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Department of Family and Community Medicine, Saint Louis University School of Medicine, St. Louis, MissouriResearch Service, Harry S. Truman Veterans Administration Medical Center, Columbia, MissouriSaint Louis University Center for Outcomes Research, St. Louis, Missouri
Center for Applied Health Research, Baylor Scott & White Health, and Central Texas Veterans Health Care System, Temple, TexasDepartment of Medicine, Texas A&M Health Science Center, Bryan, TexasDepartment of Psychiatry, UT Health Science Center, San Antonio, Texas
Department of Psychiatry, Washington University School of Medicine, St. Louis, MissouriMental Health Service, The Bell Street Clinic, VA St. Louis Health Care System – John Cochran Division, St. Louis, Missouri
Opioid exposure associated with over two-fold risk of depression recurrence.
This association is independent of pain and other measured confounders.
Prescription opioids may limit depression recovery or worsen residual symptoms.
Repeated depression screening during opioid therapy may be warranted.
Several studies have shown that chronic opioid analgesic use is associated with increased risk of new-onset depression. It is not known if patients with remitted depression are at increased risk of relapse after exposure to opioid analgesics. A retrospective cohort design using patient data from the Veterans Health Administration (VHA; n = 5,400), and Baylor Scott & White Health (BSWH; n = 842) was performed with an observation period in the VHA from 2002 to 2012 and in the BSWH from 2003 to 2012. Eligible patients had a diagnosis of depression at baseline and experienced a period of remission. Risk of depression recurrence was modeled in patients that either started taking an opioid or continued without opioid prescriptions before or during remission. Cox proportional hazard models were used to measure the association between opioid use and depression recurrence controlling for pain, and other confounders. Patients exposed to an opioid compared with those unexposed had a significantly greater risk of depression recurrence in both patient populations (VHA: hazard ratio [HR] = 2.17, 95% confidence interval [CI], 2.01–2.34; BSWH: HR = 1.77; 95% CI, 1.42–2.21). These results suggest opioid use doubles the risk of depression recurrence even after controlling for pain, psychiatric disorders, and opioid misuse. Further work is needed to determine if risk increases with duration of use. Repeated screening for depression after opioid initiation may be warranted.
In 2 large patient cohorts with large differences in demographic characteristics and comorbidity, patients with remitted depression who were exposed to opioid analgesics were 77% to 117% more likely to experience a recurrence of depression than those who remained opioid -free. Routine, not just at initiation of treatment, screening for depression is warranted.
found that neck, back, head, orofacial, chest, abdominal and joint pain, and number of pain conditions, measured during remission, were significantly associated with increased risk of depression recurrence. Because pain and depression have been shown to be closely linked and pain is a predictor of depression recurrence, evaluating the independent contribution of opioid analgesic use (OAU) to risk of depression recurrence must be done with rigorous control for confounding by pain.
Depression and opioid use are known to be associated. Patients with depression are more likely to use opioids even when functioning is good.
A well established literature supports the conclusion that patients with chronic pain and comorbid depression are more likely to be prescribed opioids, receive higher doses, use for a longer duration and at higher doses, and misuse or abuse opioids compared with patients without depression.
Specifically, we have previously reported that Veterans Health Administration (VHA) patients receiving opioids for >180 days were 51% more likely to have an incident depression diagnosis, compared with patients exposed for <90 days.
More recently, we found that the duration of opioid use, but not morphine equivalent dose (MED) was associated with a twofold increased risk of incident depression. We found no association between maximum MED, modeled as 1 to 50 mg, 51 to 100 mg, and >100 mg, and incident depression after controlling for duration of use and pain. We observed up to a twofold increased risk of incident depression among patients who used for 90 days or longer compared with those who used for 1 to 30 days. This risk remained after controlling for MED and pain.
Our findings were consistent across 3 separate patient populations drawn from health care systems with large differences in demographic characteristics and comorbidity. Importantly, our studies showed chronic OAU leads to depression independent of pain, opioid misuse, and psychiatric and physical comorbidity. These studies were conducted with patients selected to be free of a depression diagnosis for 2 years before baseline. Therefore, we do not know if opioid use among patients with a recent history of depression promotes depression recurrence. If opioid use is associated with increased risk of depression recurrence, the benefits versus risks of opioids in chronic, noncancer pain patients with recent depression will need to be carefully and frequently re-evaluated.
This current study specifically sought to determine whether 1) in a cohort of VHA patients in depression remission, initiation of an opioid prescription for noncancer pain increases risk of recurrence after controlling for confounding from pain and other sources of confounding, and 2) results generalize to a patient cohort derived from a private-sector health care system.
Patient data were obtained from the VHA and Baylor Scott & White Health System (BSWH) electronic medical record files. BSWH data are part of the Health Care Systems Research Network Virtual Data Warehouse.
VHA medical records included clinic encounters from January 1, 2000 through December 31, 2012, and BSWH data included encounters from January 1, 2003 through December 31, 2012. Patient data used in the present study included International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) diagnostic codes, prescription records, vital signs, and demographic data.
In both patient cohorts, we restricted the cohort to patients 18 to 80 years of age at baseline and free of a diagnosis of cancer or HIV. Baseline was January 1, 2002 in the VHA data and January 1, 2005 in the BSWH data. Further, as shown in Figs 1A and 1B, patients must have been regular users (ie, have a visit at least once each year), of their health care system in the 2 years before baseline. These 2 years before baseline are called the “washout period” and were used to exclude patients with existing opioid use and those with remitted depression (eg, diagnosed with depression in year 1 of washout and remitted in year 2 of washout). Last, patients initiating opioid use on or after the date of depression recurrence were excluded because they were not informative to the temporal order of the research question; that is, to determine if opioid use in remitted patients increases risk of depression recurrence. Eligibility criteria resulted in 5,400 VHA and 842 BSWH patients free of opioid use for at least 2 years and with a depression diagnosis. All patients must have experienced depression remission during follow-up. As shown in Fig 2, some patients could have experienced the beginning of a period of remission at the end of washout and others had yet to enter a period of remission.
Opioid Exposure Variable
Patients were considered opioid-exposed if they received a prescription for any of the following medications: codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, oxycodone, oxymorphone, morphine, and pentazocine, for any number of days and any daily dose. We created a binary variable indicating ever receiving an opioid versus remaining opioid-free during follow-up. We did not have a sufficient sample size to estimate the duration of exposure or groups defined according to dose.
Outcome Variable: Depression Recurrence
Patients were defined as having depression if they had 2 or more visits in the same 12-month period and/or 1 hospital discharge diagnosis with an ICD-9-CM code for depression (ie, 296.2, 296.3, and 311). This algorithm, commonly used in studies of depression in administrative data, has excellent concordance compared with written medical records
The lack of consistently recorded depression severity (eg, administrations of the Patient Health Questionnaire [PHQ-9]) in administrative medical record data precludes defining the course of depression, including onset of remission, relapse, and recurrence with the precision outlined in treatment trials.
Within the limits of our data we were able to determine when patients were no longer being treated for depression but less able to distinguish remission from recovery, and distinguish relapse, which occurs early in the process of recovery, from recurrence, which occurs after many months of remission. In the present study, we acknowledge recurrence may better reflect relapse in some cases and remission may be partial or complete. With this caveat, and in the interest of using a consistent terminology, we defined periods of “remission” and “recurrence” using an algorithm previously reported in studies on the basis of administrative medical record data.
First, a period without depression was defined by at least 120 consecutive days with no record of a depression diagnosis including at least 90 days with no prescription for antidepressants. That is, patients were visiting the medical center but the medical record data indicated 4 months of care without a diagnosis and 3 months without pharmacotherapy for depression. Patients meeting this criteria were considered in remission. Depression recurrence was then defined as a new diagnosis for depression after a period of remission. The date of recurrence was the date of an inpatient diagnosis or the date of the first diagnosis when 2 diagnoses in the same 12-month period defined depression.
Both patient data sets contained the same covariate measures with the exception of pain scores and marital status, which were only available in VHA data. We selected covariates that might confound the association between opioid initiation and depression recurrence.
Importantly, the combination of covariates had to be a good predictor of opioid initiation to compute a propensity score that could be used to balance covariates between opioid users and never users as described in more detail below. Covariates included demographic characteristics, and psychiatric and substance use disorders, the latter including opioid abuse/dependence, chronic physical conditions associated with depression, painful conditions, self-reported pain scores, and volume of health services use.
Demographic characteristics included age, race, sex, and marital status. A measure of insurance coverage was included to control for access to care outside of the VHA, and in the private sector data, Medicare served as a proxy for low-cost medication coverage. Psychiatric disorders, measured using the ICD-9-CM codes, included post-traumatic stress disorder and a composite anxiety disorder variable, which included panic disorder, generalized anxiety disorder, social phobia, obsessive-compulsive disorder, and anxiety disorder not otherwise specified. Substance use disorder included ICD-9-CM codes for nicotine dependence or a code indicating any history of smoking, alcohol abuse/dependence, and any drug abuse/dependence. Physical conditions identified by ICD-9-CM codes included type 2 diabetes, hypertension, cardiovascular and cerebrovascular disease, obesity, low testosterone, and sleep apnea (the latter 2 variables may be confounders or may be in the causal pathway in that opioids lead to low testosterone and sleep apnea, which in turn lead to depression recurrence). Volume of health services utilization defined by the quartile of mean clinic visits per month was used to adjust for detection bias, which is the potential for finding a condition or other patient variable because of a greater number of contacts with health care providers.
Pain was measured according to ICD-9-CM diagnosis codes for >900 conditions for which an opioid may be prescribed.
These conditions were collapsed into 5 categories: arthritis, back pain, headache, musculoskeletal pain, and neuropathic pain. Pain scores, available in VHA data, were measured on a 10-point scale with higher scores designating worse pain. We adjusted for the maximum pain score (ie, worst pain, reported any time before the end of follow-up).
Propensity score (PS) was computed to control for confounding by indication (ie, pain diagnoses), and to control for other confounders. In this study, the PS is a measure of the probability of a patient being prescribed an opioid. The PS was calculated using a multivariate logistic regression model containing covariates and interaction terms. The model selected for weighting data was determined by optimization of the Akaike Information Criterion with a c-statistic >.80. The PS was used to balance covariates in the opioid-treated and untreated groups via conventional inverse probability of treatment weighting (IPTW) methods.
Patient data were weighted by the inverse probability of receiving opioid treatment. IPTW retains all patients and thus was chosen over matching techniques, which often results in many lost observations. The model terms used to compute the PS and IPTW in VHA data were the same as those applied in BSWH data. In the VHA data the mean weight was .98, SD = .80, minimum = .48, and maximum = 9.59, and in BSWH data the mean weight was 1.01, SD = .49, minimum = .50, and maximum = 9.34.
Bivariate analysis included t-tests and χ2 tests computed to measure the associations among opioid use, covariates, and depression recurrence. Bivariate associations were computed first in unweighted data and then in weighted data. Results of bivariate analysis using weighted data were evaluated to determine if the PS model and IPTW were successful in balancing potential confounders in opioid-exposed and unexposed patients. This was determined by showing that covariates were similarly distributed and not significantly associated with opioid treatment after applying IPTW.
Using unweighted and weighted data, we computed Cox proportional hazard models to estimate the association between opioid treatment and time to depression recurrence. Cox models using weighted data controlled for confounding via weighting were used and we computed a final model that allowed for further adjustment for each pain condition and maximum pain score that could occur any time before the end of follow-up. This additional adjustment controlled for pain after initiation of opioid use. The unit of follow-up time was in months, and the end of follow-up was defined by depression recurrence, last patient encounter, or end of the observation period. Cox proportional hazard models were computed using the PHREG procedure in SAS version 9.4 (SAS Institute, Cary, NC) with α set at .05. Two-tailed tests were used in all analysis. The proportional hazard assumption was violated in BSWH at the early part of follow-up, however, use of time-dependent covariates overcomes concerns about violating the assumption. This study was reviewed and approved by the institutional review boards of participating institutions.
Patient characteristics in the VHA and BSWH cohorts are shown in Table 1. On average, compared with BSWH, VHA patients were older (mean = 50.4 ± 12.4 vs 42.1 ± 15.2 years) and predominantly male (86.8% vs 23.9%). Both patient groups were mostly white (>79%).
Table 1Distribution of Opioid Exposure and Covariates According to Health Care Organization
During the follow-up period, 52.0% of VHA and 46.9% of BSWH patients received at least 1 opioid prescription. Comorbid psychiatric disorders were more common among VHA patients as were physical health conditions with the exception of sleep apnea, which was diagnosed in approximately 8% of both patient groups.
More than 50% of both patient groups had at least 1 painful condition. Arthritis, back pain, and neuropathic pain were more common in VHA patients and headaches and musculoskeletal conditions were more often diagnosed in BSWH patients. The average maximum pain score reported by VHA patients was 8.0 ± 2.6, on a 10-point scale.
The unweighted distributions of depression recurrence and covariates according to opioid exposure are shown in Table 2. The cumulative incidence of depression in exposed and unexposed patients was similar (57.7% and 60.1%, respectively, P = .08). However, this is an artifact of not accounting for how fast depression onset in the 2 groups. For instance, when examining incidence rate in VHA data, results showed that opioid-exposed had a higher rate of depression recurrence (incidence rate = 130.1/1,000 person-years, confidence interval [CI], 123.9–136.6) than nonexposed (incidence rate = 114.4/1,000 person-years, CI, 108.8–120.2).
Table 2Unweighted OAU Exposure With Outcome and Covariates, According to Health Care Organization
In VHA patients, opioid exposure was significantly associated with younger age (P < .0001), and significantly fewer opioid-exposed patients were male and white (P < .05 and P < .0001, respectively). All psychiatric comorbidities were more common among opioid-exposed compared with nonexposed patients (P < .0001). Physical health conditions, painful conditions, pain score, and health services utilization were all more prevalent among patients receiving at least 1 opioid prescription compared with those who were not opioid-exposed (P < .0001). Among BSWH patients, patients prescribed at least 1 opioid were significantly more likely to have a comorbid health diagnosis (P < .5–P < .0001) with the exception of cerebrovascular disease and sleep apnea. The only psychiatric disorder significantly associated with opioid exposure was nicotine dependence/history of smoking (P < .05). Last, contrary to the VHA patient sample, opioid-exposed BSWH patients had a significantly lower volume of health care utilization compared with nonexposed (P < .0001).
After weighting data, covariates were no longer significantly associated with opioid exposure in VHA and BSWH patients (Table 3). Mean pain scores among VHA opioid-exposed and unexposed patients were nearly identical (mean = 8.0 nonexposed vs mean = 8.2 exposed). Overall, IPTW successfully balanced the distribution of covariates and, importantly, the percentage of painful conditions was nearly the same in opioid-exposed and nonexposed persons in both patient populations.
Table 3Weighted by Inverse Probability of OAU Exposure (%) With Covariates, According to Health Care Organization
Results of Cox proportional hazard models are shown in Table 4. Before weighting data in model 1, VHA and BSWH patients who initiated opioid use, compared with those who did not, were significantly more likely to have a depression recurrence (hazard ratio [HR] = 1.87; 95% CI, 1.74–2.02 and HR = 1.50, 95% CI, 1.19–1.88, respectively) in this univariate model. In model 2, after correcting for confounding via data-weighting, but without additional covariate adjustment, the association between opioid initiation and depression recurrence increased and remained significant in VHA and BSWH patient samples. The magnitude of association between opioid exposure and depression recurrence remained similar in model 3, which included additional adjustment for painful conditions, and pain scores in VHA data, that may have occurred between initiation of an opioid and depression recurrence. In this model, we observed that VHA and BSWH opioid-exposed patients had up to a twofold increased risk of depression recurrence relative to their unexposed counterparts (HR = 2.17, 95% CI, 2.01–2.34 in VHA and HR = 1.77, 95% CI, 1.42–2.21 in BSWH). Survival curves illustrating the association between opioid exposure and time to depression recurrence are shown in Fig 3A (VHA patients) and Fig 3B (BSWH patients).
Table 4Association Between Opioid Use and Incident Depression Relapse, Unweighted and Weighted by Inverse Probability of Opioid Use Exposure
We computed post hoc analysis in the VHA patient cohort to determine if risk of recurrence differed in patients who began opioids before entering a period of remission versus initiating while in a period of remission. Among 2,809 opioid starts in VHA patients, 30.8% occurred before remission (n = 865) and 69.2% occurred during the remission period (n = 1,944). We computed an unadjusted survival model comparing risk of depression recurrence among patients who started opioids before remission versus those who started while in remission. Results indicated starting opioids while depressed was associated with a significant risk of depression recurrence compared with starting opioids during remission (HR = 1.87, 95% CI, 1.70–2.07). This finding is preliminary because confounders were not balanced between these 2 groups. Although sample size prohibited computing survival models with an exposure variable for the duration of opioid use, we observed that the distribution of VHA patients who used for 1 to 30 days, 31 to 90 days, and >90 days was similar in those who did and did not experience recurrence. Among the VHA patients who experienced a depression recurrence, 75.5% used opioids for 1 to 30 days, 12.7% used for 31 to 90 days, and 11.8% used opioids for >90 days. Among VHA patients who did not experience a depression recurrence, 75.6% used opioids for 1 to 30 days, 13.6% for 31 to 90 days, and 10.8% for >90 days. We also found MED was similarly distributed in patients with and without depression recurrence.
Last, to overcome immortal time bias, we computed the association between duration of opioid use in VHA data and risk of recurrence by restricting opioid use to start at least 1 year after remission. In balanced data, compared with patients who used for 1 to 30 days, we found that 31 to 90 days of continuous use and >90 days of continuous opioid use were not significantly associated with increased risk of recurrence but point estimates were in the direction of increasing risk with longer duration of use (HR = 1.04; 95% CI, .80–1.35 and HR = 1.17, 95% CI, .88–1.58).
In 2 large patient cohorts with large differences in demographic characteristics and comorbidity burden, we observed that patients who were in a period of depression remission had an approximately twofold greater risk of depression recurrence if they initiated an opioid medication compared with patients who remained unexposed to opioids. Although a growing body of evidence supports the association between longer duration of opioid use and increasing risk of new-onset depression,
to our knowledge, this study is novel in showing that opioid therapy increases the risk of depression recurrence among patients with remitted depression.
Additional research is necessary to determine the mechanisms underlying our findings. However, one potential explanation is that opioid exposure acts to prevent full remission and then opioids worsen partly remitted depression which leads to recurrence. Patients who start opioid medication before a period of remission may experience partial remission and be more vulnerable to worsening depression and recurrence. Although limited, supplemental analysis indicated opioid initiation while depressed compared with during remission was associated with increased risk of recurrence (HR = 1.87). This provides limited evidence that risk of recurrence may be driven by opioid use leading to incomplete remission, which in turn places patients at risk for recurrence.
In this study, we did not find evidence for an association between longer duration or higher dose of opioids and increased risk of depression recurrence. This contrasts with our studies of incident depression in which longer duration was associated with increasing risk.
We speculate that the role of opioid dose and duration in risk of incident depression may not apply to risk of depression recurrence for which risk may not be increased as a function of dose or longer duration. As suggested by supplementary data analysis, there is very limited evidence that duration is associated with risk of recurrence.
Opioid exposure was determined on the basis of prescription fills and it is impossible to know whether patients took their medications as prescribed. If patients did not use their prescription, and were misclassified as opioid exposed, the error would bias results to the null and our hazard ratios may actually underestimate risk of recurrence.
The algorithms for remission and recurrence are imperfect indicators of the course of disease. If consistently available for all patients, repeated, monthly assessments of depression symptoms would have allowed for more precise measures of remission and recurrence; however, such data are rarely available in retrospective medical record databases. In the VHA patient sample, 638 had PHQ-9 scores during remission and recurrence. Of these, 259 were not exposed to opioids and 379 did initiate an opioid. On average, PHQ-9 scores among opioid-free patients were 10.9 ± 7.6 during remission and 10.9 ± 7.6 at recurrence compared with 11.5 ± 7.1 during remission and 11.4 ± 7.3 during recurrence in opioid-exposed patients. A PHQ-9 score of 10 is the cut point for moderate depression and these values may point to reinitiating treatment for those who did not experience full remission. These data are limited to a small subsample of the VHA patients and do not include preremission depression severity measures. Although these PHQ-9 scores raise the possibility that opioid exposure is not associated with limited remission, they could also indicate that patients with more persistent symptoms are also the patients receiving multiple PHQ-9 measures. In sum, these data were insufficient to determine if opioids limit depression remission. Further research with prospective data collection is needed to understand how opioid use affects the course of depression.
Prescription opioid use among patients with a recent history of depression increases the chance of recurrence and this effect is independent of pain diagnoses and pain intensity scores. In addition to monitoring pain patients for new-onset depression, clinicians should be aware and discuss the probability of depression recurrence with patients considering opioid therapy.
As of 2013, in the developed world, back pain and depression were ranked number 1 and 2 in the top 10 causes of years lived with disability.
Global Burden of Disease Study 2013 Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013.
The burden of disease due to these conditions may be increased if opioid treatment for chronic pain, especially back pain, leads to persistent depression. The present findings highlight a particularly challenging situation faced by clinicians and pain patients and point to the need for careful consideration of depression in the assessment of benefit and risk. To improve clinical outcomes and for public health, the current study highlights the need to develop effective nonopioid pain medication and nonpharmacological therapies for chronic pain.
Von Korff M.
Trends in long-term opioid therapy for noncancer pain among persons with a history of depression.
Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013.
This study was supported by the National Institute of Mental Health, Prescription Opioid Analgesics and Risk of Depression, R21MH101389. This work also received support from the Veterans Health Administration. The views are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs.
The authors have no conflicts of interest to declare.
We read with interest the article by Scherrer and colleagues3 published in The Journal of Pain. The authors conducted a retrospective study using data from Veterans Health Administration (VA; n = 5,400), and Baylor Scott & White Health (n = 842). They reported that patients exposed to an opioid compared with those unexposed had a significantly greater risk of depression recurrence in both patient populations. They conclude that their results suggest opioid use doubles the risk of depression recurrence even after controlling for pain, psychiatric disorders, and opioid misuse.