Periodic Reporting for period 4 - OPIOIDREWARD (How distress alters opioid drug effects and abuse liability)
Reporting period: 2024-01-01 to 2025-11-30
Summary of the context and overall objectives of the project
Why are opioids so addictive? Non-human animal research links addiction with the powerful relief opioids can offer to animals in distress. In humans, epidemiological and clinical studies converge upon social stressors and a poor social support network as key risk factors for addiction. We asked how pre-drug distress might alter opioid drug effects. Tremendous resources are dedicated to charting how people feel after taking a drug, sidestepping the potentially profound influence of how people feel before they take the drug. Using acute social stress induction before iv opioid administration in healthy humans, we created a human model to determine the mechanisms through which social stressors increase opioids’ abuse liability.
First, we tested the hypothesis that pre-drug distress enhances drug wanting (self-administration) but not drug liking (self-report) compared to drug effects in a control condition. Second, we used opioid blockade to probe the hypothesis that opioid drugs ‘hijack’ brain mechanisms underpinning social support. Third, we tested the link between pre-drug distress and drug self-administration in a real-world clinical setting.
The key results confirmed a link between acute psychosocial stress and drug self-administration that was not mediated by drug liking. Drug liking and positive effects are also less frequent than broadly expected, as indicated by measures of presurgical opioid effects. Moreover, blocking endogenous opioids with an antagonist revealed intact benefits from social support during and after exposure to a stress task and horror film viewing, indicating opioid-independent pathways of social support. The project has generated key insights about endogenous and exogenous drug mechanisms in humans that challenge core assumptions in the fields of pain medicine and addiction, and public health.
First, we tested the hypothesis that pre-drug distress enhances drug wanting (self-administration) but not drug liking (self-report) compared to drug effects in a control condition. Second, we used opioid blockade to probe the hypothesis that opioid drugs ‘hijack’ brain mechanisms underpinning social support. Third, we tested the link between pre-drug distress and drug self-administration in a real-world clinical setting.
The key results confirmed a link between acute psychosocial stress and drug self-administration that was not mediated by drug liking. Drug liking and positive effects are also less frequent than broadly expected, as indicated by measures of presurgical opioid effects. Moreover, blocking endogenous opioids with an antagonist revealed intact benefits from social support during and after exposure to a stress task and horror film viewing, indicating opioid-independent pathways of social support. The project has generated key insights about endogenous and exogenous drug mechanisms in humans that challenge core assumptions in the fields of pain medicine and addiction, and public health.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We established two novel stress induction paradigms optimised for testing key hypotheses that were combined with opioid agonist and antagonist administration.
Does psychosocial stress increase motivation to take opioids?
To test this hypothesis, we developed an hybrid stress induction with the participant present in the lab, while the stress induction panel interacts with the participants on zoom. The hybrid solution had two major benefits: i) it was compatible with infection control restrictions due to COVID-19, and ii) it allowed for blinding (masking) of test personnel not only to the participant’s drug condition, but also to their stress condition (stress or no-stress control interaction), preventing any bias in the data related to experimenter expectation effects.
Moreover, we designed the setup to be suitable for repeated within-subjects stress induction.
We also designed improved control tasks for both stress inductions, including a (hybrid) social interaction in which participants complete colour and sound preference tasks (to match the job talk and singing task) as well as easy maths tasks to control for the mental arithmetic part of the stress inductions.
The stress and drug manipulations were successful as defined in the preregistered analysis plan (https://osf.io/v8dxy/(opens in new window)) and the main paper has been submitted for publication. In brief, the results confirm the hypothesis that pre-drug stress enhances opioids’ abuse liability. However, we find evidence of a strong interaction with participant sex, such that stress enhances opioid drug self-administration in male but not in female participants. This finding points to a putative stress-related mechanism that could help explain the overrepresentation of men in addiction.
Does stress enhance responses to clinical opioids?
In addition, our team gained the opportunity to test the same hypothesis in a real-world, clinical setting. Drawing on data from a quality control study of 259 day surgery patients treated at Kongsberg Hospital in Norway between 2018 and 2021, we quantified subjective responses to opioid treatment on the operating table in the minutes before anaesthesia. The minutes before surgery are associated with substantial stress, which varies naturally between individuals. After calculating the main group effect of each drug (high doses of iv. remifentanil and oxycodone), we were therefore able to analyse the relationship between pre-surgical negative affect and opioid responses. As reported in Eikemo et al, 2023, Anaesthesia, pre-surgical negative affect was (weakly) associated with a more positive response to the medications. We did not find that pre-surgical negative affect or a positive medication response significantly predicted postsurgical opioid use however, based on phone interview data from 1-2 days after surgery and long-term follow-up data (>4 months after surgery), as reported in Meier et al, 2023, Regional Anaesthesia and Pain Medicine). Finally, we probed the relationship between early life stress (measured using the Childhood Trauma Questionnaire) and medication responses, as reported in a registered report by Carlyle et al, 2023 (Peer Community In; Addiction Research and Theory). Following up on the inconclusive results from this analysis of surgery patients, we were also able to conduct a secondary analysis of data collected in a series of psychopharmacology studies in the lab of collaborator Harriet de Wit (Carlyle et al, 2024, J Psychopharm).
Do social support effects depend on endogenous opioid relief mechanisms?
We developed a novel, dyadic implementation of the TSST, the Dyadic Stress and Support Task (DSST; Løseth et al, 2022, PNEC). The DSST is optimised to measure the effects of social support on stress recovery, enabling us to determine the importance of endogenous opioids for support-induced stress relief. The DSST has two parts, stress induction and recovery. During stress induction, pairs of friends complete the TSST in parallel, separated by a physical barrier such that they can hear, but not see each other. During recovery, the two friends are left to talk freely with each other (social support condition).
Results (final N=258) clearly reveal opioid-independence of the positive effects of social support from a friend and challenge the long-standing Brain Opioid Theory of Social Attachment. This evidence that alternative pathways are likely available for social thriving is very good news for sufferers of addiction and persistent pain, whose endogenous opioid systems may be disrupted.
Of the initial results so far, the below publications can be highlighted:
1. The manuscript presenting the DSST, as described above (Løseth et al, 2022, Psychoneuroendocrinology).
2. Our team has also published several peer-reviewed comments and review articles on the topics studied in OPIOIDREWARD. In Leknes & Atlas, 2020, British Journal of Anaesthesia, we present a checklist for psychopharmacology studies, highlighting and explaining the importance of placebo control and double-blinding; counterbalancing of conditions; choice of drug, dose and administration method; construct validity; study population and generalisability; and reproducibility and reporting. Eikemo, Løseth and Leknes (2021, Pain) review effects of opioid antagonists and present a guide for how to interpret results of full and partial blockade of mu-opioid receptors. Meier, Eikemo and Leknes (2021, Current Addiction Reports) review the psychopharmacological evidence on opioid modulation of reward and threat using a translational perspective. In brief, we find that many results in the human literature point to a preserved function of the endogenous opioid system across rodents and humans, however effect sizes are typically smaller. We conclude that the human endogenous opioid system modulates human subjective experience and related responses in concert with other neurotransmitter systems.
3. Our primer on opioid antagonism to understand endogenous opioid function and two open-access web apps to facilitate study planning (planoxone and plantrexone): Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade (Trøstheim, M Eikemo, J Haaker, JJ Frost, S Leknes
Neuropsychopharmacology 48 (2), 299-307)
4. Three papers summarizing the link between pre-drug negative affect, positive medication responses and subsequent opioid self-administration in surgery patients (by Eikemo, Meier and Carlyle et al, details described above)
5. The main paper of the project has been preprinted and describes the test of the core hypothesis, namely that receiving opioids when in a stress state increases subsequent opioid self-administration (the gold-standard measure of drug abuse liability). Our results confirm the hypothesis, but the analysis clearly shows that the effect is driven by male participants (N=31) with no stress-enhanced opioid drug wanting in female participants (N=32). Eikemo et al, 2023: https://osf.io/preprints/v8dxy/(opens in new window)).
6. We have meta-analysed the literature to chart how opioid antagonism unveils endogenous opioid mechanisms, specifically for social connectedness (Løseth et al, 2024, Translational Psychiatry) and experimental pain (Meier et al, preprint, invited resubmission pending to Pain). Both publications indicate a significant effect of modest size, contrasting with current beliefs in the public and in science and medicine.
7. We have produced a narrative review of opioid mechanisms in relation to loneliness and addiction, highlighting potential shared pathways for social connection and drug use (Løseth et al, 2025, Biological Psychiatry)
Does psychosocial stress increase motivation to take opioids?
To test this hypothesis, we developed an hybrid stress induction with the participant present in the lab, while the stress induction panel interacts with the participants on zoom. The hybrid solution had two major benefits: i) it was compatible with infection control restrictions due to COVID-19, and ii) it allowed for blinding (masking) of test personnel not only to the participant’s drug condition, but also to their stress condition (stress or no-stress control interaction), preventing any bias in the data related to experimenter expectation effects.
Moreover, we designed the setup to be suitable for repeated within-subjects stress induction.
We also designed improved control tasks for both stress inductions, including a (hybrid) social interaction in which participants complete colour and sound preference tasks (to match the job talk and singing task) as well as easy maths tasks to control for the mental arithmetic part of the stress inductions.
The stress and drug manipulations were successful as defined in the preregistered analysis plan (https://osf.io/v8dxy/(opens in new window)) and the main paper has been submitted for publication. In brief, the results confirm the hypothesis that pre-drug stress enhances opioids’ abuse liability. However, we find evidence of a strong interaction with participant sex, such that stress enhances opioid drug self-administration in male but not in female participants. This finding points to a putative stress-related mechanism that could help explain the overrepresentation of men in addiction.
Does stress enhance responses to clinical opioids?
In addition, our team gained the opportunity to test the same hypothesis in a real-world, clinical setting. Drawing on data from a quality control study of 259 day surgery patients treated at Kongsberg Hospital in Norway between 2018 and 2021, we quantified subjective responses to opioid treatment on the operating table in the minutes before anaesthesia. The minutes before surgery are associated with substantial stress, which varies naturally between individuals. After calculating the main group effect of each drug (high doses of iv. remifentanil and oxycodone), we were therefore able to analyse the relationship between pre-surgical negative affect and opioid responses. As reported in Eikemo et al, 2023, Anaesthesia, pre-surgical negative affect was (weakly) associated with a more positive response to the medications. We did not find that pre-surgical negative affect or a positive medication response significantly predicted postsurgical opioid use however, based on phone interview data from 1-2 days after surgery and long-term follow-up data (>4 months after surgery), as reported in Meier et al, 2023, Regional Anaesthesia and Pain Medicine). Finally, we probed the relationship between early life stress (measured using the Childhood Trauma Questionnaire) and medication responses, as reported in a registered report by Carlyle et al, 2023 (Peer Community In; Addiction Research and Theory). Following up on the inconclusive results from this analysis of surgery patients, we were also able to conduct a secondary analysis of data collected in a series of psychopharmacology studies in the lab of collaborator Harriet de Wit (Carlyle et al, 2024, J Psychopharm).
Do social support effects depend on endogenous opioid relief mechanisms?
We developed a novel, dyadic implementation of the TSST, the Dyadic Stress and Support Task (DSST; Løseth et al, 2022, PNEC). The DSST is optimised to measure the effects of social support on stress recovery, enabling us to determine the importance of endogenous opioids for support-induced stress relief. The DSST has two parts, stress induction and recovery. During stress induction, pairs of friends complete the TSST in parallel, separated by a physical barrier such that they can hear, but not see each other. During recovery, the two friends are left to talk freely with each other (social support condition).
Results (final N=258) clearly reveal opioid-independence of the positive effects of social support from a friend and challenge the long-standing Brain Opioid Theory of Social Attachment. This evidence that alternative pathways are likely available for social thriving is very good news for sufferers of addiction and persistent pain, whose endogenous opioid systems may be disrupted.
Of the initial results so far, the below publications can be highlighted:
1. The manuscript presenting the DSST, as described above (Løseth et al, 2022, Psychoneuroendocrinology).
2. Our team has also published several peer-reviewed comments and review articles on the topics studied in OPIOIDREWARD. In Leknes & Atlas, 2020, British Journal of Anaesthesia, we present a checklist for psychopharmacology studies, highlighting and explaining the importance of placebo control and double-blinding; counterbalancing of conditions; choice of drug, dose and administration method; construct validity; study population and generalisability; and reproducibility and reporting. Eikemo, Løseth and Leknes (2021, Pain) review effects of opioid antagonists and present a guide for how to interpret results of full and partial blockade of mu-opioid receptors. Meier, Eikemo and Leknes (2021, Current Addiction Reports) review the psychopharmacological evidence on opioid modulation of reward and threat using a translational perspective. In brief, we find that many results in the human literature point to a preserved function of the endogenous opioid system across rodents and humans, however effect sizes are typically smaller. We conclude that the human endogenous opioid system modulates human subjective experience and related responses in concert with other neurotransmitter systems.
3. Our primer on opioid antagonism to understand endogenous opioid function and two open-access web apps to facilitate study planning (planoxone and plantrexone): Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade (Trøstheim, M Eikemo, J Haaker, JJ Frost, S Leknes
Neuropsychopharmacology 48 (2), 299-307)
4. Three papers summarizing the link between pre-drug negative affect, positive medication responses and subsequent opioid self-administration in surgery patients (by Eikemo, Meier and Carlyle et al, details described above)
5. The main paper of the project has been preprinted and describes the test of the core hypothesis, namely that receiving opioids when in a stress state increases subsequent opioid self-administration (the gold-standard measure of drug abuse liability). Our results confirm the hypothesis, but the analysis clearly shows that the effect is driven by male participants (N=31) with no stress-enhanced opioid drug wanting in female participants (N=32). Eikemo et al, 2023: https://osf.io/preprints/v8dxy/(opens in new window)).
6. We have meta-analysed the literature to chart how opioid antagonism unveils endogenous opioid mechanisms, specifically for social connectedness (Løseth et al, 2024, Translational Psychiatry) and experimental pain (Meier et al, preprint, invited resubmission pending to Pain). Both publications indicate a significant effect of modest size, contrasting with current beliefs in the public and in science and medicine.
7. We have produced a narrative review of opioid mechanisms in relation to loneliness and addiction, highlighting potential shared pathways for social connection and drug use (Løseth et al, 2025, Biological Psychiatry)
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
The methodological advances described above constitute progress beyond the state of the art with respect to psychological interventions. We have also made substantial progress with respect to pharmacological interventions:
First, we have conducted pilot testing to establish the drug, dose and administration method optimised to induce drug reward in healthy non-opioid users in the non-stress condition. Initial dose testing was conducted using intravenous morphine administered in a five-minute infusion. Participants were asked to report qualitatively on their responses and where relevant, to compare the effects to those of alcohol. Two participants received 5 mg/70 iv morphine, which was insufficient (‘I’m out drinking but I’m one beer short’). The next participants received 10 mg/70 kg, which was too much (‘I’m out drinking, it’s 3 am and I want to go to bed soon’). 7 mg/70 kg yielded more consistently positive responses during dose piloting.
Nevertheless, pilot testing using this dose in conjunction with the full setup taught us that morphine reward was inconsistent in healthy volunteers who were not opioid users. For instance during debrief, one participant stated that they would ‘pay money to never receive this drug again’. We also saw no clear evidence of opioid-induced stress relief in the initial pilot data (42 sessions). We therefore changed from morphine to a comparable dose of oxycodone, a drug associated with a more favourable proportion of drug liking/drug disliking responses. Pilot testing with oxycodone showed that many participants chose to work for another dose of the drug. This strong evidence of incentive salience of oxycodone was even observed in participants who had vomited after the initial dose.
Second, we have conducted an in-depth investigation into the blockade profile of commonly used opioid antagonists. Synthesizing the available positron emission tomography and dual detector data on blockade of mu-opioid receptors from these drugs at varying doses and time points, we have generated several drug-to-blockade models, a primer manuscript (Trøstheim et al, 2022, NPP) and two user-friendly, open access web applications that allow researchers to convert naloxone and naltrexone doses to opioid receptor blockade. The manuscript includes a detailed set of recommendations for researchers designing new studies and evaluating existing literature using opioid antagonists in humans.
Our clinical work, in which we assess subjective effects of commonly administered opioids in perisurgical settings, are also proving highly innovative and informative and contribute to changing clinical practice. We now collaborate with several key anaesthesiology clinical research groups and disseminate actively to clinical audiences.
First, we have conducted pilot testing to establish the drug, dose and administration method optimised to induce drug reward in healthy non-opioid users in the non-stress condition. Initial dose testing was conducted using intravenous morphine administered in a five-minute infusion. Participants were asked to report qualitatively on their responses and where relevant, to compare the effects to those of alcohol. Two participants received 5 mg/70 iv morphine, which was insufficient (‘I’m out drinking but I’m one beer short’). The next participants received 10 mg/70 kg, which was too much (‘I’m out drinking, it’s 3 am and I want to go to bed soon’). 7 mg/70 kg yielded more consistently positive responses during dose piloting.
Nevertheless, pilot testing using this dose in conjunction with the full setup taught us that morphine reward was inconsistent in healthy volunteers who were not opioid users. For instance during debrief, one participant stated that they would ‘pay money to never receive this drug again’. We also saw no clear evidence of opioid-induced stress relief in the initial pilot data (42 sessions). We therefore changed from morphine to a comparable dose of oxycodone, a drug associated with a more favourable proportion of drug liking/drug disliking responses. Pilot testing with oxycodone showed that many participants chose to work for another dose of the drug. This strong evidence of incentive salience of oxycodone was even observed in participants who had vomited after the initial dose.
Second, we have conducted an in-depth investigation into the blockade profile of commonly used opioid antagonists. Synthesizing the available positron emission tomography and dual detector data on blockade of mu-opioid receptors from these drugs at varying doses and time points, we have generated several drug-to-blockade models, a primer manuscript (Trøstheim et al, 2022, NPP) and two user-friendly, open access web applications that allow researchers to convert naloxone and naltrexone doses to opioid receptor blockade. The manuscript includes a detailed set of recommendations for researchers designing new studies and evaluating existing literature using opioid antagonists in humans.
Our clinical work, in which we assess subjective effects of commonly administered opioids in perisurgical settings, are also proving highly innovative and informative and contribute to changing clinical practice. We now collaborate with several key anaesthesiology clinical research groups and disseminate actively to clinical audiences.