The journal of pain : official journal of the American Pain Society
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The use of paclitaxel (Taxol), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy [CIPN]), which predominantly results in sensory dysfunction, including chronic pain. Here we show that paclitaxel CIPN was associated with induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia. Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons whereas CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in dorsal root ganglia large and medium-sized neurons but not in small neurons mainly dissociated from paclitaxel-treated but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes, but no CCR2 signal was detected in the spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between dorsal root ganglion neurons plays a critical role in the development of paclitaxel CIPN, and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. ⋯ CIPN is a severe side effect accompanying paclitaxel chemotherapy and lacks effective treatments. The current study suggests that blocking MCP-1/CCR2 signaling could be a new therapeutic strategy to prevent or reverse paclitaxel CIPN. This preclinical evidence encourages future clinical evaluation of this strategy.
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Genetic variation in the COMT gene is thought to have clinical implications for pain perception and pain treatment. In the present study, we first evaluated the association between COMT rs4680 and the analgesic response to intrathecal morphine in patients with chronic low back pain to provide confirmation of previously reported positive findings. Next, we assessed the relationship between rs4680 and headache response to triptans in 2 independent cohorts of migraine patients. In patients with chronic low back pain (n = 74), logistic stepwise regression analysis showed that age (odds ratio [OR]: .90, 95% confidence interval [CI]: .85-.96, P = .002) and the presence of the COMT Met allele (vs Val/Val, OR: .21, 95% CI: .04-.98, P = .048) were predictive factors for lower risk of poor analgesic response to intrathecal morphine. Intriguingly, in migraine patients, the COMT rs4680 polymorphism influenced headache response to triptans in the opposite direction. Indeed, in an exploratory cohort of migraine patients without aura (n = 75), homozygous carriers of the COMT 158Met allele were found at increased risk to be poor responders to frovatriptan when compared to homozygous patients for the Val allele (OR: 5.20, 95% CI: 1.25-21.57, P = .023). In the validation cohort of migraine patients treated with triptans other than frovatriptan (n = 123), logistic stepwise regression analysis showed that use of prophylactic medications (OR: .43, 95% CI: .19-.99, P = .048) and COMT Met/Met genotype (vs Val/Val, OR: 4.29, 95% CI: 1.10-16.71, P = .036) were independent risk factors for poor response to triptans. ⋯ This study highlights the importance of COMT rs4680 in influencing the clinical response to drugs used for chronic pain, including opioid analgesics and triptans. These findings also underline a complex relationship between COMT genotypes and pain responder status.
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Little is known about how far opioid shoppers travel or how often they cross state lines to fill their opioid prescriptions. This retrospective cohort study evaluated these measures for opioid shoppers and nonshoppers using a large U.S. prescription database. Patients with ≥3 opioid dispensings were followed for 18 months. A subject was considered a shopper when he or she filled overlapping opioid prescriptions written by >1 prescriber at ≥3 pharmacies. A heavy shopper had ≥5 shopping episodes. Outcomes assessed were distance traveled among pharmacies and number of states visited to fill opioid prescriptions. A total of 10,910,451 subjects were included; .7% developed any shopping behavior and their prescriptions accounted for 8.6% of all opioid dispensings. Shoppers and heavy shoppers were younger than the nonshoppers. Shoppers traveled a median of 83.8 miles, heavy shoppers 199.5 miles, and nonshoppers 0 miles. Almost 20% of shoppers or heavy shoppers, but only 4% of nonshoppers, visited >1 state. Shoppers traveled greater distances and more often crossed state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. Sharing of data among prescription-monitoring programs will likely strengthen those programs and may decrease shopping behavior. ⋯ This study shows that opioid shoppers travel greater distances and more often cross state borders to fill opioid prescriptions than nonshoppers, and their dispensings accounted for a disproportionate number of opioid dispensings. The findings support the need for data sharing among prescription-monitoring programs to deter opioid shopping behavior.
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Primary dysmenorrhea is a common painful condition in women that recurs every month across the reproductive years. The recurrent nociceptive input into the central nervous system that occurs during menstruation each month in women with dysmenorrhea is hypothesized to lead to increased sensitivity to painful stimuli. We investigated whether women with primary dysmenorrhea are hyperalgesic to deep muscle pain induced by a cleanly nociceptive method of hypertonic saline injection. Pain stimulation was applied both within an area of referred menstrual pain (lower back) and at a remote site outside of referred menstrual pain (forearm) in 12 healthy women with severe dysmenorrhea and 9 healthy women without dysmenorrhea, at 3 phases of the menstrual cycle: menstruation and follicular and luteal phases. Women rated their pain severity on a 100-mm visual analog scale every 30 seconds after injection until the pain subsided. In both groups of women, menstrual cycle phase had no effect on the reported intensity and duration of muscle pain. However, women with dysmenorrhea had increased sensitivity to experimental muscle pain both at the site of referred pain and at a remote nonpainful site, as assessed by peak pain severity visual analog scale rating, area under the visual analog scale curve, and pain duration, compared to women without dysmenorrhea. These data show that women with severe primary dysmenorrhea, who experience monthly menstrual pain, are hyperalgesic to deep muscle pain compared to women without dysmenorrhea. ⋯ Our findings that dysmenorrheic women are hyperalgesic to a clinically relevant, deep muscle pain in areas within and outside of referred menstrual pain indicates lasting changes in pain sensitivity outside of the painful period during menstruation.
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In this study, effects of chronic pain and pain-related fear on orienting and maintenance of attention toward pain stimuli were evaluated by tracking eye movements within a dot-probe paradigm. The sample comprised matched chronic pain (n = 24) and pain-free (n = 24) groups, each of which included lower and higher fear of pain subgroups. Participants completed a dot-probe task wherein eye movements were assessed during the presentation of sensory pain-neutral, health catastrophe-neutral, and neutral-neutral word pairs. Higher fear of pain levels were associated with biases in 1) directing initial gaze toward health catastrophe words and, among participants with chronic pain, 2) subsequent avoidance of threat as reflected by shorter first fixation durations on health catastrophe words compared to pain-free cohorts. As stimulus word pairs persisted for 2,000 ms, no group differences were observed for overall gaze durations or reaction times to probes that followed. In sum, this research identified specific biases in visual attention related to fear of pain and chronic pain during early stages of information processing that were not evident on the basis of later behavior responses to probes. ⋯ Effects of chronic pain and fear of pain on attention were examined by tracking eye movements within a dot-probe paradigm. Heightened fear of pain corresponded to biases in initial gaze toward health catastrophe words and, among participants with chronic pain, subsequent gaze shifts away from these words. No reaction time differences emerged.