in quality of life following 12 weeks of treatment.
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Nociceptive stimuli can induce a transient suppression of electroencephalographic oscillations in the alpha frequency band (ie, alpha event-related desynchronization, α-ERD). Here we investigated whether α-ERD could be functionally distinguished in 2 temporally and spatially segregated subcomponents as suggested by previous studies. In addition, we tested whether the degree of dependence of nociceptive-induced α-ERD magnitude on the prestimulus α-power would have been larger than the degree of dependence on the poststimulus α-power. Our findings confirmed the dissociation between a sensory-related α-ERD maximally distributed over contralateral central electrodes, and a task-related α-ERD (possibly affected by motor-related activity), maximally distributed at posterior parietal and occipital electrodes. The cortical sources of these activities were estimated to be located at the level of sensorimotor and bilateral occipital cortices, respectively. Importantly, the time course of the α-ERD revealed that functional segregation emerged only at late latencies (400 to 750 ms) whereas topographic similarity was observed at earlier latencies (250 to 350 ms). Furthermore, the nociceptive-induced α-ERD magnitude was significantly more dependent on prestimulus than poststimulus α-power. Altogether these findings provide direct evidence that the nociceptive-induced α-ERD reflects the summation of sensory-related and task-related cortical processes, and that prestimulus fluctuations can remarkably influence the non-phase-locked nociceptive α-ERD. ⋯ Present results extend the functional understanding of α-oscillation suppression during pain perception and demonstrate the influence of prestimulus variability on this cortical phenomenon. This work has the potential to guide pain clinicians in a more accurate interpretation on physiological and psychological modulations of α-oscillations.