The Chronic Overlapping Pain Condition Screener.

Ten Chronic Overlapping Pain Conditions (COPCs) are currently recognized by the National Institutes of Health Pain Consortium (eg, irritable bowel syndrome, chronic migraine headache, and chronic low back pain). These conditions affect millions of Americans; however, assessing these conditions, their co-occurrence, and their relationship to treatment has proven challenging due to time constraints and a lack of standardized measures. We present a Chronic Overlapping Pain Condition-Screener (COPC-S) that is logic-driven, efficient, and freely available in electronic format to nonprofit entities. Thirty experts were convened to identify and modify self-report criteria for each COPC as well as criteria that trigger the administration of the diagnostic criteria from a body map and a brief series of questions. Their recommendations were then programmed into the Research Electronic Data Capture platform and refined for comprehensibility and ease of use by patient focus groups. The electronic screener and physician-administered criteria were both administered to patients with known COPCs in a counter-balanced fashion to determine the level of agreement between methods. The expert panel identified screening items/body map regions and diagnostic criteria for all 10 COPCs. Patients found the content comprehensible and the platform easy to use. Cohen's Kappa statistics suggested good agreement between the electronic COPC-S and criteria administered by a physician (κ = .813). The COPC-S is an efficient tool for screening multiple COPCs and has applicability to research studies, clinical trials, and clinical practice. PERSPECTIVE: Assessing COPCs remains a challenge for researchers and clinicians. The COPC-S is an efficient and logic-driven electronic tool that allows for the rapid screening assessment of 10 COPCs. The instrument may have utility in research and clinical settings.

Applying the Rapid OPPERA Algorithm to Predict Persistent Pain Outcomes Among a Cohort of Women Undergoing Breast Cancer Surgery.

Persistent postmastectomy pain after breast surgery is variable in duration and severity across patients, due in part to interindividual variability in pain processing. The Rapid OPPERA Algorithm (ROPA) empirically identified 3 clusters of patients with different risk of chronic pain based on 4 key psychophysical and psychosocial characteristics. We aimed to test this type of group-based clustering within in a perioperative cohort undergoing breast surgery to investigate differences in postsurgical pain outcomes. Women (N = 228) scheduled for breast cancer surgery were prospectively enrolled in a longitudinal observational study. Pressure pain threshold (PPT), anxiety, depression, and somatization were assessed preoperatively. At 2-weeks, 3, 6, and 12-months after surgery, patients reported surgical area pain severity, impact of pain on cognitive/emotional and physical functioning, and pain catastrophizing. The ROPA clustering, which used patients' preoperative anxiety, depression, somatization, and PPT scores, assigned patients to 3 groups: Adaptive (low psychosocial scores, high PPT), Pain Sensitive (moderate psychosocial scores, low PPT), and Global Symptoms (high psychosocial scores, moderate PPT). The Global Symptoms cluster, compared to other clusters, reported significantly worse persistent pain outcomes following surgery. Findings suggest that patient characteristic-based clustering algorithms, like ROPA, may generalize across diverse diagnoses and clinical settings, indicating the importance of "person type" in understanding pain variability. PERSPECTIVE: This article presents the practical translation of a previously developed patient clustering solution, based within a chronic pain cohort, to a perioperative cohort of women undergoing breast cancer surgery. Such preoperative characterization could potentially help clinicians apply personalized interventions based on predictions concerning postsurgical pain.

Association of Hormonal Contraceptive Use with Headache and Temporomandibular Pain: The OPPERA Study.

AIMS: To determine the relationship between hormonal contraceptive (HC) use and painful symptoms, particularly those associated with headache and painful temporomandibular disorders (TMD). METHODS: Data from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study were used. During the 2.5-year median follow-up period, quarterly health update (QHU) questionnaires were completed by 1,475 women aged 18 to 44 years who did not have TMD, menopause, hysterectomy, or hormone replacement therapy use at baseline. QHU questionnaires evaluated HC use, symptoms of headache and TMD, and pain of ≥ 1 day duration in 12 body regions. Participants who developed TMD symptoms were examined to classify clinical TMD. Headache symptoms were classified based on the International Classification of Headache Disorders 3 (ICHD-3). Associations between HC use and pain symptoms were analyzed using generalized estimating equations and Cox models. RESULTS: HC use, endorsed in 33.7% of QHU questionnaires, was significantly associated with concurrent symptoms of TMD (odds ratio [OR]: 1.20, 95% CI: 1.06 to 1.35) and headache (OR: 1.26, 95% CI: 1.11 to 1.43). HC use was also significantly associated with concurrent pain of ≥ 1 day duration in the head (OR: 1.38, 95% CI: 1.16 to 1.63), face (OR: 1.44, 95% CI: 1.13 to 1.83), and legs (OR: 1.22, 95% CI: 1.01 to 1.47), but not elsewhere. Initiation of HC use was associated with increased odds of subsequent TMD symptoms (OR: 1.37, 95% CI: 1.13 to 1.66) and pain of ≥ 1 day in the head (OR: 1.37, 95% CI: 1.01 to 1.85). Discontinuing HC use was associated with lower odds of subsequent headache (OR: 0.82, 95% CI: 0.67 to 0.99). HC use was not significantly associated with subsequent onset of examiner-classified TMD. CONCLUSION: These findings imply that HC influences craniofacial pain, and that this pain diminishes after cessation of HC use.

Identification and characterization of novel candidate compounds targeting 6- and 7-transmembrane µ-opioid receptor isoforms.

BACKGROUND AND PURPOSE: The µ-opioid receptor (µ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM µ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-µ receptors to further our understanding of the pharmacodynamic properties of µ receptors. EXPERIMENTAL APPROACH: We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM- and 6TM-µ receptor structural models and identified potential compounds that are selective for 6TM- and/or 7TM-µ receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies. KEY RESULTS: Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5, 10, 11 and 25) that demonstrated 6TM- or 7TM-µ receptor-dependent NO release. In in vivo pain assays these compounds also produced dose-dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the µ receptor-dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM- (#10) and 7TM-µ receptor (#5) ligands. CONCLUSION AND IMPLICATIONS: Our novel compounds represent a new class of ligands for µ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.

Baroreceptor Modulation of the Cardiovascular System, Pain, Consciousness, and Cognition.

Baroreceptors are mechanosensitive elements of the peripheral nervous system that maintain cardiovascular homeostasis by coordinating the responses to external and internal environmental stressors. While it is well known that carotid and cardiopulmonary baroreceptors modulate sympathetic vasomotor and parasympathetic cardiac neural autonomic drive, to avoid excessive fluctuations in vascular tone and maintain intravascular volume, there is increasing recognition that baroreceptors also modulate a wide range of non-cardiovascular physiological responses via projections from the nucleus of the solitary tract to regions of the central nervous system, including the spinal cord. These projections regulate pain perception, sleep, consciousness, and cognition. In this article, we summarize the physiology of baroreceptor pathways and responses to baroreceptor activation with an emphasis on the mechanisms influencing cardiovascular function, pain perception, consciousness, and cognition. Understanding baroreceptor-mediated effects on cardiac and extra-cardiac autonomic activities will further our understanding of the pathophysiology of multiple common clinical conditions, such as chronic pain, disorders of consciousness (e.g., abnormalities in sleep-wake), and cognitive impairment, which may result in the identification and implementation of novel treatment modalities. © 2021 American Physiological Society. Compr Physiol 11:1373-1423, 2021.

STING controls nociception via type I interferon signalling in sensory neurons.

The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain.

Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients.

ABSTRACT: Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo.

Intracellular calcium is critical in orchestrating neuronal excitability and analgesia. Carbonic anhydrase-8 (CA8) regulates intracellular calcium signaling through allosteric inhibition of neuronal inositol trisphosphate receptor 1 (ITPR1) to produce profound analgesia. Recently, we reported the "G" allele at rs6471859 represents cis-eQTL regulating alternative splicing of a 1697 bp transcript (CA8-204G) with a retained intron, alternative polyadenylation site and a new stop codon producing a functional 26 kDa peptide with an extended exon 3. In this study we show the reversion mutation (G to C) at rs6471859 within the CA8-204G expression vector also produced a stable 1697 bp transcript (CA8-204C) coding for a smaller peptide (~ 22 kDa) containing only the first three CA8 exons. Surprisingly, this peptide inhibited ITPR1 (pITPR1) activation, ITPR1-mediated calcium release in vitro; and produced profound analgesia in vivo. This is the first report showing CA8-204C codes for a functional peptide sufficient to regulate calcium signaling and produce profound analgesia.

Overlap of Five Chronic Pain Conditions: Temporomandibular Disorders, Headache, Back Pain, Irritable Bowel Syndrome, and Fibromyalgia.

AIMS: To assess cohort retention in the OPPERA project and to compare the degree of overlap between pairs of chronic overlapping pain conditions (COPCs) using a cross-sectional analysis of data from 655 adults who completed follow-up in the OPPERA study. METHODS: Subjects were classified for the absence or presence of each of the five COPCs. The extent of overlap beyond chance was quantified using odds ratios, which were calculated using binary logistic regression models. RESULTS: While overlap was the norm, its magnitude varied according to COPC: 51% of people with headache had one or more overlapping COPCs, and this proportion increased to 90% for people with fibromyalgia. The degree of overlap between pairs of COPCs also varied considerably, with odds ratios being greatest for associations between musculoskeletal conditions (fibromyalgia, temporomandibular disorders, and low back pain) and less pronounced for overlap involving headache or IBS. Furthermore, univariate associations between some pairs of COPCs were nullified after adjusting for other COPCs. CONCLUSION: There was greater overlap between fibromyalgia and either temporomandibular disorders or low back pain than between other pairs of COPCs. While musculoskeletal conditions exhibited some features that could be explained by a single functional syndrome, headache and irritable bowel syndrome did not.

Experimental Pain Sensitivity in Subjects with Temporomandibular Disorders and Multiple Other Chronic Pain Conditions: The OPPERA Prospective Cohort Study.

AIMS: To investigate associations between experimental pain sensitivity and five chronic pain conditions among 655 participants in the OPPERA study. METHODS: Quantitative sensory tests were used to measure sensitivity to three modalities of nociception: blunt pressure pain, mechanical pinprick pain, and thermal heat pain. Participants were also classified according to the presence or absence of five chronic pain conditions: temporomandibular disorders, headache, low back pain, irritable bowel syndrome, and fibromyalgia. RESULTS: Univariate analyses found each modality to be significantly associated with at least one pain condition, most consistently for pressure pain sensitivity (8 of 15 instances) and least consistently for heat pain sensitivity (5 of 35 instances). Yet, multivariable analyses that evaluated the independent contributions of all five pain conditions found few significant associations (12 of 75 instances). Instead, pain sensitivity consistently varied according to the total number of pain conditions a person experienced, implying that the combination of pain conditions influences each nociceptive modality. CONCLUSION: When evaluating nociceptive sensitivity in a chronic pain patient, comorbid pain conditions should be considered, as the more salient feature underlying sensitivity is likely the number rather than the type(s) of pain conditions.

Associations of Psychologic Factors with Multiple Chronic Overlapping Pain Conditions.

AIMS: To characterize psychologic functioning across five chronic overlapping pain conditions (COPCs)-temporomandibular disorders, fibromyalgia, low back pain, headache, and irritable bowel syndrome-and their overlaps. METHODS: Participants were 655 adults in the OPPERA study. Psychologic variables were standardized in separate logistic regression models to compare their relative strength of association with each COPC. Random forest regression was used to explore the association of all psychologic measures with COPCs simultaneously. Linear regression analyses examined whether the count of COPCs was associated with psychologic measures. RESULTS: In univariate and multivariable analyses, measures of somatic symptom burden showed the strongest associations with individual COPCs and with the number of COPCs. Additional psychologic variables that showed significant associations with individual COPCs and their overlap included negative mood, perceived stress, and pain catastrophizing. CONCLUSION: These findings highlight the importance of psychologic functioning in the assessment and management of these overlapping pain conditions.

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain.

Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia.

Alterations in cellular energy metabolism have been implicated in chronic pain, suggesting a role for mitochondrial DNA. Previous studies reported associations of a limited number of mitochondrial DNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPCs) was examined. Mitochondrial DNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with 5 CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (odds ratio [OR] = 4.6, P = 4.3 × 10). This relationship was even stronger in women (OR = 5.1, P = 2.8 × 10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR = 4.3, P = 2.6 × 10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.

Neuroimmune modulation of pain and regenerative pain medicine.

Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Anatomical and clinical implications of vagal modulation of the spleen.

The vagus nerve coordinates most physiologic functions including the cardiovascular and immune systems. This mechanism has significant clinical implications because electrical stimulation of the vagus nerve can control inflammation and organ injury in infectious and inflammatory disorders. The complex mechanisms that mediate vagal modulation of systemic inflammation are mainly regulated via the spleen. More specifically, vagal stimulation prevents organ injury and systemic inflammation by inhibiting the production of cytokines in the spleen. However, the neuronal regulation of the spleen is controversial suggesting that it can be mediated by either monosynaptic innervation of the splenic parenchyma or secondary neurons from the celiac ganglion depending on the experimental conditions. Recent physiologic and anatomic studies suggest that inflammation is regulated by neuro-immune multi-synaptic interactions between the vagus and the splanchnic nerves to modulate the spleen. Here, we review the current knowledge on these interactions, and discuss their experimental and clinical implications in infectious and inflammatory disorders.

The dichotomous role of epiregulin in pain.

It has recently been shown that epidermal growth factor receptor (EGFR) contributes to the pathogenesis of pain. We scanned genetic markers within genes coding for receptors of the EGFR family (EGFR, ERBB2, ERBB3, and ERBB4) and their ligands (AREG, BTC, EGF, EPGN, EREG, HBEGF, MUC4, NRG1, NRG2, NRG3, NRG4, and TGFA) for association with self-reported pain intensity in patients with chronic facial pain who participated in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort. We found that only epiregulin (EREG) was associated with pain. The strongest effect was observed for a minor allele at rs6836436 in EREG, which was associated with lower chronic pain intensity. However, the same allele was associated with higher facial pain intensity among cases with recent onset of facial pain. Similar trends were observed in an independent cohort of UK Biobank (UKB) where the minor allele at rs6836436 was associated with a higher number of acute pain sites but a lower number of chronic pain sites. Expression quantitative trait loci analyses established rs6836436 as a loss-of-function variant of EREG. Finally, we investigated the functional role of EREG using mouse models of chronic and acute pain. Injecting mice with an EREG monoclonal antibody reversed established mechanosensitivity in the complete Freund's adjuvant and spared nerve injury models of chronic pain. However, the EREG monoclonal antibody prolonged allodynia when administered during the development of complete Freund's adjuvant-induced mechanosensitivity and enhanced pain behavior in the capsaicin model of acute pain.

Premorbid and concurrent predictors of TMD onset and persistence.

BACKGROUND: Multiple risk factors predict temporomandibular disorders (TMD) onset, but temporal changes in risk factors and their contribution to risk of TMD have not been evaluated. The study aims were to (a) describe changes occurring in premorbid TMD risk factors when re-measured at TMD onset and 6 months later, and (b) determine if measures of change improve accuracy in predicting TMD incidence compared to premorbid measures alone. METHODS: In this observational prospective cohort study at four university research clinics, 3,258 community-based, 18- to 44-year-olds without TMD were enrolled. During the 3-year median follow-up, 260 incident cases of first-onset TMD were identified, and 196 TMD-free subjects were selected as matched controls. Six-months later, 147 of 260 incident cases (56.6%) were re-examined revealing 72 (49%) with 'persistent TMD' and 75 (51%) whose condition had resolved ('transient TMD'). Virtually all (126) of the 127 re-examined controls remained without TMD. Questionnaires and clinical measurements evaluated risk factors from clinical, health, psychological and behavioural and neurosensory domains. RESULTS: Most risk factors across all four domains increased with TMD onset, remained elevated in the persistent group and declined in the transient group (i.e., significant ANOVA interactions, p < .05). Accuracy in predicting first-onset TMD, quantified as area under the receiver operating characteristic curve was 0.71 (95% CL 0.68, 0.73) using only premorbid measures of risk factors, which increased to 0.91 (95% CL 0.89, 0.94) after addition of change measures. CONCLUSIONS: TMD pain onset and persistence appear to be determined by enduring characteristics of the person as well as mutually interactive with temporally evolving variables. SIGNIFICANCE: TMD is known to be a complex disorder, in which onset and persistence are associated with disease-related variables in multiple domains, including environmental exposure, clinical, psychological, health status, and pain processing variables. Using a more dynamic approach in order to capture change across time, many aspects of those domains were found to worsen prior to the reporting of pain, with bidirectional influences between domains and pain emergence likely. TMD onset appears to represent the cumulative effect of multiple system dysregulation.

ICD-10 Codes for the Study of Chronic Overlapping Pain Conditions in Administrative Databases.

Chronic overlapping pain conditions (COPCs) are a set of painful chronic conditions characterized by high levels of co-occurrence. It has been hypothesized that COPCs co-occur in many cases because of common neurobiological vulnerabilities. In practice, most research on COPCs has focused upon a single index condition with little effort to assess comorbid painful conditions. This likely means that important phenotypic differences within a sample are obscured. The International Classification of Diseases (ICD) coding system contains many diagnostic classifications that may be applied to individual COPCs, but there is currently no agreed upon set of codes for identifying and studying each of the COPCs. Here we seek to address this issue through three related projects 1) we first compile a set of ICD-10 codes from expert panels for ten common COPCs, 2) we then use natural language searches of medical records to validate the presence of COPCs in association with the proposed expert codes, 3) finally, we apply the resulting codes to a large administrative medical database to derive estimates of overlap between the ten conditions as a demonstration project. The codes presented can facilitate administrative database research on COPCs. PERSPECTIVE: This article presents a set of ICD-10 codes that researchers can use to explore the presence and overlap of COPCs in administrative databases. This may serve as a tool for estimating samples for research, exploring comorbidities, and treatments for individual COPCs, and identifying mechanisms associated with their overlap.