Introduction
Opioid use disorder (OUD) is a chronic condition associated with significant morbidity and mortality.
1 Chronic pain is a common co-occurring condition present in approximately two-thirds of patients with OUD.
2-4 Chronic pain and OUD are related, and worsening of either condition may result in exacerbation and maintenance of both conditions over time.
5 Complicating matters further, mental health conditions such as depressive disorders, anxiety disorders, and posttraumatic stress disorder (PTSD) commonly occur among both patients with OUD and patients with Chronic pain.
6-9 Major depressive disorder, in particular, is implicated in the development and maintenance of both OUD and Chronic pain.
10,11 The relationships between OUD, Chronic pain, and mental health conditions are complex and may be mediated by a variety of mechanisms including allostatic overload (eg, the cumulative impact of attempts to maintain physiologic stability in the face of stressors), negative reinforcement, and social, emotional, and cognitive processes.
5Pharmacologic treatment of OUD with methadone, a full opioid agonist, or buprenorphine, a partial opioid agonist, is associated with substantial reductions in all cause and overdose mortality.
12 Buprenorphine exerts its analgesic effect through partial agonism at the mu opioid receptor. It is also an antagonist at the kappa opioid receptor and is being explored as a possible treatment option for patients with major depressive disorder, treatment resistant depression, and suicidal ideation.
13,14 Despite its analgesic (buprenorphine and methadone) and antidepressant (buprenorphine) effects, a subset of patients with OUD and Chronic pain treated with medications for OUD (MOUD) continue to experience high levels of pain interference (the interference of pain on daily activities
15), poor social functioning, mental health distress, nonprescribed substance use, and low utilization of coping strategies.
16-21 Patients with co-occurring OUD and Chronic pain treated with MOUD are more likely to report cravings for opioids than patients without Chronic pain.
22 Although presence of Chronic pain in people with OUD is not associated with a return to nonprescribed opioid use,
22,23 highly volatile pain (ie, significant fluctuation or variability of pain scores over time) and severe pain are risk factors for return to use.
24-26 Similarly, high levels of depression and/or high pain severity throughout treatment also appear to be risk factors for return to substance use.
27While numerous studies demonstrate a relationship between mental health distress and the presence and severity of Chronic pain among persons stabilized on either buprenorphine or methadone, there is a paucity of research specifically exploring the relationship between mental health conditions and pain interference in this population.
6,21,28-30 Pain interference is important to measure as it is significantly related to Chronic pain treatment targets such as functional status, pain acceptance, and pain catastrophizing.
31,32 A secondary analysis of the Prescription Opioid Addiction Treatment Study demonstrated an association between the severity of depression and pain interference.
33 However, the relationship of other mental health conditions with pain interference was not assessed. In another trial, patients with co-occurring Chronic pain, OUD on buprenorphine, and PTSD had higher pain severity and pain interference than patients without PTSD.
34 Other studies show a relationship between a combined measure of pain severity and interference and PTSD, depression, and anxiety.
7,8,35 However, the specific relationship of pain interference to these mental health conditions is not fully explored. Furthermore, there is little understanding of the impact of co-occurring mental health conditions on Chronic pain interference in this population.
This study examines data collected at baseline for a randomized trial of Mindful Awareness in Body-Oriented Therapy (MABT) in patients stabilized on either buprenorphine or methadone. The purpose of the present exploratory study is to examine the relationship between Chronic pain and mental health conditions among patients stabilized on buprenorphine or methadone. Specific objectives include the following: (1) compare mental health conditions (anxiety, depression, PTSD) in those with versus without Chronic pain; (2) examine whether anxiety, depression, and PTSD are associated with pain severity and interference among patients with Chronic pain; (3) explore whether the number of co-occurring mental health conditions (ie, anxiety, depression, and PTSD alone or in combination) are associated with pain severity and interference among patients with Chronic pain.
Methods
Setting
We report data collected at baseline from a 2-group randomized trial (N = 303) of MABT as an adjunct to MOUD treatment. Participants were recruited from 5 Washington state outpatient clinics in urban and rural settings. One clinic was an urban opioid treatment program prescribing predominantly methadone. One clinic was a mental health clinic offering buprenorphine treatment. Three clinics were primary care clinics with embedded buprenorphine programs.
Participants
We included all participants (N = 303) enrolled in the MABT randomized trial described above. In the trial, patients with adequate treatment engagement and clinical stability to participate in the MABT intervention were recruited. For buprenorphine, this was defined as at least 4 weeks of medication treatment and appointment frequency less than once weekly. Because it typically takes a longer period of time to reach a therapeutic dose of methadone, medication dose stability was defined as at least 90 days in methadone treatment with a minimum dose of 60 mg and no more than 3 missed doses or any missed dose evaluation appointments in the past 30 days. Patients also needed to speak English and be willing to attend MABT sessions when offered. They were excluded if they were not willing or able to remain in MOUD treatment for the duration of the 1-year trial, or if they showed evidence of overt psychosis or cognitive impairment.
Measures
Demographics, socioeconomic, and health attributes were assessed by patient self-report. Substance use was assessed using the Timeline Follow-Back Interview (TLFB).
36 The TLFB is a calendar method used to identify past 90-day substance use, including frequency and quantity of use.
Mental health distress was measured with 3 well-validated scales. The Patient Health Questionnaire-9 (PHQ-9) is a 9-item scale designed to assess levels and severity of depression, with a cutoff point of ≥10 for moderate-severe depression.
37(p9) The General Anxiety Disorder-7 (GAD-7) is a 7-item scale designed to assess levels and severity of generalized anxiety, with a cutoff point of ≥10 for moderate-severe anxiety.
38 The Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 (PCL-5) is a validated 20-item self-report measure that assesses the DSM-5 symptoms of PTSD; a cutoff score of 33 was used to indicate probable PTSD.
39The presence of Chronic pain was determined by a survey question: “Are you currently experiencing any bodily pain that has been present for 3 months or more?” Pain severity and interference were measured using the Brief Pain Inventory (BPI).
40 The BPI is a well-validated, widely used measurement tool for assessing clinical pain. The assessment includes 11 questions, which provide information on pain severity and pain interference in the past week. Pain severity is rated from 0 (“No pain”) to 10 (“Worst pain ever”), and participants are asked to rate their pain currently, at its worst and its best over the past week, and on average for the past 3 months. Pain interference is the average of 7 items asking about the impact of pain on daily activities, mood, and enjoyment of life, which participants rate on a scale from 0 (does not interfere) to 10 (completely interferes). Different cut points have been validated for different painful conditions, and per national guidelines regarding pain measures in clinical trials, a minimally important difference on the pain interference scale is a decrease of 1 point.
41,42Data Analysis
Demographic and clinical characteristics were summarized using descriptive statistics. To examine differences between participants with and without Chronic pain, independent sample t tests were used for continuous measures and chi-square tests for categorical measures. Two-sided significance tests were used for all analyses with a significance level of P < .05. Differences in clinical characteristics including time in treatment, MOUD type, percent days abstinent, pain severity, pain interference, and binary measures of mental health conditions (moderate to severe symptoms vs no or mild symptoms) and a categorical measure of the number of mental health conditions were compared by Chronic pain status.
Among the subgroup of patients who reported Chronic pain, we first examined differences in pain severity and interference by groups based on each mental health condition (anxiety, depression, and PTSD). To examine the effect of the number of mental health conditions on pain severity and interference we conducted 1-way ANOVAs to compare the means of these groups using a Bonferroni correction for multiple comparisons. To examine differences in pain severity and interference by combinations of mental health conditions, we classified patients in 8 categories: no mental health conditions, anxiety, depression, PTSD, anxiety and depression, depression and PTSD, anxiety and PTSD, and anxiety, depression, and PTSD. Box plots were used to show the range, quartiles, and medians of these differences by category since the study was not powered to detect differences between specific combinations of mental health conditions. A sensitivity analysis was performed to examine for differences in these analyses based on medication (buprenorphine or methadone). Because the sensitivity analysis yielded only one significantly different result (the ANOVA test reported in the Results section), we looked at a combined group (ie, participants on either buprenorphine or methadone) for the primary analyses, which increased the power of the study.
Data analyses were performed using Stata version 18 (StataCorp LLC, College Station, TX, USA).
Discussion
In this sample of patients with OUD stabilized on either buprenorphine or methadone, highly symptomatic and co-occurring mental health conditions are prevalent, and are associated with increased pain interference. Previous research has examined an association between individual mental health conditions and Chronic pain in patients treated with MOUD.
6,7,17,18,20,27,28 However, our study is the first to report that the presence of multiple, co-occurring mental health conditions are associated with higher pain interference. These findings have implications for the longitudinal care of patients treated with MOUD, especially those also experiencing Chronic pain.
Despite participant stability on MOUD (two-thirds of the sample were engaged in treatment for >1 year and rates of abstinence were high), moderate-severe anxiety, moderate-severe depression, and PTSD were highly prevalent, and frequently co-occurring, with one-quarter of the cohort screening positive for all 3 mental health conditions. Over half of participants experienced Chronic pain and had an average pain severity and interference of 4.9 and 5.0, respectively. This corresponds to moderate-severe pain, depending on the clinical cut points used.
43-45 These findings comport with previously published studies demonstrating that despite the antidepressant, analgesic, and anxiolytic properties of buprenorphine, a subset of patients continue to experience high levels of pain and mental health distress.
19,20,27Compared to participants without Chronic pain, participants with Chronic pain were more likely to screen positive for moderate-severe anxiety and moderate-severe depression. This finding is congruent with previously published research that described high rates of co-occurring Chronic pain, anxiety, and depression within the general population
46-49 and, specifically, among patients with OUD.
2,50,51 A high prevalence of co-occurring PTSD and Chronic pain severity and interference have also been established among the general population,
52 veterans,
53 and patients with OUD receiving MOUD.
8,9 In the present study, PTSD was more prevalent in participants with Chronic pain (45% vs 36%), but the association was not statistically significant (
P = .119). Clearly, patients with Chronic pain require careful assessment of multiple mental health comorbidities.
Notably, almost one-third of participants with Chronic pain screened positive for all 3 conditions (ie, anxiety, depression, and PTSD), compared to 18% of participants without Chronic pain. Furthermore, there was an additive effect that was both statistically and clinically significant. Per Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines, a difference of 1 point on the pain interference scale indicates a minimally important difference in clinical trials.
42 We found, for example, a 1.3-point higher mean pain interference score in participants with 3 mental health conditions compared to those with 1 mental health condition. Similar findings have been reported among the general population. For example, results from a large nationally representative cross-sectional survey commissioned by the New Zealand Ministry of Health revealed that symptoms of anxiety and depression interacted synergistically with Chronic pain to increase the odds of reporting Chronic pain.
54 We extend these findings to include PTSD and document the additive effects of the number of mental health conditions on Chronic pain among a sample of patients with OUD stabilized on either buprenorphine or methadone.
Our results show that among participants with Chronic pain, co-occurring mental health conditions were more strongly associated with pain interference than pain severity. This finding has clinical implications as patients are most often asked to report their pain using a brief “0-to-10” assessment of pain intensity. Pain intensity is an important component of pain assessments; however, it does not allow for recognition of the multidimensional nature of pain. Assessing pain interference, in addition to pain severity, aids the measurement of the amount or frequency of “the interference of pain on daily activities” with the inclusion of physical, psychological, and social activities
15 and thus is more clinically relevant, particularly in light of its demonstrated relationship to mental health distress.
Results revealing additive effects of co-occurring mental health conditions on patient-reported pain may be explained through models of allostatic load.
55,56 Simplistically, allostasis encompasses the mechanisms through which individuals adapt to stressors to maintain physiological stability. Allostatic (over)load is the cumulative effect on the brain and body arising from attempts to adapt and maintain allostasis. Psychological, behavioral, and social demands relating to the management of multiple mental health conditions, or more directly through dysregulated physiological mechanisms, may limit and/or impair coping strategies. Poor coping strategies, such as avoidance, have been found to contribute to poor emotion regulation, a trans-diagnostic factor underlying mental health disorders and substance use disorder,
31,32 and critical for the capacity to manage mental health distress and Chronic pain
57 and highly relevant to those with OUD.
57,58Clinically, these findings support the identified need for greater mental health support for individuals receiving methadone or buprenorphine treatment, and point to the importance of complementary and integrative health (CIH) approaches that promote regulatory skills.
57 CIH approaches, and specifically mind-body interventions, are considered best practice for the treatment of Chronic pain and stress-related disease.
59,60 Theoretical models of mindfulness,
61,62 including the mindfulness stress buffering theory, postulate that mind-body training can facilitate the capacity to observe and experience internal reactions to a stressor with acceptance and equanimity. In turn, this impartial receptiveness buffers initial threat appraisals and, subsequently, reduces emotional reactivity,
63 leading to greater emotional and physical regulation and improved health.
64 Therefore, mind-body interventions may promote more adaptive responses to stressors, increasing the capacity to manage mental health distress and Chronic pain within the context of OUD.
This study has multiple strengths. First, it is a multisite study including participants from urban and rural areas and multiple practice settings (opioid treatment program, mental health clinic, addiction clinic, and primary care clinic). Patients reported a high proportion of days abstinent, and most had been engaged in methadone or buprenorphine treatment for over a year, reducing the possibility that mental health symptoms were primarily substance-induced. In addition to presence or absence of Chronic pain, pain severity and interference were measured using the BPI. Pain interference is significantly related to Chronic pain treatment targets such as functional status, pain acceptance, and pain catastrophizing.
31,32 There is a paucity of literature on the relationship between pain interference and mental health conditions in patients with OUD treated with MOUD. This study extends current knowledge by demonstrating an additive association between multiple mental health conditions and pain interference.
There are also several limitations worth noting. This was a convenience sample of participants already stabilized on MOUD, and results may not be generalizable to less stable populations of patients who are actively using substances. The majority (97%) indicated stable housing. Of note, this is not necessarily an indicator of permanent housing, but that housing was perceived to be stable by the participant. Though the screening forms for mental health conditions are well-validated, patients were not assessed using the gold standard DSM-5 diagnostic interview. Different BPI cut points and minimally important clinical differences have been validated for different painful conditions, but to our knowledge, there are no standardized cut points specifically for individuals with Chronic pain and OUD.
34 Because this is an analysis of the baseline data only, we are unable to comment on the directionality of observed associations between mental health conditions and Chronic pain severity and interference. Most patients received buprenorphine (88%), and the present analysis was not designed to assess differences in the relationship between Chronic pain and mental health distress by MOUD type. Because most patients received buprenorphine, the results of the present study may not be generalizable to patients receiving methadone. We did not collect data on use of other medications (including medications for pain, depression, anxiety, and PTSD), so we cannot comment on whether the mental health conditions were treatment resistant. Finally, although we include an exploratory analysis, the study was not powered to detect interactions between specific combinations of mental health conditions (eg, PTSD + depression vs PTSD + anxiety), a potential question for further research.
Conclusions
Among patients with OUD stabilized on either buprenorphine or methadone, highly symptomatic and co-occurring mental health conditions are common, and are associated with increased pain interference. Treatment should not stop with MOUD; increased screening and treatment for Chronic pain and mental health conditions in this population are needed.