Accepted

Considering that insomnia and chronic pain are often comorbid, we aimed to compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), cognitive behavioral therapy for pain (CBT-P), and cognitive behavioral therapy for insomnia and pain (CBT-IP) in individuals with comorbid insomnia and chronic pain. We used PubMed, PsycINFO, CENTRAL, and Web of Science for our literature search. The outcomes included sleep, pain, disability, and depression at post-treatment and follow-up (3-12 months). Sixteen randomized controlled trials with 1094 participants were included. In the Bayesian network meta-analysis, CBT-I [standard mean difference (SMD) = -0.99, 95% credible interval (CrI) = -1.50 to -0.54] and CBT-IP (SMD = -0.70, 95% CrI = -1.60 to -0.08) were significantly more effective than the control for sleep at post-treatment. Additionally, CBT-I was significantly more effective than the control for pain, disability, and depression at post-treatment and sleep at follow-up. However, there were no significant differences in effectiveness between CBT-P and the control for any outcomes. Thus, CBT-I might be the most effective treatment option for individuals with comorbid insomnia and chronic pain. However, given the small sample sizes and high risk of bias of the included studies, these results must be interpreted with caution.

The relationship between sarcopenia and pain remains unclear; thus, this study evaluated whether muscle strength is independently associated with neuropathic-like pain symptoms in patients with chronic musculoskeletal pain. A cut-off score of painDETECT ≥13 was used to indicate a possible neuropathic component. Handgrip strength was measured, and muscle mass was estimated. A total of 2599 patients, including 439 patients who reported neuropathic-like pain symptoms (16.9%), were included for analysis. Handgrip strength was significantly lower in patients experiencing neuropathic-like pain symptoms (23.23 ± 10.57 vs. 24.82 ± 10.43 kg, < 0.001), and this result was chiefly found in female patients. However, there was no difference in estimated muscle mass. Shorter duration of pain, opioid usage, pain in lower limbs, sleep disturbance, and lower handgrip strength were significantly associated with neuropathic-like pain symptoms. In patients with handgrip strength below the reference values by sex, experiencing radiating pain and at least moderate sensory symptoms by light touch and thermal stimulation were more frequently reported. In conclusion, lower handgrip strength appeared to be an independent factor associated with symptoms suggestive of neuropathic pain in this population. Interventional studies are required to determine whether improvement in muscle strength can reduce the neuropathic pain component in chronic musculoskeletal pain.

The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.

Nucleoredoxin is a thioredoxin-like oxidoreductase that mainly acts as oxidase and thereby regulates calcium calmodulin kinase Camk2a, an effector of nitric oxide mediated synaptic potentiation and nociceptive sensitization. We asked here if and how NXN affects thermal sensation and nociception in mice using pan-neuronal NXN deletion driven by Nestin-Cre, and sensory neuron specific deletion driven by Advillin-Cre. In a thermal gradient ring, where mice can freely choose the temperature of well-being, Nestin-NXN mice avoided unpleasant cold temperatures. In neuropathic and inflammatory nociceptive models, Nestin-NXN and Advillin-NXN mice displayed subtle phenotypes of heightened heat nociception. Abnormal thermal in vivo responses were associated with heightened calcium influx upon stimulation of transient receptor channels, with heightened oxygen consumption upon disruption of the mitochondrial membrane potential and with higher density of neurite trees of primary sensory neurons of the dorsal root ganglia in cultures. The data suggest that loss of NXN's balancing redox functions leads to maladaptive changes in sensory neurons that manifest in vivo as polyneuropathy-like abnormal cold sensitivity and heat "pain".

Chronic abdominal pain (CAP) represents a common pediatric primary pain disorder that can have long-term effects on physical and mental health into adulthood. Pediatric CAP and Control cohorts recruited in childhood (∼11 years old, T1) and then assessed in emerging adulthood (∼20 years old, T2) were evaluated again for health outcomes in early adulthood (∼30 years old, T3) for the current study. Further, the study evaluated the mental and physical health of offspring of participants who had become parents. Participants who agreed to enroll at T3 (CAP: n = 90, Control: n = 55) completed measures regarding current health, health-related quality of life (HRQoL), and their child's health when applicable. Results indicated close to 20% of the CAP cohort reported recurrent CAP across all three timepoints. Participants with current CAP reported poorer HRQoL compared to participants with remitted CAP who reported poorer HRQoL compared to Control participants. The CAP cohort reported higher health-related anxiety compared to the Control cohort regardless of current pain status. CAP compared to Control participants reported greater emotional problems and fewer conduct problems in their children. Longitudinal studies are needed to assess the developmental course of pediatric chronic pain and intergenerational pathways of risk and resilience. Perspective: This article evaluates patterns of chronic abdominal pain from childhood into early adulthood. Patients with pediatric chronic abdominal pain continue to present with health-related anxiety in adulthood and report greater emotional problems in offspring.

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons. Using 2D difference gel electrophoresis with tandem mass spectrometry, we have identified that the scaffolding protein 14-3-3γ is upregulated in peripheral sensory neurons following activation of JNK with norBNI. Knockdown of 14-3-3γ by siRNA eliminates the long-term reduction in KOR-mediated cAMP signaling by norBNI in peripheral sensory neurons in culture. Similarly, knockdown of 14-3-3γ in the rat hind paw abolished the norBNI-mediated long-term reduction in peripheral KOR-mediated antinociception. Further, overexpression of 14-3-3γ in KOR expressing CHO cells prevented KOR-mediated inhibition of cAMP signaling. These long-term effects are selective for KOR as heterologous regulation of other receptor systems was not observed. These data suggest that 14-3-3γ is both necessary and sufficient for the long-term inhibition of KOR by norBNI in peripheral sensory neurons.

Somatic symptom disorder (SSD), which occurs in about 5-7 percent of the adult population, involves heightened physical and emotional sensitivity to pain. However, its neural mechanism remains elusive and thus hinders effective clinical intervention. In this study, we employed chronic restraint stress (CRS)-induced hyperalgesia as a mouse model to investigate the neural mechanism underlying SSD and its pharmacological treatment. We found that CRS induced hyperactivity of anterior cingulate cortex (ACC), whereas chemogenetic inhibition of such hyperactivity could prevent CRS-induced hyperalgesia. Systematic application and ACC local infusion of fluoxetine alleviated CRS-induced hyperalgesia. Moreover, we found that fluoxetine exerted its anti-hyperalgesic effects through inhibiting the hyperactivity of ACC and upregulating 5-HT1A receptors. Our study thus uncovers the functional role of 5-HT signaling in modulating pain sensation and provides a neural basis for developing precise clinical intervention for SSD.

Chronic neck pain is a common musculoskeletal disorder. Previous studies have found that chronic neck pain is associated with changes in neck muscle morphology and fat infiltration (FI). This systematic review summarizes and analyzes all studies on neck muscle morphology in patients with chronic nonspecific neck pain (CNNP).

Chronic migraine is a common neurovascular brain disorder with substantial economic costs. We performed a systematic review to identify economic evaluations of pharmacological treatments for adults with chronic migraine.