Human Studies

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Persistent pain (PP) and long-term conditions are all associated with psychological well-being. Less is known about their associations with reduced psychological well-being when co-occurring. We investigated how PP and long-term physical and mental conditions relate to psychological well-being when occurring together.

Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.

Use of prescription opioids and problems of abuse and addiction have increased over the past decade. Claims-based studies have documented substantial economic burden of opioid abuse. This study utilized electronic health record (EHR) data to identify chronic opioid therapy (COT) patients with problem opioid use (POU) and compared costs with those for COT patients without POU. This study utilized EHR and claims data from an integrated health care system. Patients received COT (≥70 days' supply in ≥1 calendar quarter, 2006-2012). Natural language processing (NLP) identified notations of opioid addiction, abuse, misuse, or overuse, and manual validation was performed. Cases had evidence of POU (index = first POU notation), and controls, sampled 9:1, did not. Health care resource utilization was measured and costs estimated using Medicare reimbursement rates. A longitudinal analysis of costs was conducted using generalized estimating equations. Adjusted analyses controlled for baseline age, gender, region, specific comorbidities, and a comorbidity index. The analysis population included 1,125 cases and 10,128 controls. Unadjusted costs were higher for cases in all three years. After controlling for covariates, total costs remained higher in cases and were significantly higher in the first year of follow-up ($38,064 vs. $31,674, P = .0048). The largest cost difference was observed in the first month of follow-up. COT patients with POU experienced significantly higher costs compared with COT patients without POU in the first year of follow-up. The greatest difference in costs was observed around identification of POU.

Chronic pain conditions affect up to one third of the adult population in the United Kingdom. Sleep problems are prevalent and negatively impact quality of life. Lack of standardised tools for routine screening and assessment of sleep changes have been a barrier for sleep management. Novel sleep wearables offer an exciting and accessible way to measure sleep but have not been tested outside of the consumer-led landscape and are not commonly used in research and clinical settings.

Chronic pain (CP) patients often display lower heart rate variability (HRV) and baroreceptor sensitivity (BRS), which are associated with increased evoked pain intensity and decreased pain tolerance.