Human Studies

Up to 30% of patients experience persistent pain and functional limitations following total knee replacement (TKR). Rapid symptom relief in the early postoperative period may be linked to longer-term outcome improvements. We sought to identify early improvement trajectories and to identify risk factors for suboptimal outcomes.

The descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures.

Osteoarthritis (OA) is the most common cause of pain in people aged >45 years, and the knee is the most commonly affected joint. There is a growing interest in understanding the biological factors that influence pain among older adults, but few studies have examined the relationship between β-endorphin and experimental pain sensitivity in older adults with knee OA pain. The purpose of this study was to investigate the relationship between resting plasma levels of β-endorphin and experimental pain sensitivity. This study was a secondary analysis of data for 40 adults with knee OA pain in whom quantitative sensory testing was used to measure experimental sensitivity to heat- and mechanically induced pain. The mean age of the sample was 60 years ( SD = 9 years), and approximately half were female (53%). Regression analyses indicated that β-endorphin level was negatively related to pressure pain threshold (β = -17.18, p = .02) and positively related to punctate mechanical pain (β = 17.13, p = .04), after controlling for age, gender, and OA severity. We did not find a significant relationship between β-endorphin and heat pain tolerance. The results suggest that higher circulating levels of β-endorphin at rest are associated with increased sensitivity to mechanical pain in older adults with knee OA. These findings add to the literature regarding biological factors associated with pain sensitivity in older adults with chronic pain. Additional studies are needed to identify mediators of the relationship between β-endorphin and pain sensitivity in OA and other musculoskeletal pain conditions.

Cross-sectional studies confirm, as expected, a positive association between jaw injury and painful temporomandibular disorders (TMDs), but prospective evaluations are lacking. We prospectively assessed incident jaw injury, injury type, and development of TMD in adults ages 18-44 years.Data were collected from 3,258 individuals from communities surrounding four U.S. academic institutes between 2006 and 2008. At enrollment, participants reported no TMD history and no facial injuries in the previous 6 months. Quarterly follow-up questionnaires assessed incident jaw injury, which was classified as intrinsic (attributed to yawning or prolonged mouth opening) or extrinsic (attributed to other causes). Examiners classified incident TMD during a median follow-up period of 2.8 years (range 0.2-5.2 years). Cox regression models used jaw injury as a time-dependent covariate to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with incident TMD.Among 1,729 participants with complete data, 175 developed TMD. Eighty percent of injuries were intrinsic. TMD annual incidence was nearly twice as high in those experiencing jaw injury (5.37%) compared to those who did not (3.44%). In the Cox model that accounted for timing of injury, the corresponding HR was 3.94 (95%CI=2.82-5.50) after adjusting for study site, age, race, and gender. Hazard ratios did not differ (p=0.91) for extrinsic injuries (HR=4.03, 95%CI=2.00-8.12) and intrinsic injuries (HR=3.85, 95%CI=2.70-5.49).Jaw injury was strongly associated with incident TMD. If surveillance and intervention following jaw injury is to be effective in preventing TMD, they should focus on both intrinsic and extrinsic injuries.

The canonical view is that touch is signaled by fast-conducting, thickly myelinated afferents, whereas pain is signaled by slow-conducting, thinly myelinated ("fast" pain) or unmyelinated ("slow" pain) afferents. While other mammals have thickly myelinated afferents signaling pain (ultrafast nociceptors), these have not been demonstrated in humans. Here, we performed single-unit axonal recordings (microneurography) from cutaneous mechanoreceptive afferents in healthy participants. We identified A-fiber high-threshold mechanoreceptors (A-HTMRs) that were insensitive to gentle touch, encoded noxious skin indentations, and displayed conduction velocities similar to A-fiber low-threshold mechanoreceptors. Intraneural electrical stimulation of single ultrafast A-HTMRs evoked painful percepts. Testing in patients with selective deafferentation revealed impaired pain judgments to graded mechanical stimuli only when thickly myelinated fibers were absent. This function was preserved in patients with a loss-of-function mutation in mechanotransduction channel PIEZO2. These findings demonstrate that human mechanical pain does not require PIEZO2 and can be signaled by fast-conducting, thickly myelinated afferents.