Preclinical, epidemiological, and clinical studies converge upon psychosocial stress as a key risk factor for opioid misuse. Opioids are nevertheless frequently administered under conditions of stress, such as trauma or surgery. Here, we tested the hypothesis that acute psychosocial stress would increase opioid self-administration in healthy men and women with limited prior opioid exposure. In this triple-blind, block-randomized, placebo- and state-induction controlled, four-way crossover trial, social stress or a neutral control state was induced in a laboratory setting (2021-2022) prior to administration of a sampling dose of oxycodone (3mg/70kg iv) or saline. The primary outcomes were amount of oxycodone self-administered in an effortful task and self-reported drug desire (stress versus control). Changes in mood ratings, heart rate, and cortisol were also determined. Of 85 randomized participants (N=20-22 to each of four sequences), data from 66 participants comprising 257 sessions were eligible for analysis. Oxycodone induced a drug high but did not improve mood ratings or relieve stress compared to placebo. Expected opioid side effects were reported but no serious adverse events occurred. Hierarchical ordinal Bayesian regression models showed that stress credibly increased oxycodone self-administration by 6 percentage points (95% CrI [1, 10], Pr > 0.99). Moreover, a robust sex difference (19 percentage points, 95% CrI [10, 28] Pr >0.99) reflected that this effect was driven by male participants. Stress-enhanced opioid self-administration was not observed in the women tested here, nor linked to positive drug effects or stress relief in men or women. The results are consistent with heightened risk for persistent opioid use after exposure to opioid analgesics during high psychosocial stress burden.

Preclinical, epidemiological and clinical studies converge upon psychosocial stress as a key risk factor for opioid misuse. Opioids are nevertheless frequently administered under conditions of stress, such as trauma or surgery. Here we tested the hypothesis that acute psychosocial stress would increase opioid self-administration in healthy men and women with limited prior opioid exposure. In this triple-blind, block-randomized, placebo- and state-induction controlled, four-way crossover trial, social stress or a neutral control state was induced in a laboratory setting (2021–2022) before administration of a sampling dose of oxycodone (3 mg 70 kg−1 intravenous) or saline. The primary outcomes were amount of oxycodone self-administered in an effortful task and self-reported drug desire (stress versus control). Changes in mood ratings, heart rate and cortisol were also determined. Of 85 randomized participants (N = 20–22 to each of four sequences), data from 66 participants comprising 257 sessions were eligible for analysis. Oxycodone induced a drug high but did not improve mood ratings or relieve stress compared with placebo. Expected opioid side effects were reported, but no serious adverse events occurred. Hierarchical ordinal Bayesian regression models showed that stress credibly increased oxycodone self-administration by 6 percentage points (95% credible interval 1 to 10, posterior probability >0.99). Moreover, a robust sex difference (19 percentage points, 95% credible interval 10 to 28, posterior probability >0.99) reflected that this effect was driven by male participants. Stress-enhanced opioid self-administration was not observed in the women tested here nor linked to positive drug effects or stress relief in men or women. The results are consistent with heightened risk for persistent opioid use after exposure to opioid analgesics during high psychosocial stress burden. ClinicalTrials.gov registration: NCT06485817 . Funded by the European Research Council (grant no. 802885) and the Swedish Research Council (grant no. 2013-07434). In this triple-blind, randomized, placebo-controlled crossover trial, Eikemo et al. tested whether acute psychosocial stress increases opioid self-administration using controlled stress induction, oxycodone exposure, and behavioral and physiological measures.

Background. Disrupted reward processing is a core component in neurobiological theories of addictions, including opioid use disorder (OUD). While acute opioid agonist and antagonist administration can modulate reward behavior and experiences, it remains unclear how typical long-term OUD treatment with these medications impact patients’ sensitivity to substance-free rewards. We therefore conducted a cross-sectional study of reward sensitivity in opioid agonist- and antagonist-treated OUD patients, and healthy volunteers.Methods. Ninety-six OUD patients on extended-release naltrexone (n=45) or opioid agonists (n=51) and 50 healthy volunteers completed a probabilistic reward task (PRT) and self-report measures of anhedonia, depression, preoccupation with immediate consequences, substance craving and life satisfaction in a single session. We used signal detection analysis and drift diffusion modeling to derive behavioral reward bias measures from PRT performance. Group differences were modeled with beta and linear regression.Results. Patients reported significantly greater anhedonia (Cohen’s ds≥0.64), depression (ds≥0.53) and preoccupation with immediate consequences (ds≥0.54) than heathy volunteers, but differences between naltrexone- and opioid agonist-treated patients were non-significant (ds≤0.26). Group differences in behavioral reward bias were small and non-significant (ps=1, BF01s≥84.13). Anhedonia was significantly associated with lower life satisfaction (OR [95% CI]=1.10 [1.04, 1.17]). There were no other significant associations between reward sensitivity measures and life satisfaction or craving (ps≥0.31, BF01s≥2.58).Conclusion. These data support an association between OUD and reduced well-being irrespective of opioid agonist or antagonist treatment, highlighting patients’ need for psychosocial support and/or adjunct interventions. Major detrimental effects of naltrexone treatment on well-being seem unlikely from these and previous results.

Importance: Endogenous opioids are widely regarded as the body’s natural painkillers, lending credibility to the status of opioid medications as the gold-standard analgesics. When and how much endogenous opioids down-regulate pain in humans remains unclear, however. Objective: To determine whether and under which conditions pharmacological opioid receptor blockade is associated with increased pain responses in healthy volunteers.Data Sources: We searched Web of Science, Scopus, PubMed and EMBASE between October 7, 2020 and June 10, 2025. Study selection: Double-blind, randomized, and placebo-controlled studies that used peripheral pain interventions and administered a centrally active opioid antagonist were included. Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 5 reviewers. Individual study quality was rated on the Jadad scale, while Egger’s test and funnel plots were used to evaluate reporting bias. Three-level random-effects meta-regressions were used to estimate pain perception during mu-opioid blockade compared to placebo. The reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIS-MA) guidelines.Main Outcomes and Measures: The primary outcomes were estimated standardized mean difference (Hedges’ g) in pain intensity, tolerance, unpleasantness and threshold between antagonist and placebo. In secondary analyses, to determine under which conditions pain would be higher during mu-opioid blockade, we assessed the potential moderating role of study characteristics including pain modality, location, duration, non-drug interventions, and sample sex distributions.Results: A total of 67 studies were included (N=2706). Across the four pain outcomes, pain was slightly higher during mu-opioid antagonism compared to placebo (Hedges’ g [95% CI]=0.18 [0.11, 0.25]), approximately 2.8 points on a 0-100 pain intensity scale. Due to indications of re-porting bias, the effect size was suggested to be slightly overestimated. There was substantial residual heterogeneity (I2=66%), but study characteristics explained little or none of this variance. The most credible evidence of endogenous opioid pain regulation was found for placebo hypoalgesia. Conclusion and Relevance: Overall, the slightly higher pain sensitivity during experimental pain in healthy humans during opioid blockade indicates a minor role of endogenous opioids in human pain regulation.

Men are disproportionately likely to develop opioid use disorder, yet the mechanisms of addiction risk in men and women remain poorly understood. Preclinical, epidemiological and clinical studies converge upon stress as a key risk factor. To determine the mechanisms through which stress alters abuse liability, we measured opioid self-administration after acute stress induction in healthy men and women. Sixty-three healthy participants (31 men) completed four sessions in this repeated-measures, double-blind placebo-controlled randomized study. Social stress or a neutral control state was induced before injection of oxycodone (3.1mg/70kg) or saline. The primary outcome was amount of additional oxycodone obtained in an effortful self-administration task (0-125% of the sampling dose effect). The resulting dose was administered ~40 minutes later. Subjective, autonomic and endocrine responses were collected throughout sessions. Data were analyzed using Hierarchical Bayesian regressions. Pre-exposure to stress increased oxycodone self-administration by 5 percentage points (95% credible interval, 1 to 10, Posterior probability (Pr) > 0.99), but with a robust sex difference (16 percentage points; 95% credible interval, 7 to 24; Pr > 0.99). Stress induction only increased self-administration in men, although women showed higher stress responses. In both sexes, oxycodone induced drug high but did not improve mood or cause clear stress relief. We found no evidence that stress-enhanced drug wanting was related to stress relief or drug liking in men or women. By demonstrating a robust sex difference in stress-enhanced opioid self-administration, the study unveils a putative mechanism for men’s higher vulnerability to opioid addiction.

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 (%Delta) 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; %Delta, -22%; g = -0.5) and 29-seconds lower pain tolerance (95% CI, -39 to -18; t test P < .001; %Delta, -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.

Loneliness heightens the risk of substance use disorder, and a desire to escape this negative feeling motivates drug use. Opioid drugs in particular are believed to target neurobiological circuits involved in social bonding, increasing vulnerability to opioid addiction when social connectedness is lacking. In this narrative review, we consider how current understanding of μ opioid modulation of reward and threat processing across domains sheds light on the mechanisms that link loneliness and substance use. We discuss evidence for state- and context-dependent μ opioid modulation of social affect and behaviors, which appears to promote prioritization of high-value reward options also in the context of threat. Tying this literature to the model of social homeostasis, we argue for a role of μ opioids in regulating social homeostasis across species. Finally, we explore how disruption of social homeostasis in chronic opioid use contributes to continued drug use. We highlight how increasing patients' psychosocial resources and opportunities for social bonding can improve recovery from drug addiction. Throughout, we consider the translational robustness and generalizability of the nonhuman animal evidence in light of existing human research.

IntroductionOpioid analgesic treatment during surgery entails the risk of persistent use. Experiences of childhood adversity have been shown to increase opioid reward in preclinical models, a finding recently extended to healthy humans. We tested whether childhood adversity similarly increased opioid reward, operationalized as drug-induced feeling good and drug liking, in outpatients receiving opioids on the operating table.MethodsThis observational study recruited patients entering a Norwegian hospital for an outpatient surgical procedure. An opioid intravenous opioid analgesic (remifentanil [Minto model, effect-site concentration: 5 ng/ml], or oxycodone [5 mg]) was administered in the minutes before general anesthesia. Verbal numerical ratings of feeling good and anxious were collected 1 min before, and 1-3 min after opioid infusion. Ratings of drug liking, disliking, and feeling high were also collected after infusion. Patients (n = 151) completed measures of childhood adversity at a later date.ResultsRegression analyses revealed a modest yet significant negative association between childhood adversity and post-opioid liking (b = -0.06, p = 0.046) but no significant effect on feeling good (b = 0.01, p = 0.690) after the pre-operative opioid dose. Exploratory analyses showed that more childhood adversity was significantly associated with higher reports of anxiety, depression, loneliness, and pain catastrophising, however not with alcohol or other drug use, or with any other subjective drug effects.DiscussionRatings of feeling good and drug liking of medically prescribed opioids given before surgery were not higher after childhood adversity, and previous findings were not conceptually replicated. The discrepancy between current and prior results may be due to the context and stress related to the impending surgery, the short duration of drug exposure, and the relatively limited levels of high childhood adversity in the current sample compared to the original study. Exploratory analysis was consistent with the possibility of a nonlinear relationship between positive opioid effects and childhood adversity scores. Future research should assess the link between childhood adversity, subjective effects, and use of the prescribed opioids after surgery.

ImportanceShort-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.ObjectiveTo critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use.Data SourcesWeb of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched.Study SelectionStudies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included.Data Extraction and SynthesisMultilevel 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 MeasuresMain 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.ResultsThirty-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 RelevancePatients 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.

BackgroundOpioid exposure after surgery increases risk of persistent opioid use. Here, we characterize at-home use of opioid rescue medication during 1–2 days after outpatient surgery (N=270) in a postoperative opioid-sparing context at a Norwegian hospital.MethodsThe postsurgical pain management plan included non-steroidal anti-inflammatory drugs and up to six pills of 5 mg oxycodone as rescue analgesics. In this observational study we assessed risk factors for taking rescue opioids after surgery, by comparing patients who did, with those who did not.ResultsOnly 35% (N=228) of patients reported taking rescue opioids 1–2 days after discharge. Patients taking rescue opioids after surgery (opioid-takers) differed from non-takers by prevalence of preoperative chronic pain (>3 months; 74% vs 48%), higher pain severity and interference before and after surgery, reporting lower ability to cope with postsurgical pain, higher nervousness about the surgery, being younger, and having received more opioid analgesics in the recovery room. Exploratory predictive modeling identified opioid administration in the recovery room as the most important predictor of at-home rescue medication use. Follow-up after >4 months indicated low acute pain levels (mean±SD = 1.1±1.8), with only four patients (2%, N=217) reporting opioid analgesic use.ConclusionFactors related to at-home rescue medication use closely mirrored known risk factors for persistent opioid use after surgery, such as prior chronic pain, prior substance use, affective disturbances, and pain severity before surgery. These findings are potential targets in patient-centered care. Nevertheless, and reassuringly, findings are consistent with the idea that opioid-sparing postsurgical care can prevent large-scale chronic opioid use.

Dr. Kelly Dunn and colleagues have published an intriguing exploration of heterogeneity and individual differences in the affective and side effects of opioids.1 Their analysis is based on a rich psychopharmacological dataset in which 100 healthy volunteers received four doses of hydromorphone and placebo over five test days. It is vital and urgent that we understand how these pain management medications affect individuals to identify risks. The debate on how opioids affect the experience of pleasure and pain has roots at least as far back as 1925, when Lorenz Kolb shared his observation that opioids rarely caused pleasure (as opposed to relief) in 'any one except the emotionally unstable, the psychopath or the neurotic' (p. 699).2 After the development of randomized controlled trials, a seminal 1955 study measured the effects of double-blinded doses of morphine and heroin, among other drug classes, in 20 healthy male college students. The average response to opioids was not pleasure, but dysphoria.3 This early conclusion was not supported in a more nuanced investigation, however. Based on qualitative interviews with heroin-addicted individuals, observations of college students trying heroin for the first time, and a reanalysis of the 1955 RCT data, MacAuliffe4 argued that a significant minority of participants did report positive effects from opioids. He also provided evidence that negative initial responses to heroin were frequent in addicted populations, but that social support within groups of addicted individuals promoted perseverance (through several injections of heroin) until the opioid's desirable effects outweighed the initial nausea and vomiting it caused. In the recent paper, Dunn and colleagues draw inspiration from the alcohol literature, where people with minimal responses to early drinking have been reported to have a higher risk of developing problematic alcohol use. They also draw on findings related to variation in the mu-opioid receptor gene, specifically the A118G polymorphism. Despite initial high expectations and early evidence linking the polymorphism to differential alcohol and nicotine responses,5 relatively few studies have examined the impact of A118G on acute opioid effects.6 The scarce evidence likely relates to increasing recognition that the explanatory value of individual genetic polymorphisms is typically insufficient for an average-sized drug study. Inspired by Dunn et al.'s findings, we briefly revisited our own unpublished drug effects data relating to this polymorphism. In an early study on how opioids affect reward behaviours, we selected a high proportion of G allele carriers of this specific polymorphism.7, 8 A total of 49 healthy young men (27 AA and 22 G carriers) attended three sessions, where they received either 50 mg of the non-selective opioid antagonist naltrexone, an inert placebo or a morphine pill. Our morphine dose of 10 mg is an analgesic dose, comparable to the 2 and 4 mg doses of hydromorphone used in Dr. Dunn's study. Consistent with Dunn et al.'s findings of higher stimulating and pleasant drug effects in G-carriers compared with AA-carrying participants, our group of G-carriers showed the highest morphine liking ratings (Figure 1A). Drug liking was significantly higher for morphine compared with placebo in G-carriers. In contrast, the AA group's average ratings were comparable between drugs. Unsurprisingly, given our limited number of participants for a candidate gene analysis, the interaction between genotype and drug type was not significant, nor did we find other convincing evidence linking the A116G polymorphism to addiction-relevant measures in our dataset. Exploration of genotype effects on other pleasure-related ratings revealed significant group * drug interactions that we show here for potential hypothesis generation: morphine-enhanced ratings of predicted pleasure for non-social rewards in AA carriers and for social rewards in G carriers (see Figure 1B,C). To measure drug effects on levels of predicted pleasure, we created a state visual analogue scale (VAS 0–100) version7 of the Snaith–Hamilton Pleasure Scale and analysed changes from pre-drug baseline. The planned examination of the polymorphism-by-medication interaction onresponses to different reward modalities was eventually halted by our lab due to the realization that either very large samples or very precise measures of high relevance to the polymorphism in question are necessary to gain robust and reproducible findings. We were therefore excited and encouraged by Dr. Dunn et al.'s rationale and findings and would like to take this opportunity to issue a call to the larger field: let us pool our resources and datasets! As a start, we have made the data reported here openly available (osf.io/ny3jw/). Understanding how opioids affect individuals, both acutely and over time, is key to both pain management (a high proportion of patients terminate treatment after mere days due to intolerable side effects) and to understand the contexts and individual factors associated with opioids' abuse potential. In addition to the rich, detailed and precise measurements routinely collected in the handful of outstanding psychopharmacology laboratories, such as those of Dr. Dunn, Dr. Harriet De Wit and Dr. Sandra Comer, relevant opioid effects data are available from studies by several medical specialities.9 Opioids remain vital to the management of acute, and for many, also chronic pain. It is high time that the opioid field take a leaf from the book of fields where researchers have harmonized data into large-scale databases. In addition to genetics, which has moved from candidate gene approaches to samples reaching hundreds of thousands, we can also look to neuroimaging and experimental psychology approaches such as the Consortium of Placebo Effects.10 Many important new insights were gained from this consortium due to the pooling of rich datasets into a database of individual brain and behavioural responses to placebo treatments for pain. A database resource on individual responses to opioids would ensure sufficient statistical power to both explore and replicate findings on how these vital medications act in different individuals and at different times. Dr. Kelly Dunn and colleagues have made an impressive start to the important emerging field of individual differences in opioid effects. The original study was supported by the Research Council of Norway; the authors are currently supported by the European Research Council (grant agreement no. 802885). The authors report no conflicts of interest. The data that support the findings of this study are openly available in OSF at https://osf.io/ny3jw/.

Exposure to opioid analgesics due to surgery increases the risk of new persistent opioid use. A mechanistic hypothesis for opioids' abuse liability rests on the belief that, in addition to pain relief, acute opioid treatment improves well-being (e.g. via euphoria) and relieves anxiety. However, opioids do not consistently improve mood in laboratory studies of healthy non-opioid users. This observational study determined how two commonly used opioid analgesics affected patients' subjective well-being in standard clinical practice. Day surgery patients rated how good and how anxious they felt before and after an open-label infusion of remifentanil (n = 159) or oxycodone (n = 110) in the operating theatre before general anaesthesia. One minute after drug injection, patients reported feeling intoxicated (> 6/10 points). Anxiety was reduced after opioids, but this anxiolytic effect was modest (remifentanil Cohen's d = 0.21; oxycodone d = 0.31). There was moderate to strong evidence against a concurrent improvement in well-being (Bayes factors > 6). After remifentanil, ratings of 'feeling good' were significantly reduced from pre-drug ratings (d = 0.28). After oxycodone, one in three participants felt better than pre-drug. Exploratory ordered logistic regressions revealed a link between previous opioid exposure and opioid effects on well-being, as only 14 of the 80 opioid-naïve patients reported feeling better after opioid injection. The odds of improved well-being ratings after opioids were higher in patients with previous opioid exposure and highest in patients with > 2 weeks previous opioid use (adjusted OR = 4.4). These data suggest that opioid-induced improvement of well-being is infrequent in opioid-naïve patients. We speculate that peri-operative exposure could increase risk of persistent use by rendering subsequent positive opioid effects on well-being more likely.

In non-human animals, attachment processes1,2 and social distress relief1 rely on opioid signalling. In this planned study, we will test the assumption that social support relies on opioid mechanisms to produce relief and buffer effects of stress in humans.

Exposure to opioid analgesics due to surgery increases the risk of new persistent opioid use. A mechanistic hypothesis for opioids’ abuse liability rests on the belief that in addition to pain relief, acute opioid treatment improves mood, e.g. via euphoria and anxiety relief. However, opioids do not consistently improve mood in laboratory studies of healthy non-opioid users. Here, we determined how two commonly used opioid analgesics affected patients’ subjective well-being in standard clinical practice. Day surgery patients rated their mood before and after open-label infusion of remifentanil (N=159) or oxycodone (N=110) on the operating table before general anesthesia. One minute after drug injection, patients reported feeling intoxicated (>6/10 points). As hypothesized, anxiety was reduced after opioids; this anxiolytic effect was however modest (remifentanil Cohen’s d=0.21; oxycodone d=0.31). Unexpectedly, we found moderate to strong evidence against a concurrent improvement in positive affect (Bayes Factors >6.5). After remifentanil, ratings of ‘feeling good’ were even significantly reduced from pre-drug ratings (d=0.28). After oxycodone, only 1 in 3 participants felt better than pre-drug. Ordered logistic regressions revealed a link between prior drug exposure and opioid mood effects: while opioid-naïve patients were unlikely to feel better (21%) after opioids, the odds were >4 times higher given a history of prolonged opioid use (>2 weeks, adjusted OR=4.4). In sum, these ecologically valid data suggest that mood improvement by opioids in opioid-naïve patients is infrequent. Nevertheless, perioperative exposure could mechanistically increase risk of persistent use by elevating the likelihood of positive mood improvement during post-operative opioid treatment.

How does social support bolster resilience? Here, we present a new dyadic paradigm to study causal mechanisms of acute and ecologically valid social support in the laboratory. The Dyadic Stress and Support Task (DSST) consists of a psychosocial stress phase and a recovery phase. During DSST stress, a pair of participants take turns to perform public speaking and mental arithmetic in front of a panel. Unable to see or touch each other, they witness each other’s performance and feedback. During DSST recovery, the pair either interact freely with each other for 5 minutes (social support condition) or interact separately with an experimenter (non-support condition). To establish the validity of the DSST, we tested 21 pairs of long-term close friends in a pilot study. Primary outcome measures were ratings of affective state and bodily arousal (VAS scales 0-100). Secondary outcome measures were heart rate and salivary cortisol. DSST stress successfully induced subjective Stress Activation, increased Negative Affect and decreased Positive Affect. We also observed increased heart rate and salivary cortisol. After DSST recovery, Stress Activation and Negative Affect ratings were reduced in both groups. Positive Affect was completely restored to pre-stress baseline levels in the Social support group, while remaining significantly lower in the Non-support group. The DSST successfully induced stress and negative affect and captured stress recovery in both groups. Free-form interaction with the friend enhanced recovery of affective state, supporting the validity of spontaneous interaction between friends as a model of social support.

Non-human animal studies outline precise mechanisms of central mu-opioid regulation of pain, stress, affiliation and reward processing. In humans, pharmacological blockade with non-selective opioid antagonists such as naloxone and naltrexone is typically used to assess involvement of the mu-opioid system in such processing. However, robust estimates of the opioid receptor blockade achieved by opioid antagonists are missing. Dose and timing schedules are highly variable and often based on single studies. Here, we provide a detailed analysis of central opioid receptor blockade after opioid antagonism based on existing positron emission tomography data. We also create models for estimating opioid receptor blockade with intravenous naloxone and oral naltrexone. We find that common doses of intravenous naloxone (0.10–0.15 mg/kg) and oral naltrexone (50 mg) are more than sufficient to produce full blockade of central MOR (>90% receptor occupancy) for the duration of a typical experimental session (~60 min), presumably due to initial super saturation of receptors. Simulations indicate that these doses also produce high KOR blockade (78–100%) and some DOR blockade (10% with naltrexone and 48–74% with naloxone). Lower doses (e.g., 0.01 mg/kg intravenous naloxone) are estimated to produce less DOR and KOR blockade while still achieving a high level of MOR blockade for ~30 min. The models and simulations form the basis of two novel web applications for detailed planning and evaluation of experiments with opioid antagonists. These tools and recommendations enable selection of appropriate antagonists, doses and assessment time points, and determination of the achieved receptor blockade in previous studies.

Opioid exposure after surgery increases risk of persistent opioid use. Here, we characterize at-home use of opioid rescue medication during acute recovery after day surgery (N=270) in an opioid sparing context. The post-surgical pain management plan included non-steroidal anti-inflammatory drugs and up to 6 pills of 5mg oxycodone to be taken as needed. Thirty-two percent of patients reported having taken at least one dose of opioid analgesic 1-2 days after discharge. Opioid-takers differed from non-takers by prevalence of chronic pain (&gt;3 months; 74% versus 48%), significantly higher pain and pain interference levels before and after surgery, received more opioid analgesics in the recovery room, and younger age. Logistic regressions confirmed a predictive role of these measures for rescue opioid medication use during acute recovery. Opioid-takers also had lower self-reported ability to cope with pain during acute recovery, and higher worry before surgery, but did not differ significantly on prior opioid or tobacco use. Long-term follow-up (4-30 months) data included self-reported opioid use, pain catastrophising and overall substance use from 143 patients (53%); no additional differences were identified from these materials. Acute pain levels were low at long term follow-up and only four patients (2%) reported using opioid analgesics. In conclusion, pre-operative chronic and acute pain, younger age and self-reported difficulty in coping with pain during recovery emerge as valuable predictors of opioid self-administration in the acute recovery phase and could be targets in patient centred care.

Opioids are thought to be so addictive because they make people feel great, either by inducing euphoria or by relieving stress and anxiety. The endogenous opioid system is believed to similarly improve mood in the healthy human brain. Our data suggest that positive opioid effects on mood are rare in non-opioid users. Probing subjective report data from 172 healthy non-opioid users from two placebo-controlled experiments with per-oral opioids(1,2) and one open-label study with intravenous opioid effects pre-surgery, we observe variability in the subjective responses and no overall improvement of mood in individuals without a history of opioid misuse.

In the wake of the “opioid epidemic”, there is considerable concern regarding potential harmful long-term effects of prenatal opioid exposure. Opioid misuse and addiction confer increased exposure to lifestyle stressors and health burdens. Accordingly, it is challenging to disentangle effects of prenatal opioid exposure per se from factors related to maternal stress. In this study, we followed 36 women enrolled in comprehensive opioid maintenance treatment (OMT) program and their children alongside 36 age-matched mother-child dyads from a community sample (COMP) from pregnancy until child-age 8 years. Across five sessions, we used a battery of well-established questionnaires to investigate trajectories of parenting stress and mental health symptoms as well as child behavior problems. The 8-year retention was relatively high (OMT: 72%, COMP: 67%), and the OMT sample remarkably stable and well-functioning, with minimal concomitant illicit drug use. Mixed effects regressions showed significantly different trajectories of child behavior problems (F = 3.8, p = 0.024) and parenting stress (F = 3.1, p = 0.016) in the two groups. Differences in experienced stress were largely explained by more distress specifically related to the parenting role in the OMT group (F = 9.7, p = 0.003). The OMT sample also reported higher psychological distress (F = 15.6, p < 0.001) than the comparison group, but notably few participants presented with problems that warranted clinical intervention. The results underscore the benefits of tailored follow-up of children prenatally exposed to opioids and their families beyond infancy and toddlerhood. Long-term direct effects of prenatal opioid exposure on behavior problems are likely modest, given an otherwise stable caregiving environment conducive to healthy development.