Hyperalgesia in Patients With a History of Opioid Use Disorder: A Systematic Review and Meta-Analysis

Martin Trøstheim; Marie Eikemo

doi:10.1001/jamapsychiatry.2024.2176

. 2024 Aug 14;81(11):1108–1117. doi: 10.1001/jamapsychiatry.2024.2176

Hyperalgesia in Patients With a History of Opioid Use Disorder

A Systematic Review and Meta-Analysis

Martin Trøstheim ^1,^2,^✉, Marie Eikemo ^2,³

PMCID: PMC11325249 PMID: 39141367

This systematic review and meta-analysis examines evidence from 39 studies on hypersensitivity to cold pain among patients with opioid use disorder and its association with indices of opioid tolerance, withdrawal, and abstinence.

Key Points

Question

Is hyperalgesia in patients with opioid use disorder associated with opioid use?

Findings

This systematic review and meta-analysis of 39 studies and more than 1300 individuals with and 700 individuals without a history of opioid use disorder found hypersensitivity to cold pain in patients undergoing opioid agonist treatment for opioid use disorder. Evidence for a relationship between this hyperalgesia and indices of opioid tolerance, withdrawal, and abstinence was inconclusive.

Meaning

It remains unclear based on the current literature whether the observed hyperalgesia in patients with opioid use disorder is associated with opioid use or with other, non–opioid-related factors.

Abstract

Importance

Short-term and long-term opioid treatment have been associated with increased pain sensitivity (ie, opioid-induced hyperalgesia). Treatment of opioid use disorder (OUD) mainly involves maintenance with methadone and buprenorphine, and observations of heightened cold pain sensitivity among patients are often considered evidence of opioid-induced hyperalgesia.

Objective

To critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use.

Data Sources

Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched.

Study Selection

Studies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included.

Data Extraction and Synthesis

Multilevel random-effects models with robust variance estimation were used for all analyses. Study quality was rated with the JBI checklist. Funnel plots and Egger regression tests were used to assess reporting bias.

Main Outcomes and Measures

Main outcomes were pain threshold, tolerance, and intensity in patients and healthy controls, and unstandardized, standardized (Hedges g), and percentage differences (%Δ) in these measures between patients and controls. The association between pain sensitivity and opioid tolerance, withdrawal, and abstinence indices was tested with meta-regression.

Results

Thirty-nine studies (1385 patients, 741 controls) met the inclusion criteria. Most studies reported CPT data on patients undergoing opioid agonist treatment. These patients had a mean 2- to 3-seconds lower pain threshold (95% CI, −4 to −1; t test P = .01; %Δ, −22%; g = −0.5) and 29-seconds lower pain tolerance (95% CI, −39 to −18; t test P < .001; %Δ, −52%; g = −0.9) than controls. Egger tests suggested that these differences may be overestimated. There were some concerns of bias due to inadequate sample matching and participant dropout. Meta-regressions yielded no clear support for hyperalgesia being opioid related.

Conclusion and Relevance

Patients receiving opioid agonist treatment for OUD are hypersensitive to cold pain. It remains unclear whether hyperalgesia develops prior to, independent of, or as a result of long-term opioid treatment. Regardless, future studies should investigate the impact of hyperalgesia on patients’ well-being and treatment outcomes.

Introduction

Short-term and long-term opioid treatment have been associated with increased pain sensitivity, a phenomenon described as opioid-induced hyperalgesia.¹ The prevalence and mechanisms of opioid-induced hyperalgesia are only partly understood, and its importance for clinical practice is still debated.^2,3 Pain sensitivity measures from patients with history of opioid use disorder (OUD) are uniquely useful to uncover the link between long-term opioid treatment and hyperalgesia, as the primary treatment for OUD often involves years of maintenance with high doses of methadone or buprenorphine.^4,5

Despite the analgesic properties of methadone and buprenorphine,⁶ 45% of patients receiving long-term pharmacological treatment for OUD with these opioid agonists report chronic pain.⁷ While most patients received a pain diagnosis before developing OUD,⁸ some developed pain after being diagnosed with OUD.⁸ Although this could partially be explained by the increased risk of injury among patients with OUD,⁵ some authors have suggested central sensitization (ie, a heightened responsiveness of the central nervous system) and its resulting increase in pain sensitivity (eg, hyperalgesia and allodynia)⁹ as a key contributing factor to chronic pain in this population.⁷

Observations of heightened cold pain sensitivity in patients receiving opioid agonist treatment for OUD^{1,10,11,12,13} are often considered evidence of opioid-induced hyperalgesia. Challenging this interpretation, results from a recent systematic review suggest that short-term opioid administration in these patients may either produce minimal changes in pain tolerance or even result in analgesia when doses are sufficiently large.¹⁴ However, long-term daily use of methadone and buprenorphine could still contribute to hyperalgesia, eg, through development of tolerance to the opioid analgesic effects¹⁵ or through emergence of withdrawal symptoms toward the end of each daily dose.¹⁶ Reduction in pain sensitivity following abstinence from opioids would provide strong evidence for opioid-related hyperalgesia in patients with OUD. However, previous studies have yielded inconsistent results, leading some researchers to speculate that prolonged abstinence is required to reverse hyperalgesia.^10,17

The opioid antagonist naltrexone is an alternative drug used in OUD treatment that facilitates abstinence by blocking illicit opioids from binding to opioid receptors and producing rewarding effects.¹⁸ This blockade may also interfere with endogenous opioid pain regulation^19,20 and could potentially result in hyperalgesia. Initial studies indicate that 50% to 77% of patients treated with naltrexone for OUD experience chronic pain,^21,22 but it is unclear if this is due to naltrexone-induced hyperalgesia or other factors such as preexisting pain conditions.

Whether hyperalgesia in patients receiving pharmacological treatment for OUD is attributable to opioid pharmacotherapy in particular (eg, methadone, buprenorphine, or naltrexone treatment) or to opioid use in general (ie, licit and illicit) remains elusive because no previous review to our knowledge has considered pain sensitivity in patients before initiating treatment.

Little effort has been made to verify that the hypersensitivity to cold pain often observed in patients receiving opioid agonist treatment for OUD is related to opioid use. Here, we present a systematic review and meta-analysis of cold pain sensitivity in patients at 3 different stages of OUD: (1) during treatment seeking for ongoing OUD, (2) during treatment with opioid agonists or antagonists, and (3) during abstinence from opioids. To further probe whether hyperalgesia in patients with OUD is opioid related, we conduct a series of meta-regressions testing the association between cold pain sensitivity and tolerance indices (ie, agonist dose and treatment duration), withdrawal indices (ie, time since last agonist dose), and abstinence duration. Finally, we use meta-regression to test whether greater cold pain sensitivity is associated with higher chronic pain prevalence in patients receiving opioid agonist treatment for OUD.⁷

Hyperalgesia represents a challenge to treatment of OUD as the stressful nature of pain could trigger relapse to illicit opioid use²³ and thus increase the risk of negative health outcomes (eg, overdose).⁵ By increasing knowledge on the relationship between long-term opioid use and hyperalgesia, this review could inform harm prevention in the context of OUD treatment.

Methods

This systematic review and meta-analysis follows recommendations by the EQUATOR Network and is in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline²⁴ and Meta-analysis of Observational Studies in Epidemiology (MOOSE)²⁵ reporting guideline. This review was not preregistered, but detailed documentation, data, and analysis scripts are available on the Open Science Framework to ensure transparency and reproducibility.²⁶ We limited this review to studies using the commonly used¹³ opioid-modulated²⁷ cold pressor test²⁸ (CPT) to assess pain sensitivity (eMethods in Supplement 1).

Study Identification

Searches were conducted by 1 researcher (M.T.) in the databases Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, and used combinations of terms for the treatment drug (eg, methadone, buprenorphine, or naltrexone), the condition and treatment stage (eg, opioid use disorder, opioid maintenance treatment, detoxification, or abstinence), and the CPT (eg, cold pain, cold temperature, or cold water) (eMethods in Supplement 1).

Following deduplication, 1 researcher (M.T.) assessed all retrieved records for eligibility (eMethods in Supplement 1). Studies were included if CPT pain sensitivity (ie, pain threshold, tolerance, or intensity) was assessed in human patients with OUD history who were either seeking pharmacological treatment or detoxification (ie, before treatment), undergoing pharmacological treatment (ie, methadone, buprenorphine, or naltrexone), or abstinent from opioids (ie, after detoxification or during prolonged abstinence). To prevent biased estimation of hyperalgesia, we excluded studies if participants were recruited based on their CPT pain responses, if participants could not terminate the CPT at will, or if drugs other than OUD medications or placebo had been administered before the CPT.

Data Extraction

One researcher (M.T.) extracted and harmonized the following data from included records (eTable 1 in Supplement 1): sample characteristics (ie, number of participants, age, sex, treatment stage, medication, dose and duration, abstinence duration, and chronic pain), CPT characteristics (ie, water temperature and maximum duration), CPT pain sensitivity, including pain threshold (ie, time from limb submersion in cold water to first verbal report of pain), tolerance (ie, time from limb submersion to limb withdrawal) and intensity rating, and the time between previous treatment dose and the CPT. See the eMethods in Supplement 1 for details.

Statistical Analysis

All analyses were conducted in R (R Foundation)²⁹ using the package metafor³⁰ and implemented as multilevel random-effects models with the REML estimator for variance components. The data had a hierarchical structure with multiple outcomes nested within samples within studies. To account for the statistical dependency in outcomes resulting from this structure, we added random intercepts at the sample and study levels and used robust variance estimation with the clubSandwich package³¹ to calculate standard errors and confidence intervals. The inclusion of additional random intercepts depended on the hierarchical structure of the data subset used in each particular analysis.

To evaluate whether hyperalgesia in patients receiving opioid pharmacotherapy for OUD is associated with opioid use in general or opioid pharmacotherapy in particular, patient samples were grouped into the following categories: during treatment seeking for ongoing OUD (ie, before starting treatment), during agonist treatment (ie, methadone or buprenorphine), during antagonist treatment (ie, naltrexone), and during abstinence (eg, after detoxification).

Separate analyses were conducted for the main outcomes pain threshold, pain tolerance, and pain intensity. Results were considered statistically significant when t tests yielded P < .05. Heterogeneity was assessed by calculating I² and tau and conducting a Cochran Q test.

Primary Analyses

In the primary analyses, we estimated the mean cold pain threshold, tolerance, and intensity separately for healthy controls and each patient group. To determine the severity of hyperalgesia in each patient group, we estimated the mean difference (MD), standardized mean difference (Hedges g), and percentage difference (%Δ) in cold pain threshold, tolerance, and intensity between healthy controls and patients and between abstinent patients and patients undergoing agonist treatment.

Secondary Analyses

We conducted a series of secondary meta-regressions to determine whether cold pain sensitivity (ie, cold pain threshold, tolerance, and intensity) in patients with OUD history is associated with indicators of opioid tolerance (ie, agonist treatment dose and duration) and opioid withdrawal (ie, time since previous daily opioid agonist treatment dose), whether cold pain sensitivity would be lower in those with longer abstinence from opioid use, and whether chronic pain rates are positively correlated with cold pain sensitivity.⁷ See the eMethods in Supplement 1 for additional analyses.

Risk-of-Bias Assessment

The JBI checklist for quasi-experimental studies^32,33 was used to evaluate the quality of the included studies. To assess potential reporting bias in results from studies comparing patients with healthy controls, we generated funnel plots and conducted Egger regression tests.³⁴

Results

The literature search returned 528 unique records, 64 of which met the inclusion criteria (eTable 2 in Supplement 1). These were all written in English and reported in total 415 individual outcome assessments across 77 samples from 39 studies (N = 2126, 1385 patients and 741 healthy controls) (Table).³⁵ Most studies assessed cold pain tolerance (k = 39) followed by threshold (k = 27) and intensity (k = 13). The median CPT water temperature was 1 °C but ranged from 0.75 to 9 °C. The CPT was stopped after a median of 5 minutes (range, 1-7 minutes).

Table. Sample Characteristics^a.

Characteristic	Before treatment	Agonist treatment	Antagonist treatment	Abstinent	Healthy controls
No. of studies/samples/outcomes	3/4/15	31/43/236	3/3/5	11/12/67	21/21/92
No. of patients	152	976	41	347	741
Sex, %
Men, median (IQR)	66 (49-71)	63 (55-76)	84 (76-92)	100 (72-100)	60 (50-77)
Range	0-83	35-100	68-100	33-100	30-100
Women, median (IQR)	34 (29-51)	37 (25-45)	16 (8-24)	0 (0-28)	40 (23-50)
Range	17-100	0-65	0-32	0-67	0-70
No. of missing samples	0	8	1	2	4
Age, y
Median (IQR)	33 (33-34)	43 (39-46)	27 (27-27)	33 (31-40)	31 (30-36)
Range	33-35	31-59	27-27	27-46	23-52
No. of missing samples	1	9	2	2	3
Duration, mo
Median (IQR)	NA	28 (18-35)	2 (1-3)	8 (1-17)	NA
Range	NA	8-52	0-4	0-44	NA
No. of missing samples	NA	30	1	0	NA
MME dose, median (IQR) [range], mg/d^b	NA	724 (655-857) [450-1416]	NA	NA	NA
Naltrexone dose, median (IQR) [range], mg/d	NA	NA	48 (26-49) [5-50]	NA	NA
No. of missing samples	NA	11	0	NA	NA

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Abbreviations: NA, not applicable; MME, morphine milligram equivalents.

^{^a}

The median methadone dose was 72 mg/d (IQR, 64-80; range, 45-101). The median buprenorphine dose was 13 mg/d (IQR, 9-15; range, 8-18).

^{^b}

MME was converted from doses of methadone (conversion factor: ×10 mg/d) and buprenorphine (conversion factor: ×80 mg/d).³⁵

Primary Analysis

Observed differences in cold pain sensitivity between patients and controls in individual studies are presented in Figure 1 (see also eTables 3 and 4 and eFigures 1-3 in Supplement 1).³⁶ Consistent with assessments made in previous reviews, cold pain sensitivity was significantly higher in patients undergoing opioid agonist treatment (Figure 2).^{37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59} Compared with healthy controls, these patients had a mean 2 to 3 seconds lower pain threshold (MD, −2.5; 95% CI, −4.2 to −0.7; t test P = .01; %Δ, −22%; Hedges g = −0.5) and 29 seconds lower tolerance (MD, −28.6; 95% CI, −39.2 to −18.0; t test P < .001; %Δ, −52%; g = −0.9). The only study to compare cold pain intensity between these 2 groups did not find a significant difference (MD, 1.0; 95% CI, −19.4 to 21.4; t test P = .92; %Δ, 1.7; g = 0.0).³⁷ See eTables 5 and 6 in Supplement 1 for separate results for methadone and buprenorphine treatment.

Figure 2. — Forest plot showing the mean difference (MD) in cold pain threshold^{37,38,39,40,41,42,43,44,45,46,47} (A) and tolerance^{37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59} (B) between patients receiving agonist treatment and healthy controls. Squares and horizontal error bars indicate the mean and 95% CI, respectively. The vertical dotted line indicates no difference. See eTable 4 in Supplement 1 for additional and more detailed statistics. RE indicates random effects.

Patients assessed before starting treatment for OUD also displayed significantly lower cold pain tolerance than healthy controls (MD, −24.0; 95% CI, −47.3 to −0.6; t test P < .05; %Δ, −52%; g = −0.8). However, these groups did not significantly differ in cold pain threshold (MD, 0.6; 95% CI, −39.8 to 40.9; t test P = .89; %Δ, 17.8; g = 0.1), and 1 study^17,60,61,62 found pain intensity to be significantly lower in untreated patients compared with healthy controls (MD, −16.0; 95% CI, −22.5 to −9.5; t test P < .001; %Δ, −22%; g = −0.9).

Cold pain threshold, tolerance, and intensity did not significantly differ between abstinent patients and healthy controls nor between abstinent patients and patients undergoing opioid agonist treatment. See eTables 7 and 8 in Supplement 1 for separate results for recent and prolonged abstinence.

The only study to compare patients undergoing antagonist treatment with healthy controls⁶³ found significantly higher cold pain threshold (MD, 13.3; 95% CI, 8.9 to 17.6; t test P < .001; %Δ, 52%; g = 1.5) and tolerance (MD, 27.3; 95% CI, 15.5 to 39.0; t test P < .001; %Δ, 41%; g = 1.2) among patients. There was no significant difference in cold pain intensity (MD, 2.7; 95% CI, −12.0 to 17.4; t test P = .72; %Δ, 4.8; g = 0.1).

Secondary Analyses

Meta-regressions yielded inconclusive results for associations between cold pain sensitivity and indicators of opioid tolerance (ie, agonist treatment dose and duration) and withdrawal (ie, time since previous daily opioid agonist treatment dose), abstinence duration, and chronic pain (Figure 3³⁵ and eTable 9 in Supplement 1), with the exception of a significant negative association between mean time since previous daily dose and cold pain tolerance (B = −0.2; SE = 0.1; t test P = .02). See eTable 10 in Supplement 1 for separate results for methadone and buprenorphine treatment.

Figure 3. — Results from meta-regressions (eTable 9 in Supplement 1). Black solid line indicates the meta-regression line. Gray ribbon indicates the 95% CI band. Morphine milligram equivalents (MME) were converted from doses of methadone (conversion factor: ×10 mg/d) and buprenorphine (conversion factor: ×80 mg/d).³⁵ Neither opioid agonist dose (A-C) nor treatment duration (D-F) was significantly correlated with cold pain threshold, tolerance, or intensity (eTable 10 in Supplement 1). While there was no significant correlation with cold pain threshold (G) or intensity (I), lower tolerance was significantly associated with longer mean time since previous daily dose (H) (B = −0.2; SE = 0.1; t test P = .02). This corresponded to 5 seconds lower cold pain tolerance immediately before compared with immediately after the daily dose. Neither cold pain threshold (J), tolerance (K), nor intensity (L) was significantly correlated with abstinence duration (eTable 8 in Supplement 1). Meta-regressions testing the hypothesized positive correlation between chronic pain and hyperalgesia in patients undergoing opioid agonist treatment⁷ failed to show any significant relationship between chronic pain rate and cold pain threshold (M), tolerance (N), or intensity (O). VAS indicates visual analog scale.

Bias Assessments

The quality assessment identified several limitations and potential sources of bias in the included studies (Figure 4 and eFigure 4 in Supplement 1), including inadequate sample matching and participant dropout. Egger tests identified some significant funnel plot asymmetry (eFigure 5 and eTable 11 in Supplement 1), suggesting that differences in cold pain sensitivity between groups may be overestimated in the primary analyses.

Discussion

Heightened sensitivity to cold pain among patients receiving opioid agonist treatment for OUD has long been considered evidence of opioid-induced hyperalgesia.¹³ Here, we critically examined this assumption by conducting a systematic review and meta-analysis of CPT pain responses in patients with OUD history before starting treatment, during agonist and antagonist treatment, and during abstinence from opioids. To probe how hyperalgesia is linked to opioid treatment over time, we also conducted a series of meta-regressions testing the associations with tolerance indices (ie, daily agonist dose, and agonist treatment duration), withdrawal indices (ie, time since previous daily agonist dose), and opioid abstinence duration.⁶⁴

Compared with healthy controls, patients receiving opioid agonist treatment for OUD had 2 to 3 seconds lower cold pain threshold and 29 seconds lower cold pain tolerance. This corresponded to 22% lower pain threshold (g = −0.5) and 52% lower pain tolerance (g = −0.9), differences in the range typically considered clinically significant.^65,66,67 Results from individual studies were variable, and there was some risk of hyperalgesia being overestimated. Nevertheless, individual results consistently pointed toward strong hyperalgesia in this patient group. Consistent with the hyperalgesia being associated with opioid withdrawal, we found a significant correlation between time since previous daily agonist dose and cold pain tolerance so that tolerance was 5 seconds higher right after compared with right before daily dose administration. We also found evidence for lower cold pain tolerance in patients who were seeking but had not yet started pharmacotherapy for OUD. This suggests that opioid use in general and/or other factors unrelated to opioid agonist treatment could be contributing to hyperalgesia in patients with OUD. In all other analyses, we found no clear support for the notion that hyperalgesia in patients with OUD history is related to opioid use.

Opioid agonist treatment for OUD is associated with both heightened sensitivity to pain and elevated chronic pain rates.^7,12 It has been hypothesized that chronic pain in patients receiving this form of treatment could be a result of hyperalgesia.⁷ However, meta-regressions testing the correlation between chronic pain and cold pain sensitivity yielded inconclusive results. Because patients with co-occurring chronic pain were often excluded from the reviewed studies, the results from this review suggest that patients receiving opioid agonist treatment for OUD can be highly sensitive to cold pain without developing chronic pain.

Tapering or discontinuation of long-term opioid treatment has been proposed to result in hyperalgesia lasting beyond the short-term withdrawal phase,⁶⁸ and some authors have suggested that improvement in pain sensitivity may only occur following prolonged abstinence from opioids.^10,17 This review highlights the lack of data on hyperalgesia in abstinent patients with OUD history. Consequently, the current evidence for either persistent hyperalgesia or reversal of hyperalgesia in these patients also remains inconclusive.

While the opioid antagonist naltrexone promotes abstinence from illicit opioids through pharmacological blockade of mu-opioid receptors,¹⁸ it could potentially also induce hyperalgesia by interfering with endogenous opioid pain regulation. Yet the limited data currently available indicate lower rather than higher cold pain sensitivity in patients receiving naltrexone for OUD compared with healthy controls. This finding is consistent with data on long-term treatment with naltrexone showing minimal pain-related side effects in patients with alcohol use disorder⁶⁹ and no increase in pain ratings in patients with OUD.²² Together, these results suggest that the high level of chronic pain observed in patients maintained with naltrexone for OUD^21,22 may be related to factors other than hyperalgesia induced by mu-opioid receptor blockade.

Limitations

This review is not without limitations. Because most of the reviewed studies were cross-sectional, it is unclear whether hyperalgesia in patients undergoing opioid agonist treatment for OUD developed prior to, independent of, or as a result of long-term treatment with opioid agonists. Longitudinal studies would provide valuable insights into the potential fluctuations in pain sensitivity as patients go through alternating periods of treatment, abstinence, and illicit opioid use.

We conducted meta-regressions primarily to address whether cold pain sensitivity in patients with history of OUD is associated with opioid use. Other opioid-related (eg, OUD onset and severity, or preferred opioid and administration route) and non–opioid-related patient characteristics (eg, lifestyle, motivation, mental health, or concurrent nonopioid drug and medication use) were seldom reported in sufficient detail and therefore not amenable to meta-regression. These factors should be considered in future studies given the current inconclusive evidence for the hyperalgesia being opioid related.

The analyses presented here were not adjusted for water temperature. While water temperature can influence CPT pain responses,⁷⁰ most of the included studies kept the water temperature close to 1 °C, and meta-regressions did not indicate significant correlations with cold pain sensitivity (eTable 12 in Supplement 1).

Here, we focused exclusively on studies using the CPT for pain induction. Studies assessing responses to electrical, heat, pressure, and ischemic pain in patients receiving opioid agonist treatment for OUD generally find no significant differences in pain threshold or tolerance from healthy controls^{37,38,39,48,49,71,72} (though there are exceptions^39,73). The strong hyperalgesia consistently observed for cold noxious stimuli among these patients may therefore not generalize to other experimental pain modalities.^1,13 It is not evident from the current literature if heightened sensitivity to experimental pain in patients with history of OUD generalizes to experiences of short-term pain outside of the laboratory. As such, we do not currently know if and how this hyperalgesia impacts patients’ health, well-being, and functioning in everyday life.

Conclusions

Pharmacological treatments for OUD represent an important means of personal harm reduction. OUD is a chronic relapsing condition, and return to illicit opioid use confers risk of major negative health outcomes, including contraction of blood-borne viruses (eg, HIV and hepatitis C virus) and overdose.⁵ The risk of accidental and fatal overdose is further exacerbated by the recent surge in highly potent synthetic opioids like fentanyl on the illegal market.^5,74,75 To ensure health and safety among patients with OUD, it is therefore crucial to promote treatment retention and continued abstinence. Stress is known to trigger relapse,²³ and with pain being a potent source of stress that illicit opioids can provide relief from, hyperalgesia presents as a key factor potentially increasing patients’ risk of relapsing to problematic opioid use. The current literature indicates heightened cold pain sensitivity in patients receiving opioid agonist treatment for OUD, but we find inconclusive evidence for associations between this hyperalgesia and opioid use. Future studies should investigate the predictive value of hyperalgesia for important patient outcomes, including abstinence and treatment retention, well-being (ie, depression, anxiety, and pain), and social functioning.⁷⁶ If hyperalgesia increases risk of negative outcomes, further investigations into its underlying causes may prove key to developing effective preventions and interventions for OUD.

Supplement 1.

eMethods

eTable 1. Overview of extracted and harmonized data variables

eTable 2. Overview of included studies

eTable 3. Average Cold Pressor Test pain sensitivity in patients with history of OUD and healthy controls obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eTable 4. Mean difference in Cold Pressor Test pain sensitivity between patients with history of OUD and healthy controls obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eFigure 1. Orchard plots of cold pain sensitivity

eFigure 2. Orchard plots of percentage differences in cold pain sensitivity

eFigure 3. Orchard plots of standardized differences in cold pain sensitivity

eTable 5. Average Cold Pressor Test pain sensitivity in patients receiving opioid agonist treatment for OUD with methadone and buprenorphine obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eTable 6. Mean difference in Cold Pressor Test pain sensitivity between patients receiving opioid agonist treatment for OUD with methadone and buprenorphine and healthy controls obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eTable 7. Average Cold Pressor Test pain sensitivity in patients with OUD history after recent and prolonged abstinence obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eTable 8. Mean difference in Cold Pressor Test pain sensitivity between patients with OUD history after recent and prolonged abstinence and healthy controls or patients receiving opioid agonist treatment for OUD obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eTable 9. Associations between Cold Pressor Test pain sensitivity and factors related to opioid use and chronic pain in patients with history of OUD obtained with (multilevel) random-effects meta-regression with robust variance estimation

eTable 10. Associations between Cold Pressor Test pain sensitivity and factors related to opioid use and chronic pain in patients receiving opioid agonist treatment for OUD with methadone and buprenorphine obtained with (multilevel) random-effects meta-regression with robust variance estimation

eFigure 4. Traffic light plot of individual study quality

eFigure 5. Funnel plots of differences in cold pain sensitivity

eTable 11. Egger’s regression test of mean differences in Cold Pressor Test pain sensitivity between patients with history of OUD and healthy controls

eTable 12. Associations between Cold Pressor Test pain sensitivity and water temperature in patients with history of OUD and healthy controls obtained with (multilevel) random-effects meta-regression with robust variance estimation

eReferences

jamapsychiatry-e242176-s001.pdf^{(775.9KB, pdf)}

Supplement 2.

Data sharing statement

jamapsychiatry-e242176-s002.pdf^{(17.2KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods

eTable 1. Overview of extracted and harmonized data variables

eTable 2. Overview of included studies

eTable 3. Average Cold Pressor Test pain sensitivity in patients with history of OUD and healthy controls obtained with (multilevel) random-effects meta-analysis with robust variance estimation

eFigure 1. Orchard plots of cold pain sensitivity

eFigure 2. Orchard plots of percentage differences in cold pain sensitivity

eFigure 3. Orchard plots of standardized differences in cold pain sensitivity

eFigure 4. Traffic light plot of individual study quality

eFigure 5. Funnel plots of differences in cold pain sensitivity

eTable 11. Egger’s regression test of mean differences in Cold Pressor Test pain sensitivity between patients with history of OUD and healthy controls

eReferences

jamapsychiatry-e242176-s001.pdf^{(775.9KB, pdf)}

Supplement 2.

Data sharing statement

jamapsychiatry-e242176-s002.pdf^{(17.2KB, pdf)}

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PERMALINK

Hyperalgesia in Patients With a History of Opioid Use Disorder

Martin Trøstheim, MS

Marie Eikemo, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusion and Relevance

Introduction

Methods

Study Identification

Data Extraction

Statistical Analysis

Primary Analyses

Secondary Analyses

Risk-of-Bias Assessment

Results

Table. Sample Characteristicsa.

Primary Analysis

Figure 1. Orchard Plots of Differences in Cold Pain Sensitivity.

Figure 2. Forest Plots of Differences in Cold Pain Sensitivity.

Secondary Analyses

Figure 3. Associations Between Cold Pain Sensitivity and Opioid Use and Chronic Pain.

Bias Assessments

Figure 4. Risk-of-Bias Summary Plot.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Table. Sample Characteristics^a.