Pharmacological and behavioral pain treatment strategies for patients with opioid use disorder.

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Published in final edited form as: Expert Opin Pharmacother. 2025 May 17;26(9):1041–1054. doi: 10.1080/14656566.2025.2506688 Pharmacological and behavioral pain treatment strategies for patients with opioid use disorder Victoria Ameral a, b, * , Thomas R Hickey c, d, * , Erin Dawna Reilly a, b , Jessica A Patterson e , Mehmet Sofuoglu f, g Author information Article notes Copyright and License information a VISN 1 Mental Illness Research, Education, and Clinical Center (MIRECC), VA Bedford Healthcare System, Bedford, MA, USA b Department of Psychiatry, UMass Chan Medical School, Worcester, MA, USA c Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA d Department of Anesthesiology, VA Connecticut Healthcare System, West Haven, CT, USA e VISN 1 Knowledge Library, VA Connecticut Healthcare System, West Haven, CT, USA f VISN 1 Mental Illness Research, Education, and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA g Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA * Contributed equally to the work. ✉ CONTACT Mehmet Sofuoglu, Mehmet.Sofuoglu@va.gov , VISN 1 Mental Illness Research, Education, and Clinical Center (MIRECC), VA Connecticut Healthcare System, 950 Campbell Ave, 151D, West Haven, CT 06516, USA Issue date 2025 Jun. PMC Copyright notice PMCID: PMC12202159  NIHMSID: NIHMS2085325  PMID: 40366730 The publisher's version of this article is available at Expert Opin Pharmacother Abstract Introduction: A critical challenge in providing effective medical care for individuals in opioid agonist treatment (OAT) for opioid use disorder is the effective management of acute and chronic pain. While pain commonly co-occurs with opioid use disorder, there is limited research to guide effective management of pain in this population. Areas covered: We first provide an overview of the etiology and treatment of acute and chronic pain, highlighting areas of complexity for patients receiving OAT. We then describe the search strategy, which involved a date-inclusive search for relevant terms in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. After summarizing the results of this search on the evidence for pharmacological and behavioral treatments of acute and chronic pain for individuals on OAT, we conclude with a discussion of these findings and a summarized expert opinion on the state of the evidence. Expert opinion: The evidence suggests that while research on effective treatment of acute and chronic pain in individuals in OAT is limited, promising work is ongoing to translate existing treatments, particularly behavioral treatments for chronic pain, to support this population. However, further research is warranted, particularly regarding pharmacological options. Keywords: Opioid use disorder, opioid agonist treatment, acute pain, chronic pain, pharmacological treatment, behavioral treatment 1. Introduction Opioid Use Disorder (OUD) is a chronic condition characterized by compulsive opioid use leading to harmful consequences, including physical and mental health problems, social dysfunction, and increased risk of overdose and death. OUD affects over 40 million people worldwide [ 1 ], with over 9 million cases in the United States (US) alone [ 2 ]. OUD and pain commonly co-occur and are intricately linked; initial exposure to opioids frequently occurs during the treatment of acute pain [ 3 ], chronic pain is common among individuals with OUD [ 4 ], and pain is an important predictor of OUD treatment outcomes [ 5 ]. Opioid Agonist Treatment (OAT), involving long-acting opioid medications like methadone or buprenorphine, is a gold-standard treatment for OUD that is highly effective in reducing cravings, withdrawal symptoms, and overdose risk. Unfortunately, managing acute and chronic pain for individuals in OAT presents unique challenges. Healthcare providers treating patients with OUD may be reluctant to prescribe pain medications, refer patients on OAT to pain specialists, or prioritize treating one condition at the expense of the other. Thus, guidance on effective treatments for co-occurring pain and OUD is urgently needed. This scoping review examines existing research on pharmacological and behavioral treatment strategies for pain in individuals receiving OAT for OUD. We first provide an overview of acute and chronic pain and their standard treatments, followed by a summary of the challenges of pain treatment for patients on OAT. We then provide the results of our review followed by a discussion of the findings with respect to the quality of evidence, current best practices, and gaps in the literature. 2. Etiology and treatment of acute and chronic pain Acute and chronic pain differ significantly in their origins, functional impacts, and treatments. Acute pain primarily arises from tissue damage, such as injuries, acute illnesses, or surgical procedures; it is typically short-lived, lasting from days to weeks [ 6 ]. Primarily eliciting anxiety and fear related to the immediate threat or injury, acute pain can temporarily impair cognitive function, activities of daily living, and social interactions [ 7 , 8 ], all of which typically resolve once pain subsides. As such, treatment is focused on immediate relief and recovery. In a presumably opioid naïve population, multiple modalities, including analgesic drugs, surgery, or other medical interventions, are often effective in alleviating acute pain [ 9 ]. In the perioperative setting, for example, recommendations with high level supporting evidence include multimodal analgesia (pharmacologic and non-pharmacologic), non-steroidal anti-inflammatory drugs (NSAIDs) and or acetaminophen, and regional and or neuraxial techniques (when appropriate) [ 10 ]. Notably, interest is growing in the potential for perioperative use of methadone and buprenorphine in opioid naïve individuals, given improved pain outcomes and an overall opioid-sparing effect compared with standard full agonist opioids [ 11 , 12 ]. Behavioral treatments for acute pain typically focus on (1) mitigating distress in the context of surgery or other procedures (e.g. through brief interventions) or (2) reducing the risk that acute pain will progress to chronic pain [ 13 , 14 ]. Options aim to reduce the perception of pain and co-occurring anxiety while also minimizing reliance on pain medication and may include relaxation, music, and other leisure activities (e.g. art and creative therapy) [ 15 – 18 ]. Chronic pain, defined as pain lasting more than 3 months, can arise from various causes including injury, inflammation, metabolic dysfunction, nerve damage, or changes within the nervous system itself [ 19 ]. The chronic pain experience encompasses sensory, emotional, and cognitive components, with a range of emotional responses including anhedonia, depression, and fatigue [ 20 ]. Treatment for chronic pain often involves a multidisciplinary approach, including pharmacological, psychological, and physical interventions [ 21 ]. For pharmacological approaches, nonopioid analgesics such as serotonin-norepinephrine reuptake inhibitor (SNRIs), pregabalin/gabapentin, oxcarbazepine, and NSAIDs provide at least minor relief for some chronic pain conditions [ 22 ]. For opioid medications, a recent overview of Cochrane reviews on reducing lower back pain found high certainty of a small benefit to tapentadol, moderate certainty for a small benefit to ‘strong opioids,’ low certainty of a medium benefit for tramadol, and very low certainty of a small benefit for buprenorphine [ 23 ]. Despite this mixed evidence of benefit, it is notable that recent national guidelines for prescribing opioids for pain recommend optimization of non-opioid therapies (pharmacological and non-pharmacological) and a number of risk management steps to reduce potential for opioid-related harms [ 24 ]. Interventional therapies (e.g. spine injections, sympathetic nerve blocks, neuromodulation, and intrathecal therapy) offer non-opioid-based therapies for many chronic pain etiologies though these are limited by low to moderate quality research to date [ 25 ]. Behavioral treatments are an essential component of chronic pain care. Evidence-based psychological treatments such as Cognitive Behavioral Therapy (CBT) for chronic pain [ 26 ] and Acceptance and Commitment Therapy (ACT) [ 27 , 28 ] are extensively used to help reduce emotional distress, increase effective coping strategies, and improve overall functioning. Complementary and alternative method (CAM) therapies like physical therapy, yoga, exercise class, and tai chi can also help reduce pain and opioid medication use [ 29 ]. Notably, the treatment of chronic pain conditions remains a significant challenge due to the diversity of conditions and the strong influence of psychological and social factors on treatment outcomes. 3. Understanding and addressing pain for patients in OAT The challenges of both acute and chronic pain treatment for individuals on OAT are due to the complex interplay of factors related to both OUD and agonist medications themselves. Opioid tolerance and withdrawal, the two main physical symptoms of OUD, may both cause and contribute to pain experiences. Withdrawal during early abstinence is described as very or extremely painful by more than half of individuals with OUD who experience it [ 30 ]. Tolerance, the need for increasing opioid doses to achieve the desired effect, can cause a right shift of the dose–response curve [ 31 ], with one retrospective case–control study reporting postoperative opioid consumption over three times greater in those with opioid tolerance compared to those without. For those in OAT, this may differ by specific medication, as one retrospective comparison found that buprenorphine was associated with 60% lower MME compared with methadone [ 32 ]. Pain itself is also a powerful cue for opioid cravings, with individuals associating the sensation of pain and pain-related thoughts with the need for relief through opioid use. For the 40–50% of individuals in OAT meeting criteria for chronic pain conditions [ 4 ], this association can lead to a reinforcing loop, where pain triggers cravings for opioids, which in turn can increase the likelihood of returning to illicit opioid use [ 5 ]. Another contributor to pain is opioid-induced hyperalgesia (OIH), a paradoxical increase in pain sensitivity associated with long-term opioid use [ 33 ]. OIH may manifest as a lowered pain threshold, increased pain intensity, and diminished analgesic response to opioids [ 34 ]. Accurately determining the prevalence of OIH within OAT populations is challenging due to the difficulty in distinguishing OIH from both the underlying pain conditions that prompted initial opioid use and tolerance to opioid analgesia [ 34 ]. However, there is emerging evidence suggesting that OIH may be especially pronounced among those whose opioid tolerance is attributable to OUD [ 33 ] or those receiving OAT treatment for OUD [ 35 ]. In clinical settings, while these contributors to difficult-to-control pain should be recognizable, they often overlap. For example, an increase in opioid dose may address tolerance but exacerbate OIH. A decrease in opioid dose may improve OIH, expose tolerance, and create a withdrawal syndrome. Resistance to the effects of local anesthetics in opioid tolerant patients may present another challenge in pain management [ 36 ]. Beyond dependence, tolerance, and OIH, comorbid conditions frequently observed in individuals receiving OAT significantly contribute to pain experiences. These comorbidities include depression, anxiety, and sleep disorders, all of which are independently known to amplify pain sensitivity through various biological and psychological mechanisms [ 37 – 39 ]. For example, depression and anxiety can disrupt neurotransmitter systems involved in pain modulation, increase focus on pain sensations, and promote negative thought patterns that exacerbate pain perception [ 38 , 39 ]. Sleep disturbances can further impair pain processing and contribute to heightened pain sensitivity [ 37 ]. The bi-directional interaction between pain and OUD may also be influenced by various psychosocial factors. For example, pain catastrophizing is a psychological condition in which an individual interprets pain as unbearable and intolerable, resulting in a focus on the worst possible outcomes related to their pain experience [ 40 ]. Pain catastrophizing is associated with greater pain intensity, disability, and increased risk of developing chronic pain [ 41 , 42 ]. For individuals with OUD, this cycle may also influence opioid withdrawal and the risk of a return to substance use [ 43 ], though evidence for this risk pathway is mixed [ 44 ]. The adverse social impacts of OUD and chronic pain overlap substantially and include low socioeconomic status, social isolation, and chronic stress [ 45 – 47 ]. Chronic stress, often stemming from financial hardship, social instability, and discrimination, can dysregulate the body’s stress response system, further amplifying pain perception and contributing to the development of chronic pain conditions [ 47 ]. Therefore, the high prevalence of chronic pain among those receiving OAT is likely a multifactorial issue arising from the complex interaction of OIH, comorbid mental health conditions, and adverse social determinants of health. 4. Treatment of acute and chronic pain for those on OAT: the current review As summarized in Section 3 , the effectiveness of pain management treatments outlined in Section 2 for an opioid naïve population do not translate directly to patients receiving OAT treatment for OUD. Further, while there is some evidence that OAT itself has an impact on chronic pain symptoms in addition to its critical role in addressing OUD symptoms, many patients continue to experience chronic pain during OAT treatment. This may be due in part to that fact that while chronic pain patients without OUD experience moderate to large analgesic effects from OAT, those with co-occurring OUD demonstrate only minimal effects of the medication on pain [ 48 ]. Given the unique and complex challenges in treating acute and chronic pain in this population, we conducted a scoping review of the evidence base for pain treatment in this specific population. The scoping review methodology was chosen in alignment with our goal of providing an overview of the landscape for pain treatment research in this population [ 49 ]. 5. Methods The search strategy was generated by a clinical librarian (JP) with extensive experience in retrieving medical information and literature. Subject headings and other terms of relevance were gathered by utilizing the National Library of Medicine’s controlled vocabulary thesaurus, MeSH, as well as Elsevier’s life science thesaurus, Emtree. Other relevant terms and keywords were suggested by the team of experts, as well as by reviewing abstracts of relevant papers. The following databases were searched for relevant literature: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. The full search strategies, including all keywords, subject headings, combined searches, and limiters, for the PubMed, EMBASE and Cochrane databases are reported in the supplementary material [Appendix 1] . The search conducted in PubMed, utilized the filters ‘Clinical Study,’ ‘Clinical Trial,’ ‘Clinical Trial Protocol,’ ‘Controlled Clinical Trial,’ ‘Randomized Controlled Trial,’ ‘English,’ and ‘Humans.’ The search conducted in EMBASE utilized the filters ‘Human,’ ‘English Language,’ ‘Clinical Trial,’ ‘Randomized Control Trial,’ ‘Controlled Clinical Trial,’ and ‘Articles.’ The search conducted in the Cochrane Central Register of Controlled Trials used the filter ‘In Trials’ to exclude all systematic reviews. Examples of keywords (including Medical Subject Headings/MeSH terms, noted in Appendix 1 where applicable) employed in the search strategy include: ‘Opioid-Related Disorders,’ ‘Opioid Use Disorder,’ ‘Opioid Dependence,’ ‘Opioid Maintenance Treatment,’ ‘Opioid Agonist Treatment,’ ‘Opioid Medication-Assisted Treatment,’ ‘Buprenorphine-Maintained,’ ‘Buprenorphine,’ ‘Methadone,’ ‘MOUD,’ ‘Procedural Pain,’ ‘Postoperative Pain,’ ‘Breakthrough Pain,’ ‘Nociceptive Pain,’ ‘Pain Assessment,’ ‘Chronic Pain,’ ‘Musculoskeletal Pain,’ ‘Acute Pain,’ ‘Pain,’ ‘Analgesia,’ ‘Pain Management,’ ‘Pain Intensity,’ ‘Pain Severity,’ ‘Pain Interference,’ ‘Postoperative Period’ and, ‘Postoperative Procedure.’ Boolean and proximity operators used are also outlined in Appendix 1 . All searches were conducted on January 6th, 7th, and 8th of 2025. There were no restrictions placed on date of publication. A total of 774 results from all three databases were imported into EndNote, a citation management software. Duplicates were first automatically located and deleted, and then manually verified to be removed. The ‘Type of Work’ function was utilized to remove conference abstracts from the results. The results were then screened to manually remove unlabeled conference abstracts/proceedings, systematic reviews, and case studies. This decreased the results to 488 total records. These results were imported into Covidence, a screening and data extraction workflow tool for systematic reviews for team evaluation of relevant literature. An additional n = 6 were added to the screening from citation searching of identified review papers, for a total of n = 494 to be screened. At the screening stage, articles were included if they were original research on a pharmacological, behavioral, technology-based, or integrated treatment for acute or chronic pain for human subject participants receiving agonist treatment for OUD. Studies also needed to evaluate acute or chronic pain as a study outcome. We excluded studies that were experimental, reviews/meta-analyses, commentaries, or case studies. Studies were also excluded if they focused exclusively on withdrawal symptom management or other OUD-only outcomes or if the OAT itself was the intervention (e.g. studies comparing buprenorphine to methadone or different dosing). Secondary analyses were excluded except for two cases in which the primary paper reported only on withdrawal or OUD-related outcomes [ 50 , 51 ]. All 494 articles were screened for inclusion by two authors from the team of four coders (VA, TH, EDR, and MS). Title and abstract screening results were discussed, and disagreements were resolved by consensus among all four coding authors during regularly scheduled meetings. The team identified 31 articles for full-text review, excluding 8 studies at this stage [ 52 – 59 ], for a total of 23 articles meeting criteria for inclusion [ 50 , 51 , 60 – 80 ](see Figure 1 for PRISMA diagram). Figure 1. Open in a new tab PRISMA diagram of search strategy and results. The study codebook was drafted by VA and adapted through consensus with the rest of the coding team (TH, EDR, and MS). We extracted study characteristics (country where the study was conducted, study sample size, study design), participant information (demographic distributions, pain type, and current agonist treatment), intervention information (type, name, and duration), pain outcome(s) measured, and primary study findings. Beyond study design, information on methodological quality of the studies was not systematically extracted, aligning with the methodological recommendations for scoping reviews in health science [ 81 , 82 ]. Two coders completed extraction for each study, with reconciliation led by VA and TH with team consultation as needed. 6. Results 6.1. Overview Tables 1 and 2 summarize the included studies and key findings for pharmacological and behavioral interventions, respectively. The majority of the studies were conducted in the U.S., one in India [ 64 ], and one in Iran [ 63 ]. Participants were on methadone maintenance in seven studies, buprenorphine maintenance in eight studies, a mixture of both in five studies, and the type of OAT was unreported in the three remaining studies. Most studies focused on chronic ( n = 16) rather than acute pain ( n = 7). The intervention type was behavioral in 13 studies and medication-based in 10 studies. Key findings are summarized below. Table 1. Identified studies investigating pharmacological interventions for the treatment of pain in patients on opioid agonist therapy. Author Year Country Population Number (active; control) Pain Type OAT Design Intervention(s) Duration Pain outcome(s) measured Primary Pain findings Primary OUD or other findings Cobb [ 60 ] U.S. Adult women 26 (18; 8) Acute: Post-cesarean delivery Unspecified ‘medication-assisted treatment for OUD’ Retrospective cohort Low dose ketamine infusion 24 h Post-surgical opioid consumption (MME), pain scores, analgesic consumption - Median MME 71 (15–463) active vs. 90 (38–200) in control - Mean pain scores comparable across groups - Three ketamine had temporary, mild adverse effects (nausea, diplopia, insomnia) Cook [ 61 ] U.S. Active Mage = 30.5 86% white 86% single 100% women Control Mage 28 85% white 79% single 100% women 160 (22; 138) Acute: Post-cesarean delivery 51.9% BUP, 22.5% methadone, 25.6% none Retrospective cohort Spinal anesthesia with or without intrathecal clonidine 24 h Post-surgical opioid consumption, medications during surgery, time to first analgesic, maximum and lowest pain scores, PCA requirements, regional block requirements - Significantly reduced oxycodone equivalent in active group - Longer time to first analgesic in active group (207 min vs 153) - Mostly no differences in pain scores - Clonidine group got more IT bupivacaine, more IT morphine - Clonidine group had more hypotension & treatment of hypotension - Clonidine group had shorter delivery-to-discharge interval Ende [ 62 ] U.S. Active Mage = 29 100% women Control Mage = 20 100% women 214 (64; 150) Acute: Post-cesarean delivery BUP Retrospective cohort Gabapentin vs. no gabapentin 72 h Opioid consumption (MME) and NRS pain scores over 24 h post-surgery - No significant difference in MME across all time points - No significant difference in NRS pain 0–24 h, 24–48 h - Pain higher in gabapentin in 48–72 h - Gabapentin more likely to receive neuraxial fentanyl, transversus abdominis plane block, ketorolac and acetaminophen Forghani [ 63 ] Iran Active Mage = 37.7 100% men Control Mage = 35.3 100% men 100 (50; 50) Acute: Limb fracture (upper or lower) Methadone Double blind RCT IV fentanyl vs. IV ketamine 60 min Pain severity (VAS) - Reduced pain in ketamine group at 15 min - No difference at 30 and 60 min Adverse events not statistically significant between groups Goyal [ 64 ] India Mage = 33.7 100% men Active 43% single Control 41% single 100 (51; 49) Chronic: Type not specified BUP Double-blind, placebo-controlled, parallel, randomized trial Trazodone vs. placebo 6 weeks Pain severity and interference (BPI) - Pain severity and interference did not improve significantly for either group - Primary sleep outcomes did improve significantly - No significant difference in sedation, withdrawal or craving scores, depression or anxiety scores Gupta [ 65 ] U.S. Active Mage = 25.1 100% women Control Mage = 24.5 100% women 19 Acute: Labor analgesia, post-cesarean delivery BUP Retrospective cohort Neuraxial opioids vs. no neuraxial opioids Until discharge (3–4 days) ‘Rescue analgesics’ of hydromorphone, ibuprofen, acetaminophen - No group differences on ‘rescue analgesics’ across delivery types - Clinical trend for higher analgesics for emergent cesarean after failed labor - Group receiving neuraxial opioids in general required more rescue analgesia Hoyt [ 66 ] U.S. Adult women 14 Acute: Labor analgesia, post-cesarean delivery BUP Observational cohort Substitution of fentanyl with clonidine in epidural solution Until discharge Pain severity scores during and after labor (NRS), analgesia consumption - Patients experienced very good pain control with 7 of 14 avoiding supplemental FAO post-delivery - 5 patients experienced hypotension requiring treatment; one of these developed fetal decelerations Taylor [ 67 ] U.S. Active Mage = 29 100% women Control Mage = 29 100% women 196 (145; 51) Acute: Post-cesarean delivery BUP Retrospective cohort Neuraxial clonidine vs. no neuraxial clonidine 24 h First 24 hour opioid (MME) consumption and median pain scores (NRS 0–10), intraoperative anesthetic supplementation - Clonidine associated with higher 0–6 h MME, no difference for 0–24 h MME, and increased 0–24 h NRS pain scores (propensity matched results) - More baseline BUP was associated with increased opioid consumption over 0–6 h (1.74 additional MME in 20 mg BUP vs 16 mg BUP) - No differences in intraoperative anesthetic supplementation Tsui [ 50 ] U.S. Mage = 37.5 76% men 80% white 147 (72; 75) Other/ Chronic: 48%, type not specified BUP RCT (secondary analysis) Escitalopram vs. placebo 3 months Pain severity (VAS), pain interference (BPI) - Escitalopram group had greater reductions than placebo in reducing pain severity and pain interference Wilson [ 68 ] U.S. Active Mage = 47.8 100% women 100% white 100% married Control Mage = 41.0 50% women 100% white 75% single 8 (4; 4) Other/Chronic: 62.5%, type not specified Methadone Pilot RCT Hyperbaric oxygen therapy vs. sham 1 week Pain numeric rating scale (NRS), pain interference (8-item PROMIS) - Pain intensity reduced after day 2 by 2× vs. control - Pain intensity decreased in active condition, increased in control - Pain Interference decreased through follow up post-intervention (T9) in both arms, mid-sized effect by treatment group Open in a new tab OAT = opioid agonist therapy, OUD = opioid use disorder, mage = mean age, NRS = numeric rating scale, PROMIS = patient-reported outcomes measurement information system, VAS = visual analog scale, BPI = brief pain inventory, MME = milligram morphine equivalent, FAO = full agonist opioids, PCA = patient-controlled analgesia, min = minute, BUP = buprenorphine, RCT = randomized controlled trial. Table 2. Identified studies investigating behavioral interventions for the treatment of pain in patients on opioid agonist therapy. Author Year Country Population Number (active; control) Pain Type OAT Design Intervention(s) Duration Pain outcome(s) measured Primary Pain findings Primary OUD or other findings Barry [ 69 ] U.S. Mage = 38.1 63% men 85% white 85% single 40 (21; 19) Chronic: Moderate to severe, noncancer lower back pain Methadone Pilot RCT CBT for OUD & chronic pain vs. Methadone Drug Counseling 12 weeks Pain intensity and interference BPI; ‘clinically significant reduction’ of ≥2 points - No group difference in clinically significant change in pain interference ( p = 0.962) or intensity ( p = 0.894) - For weekly scores, no group effects on interference ( p ’s = 0.27 and 0.72) or intensity ( p ’s = 0.25 and 0.88) - Proportion of patients abstinent at baseline and follow up was higher for cognitive behavioral therapy compared to Methadone Drug Counseling, no treatment x time interaction Cooperman [ 70 ] U.S. Mage = 50.4 50% men 37% white 30 (15; 15) Chronic: At least mild, nonmalignant pain (8+ on Gracely Pain Scale) for ≥3 months Methadone Pilot RCT MORE vs. TAU 8 weeks Pain intensity and physical functioning (RAND 36-Item Short Form) - Treatment group reported lower pain than control p = 0.005) - Treatment group reported better physical functioning than control not statistically significant - Treatment group reported lower cravings, fewer days of use -Treatment group reported higher wellbeing, vitality, and social functioning Cooperman [ 71 ] U.S. Mage = 48.5 43% men 52% white 154 (77; 77) Chronic: Pain of ≥ 3 of 10 for ≥3 months Methadone RCT Telehealth MORE vs. TAU 8 weeks Pain intensity via EMA and BPI at baseline, 8- and 16-weeks - Decreased EMA pain scores in treatment group compared to TAU ( p <0.001) - No group differences in BPI across the three time points, F(2,272) = 0.31; p = 0.73. - Better treatment attendance & adherence, less return to use in treatment vs. TAU - Greater reduction in depression symptoms in treatment group vs. TAU Faraj [ 72 ] U.S. 73% women 53% white 73% single 15 Other/Chronic: 93.3% low-back pain, average max 24-hr severity 4.8/10 Methadone Open pilot 12-week virtual reality, therapist-guided meditative intervention 12 weeks BPI, pre- and post-session pain severity (VAS); pain ‘neuromatrix’ activation - Post-session pain decreased from pre-session ratings - Pain task-related fMRI activation in a key region of the pain neuromatrix (left post-central gyrus) decreased post-session - Opioid craving, anxiety and depression also lower at post-session - Saliva cortisol levels decreased at postsession, but not C-reactive protein Garland [ 73 ] U.S. Mage = 50.450% men 37% white 30 (15; 15) Chronic: Chronic non-cancer pain Methadone Pilot RCT MORE + mmT versus MMT + TAU 8 weeks Pain intensity (NRS) and unpleasantness (NRS), via EMA - Significantly greater reduction in pain unpleasantness, but not intensity, in treatment group compared to TAU - Number of cravings higher in treatment group vs. TAU -Craving severity and self-control significantly higher in treatment vs. TAU MacLean [ 74 ] U.S. Mage = 50.390% men 79% white 28 (15; 13) Chronic: Pain of ≥ 3 of 10 for at ≥3 months Methadone (93%) and BUP (7%) Pilot RCT Cognitive bias modification task vs. attentional bias control task. 4 weeks Attentional bias to pain at baseline and posttreatment; TLBS separated into 3 indices (toward, away, variability) - Reduction in attentional bias toward pain cues (pain TLBS toward, p = 0.018; pain TLBS variability, p = 0.03) in the active group but not the control group - Reduction in bias toward opioid cues (opioid TLBS variability, p = 0.034) also demonstrated Messina [ 51 ] U.S. 55% men 88% white 70% single 148 (74; 74) Chronic: Self report of chronic pain BUP RCT Enhanced Medication Management vs. Standard Medication Management 12 weeks Pain severity (BPI - Short Form) - Greater pain predicted greater craving ( p < 0.001) - Association between craving and opioid use reduced following the pain coping module ( p < 0.01) Greater exposure to the module associated with stronger effects ( p < 0.01) - Future opioid use predicted by craving and past-week opioid use (p’s <0.001) - Opioid use not predicted by pain ( p = .82), pain coping module ( p = 0.35), or week ( p = 0.17) Price [ 75 ] U.S. Median age = 40 48% men 79% white 71% single 303 (155; 148) Other/Chronic: 57% reported chronic pain ≥3 Months Methadone (12%); BUP (88%) RCT Mindful Awareness in Body-oriented Therapy + MOUD vs. TAU 8 weeks Pain severity and pain interference (BPI); physical symptoms (Physical Symptom Checklist) - Significant improvements in Pain Severity and Pain Activity Interference (not Affective Interference) for treatment group vs. TAU - Lower frequency of physical symptoms (incl muscle/backaches) in treatment vs. TAU - No difference in opioid or other substance use due to low rates of use in both groups - Improved PTSD symptoms and emotion regulation in treatment vs. TAU Schuman-Olivier [ 76 ] U.S. Mage = 47.4 72% men 89% white 18 Other/Chronic: 44.4% reported chronic pain, 72.2% reported ‘any pain’ BUP Open Pilot Mindful Recovery OUD Care Continuum 24 weeks Pain interference (PROMIS-PISF) - Significant reduction in pain interference at 24 weeks ( p = 0.022). - Effect size of reduction in pain interference larger in subset of participants with chronic pain ( p = 0.001) - ositive urine toxicology decreased over time for cocaine and benzodiazepines. - Anxiety scores also decreased among participants with co-morbid anxiety. Smallwood [ 77 ] U.S. Active Mage = 43.567% men Control Mage = 49.7 50% men 25 (6; 6) Chronic: Lower back pain >12 months ‘Opioid replacement therapy,’ medication not named Pilot RCT Chronic pain-focused Acceptance and Commitment Therapy ( n = 6) vs. health education ( n = 6) 4 weeks (8 sessions) Brain activation in response to experimental pain induced by pressure, assessed with fMRI. - Decreased activation during pain in the middle frontal gyrus, inferior parietal lobule, insula, ACC and posterior cingulate cortex in treatment vs. control - Measures of opioid cravings not reported in results Uebelacker [ 78 ] U.S. Mage = 43 58% women 40 (20; 20) Chronic: Pain interference ≥ 4; ‘worst pain in the last week’ ≥4/10; duration ≥3 months Methadone (50%); BUP (50%) Pilot RCT Hatha yoga vs. health education classes 12 weeks Pain interference (BPI); pain intensity (NRS) - No group differences in pain interference from pre- to posttreatment ( p = 0.94). - Among high attenders, greater reductions in pain interference in yoga group ( p = 0.38), suggesting small-to-medium effect size - Pain intensity decreased pre- to postclass for both groups, larger change in yoga group - Both groups showed significant changes pre- to post-class in sadness, anxiety, irritability and fatigue, larger improvements in yoga group - Feasibility and acceptability positive overall, some attendance challenges Wachholtz [ 79 ] U.S. Mage = 43.9 50% men 14 Chronic: 50% musculoskeletal and 50 % mixed, neuropathic/musculoskeletal Methadone (50%); BUP (50%) Open pilot Self-regulation Therapy for Opioid addiction and Pain 12 weeks Pain intensity (NRS); Pain tolerance as measured by cold pressor task; functional activity levels (Multidimensional pain inventory) - Pain intensity over time not reported. - Pain tolerance increased over treatment ( p < 0.001) - Functional activity levels improved ( p < 0.001) - No illicit drug use, per urine toxicology and timeline follow back, over the 8-week treatment - Feasibility and acceptability findings positive overall Wilson [ 81 ] U.S. Mage = 44.356% men 78% white 60 (31; 29) Chronic: Chronic non-cancer pain diagnosis, ≥ 3 months ‘MAT’ without specification of type Pilot RCT Goalistics Chronic Pain Management Program vs. waitlist attention placebo control group 8 weeks Pain severity and interference (BPI); Pain self-efficacy (PSEQ) - Pain intensity, interference, and self-efficacy higher in treatment group vs. control - Within treatment group, those who engaged in the program showed lower pain severity and interference vs. those who did not - No group differences in pain self-efficacy - Treatment group had significantly lower opioid misuse measures (COMM) and depressive symptoms (PHQ-9) after at post treatment Open in a new tab OAT = opioid agonist therapy, OUD = opioid use disorder, mage = mean age, NRS = numeric rating scale, PROMIS = patient-reported outcomes measurement information system, PISF = pain interference short form, VAS = visual analog scale, BPI = brief pain inventory, MME = milligram morphine equivalent, FAO = full agonist opioids, BUP = buprenorphine, RCT = randomized controlled trial, TAU = treatment as usual, MORE = mindfulness-oriented recovery enhancement, CBT = cognitive behavioral therapy, EMA = ecological momentary assessment, MMT = methadone maintenance treatment, TLBS = trial level bias score, PTSD = post-traumatic stress disorder, MAT = medication assisted treatment, PHQ-9 = patient health questionnaire-9, PSEQ = pain self-efficacy questionnaire, COMM = current opioid misuse measure. 6.2. Acute pain 6.2.1. Pharmacological interventions Most studies on the pharmacological interventions for acute pain in individuals on OAT were focused on labor and post-cesarean analgesia. In a retrospective chart review study of women maintained on OAT ( n = 26), low-dose ketamine infusion did not change the mean opioid dose for post-cesarean pain management [ 60 ]. Similarly, Ende et al. reported no differences in post-cesarean opioid consumption between gabapentin ( n = 64) and controls ( n = 150) in buprenorphine-maintained women [ 62 ]. Clonidine’s use for labor and post-cesarean analgesia yielded mixed results. While one study ( n = 14) found epidural clonidine effective for labor and post-cesarean analgesia, hypotension was a limitation [ 66 ]. A retrospective chart review ( n = 196) linked neuraxial clonidine with higher opioid use following cesarean section in buprenorphine-maintained women [ 67 ]. In contrast, a chart review ( n = 180, approximately 75% on opioid agonists) found that spinal anesthesia with intrathecal clonidine ( n = 22) reduced opioid requirements following cesarean section, compared to no clonidine ( n = 138), although increased hypotension was observed in the clonidine group [ 61 ]. These findings raise concerns about the safety of clonidine for post-cesarean section pain. Finally, Gupta et al. reported comparable peri-partum opioid and NSAID needs in women ( n = 19) who received neuraxial opioids compared to those who did not for labor and post-cesarean analgesia [ 65 ]. For acute analgesia in men ( n = 100) maintained on methadone being treated for limb fracture, IV ketamine provided greater pain relief than IV fentanyl, but these differences did not last beyond 15 min [ 63 ]. 6.2.2. Behavioral interventions The current review did not identify any evidence supporting behavioral interventions for acute pain in individuals receiving OAT. 6.3. Chronic pain 6.3.1. Pharmacological interventions A small feasibility study in methadone-maintained individuals ( n = 8) suggested that hyperbaric oxygen may reduce pain intensity and pain interference, warranting further studies [ 68 ]. A secondary analysis of buprenorphine-maintained individuals with depressive symptoms ( n = 147, about half of whom had chronic pain) found that escitalopram, compared to placebo, improved pain severity and pain interference [ 50 ]. Finally, a randomized controlled trial (RCT) found that trazodone, compared to placebo, improved sleep in buprenorphine-maintained individuals ( n = 100) but no differences in pain outcomes were observed [ 64 ]. However, it was unclear if the participants experienced significant pain at baseline. 6.3.2. Behavioral interventions Behavioral interventions for chronic pain in OAT-maintained individuals were mostly (10 of 13) pilot-stage trials. Mindfulness-Oriented Recovery Enhancement (MORE), a mindfulness-based treatment, showed promise in reducing pain in methadone-maintained individuals with chronic pain [ 70 , 73 ]. A larger RCT in 154 methadone-maintained individuals with chronic pain telehealth delivered MORE, compared to treatment as usual [ 71 ], reduced pain severity on EMA measures but not pain as measured by Brief Pain Inventory (BPI) assessments. A pilot trauma-informed, mindful recovery program showed reduced pain interference in buprenorphine-maintained individuals ( n = 18) with chronic pain [ 76 ]. In an RCT with 303 participants on OAT ( n = 303), mindful awareness in body-oriented therapy [ 75 ] improved pain severity and pain activity interference, compared to OAT alone. A virtual reality-based meditative intervention in methadone-maintained individuals ( n = 15) with chronic pain [ 72 ] showed reduced pain ratings and activation of the left post-central gyrus in response to pain-related tasks via functional magnetic resonance imaging (fMRI). In opioid-agonist-maintained individuals ( n = 4) with chronic pain, a hatha yoga group showed greater improvement in pain interference compared to a health education comparison group [ 78 ]. In two pilot studies, CBT provided individually [ 69 ] ( n = 40) or in group settings [ 79 ] ( n = 14) was found to be feasible and acceptable in methadone-maintained individuals with chronic pain. In a pilot RCT of Chronic pain-focused Acceptance and Commitment Therapy compared to a health education control group ( n = 12), the treatment group showed decreased activation compared to controls in relevant areas as measured by fMRI [ 77 ]. A goal-oriented chronic pain management, compared to waitlist, showed mixed results in OAT-maintained individuals with chronic pain ( n = 60) [ 80 ]. While treatment group pain intensity and interference were actually higher in the treatment group, those who engaged in the treatment had lower pain intensity, pain interference, and opioid misuse measures. In a secondary analysis of a 12-week RCT in buprenorphine-maintained individuals with chronic pain ( n = 148), enhanced medication management, compared to standard medication management, reduced the association between craving and subsequent week opioid use [ 51 ]. Finally, a cognitive bias modification intervention was found feasible and reduced attentional bias toward both pain and opioid-related cues in individuals on OAT and have chronic pain ( n = 28) [ 74 ]. 7. Discussion This manuscript sought to review the available evidence for treating acute and chronic pain in individuals receiving OAT. This is a critical clinical problem due to the increasing number of individuals receiving OAT for OUD, many of whom will need treatment for both acute and chronic pain conditions. Our review yielded several noteworthy findings. First, most acute pain studies for individuals on OAT focused on labor and cesarean section analgesia in women, with somewhat inconsistent findings. We found no studies focused on behavioral interventions for acute pain. Second, there were very few pharmacological studies for individuals on OAT with chronic pain, and these primarily addressed co-morbid conditions (e.g. depression and sleep) rather than chronic pain. Third, the landscape of behavioral interventions for chronic pain is characterized largely by mindfulness- and acceptance-based approaches, similar to chronic pain treatments for opioid naïve individuals. Finally, our review identified multiple limitations and gaps in the existing literature that need to be addressed in future studies. Managing acute pain in individuals on OAT remains a significant clinical challenge as the high degree of opioid tolerance diminishes the analgesic effectiveness of standard opioid pain medications [ 83 ]. Several studies specifically explored the use of non-opioid medications for labor and cesarean section pain in women maintained on OAT. However, these studies did not consistently support the safety and efficacy of medications including clonidine, gabapentin or ketamine for managing labor and cesarean section pain in women maintained on OAT [ 60 – 62 , 67 ]. In individuals with limb fractures, ketamine showed some benefit, compared to fentanyl, but this effect was transient [ 63 ]. Overall, the existing evidence underscores a critical need for well-designed RCTs specifically focused on identifying safe and effective acute pain treatment strategies for individuals maintained on OAT across various clinical contexts (e.g. surgical and non-surgical pain). These trials should rigorously evaluate both opioid and non-opioid analgesics to optimize pain management in this complex patient population. Managing chronic pain in individuals on OAT presents similar clinical challenges. Both chronic pain and OUD are associated with high rates of co-occurring depression and sleep disturbances, especially insomnia [ 84 , 85 ]. While treatment of insomnia with trazodone did not improve chronic pain [ 64 ], improvement of depressive symptoms with escitalopram was associated with reduced pain and pain interference [ 50 ]. These studies are an initial step toward addressing key comorbidities (i.e. insomnia and depressive disorders) that are common among those on OAT and are known to influence long-term functional outcomes for chronic pain patients [ 86 ]. Behavioral treatments like CBT have shown promise for co-occurring chronic pain, insomnia, and depressive symptoms [ 87 ] and may address these comorbid disorders for patients on OAT. In our review, mindfulness-based treatments demonstrated promising results. Mindfulness-based treatments have demonstrated effectiveness in managing chronic pain in individuals without OUD [ 88 , 89 ] and have also been explored for the prevention of long-term opioid medication use [ 90 ]. While the exact neurobiological and psychological mechanisms by which mindfulness alleviates chronic pain remain to be determined, current evidence suggests that mindfulness may improve the regulation of negative emotions (e.g. anxiety, irritability, and frustration) which frequently accompany chronic pain [ 91 ]. Additionally, by emphasizing present-moment awareness, mindfulness may reduce pain-related ruminations and catastrophizing, resulting in reduced psychological burden of chronic pain [ 41 ]. CBT is widely regarded as the gold standard behavioral treatment for chronic pain [ 26 ] and has well-established efficacy in addressing substance use disorders including OUD [ 92 ]. A key strength of CBT is its inherent adaptability [ 93 ]; treatment modules specifically targeting comorbid conditions, such as insomnia and depression, can be easily incorporated into the main CBT protocol. However, our review identified only two pilot studies that explored the feasibility of such an integrated CBT approach for individuals with chronic pain and OUD [ 69 , 79 ]. These preliminary finding underscores the need for further research, particularly larger-scale RCT, to rigorously test the efficacy of integrated CBT for chronic pain and OUD. Beyond mindfulness treatments and CBT, other behavioral interventions, including meditation, cognitive bias modification, and yoga, also warrant further study in this patient population. Physical exercise is another behavioral intervention that warrants further investigation for managing pain in individuals on OAT. Considering its potential benefit for both OUD [ 94 ] and chronic pain [ 95 ], ongoing studies are examining the effectiveness of various exercise interventions for the management of chronic pain in individuals on OAT. 7.1. Limitations of the studies Several studies were limited by their scope and methodologies, employing retrospective chart reviews or pilot feasibility designs that lacked sufficient statistical power to test efficacy. For example, except for one controlled trial, studies that focused on the pharmacological treatment of acute pain in women on OAT relied on retrospective chart reviews. While such studies can be valuable in generating hypotheses, their preliminary findings necessitate prospective controlled studies to confirm or refute clinical results. Furthermore, some studies included pain outcomes as a secondary measure, with only a subset of participants having chronic pain diagnoses at baseline. Significant variations in the type of chronic pain made across study renders direct comparisons across study findings difficult. Studies also differed in the pain assessment measures and the frequency of these assessments. These methodological limitations remain to be addressed in future clinical trials. 8. Expert opinion Because of the challenges of pain management in individuals on OAT and the stigma surrounding OUD, clinicians may be reluctant or feel ill-equipped to assess and treat pain in this population adequately [ 96 ]. However, untreated pain is a significant risk factor for relapse to opioid use and, therefore, requires careful and proactive clinical attention [ 5 ]. For individuals on OAT requiring surgery, ample evidence supports the continuation of their OAT throughout the perioperative period. This approach is essential to prevent withdrawal and associated increases in pain sensitivity (hyperalgesia) [ 97 ]. Managing acute pain in this population necessitates a careful approach. Ideally, an acute pain service with a multidisciplinary team (i.e. pain and addiction medicine, pharmacy, mental health, physical therapy) should be involved to comprehensively address pain, OUD, and contributing comorbidities. Further, this approach can facilitate care transitions and effective discharge planning with appropriate pain and addiction treatment follow-up. A multimodal analgesia strategy, prioritizing the use nonopioid analgesic medications, should be considered as first-line approach. This includes prioritization of analgesics including acetaminophen and NSAIDs, and employment of peripheral and neuraxial regional anesthesia techniques, to provide effective analgesia while minimizing opioid exposure. Novel non-opioid analgesics, such as the recently approved nonopioid sodium channel (NaV1.8) inhibitor suzetrigine, show promise in providing additional components to a multimodal strategy [ 98 ]. While opioids are often necessary to adequately manage acute pain in this population, clinicians should be aware that patients may require increased doses to achieve the intended analgesic response. Consequently, careful and frequent monitoring for adverse effects, including respiratory depression and sedation, is warranted. For chronic pain, the existing research has largely focused on examining whether adaptations of existing acceptance- and mindfulness-based approaches, effective in opioid-naïve populations, are also helpful for individuals in OAT. While such work is largely in the earliest stages, the promise of early results has led to a number of fully-powered trials that are underway examining acceptance- and mindfulness-based therapies [ 99 , 100 ] and other cognitive behavioral approaches adapted for this population [ 101 ]. While this research is ongoing, the evidence to date does align with treatment guidelines recommending the integration of behavioral therapies for pain into OUD management [ 102 ]. The interdisciplinary treatment teams and specialty care clinics where this treatment is usually coordinated for chronic pain provide a valuable starting point for further care integration. Indeed, future work should build on the success of stepped care models for chronic pain and OUD, such as the United States Veterans Health Administration’s ‘stepped care model of pain management’ [ 103 ] and ‘stepped care for opioid use disorder train the trainer’ [ 104 ] initiatives, respectively, to identify interdisciplinary models of stepped care for settings where evidence-based treatments are provided [ 105 ]. Further development of accessible, lower threshold technology-based interventions is also likely needed for patients who are unable or unwilling to attend regular psychotherapy. Supplementary Material Appendix 1 NIHMS2085325-supplement-Appendix_1.pdf (343.3KB, pdf) Supplemental data for this article can be accessed online at https://doi.org/10.1080/14656566.2025.2506688 Article highlights. Effective pain management remains a significant unmet need for individuals on opioid agonist treatment (OAT). This scoping review summarizes research on behavioral and pharmacological approaches for the management of acute and chronic pain for those on OAT. Research in this area is limited by a small number of mostly pilot studies with modest samples. Pharmacological interventions addressing both pain and contributing comorbidities (e.g. insomnia and depression) may provide benefit in this population. Behavioral treatments, especially for the management of chronic pain, show potential benefit. Future research is warranted to identify effective treatment strategies for acute and chronic pain in individuals receiving OAT. Funding V Ameral’s work was funded by VA RR&D (IK2RX003789). M Sofuoglu acknowledges funding from the VISN 1 MIRECC. The findings and interpretations of the data expressed in this paper are the sole responsibility of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Footnotes Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Reviewer disclosures Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. 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