Pain
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Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity, and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified genome-wide association study and single nucleotide polymorphism-by-sex interaction analysis for cBP defined as "Back pain for 3+ months" in 202,077 males and 237,754 females of European ancestry from UK Biobank. ⋯ There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disk degeneration in males than in females (0.889 vs 0.638; P = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites.
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Mechanism-based classification of pain has been advocated widely to aid tailoring of interventions for individuals experiencing persistent musculoskeletal pain. Three pain mechanism categories (PMCs) are defined by the International Association for the Study of Pain: nociceptive, neuropathic, and nociplastic pain. Discrimination between them remains challenging. ⋯ A combination of features and methods, rather than a single method, was generally recommended to discriminate between PMCs. Two major limitations were identified: an overlap of findings of methods between categories due to mixed presentations and many methods considered discrimination between 2 PMCs but not others. The results of this review provide a foundation to refine methods to differentiate mechanisms for musculoskeletal pain.
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Intradermal administration of low-molecular-weight hyaluronan (LMWH) in the hind paw induced dose-dependent (0.1, 1, or 10 µg) mechanical hyperalgesia of similar magnitude in male and female rats. However, the duration of LMWH hyperalgesia was greater in females. This sexual dimorphism was eliminated by bilateral ovariectomy and by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to the G-protein-coupled estrogen receptor (GPR30) mRNA in females, indicating estrogen dependence. ⋯ Low-molecular-weight hyaluronan-induced hyperalgesia was significantly attenuated by pretreatment with high-molecular-weight hyaluronan (HMWH) in male, but not in female rats. After gonadectomy or treatment with ODN antisense to GPR30 expression in females, HMWH produced similar attenuation of LMWH-induced hyperalgesia to that seen in males. These experiments identify nociceptors at which LMWH acts to produce mechanical hyperalgesia, establishes estrogen dependence in the role of RHAMM in female rats, and establishes estrogen dependence in the inhibition of LMWH-induced hyperalgesia by HMWH.
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Codeine is one of the most commonly used opioid analgesics. Significant codeine-related morbidity and mortality prompted regulatory responses, with the up-scheduling of codeine combination analgesics to prescription-only medicines implemented in Australia in February 2018. This study investigated the impact of codeine up-scheduling on the number of codeine and other (noncodeine) prescription opioid-related emergency department (ED) presentations in a large metropolitan tertiary hospital. ⋯ Noncodeine prescription opioid-related (B = -1.90, P = 0.446) and ED presentations overall (B = -118.04, P = 0.140) remained unchanged immediately post-up-scheduling, with a significant change in trend from upward to downward for noncodeine (B = -0.76; P = 0.002) and ED presentations overall (B = -19.34, P = 0.022). A significant reduction of 4.58 (B = -4.58, P = 0.009) in codeine presentations involving subsequent hospital admission immediately post-up-scheduling was found; but no immediate reduction in codeine-related suicide-related overdoses, length of inpatient stay, or re-presentations (P > 0.0125; adjusted for multiple comparisons). Restricting supply of codeine to prescription-only may have resulted in less harmful codeine-related use in the community, without a corresponding immediate decrease in other opioid-related harms.
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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-functional magnetic resonance imaging data from 220 participants: 155 healthy controls and 65 individuals with chronic low back pain due to ankylosing spondylitis, a form of arthritis. ⋯ Females exhibited atypically higher functional segregation in the mid cingulate cortex and subgenual anterior cingulate cortex and lower connectivity in the network with the default mode and frontoparietal modules, whereas males exhibited stronger connectivity with the sensorimotor module. Classification models on nodal graph metrics could classify an individual's sex and whether they have chronic pain with high accuracies (77%-92%). These findings highlight the organizational abnormalities of resting-state-brain networks in people with chronic pain and provide a framework to consider sex-specific pain therapeutics.