The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial Comparative Study
Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy.
Evidence suggests that patients on opiate maintenance therapy for the treatment of addiction present with opioid-induced hyperalgesia. This study compared the experimental (cold-pressor, electrical stimulation) pain responses of 82 treatment-seeking heroin-dependent adults, randomized to methadone (METH, n = 11) or buprenorphine (BUP, n = 64) therapy, with matched drug free controls (n = 21). Heroin-dependent participants were evaluated at baseline (treatment entry), medication (METH or BUP) stabilization (4-8 weeks), and chronic administration (12-18 weeks), at trough (just prior to dosing) and peak (3 hours after dosing) plasma levels. Collection of the control group's pain responses occurred twice during a single session, 3 hours apart. Baseline comparisons indicate that heroin-dependent individuals demonstrate significantly shorter latencies to threshold and tolerance for cold-pressor pain than the control group. Across pain stimuli and time points, little change in pain responses was found over time, the exception being cold pressor pain tolerance, for which hyperalgesia significantly increased at trough METH/BUP levels in both groups as they stabilized in treatment. We conclude that heroin-dependent individuals are hyperalgesic, and that once stabilized in treatment, are not different in pain responses regardless of treatment agent. The effects of nonpharmacologic therapy and previous heroin use may explain increased hyperalgesia found with treatment. ⋯ To better understand the clinical phenomenon of opioid-induced hyperalgesia, this article describes experimental pain responses of heroin-dependent participants both prior to and over the course of maintenance therapy with methadone or buprenorphine. Hyperalgesia is present with illicit and treatment opioid use, and does not appear to appreciably improve over the course of treatment.
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This study evaluates the construct validity (including sensitivity to change) of the numerical rating scale (NRS) for pain intensity (I) and unpleasantness (U) and participant pain scale preferences in children/adolescents with acute postoperative pain. Eighty-three children aged 8 to 18 years (mean = 13.8, SD = 2.4) completed 3 pain scales including NRS, Verbal Rating Scale (VRS), and faces scales (Faces Pain Scale-Revised [FPS-R] and Facial Affective Scale [FAS], respectively) for pain intensity (I) and unpleasantness (U) 48 to 72 hours after major surgery, and the NRS, VRS and Functional Disability Index (FDI) 2 weeks after surgery. As predicted, the NRSI correlated highly with the VRSI and FPS-R and the NRSU correlated highly with the VRSU and FAS 48 to 72 hours after surgery. The FDI correlated moderately with the NRS at both time points. Scores on the NRSI and NRSU at 48 to 72 hours were significantly higher than at 2 weeks after surgery. Children found the faces scales the easiest to use while the VRS was liked the least and was the hardest to use. The NRS has adequate evidence of construct validity including sensitivity for both pain intensity and unpleasantness. This study further supports the validity of the NRS as a tool to measure both intensity and unpleasantness of acute pain in children. ⋯ This article evaluates the construct validity including sensitivity of the Numerical Rating Scale for pain intensity and pain unpleasantness over time in children after major surgery. The NRS could be used by clinicians to assess these 2 different dimensions of children's pain experience in acute pain settings.
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Understanding individual differences in the variability of fibromyalgia pain can help elucidate etiological mechanisms and treatment targets. Past research has shown that spatial extent of pain, negative mood, and aftersensation (pain ratings taken after experimental induction of pain) accounts for 40 to 50% of the variance in clinical pain. Poor sleep is hypothesized to have a reciprocal relationship with pain, and over 75% of individuals with fibromyalgia report disturbed sleep. We hypothesized that measures of sleep would increase the predictive ability of the clinical pain model. Measures of usual pain, spatial extent of pain, negative mood, and pain aftersensation were taken from 74 adults with fibromyalgia. Objective (actigraph) and subjective (diary) measures of sleep duration and nightly wake time were also obtained from the participants over 14 days. Hierarchical regression indicated that greater spatial extent (R(2) = .26), higher aftersensation ratings (R(2) = .06), and higher negative mood (R(2) = .04) accounted for 36% of the variance in clinical pain (average of 14 daily pain ratings). None of the sleep variables were significant predictors of clinical pain. Results replicate previous research and suggest that spatial extent of pain, pain aftersensation, and negative mood play important roles in clinical pain, but sleep disturbance did not aid in its prediction. ⋯ This study suggests that measures of sleep duration and nightly wake time do not predict fibromyalgia pain at the group level. Fibromyalgia patients may benefit from a 3-pronged approach to pain management: reducing pain's spatial extent, normalization of central nervous system hypersensitivity, and psychobehavioral therapies for negative mood.
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Comparative Study
Effects of the δ opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats.
The delta opioid receptor agonist SNC80 produces both antinociceptive and antidepressant effects in rodents. This profile suggests that SNC80 may also reverse prodepressant effects of pain. Accordingly, this study compared SNC80 effects in complementary assays of pain-stimulated and pain-depressed behavior in rats. Intraperitoneal injection of dilute acid served as an acute noxious visceral stimulus in rats to stimulate abdominal stretching (a pain-stimulated behavior) or depress intracranial self-stimulation of the medial forebrain bundle (ICSS; a pain-depressed behavior). When administered once per week to minimize acute tolerance, SNC80 (1-10 mg/kg IP) decreased acid-stimulated stretching but had little effect on acid-induced depression of ICSS. More frequent SNC80 administration produced tolerance to SNC80 effects on acid-stimulated stretching, but unmasked antinociception in the assay of acid-depressed ICSS. SNC80 did not facilitate ICSS in the absence of pain, and effects of SNC80 were not duplicated by ARM390, a reputed delta agonist congener of SNC80 that does not internalize delta receptors. These findings support continued consideration of delta agonists as candidate analgesics to treat prodepressant effects of pain and illustrate the potential for diametrically opposite effects of drug treatments on preclinical measures of pain-stimulated and pain-depressed behavior. ⋯ The delta opioid agonist SNC80 blocked pain-related depression of intracranial self-stimulation in rats, suggesting that delta agonists may be useful to treat prodepressant effects of pain. Repeated SNC80 produced tolerance to SNC80 antinociception in a conventional assay of pain-stimulated behavior but unmasked SNC80 antinociception in an assay of pain-depressed behavior.
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Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical for neuronal plasticity. However, how it participates in central sensitization underlying chronic pain is unclear. Here, we show that NMDA receptors are required for the functional role of spinal cord mTOR in bone cancer pain induced by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, a specific mTOR inhibitor, dose dependently attenuated the development and maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. Rapamycin alone did not affect locomotor activity and acute responses to thermal or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) was increased time dependently in L(4-5) dorsal horn and transiently in L(4-5) dorsal root ganglions on the ipsilateral side after PCC injection, although total expression of mTOR or p70S6K was not changed in these regions. The increases in dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn activation of the mTOR pathway participates in NMDA receptor-triggered dorsal central sensitization under cancer pain conditions. ⋯ The present study shows that inhibition of spinal mTOR blocks cancer-related pain without affecting acute pain and locomotor function. Given that mTOR inhibitors are FDA-approved drugs, mTOR in spinal cord may represent a potential new target for preventing and/or treating cancer-related pain.