Indices of pain variability: a paradigm shift No abstract available

Acute neuropathic pain: equivalent or different to chronic neuropathic pain? A call for gathering of scientifically based information on acute neuropathic pain No abstract available

Investigating intraindividual pain variability: methods, applications, issues, and directions Pain is a dynamic experience subject to substantial individual differences. Intensive longitudinal designs best capture the dynamical ebb and flow of the pain experience across time and settings. Thanks to the development of innovative and efficient data collection technologies, conducting an intensive longitudinal pain study has become increasingly feasible. However, the majority of longitudinal studies have tended to examine average level of pain as a predictor or as an outcome, while conceptualizing intraindividual pain variation as noise, error, or a nuisance factor. Such an approach may miss the opportunity to understand how fluctuations in pain over time are associated with pain processing, coping, other indices of adjustment, and treatment response. The present review introduces the 4 most frequently used intraindividual variability indices: the intraindividual SD/variance, autocorrelation, the mean square of successive difference, and probability of acute change. In addition, we discuss recent development in dynamic structural equation modeling in a nontechnical manner. We also consider some notable methodological issues, present a real-world example of intraindividual variability analysis, and offer suggestions for future research. Finally, we provide statistical software syntax for calculating the aforementioned intraindividual pain variability indices so that researchers can easily apply them in their research. We believe that investigating intraindividual variability of pain will provide a new perspective for understanding the complex mechanisms underlying pain coping and adjustment, as well as for enhancing efforts in precision pain medicine. Audio accompanying this abstract is available online as supplemental digital content at http://links.lww.com/PAIN/A817.

Family history of pain and risk of musculoskeletal pain in children and adolescents: a systematic review and meta-analysis Emerging evidence suggests that musculoskeletal (MSK) pain should be viewed from a biopsychosocial perspective and consider the influence of family factors. We conducted a review with meta-analysis to provide summary estimates of effect of family history of pain on childhood MSK pain and explore whether specific family pain factors influence the strength of the association (PROSPERO CRD42018090130). Included studies reported associations between family history of pain and nonspecific MSK pain in children (age <19 years). The outcome of interest was MSK pain in children. We assessed the methodological quality using a modified version of the Quality in Prognosis Studies instrument and quality of evidence for the main analyses using the GRADE criteria. After screening of 7281 titles, 6 longitudinal and 23 cross-sectional studies were included. Moderate quality evidence from 5 longitudinal studies (n = 42,131) showed that children with a family history of MSK pain had 58% increased odds of experiencing MSK pain themselves (odds ratio [OR] 1.58, 95% confidence interval 1.20-2.09). Moderate quality evidence from 18 cross-sectional studies (n = 17,274) supported this finding (OR 2.02, 95% 1.69-2.42). Subgroup analyses showed that the relationship was robust regardless of whether a child's mother, father, or sibling experienced pain. Odds were higher when both parents reported pain compared with one ([mother OR = 1.61; father OR = 1.59]; both parents OR = 2.0). Our findings show moderate quality evidence that children with a family history of pain are at higher risk of experiencing MSK pain. Understanding the mechanism by which this occurs would inform prevention and treatment efforts.

Sham surgeries for central and peripheral neural injuries persistently enhance pain-avoidance behavior as revealed by an operant conflict test Studies using rodent models of neuropathic pain use sham surgery control procedures that cause deep tissue damage. Sham surgeries would thus be expected to induce potentially long-lasting postsurgical pain, but little evidence for such pain has been reported. Operant tests of voluntary behavior can reveal negative motivational and cognitive aspects of pain that may provide sensitive tools for detecting pain-related alterations. In a previously described operant mechanical conflict test involving lengthy familiarization and training, rodents freely choose to either escape from a brightly lit chamber by crossing sharp probes or refuse to cross. Here, we describe a brief (2-day) mechanical conflict protocol that exploits rats' innate exploratory response to a novel environment to detect persistently enhanced pain-avoidance behavior after sham surgeries for 2 neural injury models: thoracic spinal cord injury and chronic constriction injury of the sciatic nerve. Pitting the combined motivations to avoid the bright light and to explore the novel device against pain from crossing noxious probes disclosed a conflicting, hyperalgesia-related reluctance to repeatedly cross the probes after injury. Rats receiving standard sham surgeries demonstrated enhanced pain-like avoidance behavior compared with naive controls, and this behavior was similar to that of corresponding chronic constriction injury or spinal cord injury rats weeks or months after injury. In the case of sham surgery for spinal cord injury, video analysis of voluntary exploratory behavior directed at the probes revealed enhanced forepaw withdrawal responses. These findings have important implications for preclinical investigations into behavioral alterations and physiological mechanisms associated with postsurgical and neuropathic pain.

A randomized trial to assess the immediate impact of acupuncture on quantitative sensory testing, pain, and functional status In this randomized clinical trial, we examined whether the effect of true acupuncture can be differentiated from sham acupuncture (pain and functionality) by analyzing quantitative sensory testing (QST) profiles in chronic pain participants. We recruited 254 healthy or chronic back and neck pain participants. Healthy subjects were included to control for a possible effect of acupuncture on baseline QST changes. Study participants received 6 sessions (twice weekly) of true acupuncture, sham acupuncture, or no acupuncture treatment (routine care). Quantitative sensory testing profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after 3 (visit 4) or 6 sessions (visit 7). A total of 204 participants were analyzed. We found no QST profile changes among 3 groups (P = 0.533 and P = 0.549, likelihood ratio tests) in either healthy or chronic pain participants. In chronic back and neck pain participants, true acupuncture reduced pain (visit 4: difference in mean [DIM] = −0.8, 95% confidence interval [CI]: −1.4 to −0.1, adjusted P = 0.168; visit 7: DIM = −1.0, 95% CI: −1.7 to −0.3, adjusted P = 0.021) and improved functional status including physical functioning (DIM = 14.21, 95% CI: 5.84-22.58, adjusted P = 0.003) and energy/fatigue (DIM = 12.28, 95% CI: 3.46-21.11, adjusted P = 0.021) as compared to routine care. Our results indicate that QST was not helpful to differentiate between true acupuncture and sham acupuncture (primary outcome) in this study, although true acupuncture reduced pain and improved functionality (secondary outcomes) when compared with routine care.

Associations of mental health and family background with opioid analgesic therapy: a nationwide Swedish register-based study There is evidence of greater opioid prescription to individuals in the United States with mental health conditions. Whether these associations generalize beyond the US prescription environment and to familial mental health and socioeconomic status (SES) has not been examined comprehensively. This study estimated associations of diverse preexisting mental health diagnoses, parental mental health history, and SES in childhood with opioid analgesic prescription patterns nationwide in Sweden. Using register-based data, we identified 5,071,193 (48.4% female) adolescents and adults who were naive to prescription opioid analgesics and followed them from 2007 to 2014. The cumulative incidence of any dispensed opioid analgesic within 3 years was 11.4% (95% CI, 11.3%-11.4%). Individuals with preexisting self-injurious behavior, as well as opioid and other substance use, attention-deficit/hyperactivity, depressive, anxiety, and bipolar disorders had greater opioid therapy initiation rates than did individuals without the respective conditions (hazard ratios from 1.24 [1.20-1.27] for bipolar disorder to 2.12 [2.04-2.21] for opioid use disorder). Among 1,298,083 opioid recipients, the cumulative incidence of long-term opioid therapy (LTOT) was 7.6% (7.6%-7.7%) within 3 years of initiation. All mental health conditions were associated with greater LTOT rates (hazard ratios from 1.66 [1.56-1.77] for bipolar disorder to 3.82 [3.51-4.15] for opioid use disorder) and were similarly associated with concurrent benzodiazepine-opioid therapy. Among 1,482,462 adolescents and young adults, initiation and LTOT rates were greater for those with parental mental health history or lower childhood SES. Efforts to understand and ameliorate potential adverse effects of opioid analgesics must account for these patterns.

Assessment of nociception and related quality-of-life measures in a porcine model of neurofibromatosis type 1 Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder resulting from germline mutations in the NF1 gene, which encodes neurofibromin. Patients experience a variety of symptoms, but pain in the context of NF1 remains largely underrecognized. Here, we characterize nociceptive signaling and pain behaviors in a miniswine harboring a disruptive NF1 mutation (exon 42 deletion). We present the first characterization of pain-related behaviors in a pig model of NF1, identifying unchanged agitation scores, lower tactile thresholds (allodynia), and decreased response latencies to thermal laser stimulation (hyperalgesia) in NF1+/ex42del (females only) pigs. Male NF1+/ex42del pigs with tumors showed reduced sleep quality and increased resting, 2 health-related quality-of-life symptoms found to be comorbid in people with NF1 pain. We explore these phenotypes in relationship to suppression of the increased activity of the N-type voltage-gated calcium (CaV2.2) channel by pharmacological antagonism of phosphorylation of a regulatory protein—the collapsin response mediator protein 2 (CRMP2), a known interactor of neurofibromin, and by targeting the interface between the α subunit of CaV2.2 and the accessory β-subunits with small molecules. Our data support the use of NF1+/ex42del pigs as a large animal model for studying NF1-associated pain and for understanding the pathophysiology of NF1. Our findings demonstrate the translational potential of 2 small molecules in reversing ion channel remodeling seen in NF1. Interfering with CaV2.2, a clinically validated target for pain management, might also be a promising therapeutic strategy for NF1-related pain management.

The glutamate to γ-aminobutyric acid ratio in the posterior insula is associated with pain perception in healthy women but not in women with borderline personality disorder This study aimed to investigate whether the differences in pain perception between patients with borderline personality disorder (BPD) and healthy subjects (HCs) can be explained by differences in the glutamate/GABA ratio in the posterior insula. In total, 29 BPD patients and 31 HCs were included in the statistical analysis. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli between 32 and 512 mN on a numeric rating scale. The metabolites were measured in the right posterior insula using the MEshcher–GArwood Point-RESolved Spectroscopy sequence for single-voxel magnetic resonance spectroscopy (1H-MRS). The 256- and the 512-mN pinprick stimuli were perceived as significantly less painful by the BPD patient group compared with HCs. No differences were found between groups for the glutamate/GABA ratios. A positive correlation between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks could be found in the combined and in the HC group. In the BPD patient group, the correlations between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks did not reach significance. In conclusion, the study showed that individual differences in pain perception may in part be explained by the individual glutamate/GABA ratio in the posterior insula. However, this possible mechanism does not explain the differences in pain perception between BPD patients and HCs.

Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.