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Females demonstrate heightened central sensitization (CS), a risk factor for chronic pain characterized by enhanced responsivity of central nervous system nociceptors to normal or subthreshold input. Sleep disruption increases pain sensitivity, but sex has rarely been evaluated as a moderator and few experiments have measured CS. We evaluated whether two nights of sleep disruption alter CS measures of secondary hyperalgesia and mechanical temporal summation in a sex-dependent manner. We also evaluated differences in measures of pain sensitivity. Seventy-nine healthy adults (female n = 46) participated in a randomized crossover experiment comparing two consecutive nights of eight pseudorandomly distributed forced awakenings (FA [-200 min sleep time]) against two nights of undisturbed sleep (US). We conducted sensory testing the mornings following Night 2; the heat-capsaicin pain model was used to induce secondary hyperalgesia. FA reduced total sleep time (REM and NREM Stage 3) more profoundly in males. We observed divergent, sex-dependent effects of FA on secondary hyperalgesia and temporal summation. FA significantly increased secondary hyperalgesia in males and significantly increased temporal summation in females. Sex differences were not attributable to differential sleep loss in males. FA also significantly reduced heat-pain threshold and cold pressor pain tolerance, independently of sex. Sleep disruption enhances different pain facilitatory measures of CS in males and females suggesting that sleep disturbance may increase risk for chronic pain in males and females via distinct pathways. Findings have implications for understanding sex differences in chronic pain and investigating sleep in chronic pain prevention efforts.

Chronic knee pain, most commonly caused by knee osteoarthritis, is a prevalent condition which in most cases can be effectively treated through conservative, non-surgical care involving exercise therapy, education, psychosocial support, and weight loss. However, most people living with chronic knee pain do not receive adequate care, leading to unnecessary use of opiates and surgical procedures. Assess the efficacy of a remotely delivered digital care program for chronic knee pain. We enrolled 162 participants into a randomized controlled trial between January and March 2017. Participants were recruited from participating employers using questionnaires for self-assessment of their knee pain, and randomized into treatment (n=101) and control (n=61) groups. Participants in the treatment group were enrolled in the Hinge Health digital care program for chronic knee pain. This is a remotely delivered, home-based 12-week intervention that includes sensor-guided exercise therapy, education, cognitive behavioral therapy, weight loss, and psychosocial support through a personal coach and team-based interactions. The control group received three education pieces regarding self-care for chronic knee pain. Both groups had access to treatment-as-usual. The primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale and KOOS Physical Function Shortform (KOOS-PS). Secondary outcomes were visual analog scales (VAS) for pain and stiffness respectively, surgery intent, and self-reported understanding of the condition and treatment options. Outcome measures were analyzed by intention to treat (excluding 7 control participants who received the digital care program due to administrative error) and per protocol. In an intent-to-treat analysis the digital care program group had a significantly greater reduction in KOOS Pain compared to the control group at the end of the program (greater reduction of 7.7, 95% CI 3.0 to 12.3, P=.002), as well as a significantly greater improvement in physical function (7.2, 95% CI 3.0 to 11.5, P=.001). This was also reflected in the secondary outcomes VAS pain (12.3, 95% CI 5.4 to 19.1, P<.001) and VAS stiffness (13.4, 95% CI 5.6 to 21.1, P=.001). Participants' self-reported likelihood (from 0% to 100%) of having surgery also reduced more strongly in the digital care program group compared to the control group over the next 1 year (-9.4 percentage points, pp, 95% CI -16.6 to -2.2, P=.01), 2 years (-11.3 pp, 95% CI -20.1 to -2.5, P=.01), and 5 years (-14.6 pp, 95% CI -23.6 to -5.5, P=.002). Interest in surgery (from 0 to 10) also reduced more so in the digital care program compared to control group (-1.0, 95% CI -1.7 to -0.2, P=.01). Participants' understanding of the condition and treatment options (on a scale from 0 to 4) increased more substantially for participants in the digital care program than those in the control group (0.9, 95% CI 0.6 to 1.3, P<.001). In an analysis on participants that completed the intervention (per protocol analysis) all primary and secondary outcomes remained significant at greater effect magnitudes compared to intention to treat, with those completing the program showing a 61% (95% CI 48 to 74) reduction in VAS pain compared to 21% (95% CI 5 to 38) in the control group (P<.001). Accounting for the cost of administering the program, we estimate net cost savings on surgery alone of US $4340 over 1 year and $7900 over 5 years for those participants completing the digital care program compared to those in the control group receiving treatment-as-usual. In an exploratory subgroup analysis including only participants exhibiting clinical symptoms of osteoarthritis the program proved equally effective. This trial provides strong evidence that a comprehensive 12-week digital care program for chronic knee pain, including osteoarthritis, yields significantly improved outcomes for pain, physical function, stiffness, surgery risk, and understanding of the condition, compared to a control group. International Standard Randomized Controlled Trial Number (ISRCTN) 13307390; http://www.isrctn.com/ISRCTN13307390 (Archived by WebCite at http://www.webcitation.org/6ycwjGL73).

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections. These neural changes may be critical for the maintenance of pathological pain.

Background & objectives: Tension-type headache (TTH) is the most common type of primary headache disorder. Its chronic form is often the most ignored and challenging to treat. Transcranial magnetic stimulation (TMS) is a novel technique in the treatment of chronic pain. The aim of this pilot study was to explore the effect of low-frequency repetitive TMS (rTMS) on pain status in chronic TTH (CTTH) by subjective and objective pain assessment. Methods: Patients (n=30) diagnosed with CTTH were randomized into rTMS (n=15) and placebo (n=15) groups in this study. Pre-intervention detailed history of patients was taken. Numerical Rating Scale (NRS) for Pain and questionnaires [Headache Impact Test-6 (HIT-6), McGill Pain Questionnaire, Pain Beliefs Questionnaire, Coping Strategies Questionnaire, State-Trait Anxiety Inventory Test, Hamilton Rating Scale for Depression and WHO-Quality of Life Questionnaire-Brief version] were filled, and objective assessments such as nociceptive flexion reflex (NFR) and conditioned pain modulation were done. The tests were repeated after 20 sessions (5 days/week). In the rTMS group, 1200 pulses in eight trains of 150 pulses each were given at 1Hz over the right dorsolateral prefrontal cortex (RDLPFC). In the placebo group, the rTMS coil was placed such that magnetic stimulation did not reach the cortex. Results: The NRS score decreased significantly (P<0.001) and NFR thresholds increased significantly (P=0.011) in the rTMS group when compared to placebo group. Interpretation & conclusions: Subjective improvements in the NRS, HIT-6, McGill Present Pain Intensity, trait of anxiety and psychological pain beliefs were observed. The increase in the thresholds of NFR served as an objective marker for improvement in pain status. Further studies need to be done to confirm our preliminary findings.

Background Modic changes (MC) are associated with low back pain (LBP), but effective treatments are lacking. The aim of this randomized, placebo-controlled, double-blinded trial was to evaluate the efficacy of zoledronic acid (ZA) for chronic LBP among patients with MC in magnetic resonance imaging (MRI). Methods Inclusion criteria were LBP lasting ≥3 months, with an intensity of ≥6 on a 10-cm VAS or an Oswestry Disability Index (ODI) of ≥30%, and MC in MRI. Patients were randomized into single intravenous infusion of ZA 5 mg (n = 20), or placebo (n = 20) groups. The primary outcome was LBP intensity, secondary outcomes leg pain intensity, ODI, health-related quality of life (RAND-36), lumbar flexibility, sick leaves and use of pain medication. The treatment differences at one month and one year were analysed using ANCOVA with adjustment for the baseline score. Results The mean difference (MD) between the groups in the primary outcome, intensity of LBP, was 1.4 (95% confidence intervals (CI) 0.01 to 2.9) in favour of ZA at one month. We observed no significant between-group difference in the intensity of LBP at one year (MD 0.7; 95% CI −1.0 to 2.4) or in secondary outcomes at any time point except that 20% of patients in the ZA group used non-steroidal anti-inflammatory drugs at one year compared to 60% in the placebo group ( P = 0.022). Acute phase reactions (fever, flu-like symptoms, arthralgia) emerged in 95% of the patients in the ZA group, compared to 35% in the placebo group. Conclusions ZA was effective in reducing the intensity of LBP in the short term and in reducing the use of NSAIDs within the time span of one year among patients with chronic LBP and MC confirmed in MRI. Although the results seem encouraging, larger studies are required to analyse the effectiveness and safety of ZA for patients with MC. Trial registration ClinicalTrial.gov identifier NCT01330238 .

Purpose. This study investigates the acute and longitudinal effects of resistance training on occupational muscle activity in office workers with chronic pain. Methods. 30 female office workers with chronic neck and shoulder pain participated for 10 weeks in high-intensity elastic resistance training for 2 minutes per day (n=15) or in control receiving weekly email-based information on general health (n=15). Electromyography (EMG) from the splenius and upper trapezius was recorded during a normal workday. Results. Adherence to training and control interventions were 86% and 89%, respectively. Compared with control, training increased isometric muscle strength 6% (P<0.05) and decreased neck/shoulder pain intensity by 40% (P<0.01). The frequency of periods with complete motor unit relaxation (EMG gaps) decreased acutely in the hours after training. By contrast, at 10-week follow-up, training increased average duration of EMG gaps by 71%, EMG gap frequency by 296% and percentage time below 0.5%, and 1.0% EMGmax by 578% and 242%, respectively, during the workday in m. splenius. Conclusion. While resistance training acutely generates a more tense muscle activity pattern, the longitudinal changes are beneficial in terms of longer and more frequent periods of complete muscular relaxation and reduced pain.

Background The mediopatellar plica is a synovial fold representing an embryonic remnant from the developmental process of the synovial cavity formation in the knee. We aimed to examine the frequency of MRI-detected mediopatellar plica and its cross-sectional association with MRI-detected cartilage damage and bone marrow lesions (BMLs) in the patellofemoral joint (PFJ) in a cohort of subjects with knee pain. Methods 342 knees with chronic frequent knee pain were evaluated for MRI-detected mediopatellar plica (type A, B or C according to the modified Sakakibara classification). Cartilage damage (scored 0 to 6) and BMLs (scored 0 to 3) were semiquantitatively assessed in four subregions of the PFJ on MRI. Hoffa-synovitis and effusion-synovitis were graded 0 to 3. Patellar length ratio (PLR), lateral patellar tilt angle (LPTA), bisect offset (BO), and sulcus angle (SA) were measured on MRI. The presence of mediopatellar plica and its association with cartilage damage and BMLs in the PFJ was assessed using logistic regression after adjusting for age, gender, body mass index, PLR, LPTA, BO, SA, and Hoffa- and effusion-synovitis. Results 163 (47.7%) knees exhibited mediopatellar plica (76 (22.2%) type A, 69 (20.2%) type B, and 18 (5.3%) type C) on MRI. Significant cross-sectional associations of MRI-detected mediopatellar plica and cartilage damage were observed for the medial patella (adjusted odds ratio (aOR) 2.12, 95% CI 1.23-3.64 for all types combined, and aOR 4.20, 95% CI 1.92-9.19 for type B lesion), but not for the anterior medial femur or the lateral PFJ. No associations were found between the presence of MRI-detected mediopatellar plica and BMLs in any patellofemoral subregion. Conclusion On MRI, types A and B mediopatellar plicae were commonly observed in this cohort of subjects with knee pain. MRI-detected mediopatellar plica was cross-sectionally associated with higher likelihood of the presence of MRI-detected medial patellar cartilage damage after adjustment for confounders.

Numerous studies have investigated the impacts of common types of chronic pain (CP) on patients’ cognitive function and observed that CP was associated with later dementia. More recently, there is a growing recognition that CP conditions frequently coexist at multiple body sites and may bring more burdens on patients’ overall health. However, whether and how multisite CP (MCP) contributes to an increased risk of dementia, compared to single-site CP (SCP) and pain-free (PF), is largely unclear. In the current study, utilizing the UK Biobank cohort, we first investigated dementia risk in individuals (n = 354,943) with different numbers of coexisting CP sites using Cox proportional hazards regression models. We then applied generalized additive models to investigate whether MCP leads to excessive deterioration of participants’ (n = 19,116) cognition and brain structure. We found that individuals with MCP were associated with significantly higher dementia risk, broader and faster cognitive impairment, and greater hippocampal atrophy than both PF individuals and those with SCP. Moreover, the detrimental effects of MCP on dementia risk and hippocampal volume aggravated along with the number of coexisting CP sites. Mediation analyses further revealed that the decline of fluid intelligence in MCP individuals was partially mediated by hippocampal atrophy. Our results suggested that cognitive decline and hippocampal atrophy interact biologically and may underlie the increased risk of dementia associated with MCP.

Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte ‘gliopathy’. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal–glial and glial–glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

Comorbid depressive symptoms (CDS) in chronic pain are a common health problem, but the neural circuit mechanisms underlying these symptoms remain unclear. Here we identify a novel pathway involving 5-hydroxytryptamine (5-HT) projections from the dorsal raphe nucleus (5-HTDRN) to somatostatin (SOM)-expressing and non-SOM interneurons in the central nucleus of the amygdala (CeA). The SOMCeA neurons project directly to the lateral habenula, an area known involved in depression. Inhibition of the 5-HTDRN→SOMCeA pathway produced depression-like behavior in a male mouse model of chronic pain. Activation of this pathway using pharmacological or optogenetic approaches reduced depression-like behavior in these mice. Human functional magnetic resonance imaging data showed that compared to healthy controls, functional connectivity between the CeA-containing centromedial amygdala and the DRN was reduced in patients with CDS but not in patients in chronic pain without depression. These findings indicate that a novel 5-HTDRN→SOMCeA→lateral habenula pathway may mediate at least some aspects of CDS.