A multi-ancestry genetic study of pain intensity in 598,339 veterans.

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, ß-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

Trajectories and predictors of high-occurrence pain flares in ambulatory cancer patients on opioids.

BACKGROUND: Pain flares have a substantive impact on the quality of life and well-being of patients with cancer. We identified longitudinal trajectories (clusters) of cancer pain flares in ambulatory patients and sociodemographic and clinical predictors of these trajectories. METHODS: In a prospective cohort study using ecological momentary assessment (mEMA), we collected patient-reported daily pain flare ratings data over 5 months and identified predictors and correlates using validated measures. RESULTS: The mean age of the sample (N = 270) was 60.9 years (SD = 11.2), 64.8% were female, and 32.6% self-identified as African American. Four pain flare clusters were identified. The "high-occurrence" cluster (23% of patients) experienced 5.5 (SD = 5.47) daily flares, whereas low-moderate clusters (77%) reported 2.4 (SD = 2.74) daily flares (P < .000). Those in the high-occurrence cluster reported higher pain scores (P = .000), increased pain-related interference (P = .000), depressive symptoms (P = .023), lower quality of life (P = .001), and reduced pain self-efficacy (P = .006). Notably, 67.2% of those prescribed opioids as needed (PRN only) were in the high-occurrence pain flare cluster, compared with 27.9% with PRN and around-the-clock opioid prescriptions (P = .024). Individual predictors of high-occurrence pain flares were income below $30 000, unemployment, being African American, lower education level, Medicaid insurance, current opioid misuse (COMM), baseline inpatient hospital stay duration, and PRN-only opioid regimen. In the multiple predictor model, lower education level, unemployment, COMM score, extended inpatient duration, and PRN-only opioid regimen remained significant. CONCLUSION: In ambulatory patients with cancer, high occurrence of pain flares may be mitigated by attention to opioid prescription factors and addressing social determinants of health needs of underserved patients.

Mental Defeat and Suicidality in Chronic Pain: A Prospective Analysis.

Living with chronic pain has been identified as a significant risk factor for suicide. Qualitative and cross-sectional studies have reported an association between mental defeat and suicidal thoughts and behavior in patients with chronic pain. In this prospective cohort study, we hypothesized that higher levels of mental defeat would be associated with increased suicide risk at a 6-month follow-up. A total of 524 patients with chronic pain completed online questionnaires measuring variables related to suicide risk, mental defeat, sociodemographic, psychological, pain, activity, and health variables. At 6 months, 70.8% (n = 371) of respondents completed the questionnaires again. Weighted univariate and multivariable regression models were run to predict suicide risk at 6 months. The clinical suicide risk cutoff was met by 38.55% of the participants at baseline and 36.66% at 6 months. Multivariable modeling revealed that mental defeat, depression, perceived stress, head pain, and active smoking status significantly increased the odds of reporting higher suicide risk, while older age reduced the odds. Receiver operating characteristic (ROC) analysis showed that assessment of mental defeat, perceived stress, and depression is effective in discriminating between 'low' and 'high' suicide risk. Awareness of the prospective links from mental defeat, depression, perceived stress, head pain, and active smoking status to increased suicide risk in patients with chronic pain may offer a novel avenue for assessment and preventative intervention. PERSPECTIVE: Results from this prospective cohort study suggest that mental defeat is a significant predictor of increased suicide risk among patients with chronic pain, along with depression, perceived stress, head pain, and active smoking status. These findings offer a novel avenue for assessment and preventative intervention before risk escalates.

Suicidal thoughts and behaviors in patients with chronic pain, with and without co-occurring opioid use disorder.

BACKGROUND: Individuals with chronic pain and a co-occurring substance use disorder present higher risk of suicide, but the individual and joint impacts of chronic pain and substance use disorders on suicide risk are not well defined. The objective of this study was to exam the factors associated with suicidal thoughts and behaviors in a cohort of patients with chronic non-cancer pain (CNCP), with or without concomitant opioid use disorder (OUD). DESIGN: Cross sectional cohort design. SETTING: Primary care clinics, pain clinics, and substance abuse treatment facilities in Pennsylvania, Washington, and Utah. SUBJECTS: In total, 609 adults with CNCP treated with long-term opioid therapy (>/= 6 months) who either developed an OUD (cases, n = 175) or displayed no evidence of OUD (controls, n = 434). METHODS: The predicted outcome was elevated suicidal behavior in patients with CNCP as indicated by a Suicide Behavior Questionnaire-Revised (SBQ-R) score of 8 or above. The presence of CNCP and OUD were key predictors. Covariates included demographics, pain severity, psychiatric history, pain coping, social support, depression, pain catastrophizing and mental defeat. RESULTS: Participants with CNCP and co-occurring OUD had an increased odds ratio of 3.44 in reporting elevated suicide scores as compared to participants with chronic pain only. Multivariable modeling revealed that mental defeat, pain catastrophizing, depression, and having chronic pain, and co-occurring OUD significantly increased the odds of elevated suicide scores. CONCLUSIONS: Patients with CNCP and co-morbid OUD are associated with a 3-fold increase in risk of suicide.

The genetic architecture of pain intensity in a sample of 598,339 U.S. veterans.

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids played a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 125 independent genetic loci, 82 of which are novel. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level, and cognitive traits. Integration of the GWAS findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, beta-blockers, and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

Impact of Cannabis Use on Least Pain Scores Among African American and White Patients with Cancer Pain: A Moderation Analysis.

INTRODUCTION: Based on many published reports, African American patients with cancer experience higher pain severity scores and lower pain relief than White patients. This disparity results from undertreatment of pain and is compounded by low adherence to prescribed non-opioid and opioid analgesics among African American patients with cancer. While nearly one in four patients use cannabis to manage cancer-related symptoms, less is known about how cannabis use influences pain relief in this patient population. METHODS: This study is based on preliminary data from an ongoing study of longitudinal outcomes of opioid therapy among African American and White patients with cancer. Linear mixed-effects models were utilized to assess the interaction of race and cannabis use on pain relief using "least pain" item scores from the Brief Pain Inventory (BPI) averaged across three time points. Models were adjusted for sociodemographic and clinical variables. RESULTS: This analysis included 136 patients (49 African American, 87 White). Overall, 30.1% of the sample reported cannabis use for cancer pain. The mean "least pain" score on BPI was 3.3 (SD=2.42) on a scale of 0-10. African American patients had a mean "least pain" score 1.32±0.48 units higher (indicating lower pain relief) than White patients (p=0.006). Cannabis use did not have a significant main effect (p=0.28). However, cannabis use was a significant moderator of the relationship between race and "least pain" (p=0.03). In the absence of cannabis use, African Americans reported higher "least pain" scores compared to Whites (mean difference=1.631±0.5, p=0.001). However, this disparity was no longer observed in African American patients reporting cannabis use (mean "least pain" difference=0.587±0.59, p=0.32). CONCLUSION: These findings point to the possible role of cannabis in cancer pain management and its potential to reduce racial disparities. These findings are preliminary and further research into the role of cannabis in cancer pain outcomes is needed.

Nonpharmacologic Treatments for Opioid Reduction in Patients With Advanced Chronic Kidney Disease.

Opioid analgesics carry risk for serious health-related harms in patients with advanced chronic kidney disease (CKD) and end-stage kidney disease. In the general population with chronic noncancer pain, there is some evidence that opioid reduction or discontinuation is associated with improved pain outcomes; however, tapering opioids abruptly or without providing supportive interventions can lead to physical and psychological harms and relapse of opioid use. There is emerging evidence that nonpharmacologic treatments such as psychosocial interventions, acupuncture, and interdisciplinary pain management programs are effective approaches to support opioid dose reduction in patients experiencing persistent pain, but research in this area still is relatively new. This review describes the current evidence for nonpharmacologic interventions to support opioid reduction in non-CKD patients with pain and discusses the application of the available evidence to patients with advanced CKD who are prescribed opioids to manage pain.

Perceived social support in patients with chronic pain with and without opioid use disorder and role of medication for opioid use disorder.

BACKGROUND: A significant predictor of treatment outcomes for patients with chronic non-cancer pain (CNCP) and opioid use disorder (OUD) is the degree and quality of social support they receive. Specifically, in patients with CNCP and on long-term opioid therapy, the development of OUD tends to be associated with losses in social support, while engagement in treatment for OUD improves support networks. Delivery of the evidence-based OUD treatment medications, methadone and buprenorphine, occurs in clinical environments which patently differ with respect to social support resources. The aims of this study were to describe perceived social support in patients with CNCP without OUD (no-OUD), with OUD and on buprenorphine (OUD-BP), and with OUD and on methadone (OUD-methadone). METHODS: Using the Duke Social Support Index (DSSI), perceived social support in a sample of Caucasian patients with CNCP and on opioid therapy was compared between no-OUDs (n = 834), OUD-methadone (n = 83) and OUD-BP (n = 99) therapy. Average DSSI scores were compared across groups and a linear regression model computed to describe association between group and perceived social support. RESULTS: No difference was observed in DSSI scores between no-OUDs and OUD-methadone, however scores were lower among OUD-BP participants than those receiving methadone (x = -5.2; 95% CI: -7.5, -2.9) and (x = -6.5, 95% CI: -8.2, -4.9). CONCLUSIONS: Patients with CNCP and OUD on methadone therapy endorse levels of social support comparable to those without OUD, however those on buprenorphine therapy report significantly less support, bringing implications for OUD treatment outcomes.

Risk of Persistent Opioid Use following Major Surgery in Matched Samples of Patients with and without Cancer.

BACKGROUND: The opioid crisis has reached epidemic proportions, yet risk of persistent opioid use following curative intent surgery for cancer and factors influencing this risk are not well understood. METHODS: We used electronic health record data from 3,901 adult patients who received a prescription for an opioid analgesic related to hysterectomy or large bowel surgery from January 1, 2013, through June 30, 2018. Patients with and without a cancer diagnosis were matched on the basis of demographic, clinical, and procedural variables and compared for persistent opioid use. RESULTS: Cancer diagnosis was associated with greater risk for persistent opioid use after hysterectomy [18.9% vs. 9.6%; adjusted OR (aOR), 2.26; 95% confidence interval (CI), 1.38-3.69; P = 0.001], but not after large bowel surgery (28.3% vs. 24.1%; aOR 1.25; 95% CI, 0.97-1.59; P = 0.09). In the cancer hysterectomy cohort, persistent opioid use was associated with cancer stage (increased rates among those with stage III cancer compared with stage I) and use of neoadjuvant or adjuvant chemotherapy; however, these factors were not associated with persistent opioid use in the large bowel cohort. CONCLUSIONS: Patients with cancer may have an increased risk of persistent opioid use following hysterectomy. IMPACT: Risks and benefits of opioid analgesia for surgical pain among patients with cancer undergoing hysterectomy should be carefully considered.

Increased Experimental Pain Sensitivity in Chronic Pain Patients Who Developed Opioid Use Disorder.

OBJECTIVE: Although the great majority of individuals who take opioids for chronic pain use them appropriately and to good effect, a certain minority will develop the problematic outcome of opioid use disorder (OUD). Characteristics associated with the development of OUD in individuals with chronic pain have been described; however, relatively unexplored is how sensitivity to pain is associated with OUD outcomes. MATERIALS AND METHODS: We examined for differences in response to static and dynamic experimental pain stimuli between individuals with chronic nonmalignant pain who developed OUD after starting opioid therapy (n=20) and those on opioid therapy who did not (n=20). During a single experimental session, participants underwent cold pressor and quantitative sensory testing pain assays, and objective and subjective responses were compared between groups; the role of pain catastrophizing in mediating pain responses was examined. RESULTS: Results suggested that both groups of opioid-dependent patients were similarly hyperalgesic to the cold pressor pain stimulus, with nonparametric testing revealing worsened central pain sensitization (temporal summation) in those who developed OUD. Significant group differences were evident on subjective ratings of experimental pain, such that those who developed OUD rated the pain as more severe than those who did not. Pain catastrophizing was unrelated to pain responses. DISCUSSION: Despite the small sample size and cross-sectional design, these findings suggest that experimental pain testing may be a novel technique in identifying patients with chronic pain likely to develop OUD, in that they are likely to evidence exacerbated temporal summation and to rate the associated pain as more severe.

Independent association of tobacco use with opioid use disorder in patients of European ancestry with chronic non-cancer pain.

BACKGROUND: The harms associated with prescription opioid abuse have become a public health crisis. There is a need for evidence-based objective markers of the risk of opioid use disorder (OUD) in patients with pain receiving opioid treatment. The objective of this study was to evaluate the independent association of tobacco use and OUD in patients with chronic non-cancer pain. METHODS: This cross-sectional naturalistic study evaluated 798 adults ≥ 18 years with chronic non-cancer pain treated with long-term opioid therapy (≥ 6 months) who either developed an OUD (cases, n = 216) or displayed no evidence of an OUD (controls, n = 582). The primary outcome was presence of OUD. In addition to current self-reported tobacco use (primary predictor), covariates included demographics, pain severity, and psychiatric history. Data were collected between November 2012 and September 2018. RESULTS: Current tobacco use independently was strongly associated with OUD [odds ratio (OR) 14.0, 95 % confidence interval (CI) 9.5-20.6, p < 0.001], and this association remained significant after adjusting for other risk factors [adjusted odds ratio (aOR) 7.6, 95 % CI 4.8-12.2, p < 0.001]. Other factors associated independently with development of OUD included age, marital status, financial status, education and pain severity. CONCLUSIONS AND RELEVANCE: Current tobacco use is significantly associated with OUD in patients with chronic pain receiving long-term opioid therapy.

Pain catastrophizing as a predictor of suicidal ideation in chronic pain patients with an opiate prescription.

Chronic pain and opioid use are associated with increased risk for suicidal ideation and behaviors (SIB) in cross-sectional studies, particularly among individuals who catastrophize about their pain. This study examined the longitudinal association between two styles of pain coping, catastrophizing and hoping/praying, as predictors of subsequent SIB, as well as possible mediators of this association among patients with chronic pain receiving long-term opioid therapy. Participants (n = 496) were adults with chronic nonmalignant pain on long-term opioid therapy who did not develop an opioid use disorder. Participants were assessed for pain coping, suicidal ideation, depression, social support and pain interference at baseline, and were reassessed for SI, depression, and pain interference at 6- and 12-month follow-ups. Catastrophizing was a significant predictor of increased subsequent SIB, whereas hoping/praying did not protect against future SIB. The relationship between catastrophizing and future SIB was mediated by depression, but not social support or pain interference. In conclusion, catastrophizing was an important predictor of subsequent SIB due to its effect on increasing depression among patients with chronic nonmalignant pain receiving long-term opioid therapy. Future research should explore the extent to which targeting catastrophizing reduces subsequent depression and suicide risk.

Association Between Diagnoses of Chronic Noncancer Pain, Substance Use Disorder, and HIV-Related Outcomes in People Living With HIV.

BACKGROUND: Chronic pain is common in people living with HIV (PLWH). Few studies have evaluated the association between the diagnoses of chronic pain, substance use disorder (SUD), and HIV-related outcomes in clinical settings over a 10-year period. METHODS: Using electronic medical records, the study described psychiatric diagnoses, pain medication, and HIV-related variables in PLWH and examined the factors associated with pain diagnosis and HIV-related outcomes. RESULTS: Among 3528 PLWH, more than one-third exhibited a chronic pain diagnosis and more than one-third a psychiatric disorder. Chronic pain diagnosis has been associated with SUD and mood and anxiety disorders and occurred before SUD or psychiatric disorders about half of the time. Opioids have been commonly prescribed for pain management, more often than nonopioid analgesic, without any change in prescription pattern over the 10-year period. A dual diagnosis of pain and SUD has been associated with more psychiatric disorders and had a negative impact on the pain management by requesting more health care utilization and higher frequency of both opioid and nonopioid medication prescriptions. Chronic pain and SUD had a negative impact on ART adherence. SUD but not chronic pain has been associated with an unsuppressed HIV viral load. CONCLUSIONS: In the current intertwining opioid prescription and opioid epidemic, opioids are still commonly prescribed in PLWH in HIV care. A diagnosis of chronic pain and/or SUD worsened the HIV-related outcomes, emphasizing the potential risk of the HIV epidemic. These findings called for a better coordinated care program in HIV clinics.

Development of the Revised Opioid Risk Tool to Predict Opioid Use Disorder in Patients with Chronic Nonmalignant Pain.

The Opioid Risk Tool (ORT) is a commonly used measure of risk of aberrant drug-related behaviors in patients with chronic pain prescribed opioid therapy. In this study, the discriminant predictive validity of the ORT was evaluated in a unique cohort of patients with chronic nonmalignant pain (CNMP) on long-term opioid therapy who displayed no evidence of developing an opioid use disorder (OUD) and a sample of patients with CNMP who developed an OUD after commencing opioid therapy. Results revealed that the original ORT was able to discriminate between patients with and without OUDs (odds ratio = 1.624; 95% confidence interval [CI] = 1.539-1.715, P < .001). A weighted ORT eliminating the gender-specific history of preadolescent sexual abuse item revealed comparable results (odds ratio = 1.648, 95% CI = 1.539-1.742, P < .001). A revised unweighted ORT removing the history of preadolescent sexual abuse item was notably superior in predicting the development of OUD in patients with CNMP on long-term opioid therapy (odds ratio = 3.085; 95% CI = 2.725-3.493; P < .001) with high specificity (.851; 95% CI = .811-.885), sensitivity (.854; 95% CI = .799-.898), positive predictive value (.757; 95% CI = .709-.799), and negative predictive value (.914; 95% CI = .885-.937). Perspective: The revised ORT is the first tool developed on a unique cohort to predict the risk of developing an OUD in patients with CNMP receiving opioid therapy, as opposed to aberrant drug-related behaviors that can reflect a number of other issues. The revised ORT has clinical usefulness in providing clinicians a simple, validated method to rapidly screen for the risk of developing OUD in patients on or being considered for opioid therapy.

Society of Behavioral Medicine (SBM) position statement: improving access to psychosocial care for individuals with persistent pain: supporting the National Pain Strategy's call for interdisciplinary pain care.

Policy makers have articulated a need for clear, evidence-based guidance to help inform pain policy. Persistent pain is common, expensive, and debilitating, and requires comprehensive assessment and treatment planning. Recently released opioid prescribing guidelines by the CDC (2016) emphasize the importance of using nonopioid therapies before considering opioid treatment for those without a malignant illness. The National Pain Strategy (2016) underscores the importance of comprehensive, interdisciplinary pain care. Unfortunately, despite persuasive evidence supporting the efficacy of psychosocial approaches, these interventions are inaccessible to the majority of Americans. Psychosocial approaches to pain management should be available for all individuals with persistent pain and in all health care settings and contexts as part of the comprehensive, interdisciplinary approach to pain care as outlined in the National Pain Strategy. To achieve this, we must prioritize reimbursement of evidence-based psychosocial approaches for pain assessment and management and improve provider training and competencies to implement these approaches.

Scope and Nature of Pain- and Analgesia-Related Content of the United States Medical Licensing Examination (USMLE).

Background: "The ongoing opioid crisis lies at the intersection of two substantial public health challenges-reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications" [1]. Improved pain education for health care providers is an essential component of the multidimensional response to both still-unmet challenges [2,3]. Despite the importance of licensing examinations in assuring competency in health care providers, there has been no prior appraisal of pain and related content within the United States Medical Licensing Examination (USMLE). Methods: An expert panel developed a novel methodology for characterizing USMLE questions based on pain core competencies and topical and public health relevance. Results: Under secure conditions, raters used this methodology to score 1,506 questions, with 28.7% (432) identified as including the word "pain." Of these, 232 questions (15.4% of the 1,506 USMLE questions reviewed) were assessed as being fully or partially related to pain, rather than just mentioning pain but not testing knowledge of its mechanisms and their implications for treatment. The large majority of questions related to pain (88%) focused on assessment rather than safe and effective pain management, or the context of pain. Conclusions: This emphasis on assessment misses other important aspects of safe and effective pain management, including those specific to opioid safety. Our findings inform ways to improve the long-term education of our medical and other graduates, thereby improving the health care of the populations they serve.

Low Risk of Producing an Opioid Use Disorder in Primary Care by Prescribing Opioids to Prescreened Patients with Chronic Noncancer Pain.

Objective: To examine the risk of developing aberrant behaviors that might lead to a substance use disorder (addiction) when prescribing opioids for the relief of chronic noncancer pain in primary care settings. Design: Longitudinal, prospective, descriptive design with repeated measures. Setting: Private community-based internal medicine and family medicine clinics. Subjects: Patients with chronic musculoskeletal pain. Methods: Standardized measures of patient status (pain, functional impairment, psychiatric disorders, family history) and treatments provided, urine drug monitoring, and medical chart audits (presence of aberrant drug-related behaviors) were obtained in a cohort of 180 patients at the time of initiating opioids for chronic noncancer pain and at three, six, and 12 months thereafter. Results: Over the 12-month follow-up period, subjects demonstrated stable, mild to moderate levels of depression (PHQ-9 scores ranging from 9.43 to 10.92), mild anxiety (BAI scores ranging from 11.80 to 14.67), minimal aberrant drug-related behaviors as assessed by chart reviews, and a low percentage of illicit drug use as revealed by results of urine drug monitoring. Less than 5% of our study population revealed any evidence of substance use disorder. Conclusions: This prospective study suggests that patients without a recent or prior history of substance use disorder who were prescribed primarily short-acting opioids in low doses for chronic noncancer pain have a low risk for developing a substance use disorder. This finding supports the importance of prescreening patients being considered for opioid therapy and that prescription of opioids for noncancer pain may carry a lower risk of abuse in selected populations such as in private, community-based practices.