Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review

Abstract

Background

Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies.

Methods

We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers.

Results

Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number.

Conclusions

Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias.

Study registration

OSF - https://osf.io/7kea3.

Editor's key points.

• •Although intraoperative pharmacologic opioid minimisation strategies can reduce opioid use, their effectiveness in improving patient-centred outcomes is uncertain.
• •Patient-centred outcomes are rarely evaluated in trials. Amongst trials that evaluated these outcomes, three strategies appeared promising (dexmedetomidine, systemic lidocaine, and COX-2 inhibitors). Some routinely used strategies were not supported by patient-centred outcomes (e.g. ketamine, gabapentinoids).
• •Researchers should include patient-centred outcomes in the evaluation of opioid minimisation strategies. Promising strategies should be further assessed to determine patient-centred effectiveness.

Amid the global opioid crisis, pharmacologic approaches aiming at reducing opioid use, known as opioid minimisation strategies, are increasingly gaining traction in perioperative care.1, 2, 3, 4, 5, 6 Such interventions are often started during surgery, specifically in the intraoperative period while the patient is under general anaesthesia. Although the use of opioid minimisation strategies is increasing, there is also unexplained variation in practices, and it is unclear if these practices are supported by patient-centred evidence.6, 7, 8, 9, 10, 11, 12, 13, 14, 15

There is a growing recognition and demand for patient-centred outcome measures in perioperative research to enhance the relevance and applicability of study findings.16, 17, 18, 19, 20 These outcome measures capture the patient's experience after surgery, including pain levels, analgesic adverse effects (e.g. nausea, vomiting, constipation, dizziness), and the impact of pain on daily life, which are key components to determine perioperative effectiveness.²¹ Opioid minimisation strategies are attractive to improve patient-centred outcomes as they can reduce opioid-related adverse effects while still providing analgesia.6, 7, 8, 9, 10, 11, 12, 13, 14, 15^,19,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 Nevertheless, patient-centred outcomes are currently underrepresented in perioperative research and clinical practice guidelines that endorse the perioperative use of opioid minimisation strategies, such as the Enhanced Recovery After Surgery Society (ERAS) guidelines.43, 44, 45 The Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC group) has established key patient-centred outcome measures and instruments for use in trials of perioperative care.^44,46,47 The integration of patient-centred outcomes in practice, research, and guidelines have also been emphasised by perioperative national and international expert consensus statements.48, 49, 50, 51, 52, 53

Previous systematic reviews have focused primarily on the effect of pharmacologic opioid minimising strategies on indirect patient outcome measures (i.e. short-term quantity of opioids administered) or unidimensional instruments (i.e. pain intensity assessment or haemodynamic stability).6, 7, 8, 9, 10, 11, 12, 13, 14, 15^,19,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 Results suggest that opioid alternatives can reduce short-term opioid use during and after surgery. However, these systematic reviews were generally of low methodological quality⁵⁴ and often neglected important patient-centred outcomes.6, 7, 8, 9, 10, 11, 12, 13, 14, 15^,19,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 Furthermore, considering the heterogeneous and complex nature of intraoperative opioid minimisation strategies,55, 56, 57 a scoping review serves as a valuable approach for assessing the extent, range, and nature of this field and provide insights for future research.⁵⁸

Therefore, we designed a scoping review of randomized controlled trials (RCTs) using a collaborative approach involving multiple interested parties and partner organisations (e.g. patient partners, perioperative clinicians, partner organisations, and methodologists). Our objectives were to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients and to identify promising pharmacologic opioid minimisation strategies.

Methods

Our scoping review was conducted in accordance with the recommendations from the Joanna Briggs Institute⁵⁹ and followed the methodological framework developed by Arksey and O'Malley.⁵⁸ We wrote this manuscript in accordance with the reporting guidelines from the Preferred Reporting Items for systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews.⁶⁰ Our protocol was published,⁶¹ and any modifications made to the original protocol were documented and posted on the Open Science Framework platform (https://osf.io/7kea3).

As detailed in our protocol and in a separate reflective article,⁶² we used a collaborative approach involving multiple partner organisations and patient partners. We defined pharmacologic opioid minimisation strategy as any non-opioid drug with antinociceptive properties administered orally, intramuscularly, subcutaneously or intravenously during the intraoperative period. Although multiple definitions are available within and across countries to describe patient-centred outcomes, we followed recommendations developed by a rigorous international consensus process specifically tailored to the perioperative care context: the StEP-COMPAC consensus.⁶³ Accordingly, we included any outcome measures falling within one of the five StEP-COMPAC consensus domains, namely: wellbeing, functional status, patient satisfaction, health-related quality of life, and life impact. In addition, based on input from our partner organisations, expert clinicians, and patient partners, we also considered two additional patient-centred domains: opioid-specific outcomes (long-term opioid use [≥1 month] and opioid-related adverse effects [multidimensional assessment]), and pain-related outcomes (acute pain [multidimensional assessment <3 months] and postoperative chronic pain [≥3 months]). A summary of important definitions can be found in Appendix 1.

Search strategy and eligibility criteria

We developed our search strategy in collaboration with method experts, clinicians, patient partners, and two information specialists. Our search strategy was applied to MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from their inception to February 2023, and the search strategy was validated according to the Peer Review of Electronic Search Strategy (PRESS) recommendations (Supplementary Fig. S1).⁶⁴ We included RCTs assessing the impact of systemic intraoperative (i.e. initiated the day of surgery, before anaesthesia emergence) pharmacologic opioid minimisation strategies. The intervention could include opioid-free anaesthesia (i.e. complete avoidance of opioids), but it was not required for eligibility. Trials must have included adult patients undergoing general anaesthesia for any surgical procedure. Eligible comparators were opioids, placebo, or no intervention. At least one patient-centred outcome must have been reported and only trials written in English or French were included. To be included, the minimal sample size required for an eligible trial was 30 participants. Further details on the eligibility criteria can be found in the protocol.⁶¹

Study selection

We used Distiller SR (https://v2dis-prod.evidencepartners.com/), a cloud-based audit-ready software designed for knowledge synthesis projects to collect citations, remove duplicates, and facilitate screening of titles and abstracts.⁶⁵ Given the anticipated large number of citations, we leveraged the active-machine learning feature of Distiller SR's artificial intelligence to prioritise and enhance title and abstract screening of citations.^66,67 To pilot test the Level 1 screening form and to train the active-machine learning tool, reviewers independently screened 100 citations and all disagreements were resolved. We performed conflicts resolution every 2–3 days to maintain reliability of the active-machine learning tool. Once we achieved a predicted recall rate of ≥90% (indicating that the active-machine leaning had identified approximately ≥90% of trials eligible for inclusion), one reviewer was replaced by the artificial intelligence in the duplicate screening process. For the full-text screening phase, we utilised the InsightScope platform (www.insightscope.ca), a web-based application that allowed the creation of a large online team to facilitate the screening of the expected large number of citations to review.⁶⁸ In order to be considered eligible as a reviewer for the project, each candidate was required to obtain at least 80% sensitivity in a test set of 50 citations validated by three senior reviewers (Supplementary Table S3) and participate in at least two training sessions.

Criteria for identifying promising opioid minimisation strategies

Our approach for identifying promising opioid minimisation strategies is detailed in our protocol that was published a priori (i.e. strategies that could be effective based on authors' findings, but that requires further systematic research assessment).⁶¹ First, we ranked patient-centred outcome measure domains of interest based on potential impact and plausibility with our patient partners and partner organisations (Table 1).⁶² Patient wellbeing, assessed with the Quality of Recovery instrument was given the highest score. We also considered within the scope of patient-centred outcomes two additional domains, namely opioid-related (long-term use [≥1 month] and adverse effects [multidimensional assessment]) and pain-related (acute pain [multidimensional assessment, <3 months] and postoperative chronic pain [≥3 months]). Next, we calculated the relative (i.e. relative to the total number of included trials) and absolute number of clinical trials reporting positive (i.e. benefit associated with the intervention) results for a pharmacologic strategy based on authors' conclusion and interpretation (i.e. aggregating authors' findings). Then, this same assessment was conducted among trials reporting at least one patient-centred outcome measurement (Supplementary Table S4) as their primary outcome of interest (wellbeing, functional outcomes, patient satisfaction, quality of life and life impact, opioid-related adverse effects, or pain-related). Finally, we summarised this evidence and discussed it with patient partners, clinicians, and researchers to confirm the potential applicability and relevance of the identified promising strategy(ies). We used no quantitative thresholds to choose promising strategies as each of the chosen promising opioid minimisation strategies will require systematic review and meta-analysis to confirm findings. Using the same approach, we also identified less promising pharmacologic strategies based on the relative and absolute number of published articles with null or negative conclusion (i.e. intervention judged as having no effect, being deleterious, or of uncertain efficacy based on authors' conclusion).

Table 1.

Standardised Endpoints in Perioperative Medicine (StEP-COMPAC) group recommendations for patient-centred outcome assessments in perioperative clinical trials³⁸ and our prioritisation order tailored to pharmacologic interventions. ∗Prioritisation based on: (1) plausibility for effect between intraoperative pharmacologic intervention and outcome; and (2) patient and knowledge user priority. ^†Quality of Recovery (QoR)-9 and -40 were also accepted for the purpose of our scoping review. ^‡EuroQol 3-Dimensions (EQ-3D-3L) was also accepted for the purpose of our scoping review.

	Patient-centred outcome domains
	Patient wellbeing	Health-related quality of life	Functional outcome	Patient satisfaction	Life impact
Instruments to be prioritised based on StEP-COMPAC recommendations	Quality of recovery-15 (QoR-15)†	EuroQol 5-Dimensions, five-level‡	WHO Disability Assessment Schedule version 2.0	Bauer patient-satisfaction measure	Days alive and out of hospital after surgery (at 30 days and 1 yr) and discharge destination
Prioritisation by our team (Steering committee)∗	1	2	3	4	5

Data abstraction, analysis, and presentation of the results

We extracted data from included trials using a standardised data abstraction document (Supplementary Table S1). At least two reviewers extracted data independently in duplicates and conflicts were resolved with a third senior reviewer when necessary.

To describe outcome measures, each instrument reported was categorised based on the classification from the StEP-COMPAC consensus (Table 1). We also described compliance with the StEP-COMPAC recommendations (Fig. 1) for each trial using stacked bar charts.⁶³ We visualised the number of trials assessing each pharmacologic opioid minimisation strategy's effectiveness according to the patient-centred outcome that was reported in the trial with a bubble chart.

Fig 1.

Compliance with Standardised Endpoints in Perioperative Medicine (StEP-COMPAC) recommendations among included trials. In RCTs of perioperative care, the most important outcome measures and instruments to be used have been established by the StEP-COMPAC group initiative and these recommendations were published in 2019. HRQOL, health-related quality of life.

Patient and public involvement

We formed a patient panel of four individuals with lived perioperative experience to co-produce this scoping review following the principles laid out in the Canadian Strategy for Patient-Oriented Research (SPOR) Patient Engagement Framework.⁶⁹ In line with these principles of inclusiveness, support, mutual respect, and co-building, the patient panel met regularly with members of the team. The patient partners were involved in all phases of research, namely designing the research question, determining the outcome choice and prioritisation, providing insight on the planned items for extraction, and co-developing grants and articles. Details of our patient engagement approach has been described in another publication.⁶²

Results

Of the 24,842 citations screened for eligibility, we included a total of 457 trials representing 67,060 participants. The screening process and reasons for exclusion at full text are summarised in Supplementary Figure S2. The artificial machine learning feature report is provided in Appendix 2. We found that 16% (457 of 2803) of published trials assessing the effectiveness of pharmacologic opioid minimisation strategies met our eligibility criteria of reporting at least one patient-centred outcome (Supplementary Fig. S2). We excluded two articles because they were retracted and recognised as fraudulent reports.^70,71

Characterising the trials evidence assessing patient-centred effectiveness of pharmacologic opioid minimisation strategies

Characteristics of the 457 included articles are summarised in Table 2 and Supplementary Table S2. The highest proportion of trials was conducted in China (18%, n=83), followed by USA (18%, n=81) and Turkey (9%, n=42). In terms of design and methodology, randomisation was at the individual level for 99% of the trials (n=454), and 92% of the trials (n=419) were conducted in a single centre. A total of 56% trials (n=253) reported a protocol or a registration number and 85% trials (n=389) reported a sample size calculation in their manuscript or their protocol.

Table 2.

General characteristics of included trials. ∗This category also includes paracetamol. ^†Multiple intervention arms: trials with two or more intervention arms. ^‡Others: opioid minimisation strategies with less than 10 trials each: beta-blockers, antidepressants, cannabinoids, non-opioid central analgesics (nefopam, metamizole), and methylxanthine.

Variable	NMDA receptor antagonists (n=76)	Alpha-2 agonists (n=71)	Systemic lidocaine (n=46)	COX-2 inhibitors (n=22)	Non-selective anti-inflammatories (n=31)	Corticosteroids (n=49)	Gabapentinoids (n=49)	Paracetamol∗ (n=19)	Combinations (n=21)	Multiple intervention arms† (n=53)	Others‡ (n=20)	Overall (n=457)
Single centre	74	67	43	17	26	40	48	17	18	50	19	419
Multicentre	2	4	3	5	5	9	1	2	3	3	1	38
Presence of study protocol
•Yes	35	43	36	6	12	32	21	13	15	22	18	253
•No	41	28	10	16	19	17	28	6	6	31	2	204
Sample size randomised:
•<50	14	10	5	3	7	6	8	1	2	1	1	58
•50–99	37	34	29	11	14	9	22	7	7	25	18	213
•100–499	24	25	12	8	9	28	19	10	12	27	1	175
•>=500	1	2	0	0	1	6	0	1	0	0	0	11
Sample size calculation
•Yes	64	60	42	19	19	42	45	17	18	45	20	391
•No	12	11	4	3	12	7	4	2	3	8	0	66
Type of surgery:
•Cardiac	4	5	3	0	0	9	5	2	0	0	1	29
•Noncardiac	72	66	43	22	31	40	44	17	21	53	19	428
Route of administration:
•I.V.	76	62	45	11	27	47	0	19	12	29	13	341
•Oral	0	7	0	11	1	1	49	0	3	14	7	93
•I.M.	0	2	0	0	2	0	0	0	0	1	0	5
•Mixed	0	0	1	0	1	1	0	0	6	9	0	18
Timing of administration:
•Intraoperative	57	59	30	11	20	31	18	6	12	30	13	287
•Intraoperative and postoperative	19	12	16	8	11	18	30	13	8	21	7	165
•Mixed	0	0	0	1	0	0	1	0	1	2	0	5

Most of the trials (84%, n=382) examined a single active agent. Among these trials, alpha-2 agonists (n=71), gabapentinoids (n=49), corticosteroids (n=49), and NMDA antagonists (n=76) were the pharmacologic strategies that were assessed most frequently (Table 2). Trials that examined a combination of agents primarily studied alpha-2 agonists with lidocaine or NMDA antagonists. Furthermore, 88% of strategies were compared with placebo (n=401 trials), and 8% (n=38) and 5% (n=25 trials) were compared with opioids or no intervention, respectively. Details of all the included pharmacologic interventions are described in Supplementary Table S5.

The median sample size of the included trials was 86 participants (range: 30–8880 participants). The median length of participant follow-up was 3 days (range: 1 day to 4 yr). Regarding the target population, 3% of the trials (n=14) focused specifically on a geriatric surgical population, and less than 1% either focused specifically on patients with chronic pain history (n=2 trials)72, 73, 74 or chronic opioid use (n=1).⁷⁵ A total of 2% of trials (n=7) included sex and gender considerations as part of their analyses.76, 77, 78, 79, 80, 81, 82 The most frequent types of surgery included were gastrointestinal (n=107), obstetric/gynaecologic (n=95), and orthopaedic (n=87; Supplementary Fig. S3).

Knowledge gaps in patient-centred outcomes according to the pharmacologic opioid minimisation strategies and compliance with Standardised Endpoints in Perioperative Medicine recommendations

The number of published trials assessing at least one patient-centred outcome per year has been increasing between the years 2000 and 2020 (Supplementary Fig. S4). More than half of the trials reporting at least one patient-centred outcome were published after 2014 (58%, n=264) and few before the year 2000 (5%, n=21). Among the included trials, 24% trials (n=107) used a patient-centred outcome as their primary outcome of interest. Reported primary patient-centred outcome measures are described in Supplementary Figure S7.

The most frequently reported outcome domains in trials were patient satisfaction (46%, n=210), wellbeing (39%, n=178), and pain-related (acute and chronic pain; 25%, n=112); whereas less frequently reported domains were the health-related quality of life (7%, n=34), functional outcomes (15%, n=67), life impact (5%, n=25), and opioid-related (adverse effects and long-term opioid use; 5%, n=21) (Fig. 1).

A list of instruments that we used to assess each domain is available in Supplementary Table S4. The most frequently studied instrument for each domain were: Quality of Recovery (QoR-40, -15, and -9 score; 49%, n=88 of 178 trials in the wellbeing domain), daily activity level (15%, n=10 of 67 trials in the functional status domain), satisfaction numerical or categorical rating scale (99%, n=207 of 210 trials in the satisfaction domain), Short Form (SF-36 and -12; 62%, n=21 of 34 trials in the health-related quality of life domain), and time to return to usual activities (40%, n=10 of 25 trials in the life impact domain). Among the trials that assessed postoperative acute pain using a multidimensional instrument, the most frequently used instrument was the Brief Pain Inventory (52%, n=14 of 27 trials). Only six trials reported a multidimensional opioid-related adverse effects assessment. At least one adverse event was assessed in 93% of the included trials (n=426 trials).

Compliance with the StEP-COMPAC recommendations (i.e. the use of the most recommended instrument to assess a patient-centred outcome domain [Table 1]) was low across all domains (range: 0–49%, Fig. 2). The highest compliance rate was observed in the domain of patient wellbeing, specifically the use of the Quality of Recovery instrument (9, 15, or 40) in 49% of trials (n=88) assessing the patient wellbeing. Overall, the compliance rate with the StEP-COMPAC recommendations was 31% from 2019 onwards (i.e. the year the StEP-COMPAC consensus on patient-centred outcome was published) and 14% before 2019 (Fig. 1).

Fig 2.

Bubble plot showing the number of trials published according to the type of opioid minimisation strategy and the patient-centred outcome measure domain reported.

Identifying potential promising pharmacologic opioid minimising strategies

Three pharmacologic strategies were identified as potentially promising (Fig. 3): dexmedetomidine, COX-2 inhibitors, and systemic lidocaine (proportion of trials reporting positive results: 85%, 82%, and 76%, respectively). Our results were consistent when restricting for trials that used a patient-centred outcome as a primary outcome measure (Supplementary Fig. S5, n=107 trials) and when the primary outcome was the patient wellbeing assessed with a Quality of Recovery instrument (Supplementary Fig. S6, n=43 trials) which was the most important patient-centred outcome measure as guided by key interested parties (Table 1). There was however no trial evaluating the effectiveness of COX-2 inhibitors using a Quality of Recovery instrument (QoR-9, -15, or -40). The less promising pharmacologic strategies based on the relative and absolute number of published articles with null or negative conclusion overall were paracetamol, ketamine, and gabapentinoids (proportion of trials reporting positive results: 35%, 47%, and 49%, respectively) (Fig. 3).

Fig 3.

Number of trials showing beneficial, no effect, deleterious, or equivocal/uncertain results for each opioid minimisation strategies based on reported findings (trials with two or more intervention arms are not shown).

Discussion

Our review demonstrates that patient-centred outcomes are rarely used to assess the effectiveness of intraoperative opioid minimisation strategies in clinical trials. Among trials that did report a patient-centred outcome, compliance with well-established recommendations was generally low across all patient-centred outcome domains. Furthermore, although it is recommended that at least one patient-centred outcome be measured and reported in all perioperative trials, the vast majority of trials (84%) did not report any.⁶³ Our analysis also identified significant knowledge gaps in terms of patient-centred outcome measures and several weaknesses in published clinical trials. As such, few trials reported outcome measures assessing life impact, health-related quality of life, and opioid-related adverse effects. We also noted that few trials were multicentred, duration of follow-up was frequently short, and half of the trials did not report a registration or a protocol publication. Additionally, based on the available evidence from published trials, we identified three promising pharmacologic intraoperative opioid minimisation strategies (dexmedetomidine, systemic lidocaine, and COX-2 inhibitors) and three strategies that are not supported by patient-oriented evidence (paracetamol, ketamine, and gabapentinoids).

Our findings align with a systematic review that examined the efficacy of perioperative pharmacotherapy in preventing postoperative chronic pain.⁸³ In that review, systemic lidocaine and NSAIDs were identified as promising strategies for reducing postoperative chronic pain. Our scoping review strengthens the existing body of evidence on these two strategies and further supports the plausible improvement of other patient-centred outcomes after surgery through the use of these strategies. We also provide further description of the patient-centred outcome knowledge gap (i.e. lack of compliance with established recommendations). Our results are consistent with a previous review⁵⁵ and cross-sectional⁸⁴ analyses of perioperative trials that identified a knowledge gap in perioperative patient-oriented clinical trials. Nevertheless, we further describe areas for methodology improvement and also describe interventions and outcomes that need further assessment. For instance, our findings indicate that less than 10% of the published trials assessing the effectiveness of pharmacologic opioid minimisation strategies were multicentre trials. We identified other important methodological weaknesses in a high proportion of trials (i.e. lack of registration, short follow-up, and the lack of a sample size calculation reported) which aligns with multiple expert consensuses and calls to action, such as the American Society for Enhanced Recovery & Perioperative Quality Initiative Joint Consensus Statement, that highlight the importance of rigorous multicentre trials in order to assess perioperative opioid alternatives.^28,50,53 We provide clear and practical guidance to inform research agendas and facilitate the planning of subsequent systematic reviews and clinical trials that could impact practices and improve patient-centred perioperative care.

Including patient-centred outcomes in the evaluation of opioid minimisation strategies is extremely important in perioperative care. Only relying on short- or long-term opioid reduction could be misleading.^16,17,21,85, 86, 87, 88 Indeed, an increase in opioid exposure does not necessarily translate into worse health outcomes, which is ultimately what matters the most.^89,90 Assessing health outcomes, through patient-centred outcomes, is also recommended from a public health perspective in order to evidence inform the judicious prescribing of opioids (i.e. avoiding over and under prescription), as highlighted by the ‘opioid ecosystem’.⁹¹

Our study has strengths that contribute to its overall quality and impact. Firstly, our scoping review was characterised by a collaborative effort involving key stakeholder organisations and content experts that actively engaged patient partners throughout the research process. This inclusive approach ensured diverse perspectives were considered, enhancing the relevance and applicability of our findings. This approach led to the prioritisation of the quality of recovery as an outcome measure, which is also supported by two different established and international guidelines for endpoint prioritisation in perioperative clinical trials (patient-centred⁶³ and patient comfort²³) from the StEP-COMPAC initiative. Secondly, we adopted an innovative approach by developing a patient-oriented scoping review that will guide future more focused systematic reviews and clinical trials. This approach optimises the use of available resources and strategically targets promising strategies for further investigation. Thirdly, our focus on patient-centred outcomes (i.e. at least one patient-centred outcome measure was needed for an eligible trial), coupled with an in-depth description of domains and instruments reported, will contribute to directly inform future systematic reviews and trials in perioperative research of opioid minimisation strategies. Additionally, we carefully adhered to established international recommendations for evaluating patient-centred outcomes in perioperative research.⁶³ By following these guidelines and involving knowledge users and patient partners, we helped ensure the scientific rigour and relevance of our study.

Our study has limitations. Firstly, we did not undertake a formal risk-of-bias assessments given our objective was to map and describe the current evidence. The risk-of-bias assessment is not generally conducted in scoping reviews for this reason.⁵⁹ Furthermore, we relied on the narrative conclusions reported by the authors and there may be discrepancies with the actual quantitative findings. Selective outcome reporting may also be present, especially considering the high proportion of trials that did not report a protocol or a registration number. Our findings need to be confirmed through multicentre trials and systematic reviews. Another limitation of our study is that the primary outcomes assessed in the eligible trials may not necessarily align with patient-centred perspectives as not all trials used a patient-centred outcome as their primary endpoint. Nevertheless, our sensitivity analyses conducted among trials that reported a patient-centred outcome as their primary endpoint consistently supported the results obtained. Outcomes definitions are also variable and could interfere with interpretation.⁹² However, this will be further addressed in future systematic reviews. Lastly, although patient-centred outcomes are recognised as outcomes that should drive clinical practice, additional outcomes that we did not included in our scoping review are also important and needed to complement clinical decision-making. For instance, opioids are useful in controlling the autonomic response to nociception (i.e. pain transmission).⁹³ This property of opioids helps maintain haemodynamic stability during general anaesthesia and also facilitates rapid emergence (through lower doses of inhalation anaesthetics).

Conclusion

Through our scoping review, we found that patient-centred outcomes are assessed in relatively few clinical trials of intraoperative opioid minimisation strategies. This demonstrates a clear need for rigorous multicentre trials assessing these important outcomes. We identified promising strategies (dexmedetomidine, systemic lidocaine, and COX-2 inhibitors) that warrant further assessment through systematic reviews and large pragmatic clinical trials. We also identified three strategies that were less promising and not supported by patient-oriented evidence (paracetamol, ketamine, and gabapentinoids). Further implementation initiatives to promote the use of established recommendations (i.e. StEP-COMPAC) for evaluating patient-centred outcomes are needed in perioperative clinical trials to ensure relevancy to the health system.

Authors’ contributions

Conceptualisation and study question: all authors

Design and methodology: MV, DF, ML, AFT, FZ, MG, ML, AG, NHL, PACT

Development of search strategy: MV, DF, ML, AFT, NHL, RS

Outcome prioritisation: all authors

Formal analysis: MV, NHL, MH, JBPL, BH

Drafting the manuscript: MV, DF, ML, NHL, MH

Critical revision of the manuscript: all authors

Guide artificial intelligence feature for screening titles and abstracts: BH

Data extraction form design: all authors

Visualisation: MV, NHL, ML, MH, JBPL, DF, PACT

Project administration: MV

Led patient engagement activities: MV, SN

Led knowledge user partnership activities: MV, DF, ML

Screening, data abstraction, and data charting: MV, NHL, MH, JBPL, LY, MK, AA, DEA, MT, PT, JA, SS, AAM, HL, AC, MA, RB, NAF

Funding acquisition: MV, NHL, ML, SN, AFT, DM, MH, JBPL, IG, BH, FZ, MG, ML, AG, MB, PP, RS, HD, GM, JM, HM, DF

All authors reviewed the content of the manuscript and approved the final version.

Acknowledgements

We would like to express our gratitude to the individuals and organisations who made this study possible. Risa Shorr, Alexandra Davis, and Frederic Bergeron played a pivotal role in developing the search strategy, Josée Skuce helped to retrieve full-text articles, and Katie O'Hearn and Ravichandra Rachamalla provided valuable support in setting up and troubleshooting the InsightScope platform. We extend our thanks to all of our partner organisations, including SolvingPain, Pain BC, Health Canada, Réseau Québécois de Recherche sur la Douleur, Choosing Wisely, Strategy for Patient-Oriented Research, the Canadian Anaesthesia Society, the Canadian Chronic Pain Network, and the Canadian Perioperative Anaesthesia Clinical Trials (PACT) group. Their invaluable contributions helped refine the research question, shape the study design, and develop the dissemination plan. We want to thank the grants and manuscripts committee of PACT, specifically Kathryn Anne Sparrow and Derek Dillane for their review of the manuscript.

We would also like to acknowledge the invaluable assistance provided by the following medical students from the University of Ottawa and McGill University's Outaouais campus who volunteered their time to support this study: Kenneth Tan, Raymond Al, Homsi, Amin Sharifan, Eugene Marais. Their dedication and hard work were essential in completing the abstract and title screening, full-text screening, data abstraction, and PDF retrieval. We are grateful for their contributions to this project.

Declaration of interest

IG has received consulting fees from GW Research, Eupraxia, Biogen, and Novaremed. The other authors declare no conflicts of interest.

Funding

Canadian Institutes of Health Research (CIHR) Project Grant, priority announcement: Patient-Oriented Research [480819] and a grant from the University of Ottawa Department of Anesthesiology and Pain Medicine. MV is supported by the Vanier Canada Graduate Scholarship Program from the CIHR, the Fonds de Recherche du Québec - Santé (FRQS)/ Ministère de la Santé et des Services Sociaux du Québec (MSSS) Resident Physician Health Research Training Program (phase 2), the Canadian Blood Services Graduate Fellowship Program, and the McLaughlin Dean's Award from Université Laval. ML is supported by University of Ottawa Junior Clinical Research Chair, Canadian Anesthesiologist's Career Scientist Award, and the Ottawa Hospital Anesthesia Alternate Funds Association. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. MB is the recipient of salary support awards from the FRQS and the Strategy for Patient-Oriented Research-Québec.

Handling Editor: Jonathan Hardman

Appendix 1. Definitions

Intraoperative period: Pharmacologic interventions administered the same day of surgery and before patient's extubation will be considered as intraoperative based on mechanism of action and effect duration properties.

Opioid minimisation strategy: Any non-opioid drug with antinociceptive properties.

Multimodal strategies: The use of different classes of drugs, combining different action mechanisms aiming to reduce adverse effects and improve benefits.

Patient-centred outcome domains: Wellbeing, functional outcomes, patient satisfaction, quality of life, life impact, opioid-related, and pain-related.

Systemic administration: Oral, i.v., i.m., or s.c. administration.

Appendix 2. Distiller SR's artificial intelligence (AI) active-machine learning report

Distiller SR's AI active-machine learning feature was used as a second reviewer for title and abstract screening once a predicted relevant reference rate of 92% (4323 references discovered/4658 references predicted, which was reached after screening by two reviewers of 16,340 citations) was reached (i.e. approximative proportion of included trials that the active-machine learning predicts we have identified at a specific time point). The AI reviewer was set to exclude all remaining records while a human reviewer inspected all remaining citations, consulting a second human reviewer anytime there was a decision that conflicted with that of the AI reviewer. We also used the audit tool to ensure that no relevant studies were excluded in error.

Appendix 3. Group authorship

Hongda Li, Allison Chhor, Malvika Agarwal, Rahym Belrachid, Katie O'Hearn, and Ravichandra Rachamalla.

Appendix A. Supplementary data

The following is the Supplementary data to this article: