Quantitative sensory testing of pain in persons with opioid use disorder on opioid agonist treatment: a scoping review

Abstract

Objective

To evaluate the use of quantitative sensory testing (QST) in assessing pain responses and mechanisms among individuals with opioid use disorder (OUD) receiving opioid agonist treatment (OAT).

Design

Scoping review following PRISMA-ScR guidelines.

Setting

Systematic literature search across 5 major databases.

Subjects

Studies investigating QST outcomes in adults with OUD receiving OAT (methadone, buprenorphine, or other opioid agonists) with or without co-occurring chronic pain.

Methods

We searched Ovid MEDLINE, Embase, APA PsycINFO, Cochrane Library, and Web of Science from inception through March 2025. Eligible studies included original research employing QST methodologies in adults with OUD receiving OAT. Data extraction focused on study characteristics, QST methodologies, and pain-related outcomes.

Results

Of 45 included studies, 64.4% employed cross-sectional designs with limited protocol standardization. Static QST measures predominated, with thermal stimuli most common. The most consistent finding was reduced cold pain tolerance in individuals with OUD compared to controls (60% of studies). Dynamic QST measures (3 studies) revealed altered pain modulation suggestive of central sensitization. Pain processing abnormalities frequently persisted despite prolonged abstinence from non-OAT opioids, suggesting lasting neuroadaptive changes. Methodological heterogeneity and inconsistent reporting of clinical variables limited synthesis.

Conclusions

QST demonstrates potential for enhancing clinical understanding of pain mechanisms in individuals receiving OAT. Future research should prioritize protocol standardization, longitudinal designs tracking pain sensitivity changes, and exploration of QST’s predictive value for treatment responses to facilitate clinical integration.

Introduction

Chronic pain, defined as persistent pain lasting at least 3 months, affects ∼20% of American adults and presents significant challenges in both assessment and treatment.¹ Traditional methods, primarily patient-reported numeric rating scales, dominate clinical pain assessments but fail to capture pain’s complex, multidimensional nature. There is strong evidence that this limitation has contributed to the ongoing opioid crisis, which was initially driven by an overreliance on these simplistic, unidimensional scales and, consequentially, inappropriate prescribing of opioids.^2,3 Despite evidence highlighting their inadequacy, numeric rating scales remain the standard approach for pain assessment within opioid treatment contexts,⁴ underscoring the urgent need for more nuanced methods.

The limitations of traditional pain assessment approaches are especially evident when considering long-term opioid treatment. Although opioids are effective for acute pain relief, their long-term efficacy in managing chronic pain is rather limited.⁵ The long-term use of opioids, including those designed to treat pain, can lead to physiological adaptations, notably tolerance and opioid-induced hyperalgesia (OIH), complicating clinical pain management.^6,7 Tolerance is characterized by the need for escalating opioid doses to achieve the same analgesic effect, whereas OIH paradoxically increases pain sensitivity following prolonged opioid exposure. Distinguishing between tolerance, OIH, and underlying progression of pain disorders remains challenging, often resulting in inappropriate opioid dose escalation. While tolerance may necessitate dose increases, OIH might respond better to opioid tapering or discontinuation.⁷ These complexities underscore the critical need for improved pain assessment methods capable of distinguishing underlying pain mechanisms and detecting subtle changes in pain responses over time, potentially enabling more targeted and effective treatment approaches.

Pain assessment becomes particularly challenging among individuals with opioid use disorder (OUD), among whom the relationship between chronic pain and OUD is intricate and bidirectional. Approximately 60% of individuals with OUD report pain as their initial reason for opioid use,⁸ and more than half continue experiencing unresolved chronic pain.⁹ Conversely, up to 10% of individuals with chronic pain eventually develop OUD.¹⁰ In 2020 alone, an estimated 9.3 million people in the US misused prescription opioids, and 2.7 million met criteria for OUD.¹¹ Despite the significant overlap between chronic pain and OUD, traditional assessment tools often result in suboptimal pain management and poorer clinical outcomes due to concerns about opioid misuse.¹²

Given these limitations, there is a pressing need for more objective and reliable pain assessment methodologies. Quantitative sensory testing (QST), a psychophysical method rooted in foundational work by Weber and Fechner, provides standardized assessments of sensory function through controlled stimuli.^13,14 Modern QST protocols include thermal, mechanical, and electrical stimuli, along with dynamic paradigms such as temporal summation and conditioned pain modulation (CPM).¹⁵ Accumulating evidence suggests QST can enhance traditional pain assessment by providing unbiased quantitative sensory profiles, identifying sensory phenotypes predictive of treatment responses, and evaluating both acute and long-term opioid effects on pain responses and its mechanisms.^16,17 Additionally, research has demonstrated its ability to detect sensory changes associated with both chronic pain conditions and in response to long-term opioid therapy.^18–20 However, despite its established clinical utility in neurologic and chronic pain disorders,^21,22 significant variability in protocols and patient populations has hindered the translation of QST into routine clinical practice specifically for individuals with OUD.

This scoping review synthesizes current evidence on the application of QST in pain assessment among individuals receiving opioid agonist treatment (OAT) for OUD, with or without co-occurring chronic pain. Our objectives are to: (1) characterize existing QST methodologies and their standardization levels; (2) synthesize findings related to pain mechanisms and evaluate QST’s potential to distinguish between opioid tolerance, OIH, and underlying pain progression; (3) critically appraise the quality and limitations of available evidence; and (4) identify specific knowledge gaps and methodological requirements needed to translate QST from a research tool to clinical practice. By systematically evaluating both the promise and current limitations of QST, we aim to provide a roadmap for advancing pain assessment in this vulnerable population.

Methods

Protocol and registration

The review protocol was prospectively registered on the Open Science Framework (osf.io/truqj)²³ and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.²⁴

Information sources and search strategy

We conducted comprehensive systematic searches across multiple electronic databases, including Ovid MEDLINE, Embase (Ovid), APA PsycINFO (Ovid), Cochrane Library, and Web of Science (Core Collection), from their inception through November 2022. To ensure literature currency, 2 subsequent search updates were implemented: The first in June 2024 and the second in March 2025. A medical librarian (M.C.F.) assisted in developing the search strategy, which underwent rigorous peer review using the Peer Review of Electronic Search Strategies (PRESS) checklist.²⁵ To maximize citation identification, reference lists from included studies and relevant review articles were manually examined for potentially eligible studies not captured through electronic searches. The complete search strategies for each database, including Boolean operators and MeSH terms, are detailed in Appendix S1.

Eligibility criteria

Studies were included if they: (1) investigated QST outcomes among adult participants (≥18 years old) who had a diagnosis of OUD and had been receiving any OAT, including methadone, buprenorphine, buprenorphine-naloxone, levomethadone, or extended-release morphine; (2) were original research, such as case series (>2 individuals), retrospective or prospective cohort studies, or clinical trials; and (3) were published in a peer-reviewed journal.

Studies were excluded if they: (1) included non-adult participants; (2) were secondary research sources (ie, reviews, meta-analyses, other evidence syntheses, editorials, descriptive, or commentary articles); (3) were animal studies or other non-human research; or (4) incomplete and ongoing studies, protocols, and abstract without available full texts.

Selection of evidence sources

Two reviewers (D.O. and M.A.C.) independently screened the titles and abstracts of all records identified by the searches using the Covidence systematic review software.²⁶ Subsequently, the full texts of potentially eligible studies were independently assessed by the 2 reviewers. Disagreements were resolved through discussion and input from a senior author (JDA) until consensus was achieved.

QST definitions

For consistency in data extraction and interpretation, we defined key QST parameters according to established experimental pain research standards.^27,28

Static QST

Static QST measures were defined as discrete sensory parameters through single stimulus applications, quantifying pain threshold, defined as the minimum intensity at which a stimulus is perceived as painful, and pain tolerance, the maximum intensity of a pain-producing stimulus a subject is able to tolerate.^27,28

Dynamic QST

Dynamic QST was defined as evaluating pain modulatory mechanisms through 2 primary paradigms: temporal summation and CPM. Temporal summation measures the progressive increase in perceived pain intensity during repeated application of identical noxious stimuli, reflecting bottom-up pain facilitation processes and serving as a psychophysical correlate of wind-up phenomenon, where spinal neurons display increased firing due to repetitive stimuli.^27,28 CPM assesses endogenous pain inhibition by measuring how pain perception of a test stimulus is attenuated by a concurrent conditioning painful stimulus applied to a remote body site, thereby evaluating the integrity of top-down, descending pain modulatory pathways. None of the included studies reported on offset analgesia.

Data extraction framework

We developed a comprehensive data extraction framework to address the methodological heterogeneity in QST research. A standardized data charting form was developed to extract relevant information from the included studies. Five different reviewers charted the data, discussed the results, and continuously updated the data charting form in an iterative process. The following data items were extracted: (1) study identification and bibliometric information (eg, title, authors, publication year, country of origin, study design); (2) population characteristics (eg, sample sizes, demographic data including age, sex distribution, and racial/ethnic composition, sample clinical description, and presence of healthy controls); (3) OAT medication type (eg, methadone, buprenorphine) and group-specific comparisons based on dosing strategies (eg, low vs high dose) and pharmacokinetics (eg, peak vs trough levels); (4) additional pharmacological interventions beyond OAT for OUD; (5) QST methodology (eg, anatomical testing sites, stimulus types and parameters, testing paradigm—static vs dynamic, equipment specifications). We also extracted study limitations and key discussion points to facilitate critical analysis. This systematic approach enabled comprehensive documentation and comparison of methodological variations, population characteristics, and outcomes across studies while maintaining standardization in data extraction.

Synthesis of results and critical appraisal of evidence sources

Our primary organization followed QST modality (thermal, mechanical, electrical), with subsequent analysis by testing paradigm, anatomical location, and measurement approach (eg, pain threshold vs pain tolerance). The extracted data were compiled and summarized in both quantitative and qualitative formats. Quantitative data were presented using descriptive statistics (eg, frequencies, means), using tables and figures. Qualitative data were synthesized narratively. We did not systematically appraise the methodological quality or risk of bias of the included studies, consistent with established scoping review methodology.²⁹

Results

Our systematic search yielded a total of 18 711 records across 3 sequential searches: 14 444 from the initial November 2022 search, 3851 from the June 2024 update, and 416 from the March 2025 update (Figure 1). After removing 7832 duplicates, 10 847 records were screened for eligibility. We excluded 10 004 records during initial screening based on titles and abstracts. The remaining 843 reports underwent full-text assessment, with 798 excluded. Finally, we included 45 eligible studies that employed QST methodologies in individuals with OUD receiving OAT with or without co-occurring chronic pain.

Figure 1.

Flow diagram of the study selection process for the scoping review. The systematic search of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines.

Studies characteristics

Of the 45 included studies,^30–74 34 focused exclusively on individuals with OUD (3094 participants) and 12 included individuals with co-occurring OUD and chronic pain (1165 participants). Most studies (29/45, 64.4%) employed a cross-sectional design, with 26 (55.6%) including healthy control groups. The study designs included 7 crossover randomized clinical trials (15.6%), 4 parallel randomized controlled trials (6.7%), 6 non-randomized clinical trials (13.3%), and 1 prospective cohort study (2.2%). Table 1 summarizes the frequency of QST methodologies employed across all included studies.

Table 1.

Frequency of quantitative sensory testing (QST) methodologies assessed in reviewed studies (N = 45).

QST category and modality	Total studies, n (%)
Static QST methods	45 (100%)
Mechanical pain sensitivity	12 (26.7%)
Thermal pain sensitivity	35 (77.8%)
Cold pain sensitivity focus	31 (68.9%)
Heat pain sensitivity focus	4 (8.9%)
Dynamic QST methods	3 (6.7%)
Temporal summation of pain	3 (6.7%)
Conditioned pain modulation	1 (2.2%)

Percentages for individual modalities sum to more than 100% because many studies employed methods from more than one modality.

Bold values indicate main QST categories.

Demographically, 24 studies (53.3%) reported race and/or ethnicity data. The research was geographically diverse, with studies conducted in the United States (n = 20, 44.4%), Israel (n = 7, 15.6%), Malaysia (n = 7, 15.6%), Australia (n = 5, 11.1%), Germany (n = 2, 4.4%), China (n = 2, 4.4%), Austria (n = 1, 2.2%), and the Netherlands (n = 1, 2.2%). Detailed descriptive summaries of study designs, objectives, sample sizes, mean ages, percentage of females, presence of healthy controls, and investigated pharmacological interventions (if applicable) are provided in Table S1.

Static QST findings

Static QST measures assess baseline nociceptive sensitivity through single stimulus applications, capturing psychophysical responses that reflect the integrity of peripheral nociceptors and ascending pathways (Table 2). These include Aδ and C-fiber function for thermal stimuli and Aβ-fiber function for mechanical stimuli. These threshold and tolerance measurements represent the baseline excitability of the nociceptive system.⁷⁵

Table 2.

Summary of key quantitative sensory testing findings in individuals receiving opioid agonist treatment.

QST modality	Major findings	Implications for clinical care and research
Cold pain sensitivity	Most consistent finding: Lower cold pain tolerance in individuals with OUD compared to controls (58% of relevant studies)32,34–36,38,42,45,56–58,65 Inconsistent findings for cold pain threshold (7 studies showed higher thresholds, 4 showed lower thresholds vs controls)33,35,40,42,45,48,49,51,56–58 Higher chronic pain levels associated with lower cold pain tolerance62	Evidence of thermal hyperalgesia consistent with opioid-induced hyperalgesia (OIH) Persistent abnormalities despite prolonged abstinence suggests lasting neuroadaptive changes61,63 No significant differences between methadone and buprenorphine treatments37,48,58 Genetic factors influence pain sensitivity50,65,67,69
Pressure/mechanical pain sensitivity	Inconsistent findings on pressure pain thresholds across studies Lower pressure pain thresholds in individuals with co-occurring OUD and chronic pain compared to controls46 Negative correlation between morphine milligram equivalents (MME) and mechanical pain threshold53	Psychological factors (perceived stress, pain catastrophizing) influence pain perception72 Pharmacological interactions affect pain responses (eg, benzodiazepines associated with higher pain thresholds)52 Significant increase in pressure pain threshold after transitioning from full opioid agonists to buprenorphine-naloxone60
Electrical pain sensitivity	No significant differences in electrical pain thresholds between individuals receiving methadone and controls31,35,42 Lower electrical pain tolerance during trough methadone levels42 Higher electrical pain tolerance during peak methadone levels42,44	Cross-tolerance to opioid analgesics: High doses of morphine (55 mg) failed to provide antinociception in electrical stimulation in individuals receiving methadone31,32 Pharmacokinetic fluctuations influence pain sensitivity throughout dosing cycle Transition to buprenorphine-naloxone improved electrical pain thresholds and tolerances60
Dynamic pain measures	Lower wind-up ratio (temporal summation) in individuals receiving OAT compared to normative values53 Lower wind-up ratio in individuals with co-occurring OUD and chronic pain compared to those with chronic pain without OUD39 Impaired conditioned pain modulation in individuals receiving OAT with negative correlation between MME and CPM efficiency53	Altered central pain processing in individuals receiving OAT Evidence of central sensitization with disrupted balance between nociceptive facilitation and inhibition Impaired endogenous pain inhibition may contribute to development and maintenance of OIH These measures could potentially guide individualized therapies

Mechanical pain sensitivity

Ten studies assessed pressure pain sensitivity, with 4 in individuals with OUD only^30,39,52,54 and 6 in individuals with co-occurring OUD and chronic pain.^{47,53,56,61,72,73} Testing was conducted across 8 anatomical locations: Thumb, finger, thenar eminence, dorsum of hand, proximal forearm (brachioradialis muscle), trapezius, rectus femoris, and musculus abductor hallucis.

Findings regarding pressure pain thresholds in individuals with OUD were inconsistent. Two studies reported no significant differences between individuals receiving methadone treatment and healthy controls.^56,73 Conversely, 2 studies found significantly lower pressure pain thresholds in individuals with co-occurring OUD and chronic pain compared to healthy individuals.^47,72

Lang-Illievich et al.⁵⁴ found significantly higher mechanical pain thresholds in individuals receiving OAT (including methadone, levomethadone, buprenorphine, and extended-release morphine) compared to normative values. Interestingly, within those receiving OAT, they identified a negative correlation between morphine milligram equivalents (MME) and mechanical pain threshold, suggesting that higher opioid doses may be associated with increased mechanical pain sensitivity, potentially reflecting the development of OIH.

Two studies^30,52 found no significant effect of adjunct opioid administration (hydromorphone or buprenorphine) on pressure pain thresholds compared to placebo. However, Veldman et al.⁶¹ reported significant increases in pressure pain threshold after transitioning from full opioid agonists to buprenorphine-naloxone.

Additional findings suggested that concomitant medication use affected pain responses, with individuals who tested positive for benzodiazepines showing higher pressure pain thresholds and lower pain intensity ratings.⁵³ Psychological factors also influenced pain perception, with higher perceived stress associated with reduced pressure pain thresholds.⁷³ Females and individuals with high pain catastrophizing reported heightened pain intensity ratings for supra-threshold stimuli.⁷³

Thermal pain sensitivity

Cold pain sensitivity

Cold pain sensitivity was the most commonly assessed modality (31/45 studies, 68.9%). Seven studies^{34,41,46,50,57,58} found higher cold pain thresholds in individuals with OUD compared to healthy controls, while 4 studies^43,44,49,59 reported lower thresholds.

The most consistent finding across studies was reduced cold pain tolerance in individuals with OUD. Eleven studies^{33,35–37,39,43,46,57–59,66} consistently reported lower cold pain tolerance in individuals with OUD compared to healthy individuals. No studies found greater cold pain tolerance in individuals with OUD than in healthy controls.

When comparing different OAT medications, 3 studies^38,49,59 found no significant differences in cold pain tolerance between individuals receiving buprenorphine versus methadone. Similarly, Trubenbacher et al.⁵⁹ reported no significant difference in cold pain thresholds between these same treatment groups.

Among individuals with co-occurring OUD and chronic pain, studies consistently reported lower cold pain thresholds^62–64 and tolerance^62,63 compared to both individuals with chronic pain who were opioid-naïve and healthy controls. Greater chronic pain severity was associated with reduced pain tolerance.⁶³ Interestingly, Peles et al.⁵⁶ found that among individuals receiving methadone, those with chronic pain exhibited higher cold pain thresholds than those without chronic pain.

Several studies examined the persistence of pain sensitivity abnormalities in individuals with OUD who achieved abstinence, though definitions of abstinence varied across studies from 6 weeks to 6 months without opioid use. Most studies found no significant differences in cold pain thresholds^49,62–64 or tolerance^49,63 between individuals currently receiving OAT and those in abstinence for at least 6 months. However, Wachholtz et al.⁶² reported that while cold pain thresholds remained unchanged, pain tolerance significantly improved with increased duration of abstinence. Similarly, Compton et al.³⁵ observed higher cold pain tolerance in individuals in abstinence for at least 6 weeks compared to those receiving OAT.

Two studies^41,52 reported increased cold pain thresholds after acute administration of analgesic medications (hydromorphone, buprenorphine, oxycodone with ibudilast) compared to placebo, while 4 studies^30,31,37,42 found no significant differences between treatment and placebo conditions.

Pharmacokinetic studies revealed that methadone plasma concentrations influenced pain sensitivity. Zahari et al.⁶⁹ reported significantly higher cold pain thresholds in individuals with plasma concentrations below 400 ng/mL compared to those with higher concentrations. MacLean et al.⁵⁵ observed a significant decrease in cold pain threshold over time in both delayed and scheduled methadone groups.

A study found that, among individuals receiving methadone for OUD, those exhibiting heightened sensitivity to cold pressor pain demonstrated significantly poorer sleep quality metrics.⁷⁴

Finally, genetic factors, including polymorphisms in CYP2B6*6, DRD2, DRD4, and 2677 GG, were associated with altered cold pain thresholds ^51,66,68,70 and tolerance,^51,68,74 with carriers of these variants generally demonstrating heightened pain sensitivity compared to non-carriers.

Heat pain sensitivity

Heat pain sensitivity was assessed in 4 studies, 3 focusing exclusively on individuals with OUD^30,52,54 and one examining individuals with co-occurring chronic pain and OUD.⁵⁶ Among individuals receiving methadone, those with chronic pain exhibited significantly higher heat pain thresholds yet reported greater suprathreshold heat pain intensity ratings compared to methadone-treated individuals without chronic pain and healthy controls.⁵⁶ High-dose methadone regimens (>100 mg/day) were associated with lower suprathreshold heat pain ratings.⁵⁶ Two studies found no significant acute opioid effects (hydromorphone or buprenorphine) on heat pain thresholds compared to placebo.^30,52 Lang-Illievich et al.,⁵⁴ as previously, reported increased mechanical pain thresholds associated with higher MME, and also found no significant differences in heat pain thresholds between individuals receiving OAT and normative values, although a similar dose-dependent trend was observed.

Electrical pain sensitivity

Seven studies examined electrical pain sensitivity (6 with individuals with OUD only and one with individuals with co-occurring OUD and chronic pain). Three studies^32,36,44 found no significant differences in electrical pain thresholds between individuals receiving methadone and healthy controls. However, individuals receiving methadone exhibited significantly lower electrical pain tolerance during both trough and peak methadone sessions compared to controls.⁴⁴

One study reported significantly lower electrical pain tolerance in individuals receiving methadone at trough methadone concentrations, while in another tolerance was significantly higher at peak concentrations compared to controls.^43,45 Two studies^32,33 found that high doses of morphine (55 mg) failed to provide antinociception during electrical stimulation in individuals receiving methadone, whereas controls experienced antinociception with lower morphine doses.

In individuals with OUD and chronic pain, Veldman et al.⁶¹ reported significant increases in electrical pain thresholds and tolerances following transition from full μ-opioid receptor agonists to buprenorphine-naloxone.

Dynamic QST findings

Dynamic QST paradigms provide psychophysical assessments of central pain processing mechanisms (Table 2). Temporal summation of pain manifests as an escalating pain response to repeated stimuli. This phenomenon reflects central sensitization at the spinal dorsal horn, driven by NMDA receptor–mediated mechanisms. Repeated activation of C-fibers produces cumulative depolarization of wide dynamic range neurons, leading to heightened excitability and an amplification of pain signals over time.⁷⁶ In contrast, CPM represents the “pain inhibits pain” phenomenon. Here, a conditioning stimulus applied at a remote site recruits descending inhibitory pathways from the periaqueductal gray and rostral ventromedial medulla. These pathways release endogenous opioids and monoamines, which suppress nociceptive transmission in the spinal cord through diffuse noxious inhibitory controls.⁷⁷ Together, temporal summation and CPM provide complementary insights into facilitatory and inhibitory components of pain modulation.

Temporal summation of pain

Three studies (2 with individuals with OUD only and one with individuals with co-occurring OUD and chronic pain) assessed temporal summation. Two studies evaluated mechanical temporal summation of pain (TSP), while one used thermal stimuli. The methodology varied considerably: Tsui et al.⁶⁰ applied mechanical punctate stimulators (8-512 mN) to the middle finger at 2-s intervals, Lang-Illievich et al.⁵⁴ used 256 mN pinprick stimulators on the thumb at 1 Hz frequency, and Compton et al.⁴⁰ utilized a Peltier thermode to apply 4 phasic heat pain stimuli (47°C) at 12-s intervals.

Tsui et al.⁶⁰ found no significant difference in mechanical TSP between individuals with OUD with HCV mono-infection, HCV/HIV co-infection, and uninfected individuals with OUD. In contrast, Lang-Illievich et al.⁵⁴ reported significantly lower wind-up ratios in individuals receiving OAT compared to normative values, indicating altered central pain processing. The wind-up ratio quantifies temporal summation by calculating the relative increase in pain between the first and last stimulus in a repeated series (typically expressed as the pain intensity of the last stimulus divided by the pain intensity of the first stimulus). A higher ratio indicates greater temporal summation and central sensitization, while a lower ratio suggests blunted central pain facilitation. Similarly, Compton et al.⁴⁰ observed a significantly lower wind-up ratio in individuals with co-occurring OUD and chronic pain compared to those with chronic pain without OUD. While these findings suggest altered central pain processing in individuals receiving OAT, the limited number of studies (n = 3) and methodological variability preclude definitive conclusions.

Conditioned pain modulation

Only Lang-Illievich et al.⁵⁴ assessed CPM. Their protocol involved immersing participants’ non-dominant hand in a hot water bath (46°C for 2 minutes) as the conditioning stimulus, with pressure pain tolerance measured before and after exposure as the test stimulus. They reported significantly lower mechanical CPM scores in individuals receiving OAT compared to normative values, with a negative correlation between MME and CPM efficiency, suggesting impaired endogenous pain inhibition in this population.

Discussion

This scoping review identified 45 studies examining QST in individuals with OUD, with or without co-occurring chronic pain. While QST demonstrates potential for objective pain assessment, the current evidence base is characterized by substantial methodological heterogeneity, predominance of cross-sectional designs, and limited investigation of dynamic pain measures. These limitations notwithstanding, consistent patterns emerged that advance our understanding of pain processing alterations in OUD, though their clinical utility remains to be established.

Nevertheless, consistent patterns emerged (Figure S1). Individuals on OAT frequently exhibit reduced cold pain tolerance, impaired pain modulatory capacity, and hyperalgesic responses that persist well beyond the period of non-medical opioid use. These observations point to fundamental neurophysiological adaptations, namely central sensitization and dysfunctional descending inhibitory pathways. Together, they produce a sustained imbalance between facilitatory and inhibitory pain circuits—contributing to paradoxical increases in pain sensitivity even with continued opioid therapy.

Principal findings

Evidence for central sensitization and OIH

Our review provides consistent evidence supporting the presence of central sensitization and OIH in individuals with OUD. The most robust finding was reduced cold pain tolerance in individuals with OUD compared to healthy individuals, observed in 58% (18/31) of studies assessing this modality. This consistent pattern suggestive of cold hyperalgesia, indicating heightened pain sensitivity to cold stimuli, indicates fundamental alterations in pain processing pathways that may persist despite treatment.

Dynamic QST measures, although less frequently assessed, revealed impaired pain modulation providing functional evidence for central changes. Based on this limited evidence, the observed enhancement of temporal summation and reduction in CPM efficiency may suggest a shift in the balance between nociceptive facilitation and inhibition characteristic of central sensitization. This altered balance may be a key mechanism driving the development and maintenance of OIH.^78,79

Notably, pain processing abnormalities were frequently observed across multiple sensory modalities, though with varying consistency. This multimodal presentation of hyperalgesia further supports the involvement of central mechanisms rather than peripheral sensitization alone.

Persistence of pain processing abnormalities

Persistent pain sensitivity abnormalities represent a clinically relevant finding. A study comparing individuals receiving OAT to comparison groups abstinent from non-medical opioids following OAT cessation revealed that hyperalgesia often continues long after non-medical opioid use stops, indicating potentially lasting neuroadaptations. While some studies indicated partial improvement in pain tolerance with increased duration of abstinence,^35,62 pain thresholds typically remained altered. This suggests that some neuroadaptive changes induced by long-term opioid exposure may persist long after discontinuation, potentially contributing to vulnerability to returning to using opioids non-medically.

Influence of opioid agonist type, dose, and pharmacokinetics on pain

The relationship between OAT differences and pain sensitivity also revealed varied patterns. Although no consistent differences emerged between methadone and buprenorphine in terms of pain processing measures, dose-dependent effects were observed in some studies, with high-dose methadone (>100 mg/day) associated with lower suprathreshold heat pain ratings.⁵⁶

Pharmacokinetic fluctuations influenced pain sensitivity, with significant differences observed between peak and trough opioid concentrations.^43,45 This suggests fluctuations in pain sensitivity throughout the dosing cycle, which may have important clinical implications for pain management in individuals with OUD.

Psychological, sex-related, non-opioid pharmacological, and genetic modulators of pain

Several studies identified factors that modulate pain perception in individuals with OUD. Psychological variables, including perceived stress and pain catastrophizing, were associated with altered pain thresholds and increased pain intensity ratings.⁷³ Sex differences were also observed, with females demonstrating greater pain sensitivity and higher ratings for supra-threshold stimuli.⁷³ Concomitant non-opioid medication use, particularly benzodiazepines, influenced pain responses,⁵³ highlighting the complex pharmacological interactions that may affect pain processing. Likewise, genetic factors, including polymorphisms in genes related to opioid metabolism and dopamine function, were associated with variations in pain sensitivity.^51,66,68,70 This suggests potential genetic contributions to individual differences in susceptibility to OIH and pain processing abnormalities.

Methodological implications

The wide variability in QST protocols across studies presents significant challenges for data synthesis and interpretation. Standardization of key methodological parameters is essential for improving reproducibility and enabling direct comparisons between studies. This includes consistent definitions of central sensitization, standardized stimulus parameters, and uniform testing procedures.

The predominance of cross-sectional designs (64.4% of included studies) limits our ability to establish causality and track the evolution of pain processing abnormalities over time. More prospective studies are needed to clarify whether alterations in pain sensitivity predispose individuals to OUD or primarily result from chronic opioid exposure.

Standardized normative values for QST in individuals with OUD remain poorly defined. While 55.6% of studies included healthy control groups, many relied on published norms from populations that may differ substantially from participants with OUD. Furthermore, the racial and ethnic homogeneity of many study samples limits generalizability, with most normative QST data derived from predominantly Caucasian samples.

Additional methodological limitations include inconsistent reporting of opioid use or abstinence duration, OUD severity, medical comorbidities, and timing between opioid administration and QST procedures. Furthermore, the reliance on small sample sizes in many studies, coupled with the absence of healthy control groups in nearly half of the papers (44.4%), severely limits the statistical power and generalizability of the findings, contributing to the inconsistent results observed across different pain modalities. Few studies systematically screened for or controlled concomitant substance use or comprehensively assessed co-occurring medical and psychiatric conditions, despite their potential influence on pain processing.

Clinical implications

QST offers significant potential to enhance understanding of pain processing in OUD and inform clinical management strategies. Just as QST has proven valuable in predicting treatment responses in conditions like distal sensory peripheral neuropathy⁸⁰ and post-herpetic neuralgia,⁸¹ similar applications could benefit OUD treatment.

The observed cross-tolerance, defined as a phenomenon where chronic exposure to one opioid reduces responsiveness to other opioids, significantly impacts acute pain management in this population. QST studies demonstrating fluctuations in pain sensitivity relative to OAT dosing cycles suggest potential strategies, such as divided daily dosing, to mitigate pain and hyperalgesia during trough periods.⁴⁵

Although differences between methadone and buprenorphine were generally inconsistent across QST measures, 2 small studies demonstrated improved pain parameters when transitioning from full agonists to buprenorphine in patients with comorbid OUD and chronic pain,^61,82 findings requiring validation in adequately powered longitudinal trials.

The persistence of hyperalgesia despite prolonged abstinence has implications for relapse prevention and pain management in individuals in recovery. Understanding the timeline for potential recovery of normal pain processing could help clinicians better address pain symptoms and anticipate analgesic requirements in this population.

Mechanistic implications

Our findings highlight the importance of understanding the neurobiological mechanisms underlying altered pain processing in OUD. Central sensitization emerges as a primary mechanism, characterized by increased excitability of central pain pathways and altered pain modulation.⁷⁸ As previously discussed, the evidence from dynamic QST paradigms strongly supports central sensitization as a key feature of OUD-related pain processing alterations.

These findings suggest a broader framework of altered body–brain communication in OUD that extends beyond traditional addiction models focused primarily on reward and motivation dysfunction. Emerging evidence suggests that disrupted interoceptive processing may represent a crucial link between altered pain sensitivity and addiction mechanisms.⁸³

The differential effects on specific nociceptive pathways, with greater sensitivity observed in response to thermal stimuli compared to mechanical or electrical stimuli, may reflect pathway-specific vulnerabilities to opioid-induced neuroadaptations. The pronounced sensitivity to cold stimuli may reflect specific adaptations within spinothalamic pathways or alterations in the function of peripheral thermoreceptors (eg, TRPM8 and TRPA1 channels).⁸⁴ The specificity of cold pain alterations, compared to less consistent findings for heat and mechanical pain, may suggest differential vulnerability of thermoreceptive pathways to opioid-induced plasticity. This pattern suggests potential targets for mechanistic studies and therapeutic interventions.

Future directions

To translate QST from a promising research methodology to a clinically applicable tool in OUD treatment, future research must address some critical priorities (Table 3). Standardization of QST protocols represents the most urgent necessity, as current methodological heterogeneity severely constrains meaningful synthesis of evidence across studies. Implementing robust longitudinal designs would address the critical knowledge gap regarding temporal evolution of pain processing abnormalities, potentially illuminating whether altered pain sensitivity represents a predisposing factor for OUD development or manifests primarily as a consequence of chronic opioid exposure. Integration of QST with comprehensive patient-reported outcomes would significantly enhance clinical relevance by correlating quantitative sensory parameters with psychological dimensions such as pain catastrophizing and self-efficacy. Finally, expanding participant diversity in future investigations would improve generalizability and facilitate development of population-specific normative data, ultimately enabling personalized treatment approaches based on individual QST profiles to optimize clinical outcomes when transitioning patients to alternative pain management strategies.

Table 3.

Evidence-based priorities for advancing QST research in opioid use disorder.

Actionable item	Goal	Specific actions
Standardize QST methodologies	Improve reproducibility and comparability	Convene expert panels; define consensus-based core set of QST modalities, stimulus types, intensities, and anatomical testing sites.
Conduct longitudinal studies	Establish causality	Track patients from active use through abstinence.
Broader populations	Generalize findings	Include control groups and broader demographics.
Study gender/sociocultural factors	Understand variability	Design subgroup analyses for gender and cultural differences.
Explore central sensitization	Target mechanistic insights	Use dynamic QST and integrate with neuroimaging.
Optimize pharmacology	Refine pain management	Compare effects of different opioid regimens and adjunctive therapies.
Phenotype-based treatment	Enable personalized care	Develop models linking QST to treatment outcomes.

Conclusion

In summary, this scoping review highlights the potential of QST as an objective tool for assessing pain and OIH in individuals receiving opioid therapy for OUD and chronic pain. QST offers a level of granularity that can complement traditional self-reported measures, providing valuable insights into the sensory alterations associated with long-term opioid use. Despite the promising applications of QST, significant challenges remain, including methodological variability, the lack of standardized protocols, and limited research on the predictive value of QST for clinical outcomes. Nevertheless, QST’s ability to detect objective sensory changes offers promise for improving pain assessment in OUD. Realizing this potential requires coordinated efforts to standardize protocols, conduct adequately powered longitudinal studies, and establish the clinical validity of QST-derived phenotypes. By addressing these challenges, we can transform QST from a promising research tool into a clinical instrument, offering a pathway to more precise and personalized pain management for this vulnerable population.

Author contributions

All authors have contributed to the manuscript and approved the submitted version.

Supplementary material

Supplementary material is available at Pain Medicine online.

Funding

J.P.D.A. is supported by grant numbers K23 DA052682, R21 DA057240, R01 DA600066, and RM1 DA0554310 from the National Institute on Drug Abuse (NIDA). He has also received support for clinical trials from Jazz Pharmaceuticals and Ananda Scientific, specifically in the form of medication provisions. Additionally, J.P.D.A. has served as a compensated consultant for Boehringer Ingelheim. D.A.F. is supported by grant number RM1 DA0554310f from NIDA. G.A.A. is supported by grant numbers R21 DA046030 and P30 DA046345 from NIDA.

Conflicts of interest: J.P.D.A. has been supported in this study by Jazz Pharmaceuticals, specifically through medication provisions. Additionally, J.P.D.A. has been a compensated consultant for Boehringer Ingelheim. The other authors declare no conflict of interest.