The Impact of Non-Pain Factors on Pain Interference Among U.S. Service Members and Veterans with Symptoms of Mild Traumatic Brain Injury.

U.S. Service members and Veterans (SM/V) experience elevated rates of traumatic brain injury (TBI), chronic pain, and other non-pain symptoms. However, the role of non-pain factors on pain interference levels remains unclear among SM/Vs, particularly those with a history of TBI. The primary objective of this study was to identify factors that differentiate high/low pain interference, given equivalent pain intensity among U.S. SM/V participating in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) national multi-center prospective longitudinal observational study. An explainable machine learning was used to identify key predictors of pain interference conditioned on equivalent pain intensity. The final sample consisted of n = 1,577 SM/Vs who were predominantly male (87%), and 83.6% had a history of mild TBI(s) (mTBI), while 16.4% were TBI negative controls. The sample was categorized according to pain interference level (Low: 19.9%, Moderate: 52.5%, and High: 27.6%). Both pain intensity scores and pain interference scores increased with the number of mTBIs (p < 0.001), and there was evidence of a dose response between the number of injuries and pain scores. Machine learning models identified fatigue and anxiety as the most important predictors of pain interference, whereas emotional control was protective. Partial dependence plots identified that marginal effects of fatigue and anxiety were associated with pain interference (p < 0.001), but the marginal effect of mTBI was not significant in models considering all variables (p > 0.05). Non-pain factors are associated with functional limitations and disability experience among SM/V with an mTBI history. The functional effects of pain may be mediated through multiple other factors. Pain is a multi-dimensional experience that may benefit most from holistic treatment approaches that target comorbidities and build supports that promote recovery.

Are opioids effective analgesics and is physiological opioid dependence benign? Revising current assumptions to effectively manage long-term opioid therapy and its deprescribing.

A re-examination of clinical principles of long-term opioid therapy (LTOT) for chronic pain is long overdue amid the ongoing opioid crisis. Most patients on LTOT report ineffectiveness (poor pain control, function and health) but still find deprescribing challenging. Although prescribed as analgesics, opioids more likely provide pain relief primarily through reward system actions (enhanced relief and motivation) and placebo effect and less through antinociceptive effects. The unavoidable physiologic LTOT dependence can automatically lead to a paradoxical worsening of pain, disability and medical instability (maladaptive opioid dependence) without addiction due to allostatic opponent neuroadaptations involving reward/antireward and nociceptive/antinociceptive systems. This opioid-induced chronic pain syndrome (OICP) can persist/progress whether LTOT dose is maintained at the same level, increased, decreased or discontinued. Current conceptualization of LTOT as a straightforward long-term analgesic therapy appears incongruous in view of the complex mechanisms of opioid action, LTOT dependence and OICP. LTOT can be more appropriately conceptualized as therapeutic induction and maintenance of an adaptive LTOT dependence for functional improvement irrespective of analgesic benefits. Adaptive LTOT dependence should be ideally used for a limited time to achieve maximum functional recovery and deprescribed while maintaining functional gains. Patients on LTOT should be regularly re-evaluated to identify if maladaptive LTOT dependence with OICP has diminished any functional gains or leads to ineffectiveness. Ineffective LTOT (with maladaptive LTOT dependence) should be modified to make it safer and more effective. An adequately functional life without opioids is the ideal healthy long-term goal for both LTOT initiation and LTOT modification.

Monotonic Association of Increasing Past-Year Substance Use Disorder across a Four-Level Trauma Post-Traumatic Stress Disorder (PTSD) Hierarchy in a Nationwide Sample.

OBJECTIVE: There is limited information on the differences in the association of substance use disorders (SUD) with four clinically relevant hierarchical groups based on trauma exposure and its consequences (1-no trauma; 2-trauma but no PTSD; 3-remitted PTSD; and 4-current PTSD). METHODS: Among adults enrolled in a large nationally representative survey, the National Epidemiologic Survey on Alcohol and Related Conditions Wave III (NESARC III), we compared differences in SUD prevalence between each of the hierarchical trauma group and the prior group adjusting for potentially confounding factors. RESULTS: Unadjusted results show that each increase in the hierarchy was associated with a greater likelihood of SUD diagnoses, even after adjusting for potentially confounding variables. However, after adjusting for covariates, comparison of adults with past to those with current PTSD showed persistence of SUD indicators. CONCLUSION: SUD prevalence increased substantially with trauma exposure even without PTSD and monotonically increased further with past and current PTSD, respectively, illustrating the differential effect of the clinical consequences of trauma.

Buprenorphine use and courses of care for opioid use disorder treatment within the Veterans Health Administration.

BACKGROUND: Retention of patients in buprenorphine medication treatment for opioid use disorder (B-MOUD) reduces harms associated with opioid use disorder (OUD). We sought to characterize the patients receiving B-MOUD and courses of B-MOUD in a large healthcare system. METHODS: We conducted a retrospective, open cohort study of patients with OUD who either did or did not receive B-MOUD courses within the Veterans Health Administration (VHA) from January 2006 through July 2019, using VHA clinical data. We compared patients receiving or not receiving B-MOUD, characterized B-MOUD courses (e.g., length and doses), and examined persistence, across patient characteristics, over time. We used analyses for normally or non-normally distributed continuous variables, categorical data, and persistence over time (Kaplan-Meier persistence curves). RESULTS: We identified 255,726 Veterans with OUD; 40,431 (15.8%) had received 63,929 B-MOUD courses. Compared to patients with OUD without B-MOUD, patients with B-MOUD were younger, more often of white race, and had more co-morbidities. The frequency of new B-MOUD starts and prevalent B-MOUD patients ranged from 1550 and 1989 in 2007 to 8146 and 16,505 in 2018, respectively. The median duration of B-MOUD was 157 (IQR: 37-537) days for all courses and 33.8% patients had more than one course. The average proportion days covered was 90% (SD: 0.15), and the average prescribed daily dose was 13.44 (SD: 6.5). CONCLUSIONS: Within a VHA B-MOUD cohort, courses increased more than 10-fold from 2006 to 2016 with nearly half of patients experiencing multiple courses. Patient demographics seem to dictate the length of courses.

Pain Management in Older Adults Before and During the First Year of COVID-19 Pandemic: Prevalence, Trends, and Correlates.

BACKGROUND: There is limited knowledge on whether and how health care access restrictions imposed by the coronavirus disease of 2019 pandemic have affected utilization of both opioid and nonpharmacological treatments among US older adults living with chronic pain. METHODS: We compared prevalence of chronic pain and high impact chronic pain (ie, chronic pain limiting life or work activities on most days or every day in the past 6 months) between 2019 (pre-pandemic) and 2020 (first year of pandemic) and utilization of opioids and nonpharmacological pain treatments among adults aged ≥65 years enrolled in the National Health Interview Survey, a nationally representative sample of noninstitutionalized civilian U.S. adults. RESULTS: Of 12 027 survey participants aged ≥65 (representing 32.6 million noninstitutionalized older adults nationally), the prevalence of chronic pain was not significantly different from 2019 (30.8%; 95% confidence interval [CI], 29.7%-32.0%) to 2020 (32.1%; 95% CI, 31.0%-33.3%; p = .06). Among older adults with chronic pain, the prevalence of high impact chronic pain was also unchanged (38.3%; 95% CI, 36.1%-40.6% in 2019 versus 37.8%; 95% CI, 34.9%-40.8% in 2020; p = .79). Use of any nonpharmacological interventions for pain management decreased significantly from 61.2% (95 CI, 58.8%-63.5%) in 2019 to 42.1% (95% CI, 40.5%-43.8%) in 2020 (p < .001) among those with chronic pain, as did opioid use in the past 12 months from 20.2% (95% CI, 18.9%-21.6%) in 2019 to 17.9% (95% CI, 16.7%-19.1%) in 2020 (p = .006). Predictors of treatment utilization were similar in both chronic pain and high-impact chronic pain. CONCLUSION: Use of pain treatments among older adults with chronic pain declined in the first year of coronavirus disease of 2019 pandemic. Future research is needed to assess long-term effects of coronavirus disease of 2019 pandemic on pain management in older adults.

Complex Persistent Opioid Dependence-an Opioid-induced Chronic Pain Syndrome.

OPINION STATEMENT: Long-term opioid therapy (LTOT) for chronic cancer and non-cancer pain is commonly ineffective in providing its stated goal of improving function through good control of pain. Opioid tapering (slow dose reduction and/or discontinuation), the logical solution, also appears to be ineffective among many patients on LTOT as it often leads to even worse pain control and function, leaving the patients and providers managing LTOT in a clinical conundrum with little treatment choices. Complex persistent opioid dependence (CPOD) was recently offered as a heuristic to explain this clinical conundrum exemplified by the ineffectiveness of both LTOT and opioid tapering. This manuscript provides a detailed description of the neurobehavioral underpinnings of CPOD, explaining how long-term opioid use can lead to more pain even while experiencing relief with each opioid dose. CPOD is characterized by the allostatic opponent mechanisms of neuroadaptations related to the progression of opioid dependence and tolerance involving nociceptive/anti-nociceptive brain systems causing opioid-induced hyperalgesia and reward/anti-reward systems causing hyperkatefia or suffering that induces pain experience through the cognitive/emotional component of pain mechanisms. "Opioid Induced Chronic Pain syndrome" (OICP) is offered as an alternate clinical diagnostic term instead of CPOD that has several limitations as a diagnosis term including poor patient acceptance due to stigma towards addiction and clinical confounding with opioid use disorder, a related but separate clinical entity. OICP with LTOT is conceptualized as a recoverable iatrogenic problem that can be managed by pain providers. Broad guidance on management of OICP is also provided.

Persistence of significant pain interference following substance use disorder remission: Negative association with psychosocial and physical recovery.

BACKGROUND: Although substance use disorder (SUD) is frequently complicated by pain, the prevalence and correlates of persistent pain and dysfunction following SUD remission have not been studied. METHODS: Using a cross-sectional sample of United States (US) adults with SUD identified in the National Epidemiologic Survey on Alcohol and Related Conditions Wave III, we evaluated the prevalence of moderate/severe pain interference (PI) in subgroups with current and remitted SUD and the independent association of SUD remission and PI with self-reported psychosocial and physical function (Mental Health Composite Score [MCS] and Physical Function Score [PFS] from the Short Form 12). RESULTS: A fifth (20.6%; 7.6 million) of estimated 36.7 million US adults with past year SUD and a slightly higher proportion (25.6%; 9.6 million) of 37.4 million with SUD remission reported PI. MCS and PFS showed independent negative associations with PI among adults with both past year SUD and SUD remission. MCS had a positive independent association with SUD remission, but a stronger negative association with PI. While PFS had no statistically significant association with SUD remission, it had a strong negative association with PI. Analysis of interaction between SUD remission and PI revealed that SUD remission had no effect on the association of PI and MCS but had significant moderating influence on the association between PI and PFS. CONCLUSIONS: Moderate to severe pain interference continues to be a significant problem among a sizable population achieving SUD remission potentially impeding recovery, and deserves focused clinical attention both active SUD and its remission.

Twelve-Month Retention in Opioid Agonist Treatment for Opioid Use Disorder Among Patients With and Without HIV.

Although opioid agonist therapy (OAT) is associated with positive health outcomes, including improved HIV management, long-term retention in OAT remains low among patients with opioid use disorder (OUD). Using data from the Veterans Aging Cohort Study (VACS), we identify variables independently associated with OAT retention overall and by HIV status. Among 7,334 patients with OUD, 13.7% initiated OAT, and 27.8% were retained 12-months later. Likelihood of initiation and retention did not vary by HIV status. Variables associated with improved likelihood of retention included receiving buprenorphine (relative to methadone), receiving both buprenorphine and methadone at some point over the 12-month period, or diagnosis of HCV. History of homelessness was associated with a lower likelihood of retention. Predictors of retention were largely distinct between patients with HIV and patients without HIV. Findings highlight the need for clinical, systems, and research initiatives to better understand and improve OAT retention.

Who Uses Veterans Mental Health Services?: A National Observational Study of Male Veteran and Nonveteran Mental Health Service Users.

ABSTRACT: Mental health (MH) research among veterans receiving services from the Veterans Health Administration (VHA) is extensive and growing and informs many clinical practice guidelines. We used nationally representative survey data to examine the generalizability of this extensive body of research by comparing sociodemographic and clinical characteristics of male veteran veterans health service (VHS) users (n = 491) with veteran non-VHS users (n = 840) and nonveteran (n = 6300) MH service users. VHS users were older, more often reported Black race, and less likely to have private or Medicaid insurance, but had similar prevalence of psychiatric or substance use disorder diagnoses but with a greater prevalence of posttraumatic stress disorder (PTSD). VHS users reported higher rates of medical diagnoses, pain interference, and poorer physical and MH status. These results suggest that VHA MH research may be reasonably generalizable to US mental health service users with caveats regarding age, PTSD diagnosis, pain, and racial distribution.

Assessment of Common Comorbidity Phenotypes Among Older Adults With Knee Osteoarthritis to Inform Integrated Care Models.

OBJECTIVE: To establish the frequency of concordant, discordant, and clinically dominant comorbidities among Medicare beneficiaries with knee osteoarthritis (KOA) and to identify common concordant condition subgroups. PARTICIPANTS AND METHODS: We used a 5% representative sample of Medicare claims data to identify beneficiaries who received a diagnosis of KOA between January 1, 2012, and September 30, 2015, and matched control group without an osteoarthritis (OA) diagnosis. Frequency of 34 comorbid conditions was categorized as concordant, discordant, or clinically dominant among those with KOA and a matched sample without OA. Comorbid condition phenotypes were characterized by concordant conditions and derived using latent class analysis among those with KOA. RESULTS: The study sample included 203,361 beneficiaries with KOA and 203,361 non-OA controls. The largest difference in frequency between the two cohorts was for co-occurring musculoskeletal conditions (23.7% absolute difference), chronic pain syndromes (6.5%), and rheumatic diseases (4.5%), all with a higher frequency among those with knee OA. Phenotypes were identified as low comorbidity (53% of cohort with classification), hypothyroid/osteoporosis (27%), vascular disease (10%), and high medical and psychological comorbidity (10%). CONCLUSIONS: Approximately 47% of Medicare beneficiaries with KOA in this sample had a phenotype characterized by one or more concordant conditions, suggesting that existing clinical pathways that rely on single or dominant providers might be insufficient for a large proportion of older adults with KOA. These findings could guide development of integrated KOA-comorbidity care pathways that are responsive to emerging priorities for personalized, value-based health care.

The association of opioid use disorder and homelessness nationally in the veterans health administration.

BACKGROUND: Substance use disorder (SUD) is a major risk factor for homelessness, but the specific association of opioid use disorder (OUD) and homelessness in the context of their shared risk factors has not been the focus of prior studies. We used national data from the United States Veterans Health Administration (VHA) to examine the association of OUD and homelessness in the context of shared risk factors. METHODS: In this cross-sectional analysis of veterans who received VHA care during Fiscal Year 2012 (N = 5,450,078), we compared the prevalence of OUD and other sociodemographic, and clinical factors among homeless and non-homeless veterans. We estimated the odds ratio for homelessness associated with OUD alone, and after adjusting for other factors through multivariate logistic regression. RESULTS: Homeless veterans had substantially higher prevalence of OUD than other VHA patients (7.7 % Vs 0.6 %) and OUD was associated with 13 times higher unadjusted odds of homelessness (Odds Ratio [OR] 13.36, 95 % CI 13.09-13.62), which decreased with adjustment for sociodemographic factors (black race, mean income and age), other SUD, medical, and psychiatric diagnoses (final OR 1.57, 95 % CI 1.53-1.61). Other SUDs (alcohol, cannabis, cocaine, and hallucinogens) showed similar or slightly higher odds of homelessness as OUD in the final model. CONCLUSIONS: OUD was strongly associated with homelessness among US veterans although this association was largely but not entirely attenuated by shared sociodemographic and co-morbid risk factors including several other SUDs. Treatment of homeless veterans with OUD should address socio-economic vulnerabilities and other co-morbidities in addition to treatments for OUD.

Association of symptom severity, pain and other behavioral and medical comorbidities with diverse measures of functioning among adults with post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is an often disabling mental disorder whose management typically focuses on reducing PTSD symptoms. Chronic pain and other comorbidities that commonly accompany PTSD symptoms may also be independently associated with disability. Using data from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions, we examined the independent association of PTSD symptom severity, pain interference, non-PTSD psychiatric and substance use disorders (SUD), and medical illnesses with each of four domains of function: mental health-related quality of life and physical functioning assessed with the Mental Health Composite Score (MCS) and Physical Function Score (PFS) of the Short Form-12; perceived social support from the Interpersonal Support and Evaluation List-12 (ISEL-12); and self-reported past year employment. Among 1779 individuals representing 11 million U.S. adults who met the Diagnostic and Statistical Manual-5 (DSM-5) criteria for Past Year PTSD, the MCS (41.2; SD 12.5), PFS (44.8; SD 13.2) and ISEL-12 (33.6; SD 7.2) indicated substantial disability when compared to population norms, and only 63.6% were employed. Multiple regression showed the MCS had a modest negative association with PTSD symptoms, pain interference, psychiatric multimorbidity and medical comorbidity although not with SUD. PFS and employment had significant negative associations with pain interference and medical comorbidity. ISEL-12 had a weak negative association with PTSD symptoms and non-PTSD psychiatric comorbidity. Common comorbidities thus significantly influence disability associated with PTSD, often more strongly than PTSD symptoms. PTSD treatment may require integrative multimorbidity management beyond a focus on PTSD symptoms.

Complex Persistent Opioid Dependence with Long-term Opioids: a Gray Area That Needs Definition, Better Understanding, Treatment Guidance, and Policy Changes.

The multitude of treatments available for tens of millions of US adults with moderate/severe chronic pain have limited efficacy. Long-term opioid therapy (LTOT) is a widely available option for controlling pain among patients with chronic pain refractory to other treatments. The recent recognition of LTOT inefficacy and complications has led to more frequent opioid tapering, which in turn has revealed its own set of complications. The occurrence of the same set of symptoms-worsening pain, declining function, and clinical instability-in contrasting contexts of LTOT ineffectiveness and opioid tapering has led to increasing recognition of the utility of complex persistent opioid dependence (CPOD), a clinically distinct but biologically similar state compared with opioid use disorder as an explanatory diagnosis/heuristic. Recent guidelines for LTOT tapering have incorporated buprenorphine treatment based on CPOD concepts as a recommended treatment for problems due to opioid tapering with limited supportive evidence. The increasing utilization of buprenorphine for both LTOT ineffectiveness and opioid tapering problems raises the urgent need for a review of the clinical definition, mechanisms, and treatment of CPOD and pertinent policies. In this manuscript, we discuss various issues related to CPOD that requires further clarification through research and policy development.

Ensuring Patient Protections When Tapering Opioids: Consensus Panel Recommendations.

Long-term opioid therapy has the potential for serious adverse outcomes and is often used in a vulnerable population. Because adverse effects or failure to maintain benefits is common with long-term use, opioid taper or discontinuation may be indicated in certain patients. Concerns about the adverse individual and population effects of opioids have led to numerous strategies aimed at reductions in prescribing. Although opioid reduction efforts have had generally beneficial effects, there have been unintended consequences. Abrupt reduction or discontinuation has been associated with harms that include serious withdrawal symptoms, psychological distress, self-medicating with illicit substances, uncontrolled pain, and suicide. Key questions remain about when and how to safely reduce or discontinue opioids in different patient populations. Thus, health care professionals who reduce or discontinue long-term opioid therapy require a clear understanding of the associated benefits and risks as well as guidance on the best practices for safe and effective opioid reduction. An interdisciplinary panel of pain clinicians and one patient advocate formulated recommendations on tapering methods and ongoing pain management in primary care with emphasis on patient-centered, integrated, comprehensive treatment models employing a biopsychosocial perspective.

Nonconsensual Dose Reduction Mandates are Not Justified Clinically or Ethically: An Analysis.

This manuscript describes the institutional and clinical considerations that apply to the question of whether to mandate opioid dose reduction in patients who have received opioids long-term. It describes how a calamitous rise in addiction and overdose involving opioids has both led to a clinical recalibration by healthcare providers, and to strong incentives favoring forcible opioid reduction by policy making agencies. Neither the 2016 Guideline issued by the Centers for Disease Control and Prevention nor clinical evidence can justify or promote such policies as safe or effective.

Trajectories of Self-Reported Opioid Use Among Patients With HIV Engaged in Care: Results From a National Cohort Study.

BACKGROUND: No prior studies have characterized long-term patterns of opioid use regardless of source or reason for use among patients with HIV (PWH). We sought to identify trajectories of self-reported opioid use and their correlates among a national sample of PWH engaged in care. SETTING: Veterans Aging Cohort Study, a prospective cohort including PWH receiving care at 8 US Veterans Health Administration (VA) sites. METHODS: Between 2002 and 2018, we assessed past year opioid use frequency based on self-reported "prescription painkillers" and/or heroin use at baseline and follow-up. We used group-based trajectory models to identify opioid use trajectories and multinomial logistic regression to determine baseline factors independently associated with escalating opioid use compared to stable, infrequent use. RESULTS: Among 3702 PWH, we identified 4 opioid use trajectories: (1) no lifetime use (25%); (2) stable, infrequent use (58%); (3) escalating use (7%); and (4) de-escalating use (11%). In bivariate analysis, anxiety; pain interference; prescribed opioids, benzodiazepines and gabapentinoids; and marijuana use were associated with escalating opioid group membership compared to stable, infrequent use. In multivariable analysis, illness severity, pain interference, receipt of prescribed benzodiazepine medications, and marijuana use were associated with escalating opioid group membership compared to stable, infrequent use. CONCLUSION: Among PWH engaged in VA care, 1 in 15 reported escalating opioid use. Future research is needed to understand the impact of psychoactive medications and marijuana use on opioid use and whether enhanced uptake of evidence-based treatment of pain and psychiatric symptoms can prevent escalating use among PWH.

Early Discontinuation of Buprenorphine Therapy for Opioid Use Disorder Among Privately Insured Adults.

OBJECTIVE: This study examined the temporal relationship between early discontinuation of buprenorphine treatment and health care expenditures before and after treatment initiation. METHODS: MarketScan commercial claims for patients who initiated buprenorphine for opioid use disorder in 2013 and had continuous insurance for the subsequent 12 months (N=6,444) were used to examine the relationship between treatment retention and health care expenditures before and after buprenorphine initiation. Analysis of covariance and generalized linear models (with gamma distribution/log link) were used to compare expenditures across four buprenorphine-retention groups (0-3, 3-6, 6-12, and 12 or more months). RESULTS: Average total health care expenditures in the 3 months prior to buprenorphine initiation ranged from a high of $7,588 among those with the shortest retention to $4,929 among those with the longest retention (p<0.001). In the 12 months after buprenorphine initiation, total health care expenditures averaged $26,332 per year, with $2,916 (11.1%) in out-of-pocket expenditures. Average annual expenditures for medication were highest among patients with the longest buprenorphine retention, and total health care expenditures were highest among those with the shortest retention. Expenditures for health care services other than medication were highest among those with early discontinuation both before the initiation of buprenorphine and during the initial period after initiation but not in subsequent quarters. CONCLUSIONS: Poorer treatment retention among privately insured adults was associated with greater clinical and financial burdens that preceded and continued during the period shortly following treatment initiation, suggesting that cost burdens may contribute to poor retention among privately insured adults.

Associations between stopping prescriptions for opioids, length of opioid treatment, and overdose or suicide deaths in US veterans: observational evaluation.

OBJECTIVE: To examine the associations between stopping treatment with opioids, length of treatment, and death from overdose or suicide in the Veterans Health Administration. DESIGN: Observational evaluation. SETTING: Veterans Health Administration. PARTICIPANTS: 1 394 102 patients in the Veterans Health Administration with an outpatient prescription for an opioid analgesic from fiscal year 2013 to the end of fiscal year 2014 (1 October 2012 to 30 September 2014). MAIN OUTCOME MEASURES: A multivariable Cox non-proportional hazards regression model examined death from overdose or suicide, with the interaction of time varying opioid cessation by length of treatment (≤30, 31-90, 91-400, and >400 days) as the main covariates. Stopping treatment with opioids was measured as the time when a patient was estimated to have no prescription for opioids, up to the end of the next fiscal year (2014) or the patient's death. RESULTS: 2887 deaths from overdose or suicide were found. The incidence of stopping opioid treatment was 57.4% (n=799 668) overall, and based on length of opioid treatment was 32.0% (≤30 days), 8.7% (31-90 days), 22.7% (91-400 days), and 36.6% (>400 days). The interaction between stopping treatment with opioids and length of treatment was significant (P<0.001); stopping treatment was associated with an increased risk of death from overdose or suicide regardless of the length of treatment, with the risk increasing the longer patients were treated. Hazard ratios for patients who stopped opioid treatment (with reference values for all other covariates) were 1.67 (≤30 days), 2.80 (31-90 days), 3.95 (91-400 days), and 6.77 (>400 days). Descriptive life table data suggested that death rates for overdose or suicide increased immediately after starting or stopping treatment with opioids, with the incidence decreasing over about three to 12 months. CONCLUSIONS: Patients were at greater risk of death from overdose or suicide after stopping opioid treatment, with an increase in the risk the longer patients had been treated before stopping. Descriptive data suggested that starting treatment with opioids was also a risk period. Strategies to mitigate the risk in these periods are not currently a focus of guidelines for long term use of opioids. The associations observed cannot be assumed to be causal; the context in which opioid prescriptions were started and stopped might contribute to risk and was not investigated. Safer prescribing of opioids should take a broader view on patient safety and mitigate the risk from the patient's perspective. Factors to address are those that place patients at risk for overdose or suicide after beginning and stopping opioid treatment, especially in the first three months.