The journal of pain : official journal of the American Pain Society
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Conditioned pain modulation (CPM) encompasses the effects of inhibitory and facilitatory pain modulatory systems and is inefficient in some chronic pain states. A proportion of healthy subjects also exhibit little or no CPM, perhaps suggesting that inherent factors such as gender or genetics may be influential. However, there is no consensus on how best to determine a meaningful CPM effect. This study aimed to determine the proportion of pain-free subjects exhibiting a meaningful CPM effect. Analyses of associations between 5HTTLPR (serotonin transporter-linked polymorphic region) polymorphisms on the serotonin transporter gene (SLC6A4), gender, and CPM effect were also carried out. A total of 125 healthy subjects (47 male; 78 female) underwent pressure pain threshold testing before, during, and after a cold pressor conditioning stimulus. A buccal cell sample was collected for analysis of 5HTTLPR genotype. Meaningful CPM effect was determined as an increase in pressure pain threshold values from baseline greater than the inherent error of measurement, calculated as 5.3%. During the conditioning stimulus, 116 subjects (92.8%) exhibited a CPM effect whereas 9 did not. CPM effect did not differ significantly between genders or between 5HTTLPR genotypes. This provides a clear basis on which to determine the proportion of patients with a chronic pain disorder that exhibit a meaningful CPM effect. ⋯ This study proposes a method for calculating meaningful CPM effect and reports the proportion and magnitude of effect elicited in a large sample. Associations between CPM, gender, and genotype were also analyzed. Clarification of normal CPM response may help to elucidate the mechanisms driving CPM inefficiency in chronic pain.
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Morphine and fentanyl produce antinociception in part by binding to mu-opioid receptors in the periaqueductal gray (PAG). The present study tested the hypothesis that the PAG also contributes to the antinociceptive effects of other commonly used opioids (oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone (32-188 μg/.4 μL) into the ventrolateral PAG of the rat produced a dose-dependent increase in hot plate latency. This antinociception was evident within 5 minutes and nearly gone by 30 minutes. In contrast, no antinociception was evident following microinjection of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range of doses and test times. Antinociception was evident following subsequent microinjection of morphine into the same injection sites or following systemic administration of buprenorphine, demonstrating that the injections sites and drugs could support antinociception. Antinociception to systemic, but not PAG, administration of buprenorphine occurred in both male and female rats. These and previous data demonstrate that the mu-opioid receptor signaling pathway for antinociception in the PAG is selectively activated by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others (eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce antinociception following systemic administration demonstrates that mu-opioid receptor signaling varies depending on location in the nervous system. ⋯ This study demonstrates that the PAG contributes to the antinociceptive effects of some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone or buprenorphine). Such functional selectivity in PAG-mediated opioid antinociception helps explain why the analgesic profile of opioids is so variable.
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Whether patients receive guideline-concordant opioid therapy (OT) is largely unknown and may vary based on provider and patient characteristics. We assessed the extent to which human immunodeficiency virus (HIV)-infected and uninfected patients initiating long-term (≥ 90 days) OT received care concordant with American Pain Society/American Academy of Pain Medicine and Department of Veterans Affairs/Department of Defense guidelines by measuring receipt of 17 indicators during the first 6 months of OT. Of 20,753 patients, HIV-infected patients (n = 6,604) were more likely than uninfected patients to receive a primary care provider visit within 1 month (52.0% vs 30.9%) and 6 months (90.7% vs 73.7%) and urine drug tests within 1 month (14.8% vs 11.5%) and 6 months (19.5% vs 15.4%; all P < .001). HIV-infected patients were also more likely to receive OT concurrent with sedatives (24.6% vs 19.6%) and a current substance use disorder (21.6% vs 17.2%). Among both patient groups, only modest changes in guideline concordance were observed over time: urine drug tests and OT concurrent with current substance use disorders increased, whereas sedative coprescriptions decreased (all Ps for trend < .001). Over a 10-year period, on average, patients received no more than 40% of recommended care. OT guideline-concordant care is rare in primary care, varies by patient/provider characteristics, and has undergone few changes over time. ⋯ The promulgation of OT clinical guidelines has not resulted in substantive changes over time in OT management, which falls well short of the standard recommended by leading medical societies. Strategies are needed to increase the provision of OT guideline-concordant care for all patients.
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Neuropathic pain is a debilitating condition caused by a lesion or disease of the somatosensory nervous system. Statins inhibit the rate-limiting step in cholesterol biosynthesis by blocking 3-hydroxy-3-methyl glutaryl coenzyme A reductase. Apart from the cholesterol-reducing actions of statins, recent studies have shown their pleiotropic actions; accordingly, their usefulness in attenuating different disease states has been described in preclinical studies. Studies in animals have also suggested their beneficial effects in attenuating neuropathic pain in various animal models of neuropathy. In these studies, their usefulness has been ascribed to cholesterol-independent actions, including anti-inflammatory, antioxidant, and neuromodulatory effects. On the contrary, clinical evidence suggests that statin administration in patients is associated with development of neuropathy, suggesting the dichotomous role of statins in neuropathic pain. The present review discusses the pain-attenuating as well as pain-inducing role of statins in preclinical and clinical studies, respectively. Furthermore, the review provides mechanistic insight to explain the paradoxical nature of this class of drugs in neuropathy in preclinical and clinical studies. ⋯ The article reviews the pain-inducing role of statins in clinical studies and its neuropathic pain-attenuating role in preclinical studies with possible mechanisms. Understanding key differences in mechanisms may help to attenuate pain induction in the clinical setting and may possibly project statins as neuropathic pain-attenuating agents.