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Background and aims Persons with chronic widespread pain (CWP) have poor medical outcomes and increased mortality. But there are no universally accepted criteria for CWP or of methods to assess it. The most common criteria come from the 1990 American College of Rheumatology (ACR) fibromyalgia (FM) criteria, but that method (WP1990) can identify CWP with as few as three pain sites, and in subjects with wide differences in illness severity. Recently, to correct WP1990 deficiencies, the 2016 fibromyalgia criteria provided a modified CWP definition (WP2016) by dividing the body into five regions of three pain sites each and requiring a minimum of four regions of pain. Although solving the geographic problem of pain distribution, the problem of just how many pain sites (pain diffuseness) are required remained a problem, as WP2016 required as few as four painful sites. To better characterize CWP, we compared four CWP definitions with respect to symmetry, extent of pain sites and association with clinical severity variables. Methods We characterized pain in 40,960 subjects, including pain at 19 individual sites and five pain regions, and calculated the widespread pain index (WPI) and polysymptomatic distress scales (PDS) from epidemiology, primary care and rheumatology databases. We developed and evaluated a new definition for CWP, (WP2019), defined as pain in four or five regions and a pain site score of at least seven of 15 sites. We also tested a definition based on the number of painful sites (WPI ≥ 7). Results In rheumatology patients, WP1990 and WPI ≥ 7 classified patients with <4 regions as WSP. CWP was noted in 51.3% by WP1990, 41.7% by WP2016, 37.6% of WPI ≥ 7 and 33.9% by WP2019. 2016 FM criteria was satisfied in WP1990 (51.1%), WP2016 (63.3%), WPI ≥ 7 (69.0%) and WP2019 (76.6%). WP2019 positive patients had more severe clinical symptoms compared with WP1990, WP2016 and WPI ≥ 7, and similar to but less than FM 2016 positive patients. In stepwise fashion, scores for functional disability, visual analog scale fatigue and pain, WPI, polysymptomatic distress score and Patient Health Questionnaire 15 (PHQ-15) worsened from WP1990 through WP2016, WPI ≥ 7 and WP2019. Conclusions WP2019 combines the high WPI scores of WPI ≥ 7 and the symmetry of WP2016, and is associated with the most abnormal clinical scores. The WP1990 does not appear to be an effective measure. We suggest that CWP can be better defined by combining 4-region pain and a total pain site score ≥7 (WP2019). This definition provides a simple, unambiguous measure that is suitable for clinical and research use as a standalone diagnosis that is integrated with fibromyalgia definitions. Implications Definitions of CWP in research and clinic care are arbitrary and have varied, and different definitions of CWP identify different sets of patients, making a universal interpretation of CWP uncertain. In addition, CWP is a mandatory component of some fibromyalgia criteria. Our study provides quantitative data on the differences between CWP definitions and their criteria, allowing better understanding of research results and a guide to the use of CWP in clinical care.
Learn More >It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.
Learn More >Background and aims Previous systematic reviews have reported manifestations of pain sensitisation as a feature of painful knee disorders, in particular osteoarthritis, with moderate evidence for pain sensitisation in patellofemoral pain (PFP). However, despite past studies recruiting female mostly adolescent PFP patients, it is unclear if sex or age plays a role. Investigation is required to determine if altered pain processing is a key feature of PFP and if a subgroup of patients is at an increased risk to help provide targeted management. The primary aim of this systematic review was to examine evidence investigating pain processing in PFP. Secondary aims were to evaluate the relationship between pain processing and (1) sex, (2) age and (3) symptom duration. Methods The protocol was prospectively registered with PROSPERO (CRD42019129851). PubMed, CINAHL, Web of Science and EMBASE were systematically searched from inception to April 2019 for studies investigating pain processing in PFP patients compared to controls using quantitative sensory testing. Each included paper was assessed for methodological quality using a modified version of Downs and Black. Means and standard deviations were extracted to calculate standardised mean differences (SMD) and 95% confidence intervals (95% CI). Where possible meta-analysis and meta-regression were performed using a random effects model. Results Eleven studies were identified, two medium and nine high quality. Meta-analysis indicates moderate evidence for decreased pressure pain thresholds (SMD -0.68, 95% CI -0.93 to -0.43), increased tactile detection thresholds (SMD 1.35, 95% CI 0.49-2.22) and increased warmth detection thresholds (SMD 0.61, 95% CI 0.30-0.92) in PFP patients compared to controls. Secondary analysis indicates moderate evidence for decreased pressure pain thresholds in female compared to male patients (SMD -0.75, 95% CI -1.34 to -0.16). Meta-regression indicates a moderate correlation between decreasing local and distal pressure pain thresholds and decreasing patient age (local R2 = 0.556, p = 0.0211; distal R2 = 0.491, p = 0.0354) but no correlation with symptom duration (p > 0.05). Conclusions Evidence from this systematic review with meta-analysis and meta-regression appears to suggest the presence of altered pain processing and sensitisation in patients with PFP with increased sensitivity indicated in female patients and younger patients. Implications With evidence of altered pain processing and sensitisation in PFP, it may be beneficial for clinicians to consider management approaches that aim specifically at adressing neuropathic pain, for example neuroscience education, to improve patients outcomes. With female patients and younger patients indicated as experiencing greater degree of sensitivity, this may be a good demographic to start screening for sensitisation, in order to better identify and treat those most affected.
Learn More >Background and aims Pain catastrophizing has consistently been related to a variety of negative outcomes within chronic pain conditions, but competing models exist explaining the role of catastrophizing. According to the fear-avoidance model (FAM), catastrophizing is primarily related to the appraisal of pain (i.e. "intrapersonal"), whereas the communal coping model (CCM) suggests that catastrophizing is a strategy to elicit support (i.e. "interpersonal"). In order to examine the interpersonal nature of catastrophizing, this cross-sectional study examined interpersonal problems as a predictor of pain catastrophizing in a sample of patients (n = 97) with chronic pain. Methods Self-report data was taken from patients entering a multidisciplinary, inpatient rehabilitation program. The four quadrants of the Inventory of Interpersonal Problems circumplex model (Hostile-Dominant, Hostile-Submissive, Friendly-Submissive, Friendly-Dominant) were used as predictors of pain catastrophizing in a series of separate, hierarchical regression analyses. Results After controlling for relevant confounding variables such as demographics (gender, age), pain severity, psychiatric symptoms (anxiety/depression, fatigue, insomnia), adverse life experiences and perceived social support, higher levels of Hostile-Dominant interpersonal problems predicted higher levels of pain catastrophizing (p ≤ 0.01, d = 0.56). Conclusions The results add support to the notion that pain catastrophizing may serve a communicative functioning, as predicted by the CCM, with cold, dominant and controlling behaviors as a maladaptive interpersonal strategy to elicit support. It may thus be useful to consider the broader interpersonal context of the individual, and not only the patient's appraisal of pain, when conceptualizing the role of pain catastrophizing in patients with chronic pain. Implications Future psychosocial research and treatment of chronic pain could be informed by including interpersonal theory as a useful theoretical framework, which may help shed more light on how interpersonal problems relates to pain catastrophizing.
Learn More >The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.
Learn More >Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.
Learn More >Dry eye disease (DED) is a multifactorial disease associated with ocular surface inflammation, pain, and nerve abnormalities. We studied the peripheral and central neuroinflammatory responses that occur during persistent DED using molecular, cellular, behavioral, and electrophysiological approaches.
Learn More >Neuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive.
Learn More >While comorbid pain in depression (CP) occurs at a high rate worldwide, the neural connections underlying the core symptoms of CP have yet to be elucidated. Here, we define a pathway whereby GABAergic neurons from the central nucleus of the amygdala (GABA) project to glutamatergic neurons in the parafascicular nucleus (Glu). These Glu neurons relay directly to neurons in the second somatosensory cortex (S2), a well-known area involved in pain signal processing. Enhanced inhibition of the GABA→Glu→S2 pathway is found in mice exhibiting CP symptoms. Reversing this pathway using chemogenetic or optogenetic approaches alleviates CP symptoms. Together, the current study demonstrates the putative importance of the GABA→Glu→S2 pathway in controlling at least some aspects of CP.
Learn More >There is evidence to suggest that a large proportion of individuals seeking care for lumbopelvic pain also have pelvic floor muscle dysfunction (PFMD). Because the majority of physical therapists do not have the requisite training to adequately assess pelvic floor musculature, determining predictors of PFMD could be clinically useful.
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