Risks and benefits of oral modified‐release compared with oral immediate‐release opioid use after surgery: a systematic review and meta‐analysis

Summary Prescription of modified‐release opioids for acute postoperative pain is widespread despite evidence to show their use may be associated with an increased risk of adverse effects. This systematic review and meta‐analysis aimed to examine the available evidence on the safety and efficacy of modified‐release, compared with immediate‐release, oral opioids for postoperative pain in adults. We searched five electronic databases from 1 January 2003 to 1 January 2023. Published randomised clinical trials and observational studies on adults who underwent surgery which compared those who received oral modified‐release opioids postoperatively with those receiving oral immediate‐release opioids were included. Two reviewers independently extracted data on the primary outcomes of safety (incidence of adverse events) and efficacy (pain intensity, analgesic and opioid use, and physical function) and secondary outcomes (length of hospital stay, hospital readmission, psychological function, costs, and quality of life) up to 12 months postoperatively. Of the eight articles included, five were randomised clinical trials and three were observational studies. The overall quality of evidence was low. Modified‐release opioid use was associated with a higher incidence of adverse events (n = 645, odds ratio (95%CI) 2.76 (1.52–5.04)) and worse pain (n = 550, standardised mean difference (95%CI) 0.2 (0.04–0.37)) compared with immediate‐release opioid use following surgery. Our narrative synthesis concluded that modified‐release opioids showed no superiority over immediate‐release opioids for analgesic consumption, length of hospital stay, hospital readmissions or physical function after surgery. One study showed that modified‐release opioid use is associated with higher rates of persistent postoperative opioid use compared with immediate‐release opioid use. None of the included studies reported on psychological function, costs or quality of life.


Introduction
Prescription of modified-release opioid analgesics for acute postoperative pain is widespread. Since their introduction in the late 1990s [1], modified-release opioid use has increased to account for over 30% of all opioids prescribed after surgery [2]. Modified-release opioids were introduced into peri-operative clinical practice where there was a dearth of effective analgesic techniques, reliance on unimodal analgesia (including as-required intramuscular morphine, patient-controlled analgesia and epidurals) and minimal use of simple analgesics (including non-steroidal anti-inflammatory drugs and paracetamol). The introduction of oral opioids coupled with the administration of non-opioid analgesics allowed shorter lengths of stay and cost savings [3,4]. The subsequent embedding of modifiedrelease opioids into routine clinical practice was driven by beliefs that: they provided greater and sustained pain relief; produced fewer`peak and trough´serum opioid concentrations, leading to a lower risk of opioid dependence; and reduced nursing workload by reducing the frequency of analgesic dosing compared with immediate-release opioid formulations [4,5].
Emerging evidence now suggests that the use of modified-release opioids for acute postoperative pain may be associated with more harm than benefit. Modifiedrelease opioid use for acute postoperative pain is associated with a greater risk of opioid-related adverse events, in particular opioid-induced ventilatory impairment [6][7][8][9]. Due to their slow onset and offset, titration of the dose of modified-release opioids is difficult, resulting in a sustained duration of any adverse effects encountered [10].
Existing studies indicate that modified-release opioids yield less effective pain relief compared with immediate-release opioids, and that a higher cumulative dose may be required [8,11]. Modified-release opioids have also been associated with prolonged hospital stay [2]. Since 2017, there has been irrefutable evidence that the use of modified-release opioids is one of the main risk factors for persistent opioid use [12], with a recent study by Lam et al. providing further evidence of this [13]. Increasing awareness of the potential harms associated with modified-release opioid use prompted the release of guidelines advising against the use of modified-release opioids for the management of acute pain internationally [14][15][16][17].
Within these guidelines, modified-release opioids are not recommended for acute pain unless there is a demonstrable need or in exceptional circumstances [17].
However, there remains a paucity of literature to describe the circumstances in which modified or immediate-release opioids may be most appropriate for the management of acute postoperative pain. Existing systematic reviews comparing modified-release with immediate-release opioids are largely limited to cancer-related pain or chronic pain contexts [18,19]. Furthermore, previous studies showing positive outcomes associated with modified-release opioid use largely involve patient-controlled analgesia as the comparator group, whereby improvements in physical function and reduced length of stay are attributable to removing the need for intravenous access and connection to a patient-controlled analgesia pump [20]. There remains a research gap on the risks and benefits of modified-release opioids compared with immediate-release oral opioids for acute pain. Therefore, this systematic review and metaanalysis aimed to examine the available evidence on their safety and efficacy for acute postoperative pain. the meta-analysis as information on safety and efficacy outcomes required to pool data was not available [29]. One study was removed from the meta-analysis of efficacy outcomes [30] and one was removed from the safety outcomes [31] due to significant methodological heterogeneity in the pain intensity and adverse event outcomes reported, respectively. The mean (SD) values reported in the study by Park et al. were reversed between modified-release and immediate-release groups to account for the direction of effect [32]. A random effects model with inverse variance was used for all meta-analyses [33]. We planned to explore publication bias using funnel plots if there were 10 or more studies included in the meta-analysis, but the number of studies included did not reach this. The a priori a level used was 0.05 for all analyses. RevMan software (version 5.4, Copenhagen, Denmark) was used to compile data and perform statistical analyses.
Of the five randomised controlled trials, two were graded as having some concerns of bias [29,31] and three as having a low risk of bias [30,32,36]. Two trials contained some concerns of bias arising from the selection of reported results because pre-specified analysis plans were not reported [29,31]. Of the three observational studies, all were graded as having a moderate risk of bias due to potential confounding and bias in the measurement of outcomes as outcome assessors were not blinded (online Supporting Information Table S3) [13,34,35].
Of the eight included studies, six reported the incidence of opioid-related adverse events after surgery [29-32, 35, 36], including five randomised controlled trials [29][30][31][32]36] and one observational study [35]. Three randomised controlled trials were included in the metaanalysis on safety outcomes ( Based on GRADE assessment, there is limited confidence that this estimate of effect lies close to the true effect due to an insufficient timeframe of outcome measurement and potential publication bias related to pharmaceuticalindustry funding ( Table 2). Minimal heterogeneity was found across studies reporting safety outcomes (Fig. 2).
Of the three studies not included in the meta-analysis, two were randomised controlled trials [29,31] and one was an observational study [35]. All three studies reported no difference in the incidence of opioid-related adverse events between patients given modified-release or immediaterelease opioids after surgery (Table 1) [29,31,35].
Three randomised controlled trials were included in the meta-analysis on pain intensity following surgery ( Table 2,   RCT, randomised controlled trial; N/A, not applicable; SMD, standardised mean difference. a High, high confidence that the true effect lies close to that of the estimate of the effect; moderate, moderate confidence that the true effect is likely to be close to the estimate of the effect, but with a possibility that it is substantially different; low, confidence and the true effect may be substantially different from the estimate of the effect; very low, very little confidence and the true effect is likely to be substantially different from estimate of effect. b Some studies only measured this outcome during hospital inpatient stay. Given modified-release opioids are often supplied following hospital discharge after surgery, this outcome timeframe may be insufficient to detect outcomes occurring after hospital discharge. c Two authors in Park et al. [33] were employees of Janssen Korea. The study by Scholz et al. [38] was funded, designed and analysed by Gr€ unenthal. d Pain intensity may be a subjective outcome measure (measured using visual analogue scale or numeric rating scale).  (Table 2). Minimal heterogeneity was found across studies reporting safety outcomes (Fig. 3).
Of the two randomised controlled trials not included in the meta-analysis [29,30], one reported that modifiedrelease oxycodone use was associated with higher visual analogue scale pain scores at all time-points compared with those patients given immediate-release oxycodone after elective coronary artery bypass graft (p < 0.05) [30]. The other randomised controlled trial reported no difference in pain intensity between modified-release and immediaterelease opioid groups following laparoscopic cholecystectomy (Table 1) [29].
Due to significant heterogeneity in reporting of opioid or rescue analgesic use between included trials, a metaanalysis was not conducted.
One randomised controlled trial reported higher oxycodone use among patients given modified-release Three trials reported no difference in the quantity of rescue analgesics used between modified-release and immediate-release opioid groups (Table 1) [29,31,32].
One trial allocated 84 participants randomly to receive modified-release or immediate-release codeine after laparoscopic cholecystectomy and reported no difference in physical function between groups (p = 0.7) [29].

Figure 2
Incidence of opioid-related adverse events during inpatient stay among participants given modified-release opioids compared with immediate-release opioids in sensitivity analysis articles with low risk of bias. MR, modified-release; IR, immediate-release; IV, Random, inverse variance random effects model used.

Figure 3
Pain intensity over the first 24 h postoperatively among participants given modified-release opioids compared with immediate-release opioids in sensitivity analysis articles with low risk of bias. MR, modified-release; IR, immediate-release; IV, Random, inverse variance random effects model used.
Two double-blind randomised controlled trials reported on the length of hospital stay and hospital readmission rates [29,30]. Both reported no difference in length of hospital stay [30] or hospital readmission rates [29,30] between modified-release and immediate-release opioid groups (Table 1). One retrospective cohort study examined the incidence of persistent postoperative opioid use among 92,863 surgical patients following hospital discharge [13]. Patients given modified-release opioids following surgery had a higher incidence of persistent

Discussion
This systematic review and meta-analysis identified eight studies examining the safety and efficacy of oral modifiedrelease opioids compared with oral immediate-release opioids after surgery. Based on low-quality evidence, modified-release opioid use was associated with a higher incidence of opioid-related adverse events and worse pain compared with immediate-release opioid use only following surgery. Modified-release opioids showed no superiority over immediate-release opioids for analgesic consumption or physical function after surgery. Few studies reported on length of hospital stay and readmission rates after discharge and, where included, no significant differences between groups overall were observed. One large observational study showed that modified-release opioid use is associated with a higher incidence of persistent postoperative opioid use compared with immediate-release opioid use only after surgery [13]. No studies examined differences in the incidence of opioidinduced ventilatory impairment, psychological functioning, costs or quality of life associated with the use of modified vs.
immediate-release opioids after surgery.
There is increasing evidence to suggest that the harms associated with modified-release opioid use for acute postoperative pain may outweigh the potential benefits. A study describing the use of modified-release opioids for postoperative pain has since been retracted as the data had been falsified [43] and was not eligible for inclusion in this review. Furthermore, five [13,29,32,35,36]  The definition of opioid-related adverse events varied between studies, which limits the accuracy and reliability of the aggregated incidence of adverse events across studies.
Furthermore, the incidence of persistent postoperative opioid use was only reported in one study, which limits the reliability of conclusions regarding this outcome. The study findings may not be generalisable to surgery types that were not included in the review. Thus, the safety and efficacy of modified-release opioids in patients undergoing these operations remain unknown. Finally, several studies showed some concerns of bias and the overall quality of the evidence was low. This may reduce confidence that the reported findings reflect the true effect of the interventions for these studies.

Supporting Information
Additional supporting information may be found online via the journal website. Table S1. Full search strategy.