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Propranolol is a nonselective β-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase () gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of , and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly ( = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction ( = 0.035). Cumulative response curves confirmed greater ( = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol's efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).
Learn More >Complex regional pain syndrome (CRPS) is a complex and often poorly understood condition, and people with CRPS will have diverse beliefs about their symptoms. According to the self-regulation model, these beliefs (termed "illness perceptions") influence health behaviors and outcomes. Previous studies have found that psychological factors influence CRPS outcomes, but few studies have investigated CRPS patients' illness perceptions specifically. The present study examined whether illness perceptions were related to pain intensity and other relevant outcomes in people with CRPS.
Learn More >Men and women can exhibit different pain sensitivities and many chronic pain conditions are more prevalent in one sex. Although there is evidence of sex differences in the brain, it is not known whether there are sex differences in the organization of large-scale functional brain networks in chronic pain. Here, we used graph theory with modular analysis and machine-learning of resting-state (RS)-fMRI data from 220 participants; 155 healthy controls and 65 individuals with chronic low back pain due to ankylosing spondylitis (AS), a form of arthritis.We found an extensive overlap in the graph partitions with the major brain intrinsic systems (i.e., default mode, central, visual and sensorimotor modules), but also sex-specific network topological characteristics in healthy people and those with chronic pain. People with chronic pain exhibited higher cross-network connectivity, and sex-specific nodal graph properties changes (i.e., Hubs disruption), some of which were associated with the severity of the chronic pain condition. Females exhibited atypically higher functional segregation in the mid- and subgenual cingulate cortex and lower connectivity in the network with the default mode and fronto-parietal modules; whereas males exhibited stronger connectivity with the sensorimotor module. Classification models on nodal graph metrics could classify an individuals' sex and whether they have chronic pain with high accuracies (77-92%). These findings highlight the organizational abnormalities of RS-brain networks in people with chronic pain and provide a framework to consider sex-specific pain therapeutics.
Learn More >Pain is a common non-motor symptom in patients with Parkinson's disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into three groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory (BPI) and McGill pain questionnaire (MPQ), PDQ-8 quality of life score, MDS-UPDRS scores, and non-motor symptoms). 159 non-demented PD patients (disease duration 10.2±7.6 years) and 37 healthy controls were recruited in four centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's BPI and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression and anxiety measures. Moderate intra- and inter-rater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.
Learn More >Intractable or recurrent chronic itch greatly reduces the patients' quality of life and impairs their daily activities. In this study, we investigated whether there are certain key signaling molecules downstream of the recently identified peptides mediating itch in the spinal cord. RNA sequencing analysis of mouse spinal cord in chronic itch models induced by squaric acid dibutylester and imiquimod showed that extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is the most significantly up-regulated gene cluster in both models. In four different mouse models of chronic itch, sustained ERK phosphorylation was detected mainly in spinal neurons, and MEK inhibitors significantly inhibited chronic itch in these models. Phosphorylated ERK (pERK) was observed in interneurons expressing receptors of different neuropeptides for itch, including GRPR, NPRA, NMBR or sst. Blocking GRPR and NPRA by genetic approaches or toxins in mice significantly attenuated or ablated spinal pERK. When HEK293T cells transfected with these receptors were exposed to their respective agonists, ERK was the most significantly activated intracellular signaling molecule. Together, our work showed that pERK is a unique marker for itch signal transmission in the spinal cord and an attractive target for the treatment of chronic itch.
Learn More >Opioids are the "gold standard" treatment for postoperative pain, but these drugs also have limiting adverse effects. Thus, adjuvant drugs might be useful in opioid therapy for postoperative pain. The aim of the present study was to evaluate the effect of Phα1β, a dual blocker of Cav2 and TRPA1 channels, on antinociceptive and adverse actions of morphine in a model of postoperative pain. Phα1β (100-300 pmol/site) or morphine (3-10 mg/kg), alone, largely reduced postoperative nociception. However, Phα1β (100 pmol/site) or morphine (10 mg/kg) also produced motor impairment. Lower doses of Phα1β (30 pmol/site) or morphine (1 mg/kg), that did not have an effect alone, showed antinociceptive effect when concomitantly administrated. Moreover, co-administration of Phα1β (30 pmol/site) with morphine (1 or 10 mg/kg) was unable to cause motor impairment. Preoperative repeated treatment with morphine increased the expression of Cav2 and TRPA1 channels in spinal cord, and caused tolerance and withdrawal syndrome, which were reversed with a single injection of Phα1β (30 pmol/site). When injected postoperatively, escalating doses of morphine worsened postoperative hyperalgesia, induced tolerance, and withdrawal syndrome. Similarly, Phα1β (30 pmol/site) reversed these adverse effects. Single or repeated morphine caused constipation, which was not altered by Phα1β. Thus, a low dose of Phα1β potentiated the analgesia, and reversed some adverse effects of morphine on operated mice, indicating the potential use of this agent as an adjuvant drug in opioid therapy for postoperative pain.
Learn More >Acupuncture for chronic cancer-related pain: a systematic review and network meta-analysis protocol.
Chronic cancer-related pain is one of the most common excruciating symptom that can be caused by the cancer (by the primary tumour or by metastases) or by its treatment (surgery, chemotherapy and radiotherapy). Although multiple clinical trials and systematic reviews have suggested that acupuncture could be effective in treating chronic cancer-related pain, the comparative efficacy and safety of these acupuncture methods remains unclear. We, therefore, performed this study to evaluate and rank the efficacy and safety of different acupuncture methods for chronic cancer-related pain.
Learn More >Not all factors that predict persistent pain and disability following whiplash injury are known. In particular, few physical factors, such as changes in movement and muscle behaviour, have been investigated. The aim of this study is to identify predictive factors that are associated with the development of persistent pain and disability following a whiplash injury by combining contemporary measures of physical function together with established psychological and pain-related predictive factors.
Learn More >Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontaneous. Given that one in three chronic pain patients do not respond to the treatments currently available, the need for more effective analgesics is evident. Two principal obstacles to the development of novel analgesic therapies are our limited understanding of how neuronal circuits that comprise these pain pathways transmit and modulate sensory information under normal circumstances and how these circuits change under pathological conditions leading to chronic pain states. In this review, we focus on the role of inhibitory interneurons in setting pain thresholds and, in particular, how disinhibition in the spinal dorsal horn can lead to aberrant sensory processing associated with chronic pain states.
Learn More >This international multidisciplinary consensus statement was developed to provide balanced guidance on the safe peri-operative use of opioids in adults. An international panel of healthcare professionals evaluated the literature relating to postoperative opioid-related harm, including persistent postoperative opioid use; opioid-induced ventilatory impairment; non-medical opioid use; opioid diversion and dependence; and driving under the influence of prescription opioids. Recommended strategies to reduce harm include pre-operative assessment of the risk of persistent postoperative opioid use; use of an assessment of patient function rather than unidimensional pain scores alone to guide adequacy of analgesia; avoidance of long-acting (modified-release and transdermal patches) opioid formulations and combination analgesics; limiting the number of tablets prescribed at discharge; providing deprescribing advice; avoidance of automatic prescription refills; safe disposal of unused medicines; reducing the risk of opioid diversion; and better education of healthcare professionals, patients and carers. This consensus statement provides a framework for better prescribing practices that could help reduce the risk of postoperative opioid-related harm in adults.
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