Impact of modified‐release opioid use on clinical outcomes following total hip and knee arthroplasty: a propensity score‐matched cohort study

Summary Modified‐release opioids are often prescribed for the management of moderate to severe acute pain following total hip and knee arthroplasty, despite recommendations against their use due to increasing concerns regarding harm. The primary objective of this multicentre study was to examine the impact of modified‐release opioid use on the incidence of opioid‐related adverse events compared with immediate‐release opioid use, among adult inpatients following total hip or knee arthroplasty. Data for total hip and knee arthroplasty inpatients receiving an opioid analgesic for postoperative analgesia during hospitalisation were collected from electronic medical records of three tertiary metropolitan hospitals in Australia. The primary outcome was the incidence of opioid‐related adverse events during hospital admission. Patients who received modified with or without immediate‐release opioids were matched to those receiving immediate‐release opioids only (1:1) using nearest neighbour propensity score matching with patient and clinical characteristics as covariates. This included total opioid dose received. In the matched cohorts, patients given modified‐release opioids (n = 347) experienced a higher incidence of opioid‐related adverse events overall, compared with those given immediate‐release opioids only (20.5%, 71/347 vs. 12.7%, 44/347; difference in proportions 7.8% [95%CI 2.3–13.3%]). Modified‐release opioid use was associated with an increased risk of harm when used for acute pain during hospitalisation after total hip or knee arthroplasty.


Summary
Modified-release opioids are often prescribed for the management of moderate to severe acute pain following total hip and knee arthroplasty, despite recommendations against their use due to increasing concerns regarding harm. The primary objective of this multicentre study was to examine the impact of modified-release opioid use on the incidence of opioid-related adverse events compared with immediate-release opioid use, among adult inpatients following total hip or knee arthroplasty. Data for total hip and knee arthroplasty inpatients receiving an opioid analgesic for postoperative analgesia during hospitalisation were collected from electronic medical records of three tertiary metropolitan hospitals in Australia. The primary outcome was the incidence of opioid-related adverse events during hospital admission. Patients who received modified with or without immediate-release opioids were matched to those receiving immediate-release opioids only (1:1) using nearest neighbour propensity score matching with patient and clinical characteristics as covariates. This included total opioid dose received. In the matched cohorts, patients given modified-release opioids (n = 347) experienced a higher incidence of opioid-related adverse events overall, compared with those given immediate-release opioids only (20.5%, 71/347 vs. 12.7%, 44/347; difference in proportions 7.8% [95%CI 2.3-13.3%]). Modified-release opioid use was associated with an increased risk of harm when used for acute pain during hospitalisation after total hip or knee arthroplasty.

Introduction
Total hip or knee arthroplasty are common worldwide [1].
Each require varied pain management approaches to cover the acute postoperative period that routinely include opioid analgesics for the management of moderate to severe acute pain [2]. A recent study of 86,058 patients reported that over 80% of patients used opioids for the management of acute pain following total hip or knee arthroplasty [2]. The types of opioid formulations prescribed for post-surgical pain after these procedures may include immediate-release and modified-release formulations. Modified-release opioid formulations were introduced in the late 1990s to provide prolonged, stable serum opioid concentrations [3] and have since become widely used for the management of post-surgical pain [4].
A cohort study highlighted that modified-release opioids accounted for over 30% of all opioids prescribed after surgery, and patients undergoing total hip or knee arthroplasty were over 10 times more likely to be prescribed a modified-release opioid [4]. This increase has been driven by the suggestion that modified-release opioids may provide improved pain relief, reduce the need for frequent immediate-release opioid administration [5], and may be less addictive due to fewer peak and trough plasma concentrations [6]. These suggestions were further potentiated by aggressive marketing and sponsorship of the`Pain as the 5th Vital Sign´campaign by pharmaceutical companies [6]. A study by Reuben et al. published in 1999 reporting superior outcomes associated with modifiedrelease opioid use after anterior cruciate ligament surgery was cited 116 times before it was retracted for falsification of data [7]. The impact of this study on the literature and practice before its retraction is unknown. A randomised controlled trial of 59 patients admitted for inpatient rehabilitation following total knee arthroplasty reported that modified-release oxycodone use was associated with improved physical function and a shorter length of hospital stay compared with placebo [8]. As a result of these findings and other studies [9,10], modified-release opioid formulations were recommended for use in some postoperative analgesia guidelines [11] and enhanced recovery pathways [12], which are increasingly being used after total hip and knee arthroplasty procedures [13].
However, several studies showing positive outcomes associated with modified-release opioids used inappropriate comparators such as placebo [8], epidurals [9], used lower oral morphine equivalent doses [10] or were not conducted in acute postoperative settings [8].
Collectively, data describing the impact of modified-release opioid use on clinical outcomes appear to be mixed, with several studies showing no benefits of modified-release compared with immediate-release opioid use [14][15][16]. Recent concerns have been raised regarding the challenges of titrating modified-release opioid doses to rapidly changing pain intensities during the postoperative period, which may lead to supratherapeutic serum opioid concentrations, sedation and opioid-induced ventilatory impairment [17]. It has been suggested that some modified-release opioids may have an 8-h duration of effect despite 12-hourly dosing [18], which may contribute towards breakthrough pain, higher opioid consumption [16] and a higher incidence of opioidrelated adverse events [4,16]. Initiation of modified-release opioid formulations is also associated with an increased risk of long-term opioid use compared with those given immediate-release opioids only [19].

International Classification of Diseases Australian
Modification (ICD-10-AM) diagnosis codes as assigned by hospital clinical coders were used to identify comorbidities and opioid-related adverse events [27]. The onset of ICD-10-AM conditions of interest relative to hospital admission were determined using the Australian Institute of Healthcare and Welfare Onset Flags [28]. We calculated the Charlson comorbidity index using ICD-10-AM codes and respective weightings used in previous literature where a higher total score indicated a greater disease burden [29]. Opioidrelated adverse events were captured using ICD-10-AM codes adapted from previous research [30] and author consensus. Opioid-related adverse events were defined as the incidence of one or more of the following: constipation; Propensity score matching was used to reduce the effects of confounding and obtain comparable groups [32].
The probability of receiving a modified-release vs. an immediate-release opioid was calculated using a multivariable logistic regression model [32]. Covariates in the propensity score model were identified using existing literature [33] and author consensus. Patients who received modified-release opioids were matched to those who received immediate-release opioids only using nearest-neighbour matching, with a 1:1 matching ratio without replacement [32]. The calliper width was calculated by using 0.1 times the standard deviation of the logit of the propensity score, as described in previous literature [34]. If a patient in the immediate-release opioid group was not found for a given modified-release opioid group patient, that patient was excluded. The balance of covariates between the matched groups were assessed using absolute standardised mean differences (SMD) rather than hypothesis testing as SMDs are not affected by sample size [35]. A SMD value < 0.1 indicated negligible differences between groups [35].
After propensity score matching, binary outcomes  Table 2).
After propensity score matching, the absolute SMDs were < 0.1, indicating similar baseline characteristics between the groups and an adequate match (Table 1; online Supporting Information Figure S1).

Discussion
In this multicentre propensity score matched cohort study, modified-release opioid use in the acute postoperative period is associated with an increased risk of experiencing  Oxycodone with naloxone accounted for more than two-thirds of modified-release opioid formulations prescribed in the study cohort. The addition of naloxone, a mu-opioid receptor antagonist which acts locally on the gastro intestinal tract, to oxycodone was promoted and used to reduce the effect of opioid-induced constipation, one of the most common adverse events associated with opioid use [38]. Despite this, constipation was found to be more common among patients given modified-release opioids after total hip or knee arthroplasty compared with those given immediate-release opioids only in this study. approximately 80% of the study cohort was prescribed a laxative after surgery. Therefore, our study findings reinforce the results of previous research suggesting that the addition of naloxone has a limited role in the context of acute pain. The extensive use of oxycodone with naloxone after total hip and knee arthroplasty may thus represent a source of unnecessary healthcare utilisation.
Future strategies to reduce the use of oxycodone with naloxone for acute pain may provide an opportunity to optimise the use of healthcare resources whilst reducing harms associated with modified-release opioid use.
Some guidelines continue to recommend the use of modified-release opioids for the management of pain after total hip or knee arthroplasty [11,12]. The modified-release opioid prescribing practices observed in the present study arose due to the enhanced recovery pathways used in the included study hospitals. These advise the provision of modified-release opioids alongside immediate-release opioid and non-opioid analgesia after total hip and knee arthroplasty to facilitate faster functional recovery and a shorter length of hospital stay. Other authors have identified additional reasons for the initiation of modified-release opioids following total hip and knee arthroplasty such as reduced nursing workload due to less frequent analgesic needs, particularly in regional or rural settings in which nurse-to-patient staffing ratios may be lower than urban settings [5]. However, there are increasing concerns that the slow onset and offset of modified-release opioid formulations may prevent appropriate dose titration to fluctuating acute pain requirements [17], which may contribute towards inadequate pain relief [16] and an increased risk of opioid-related adverse events including opioid-induced ventilatory impairment [17]. The pharmacokinetic profile of modified-release oxycodone, the main opioid formulation administered in the present cohort, has been shown to provide inadequate analgesia over the conventional 12-h dosing period, which may lead to breakthrough pain, higher opioid consumption and subsequent dose-related harm [18]. Previous literature suggest an 8-h dosing frequency of modified-release oxycodone may be more appropriate [18].
Furthermore, the use of modified-release opioids has been associated with longer term harm such as persistent opioid use, which in turn increases the risk of opioid tolerance, dependence and even mortality [17]. These risks are heightened by co-administration of opioids with other sedating drugs including benzodiazepines, which were prescribed to 8% of the study cohort against practice guidelines [17]. Thus, consideration of patient safety-related opioid group compared with the immediate-release opioidonly group following matching (below the pre-specified threshold for significance), which may be a confounder to the increase in opioid-related adverse events identified in the modified-release opioid group. In patient pain scores and functional outcomes were not collected, thus their impact on modified-release opioid prescribing is unknown.
After patients receiving modified-release opioids were matched to those taking immediate-release opioids only after total hip or knee arthroplasty, the findings of this study suggest that modified-release with or without immediaterelease opioid use is associated with a higher incidence of opioid-related adverse events compared with immediaterelease opioid use alone. Specifically, patients given modified-release opioids experienced more constipation, inhospital falls and prolonged hospital stay compared with those given immediate-release opioids only. This study adds to the increasing body of evidence that modified-release opioids do not provide benefits over immediate-release opioids, and supports the existing advice that modifiedrelease opioids should be avoided in the peri-operative period [17,[20][21][22]. If modified-release opioids are prescribed postoperatively, use should be avoided within the first 12-24 h after surgery to comply with the product licences, unless within the context of a registered clinical study.

Supporting Information
Additional supporting information may be found online via the journal website. Figure S1. Love plot of covariate balance before and after propensity score matching for the modified-and immediate-opioid vs. the immediate-release opioid only groups. Table S1. Australian Classification of Health Intervention 10th Edition procedure codes used to identify patients who underwent primary total hip or knee arthroplasty. Table S2. International Classification of Diseases 10th Edition Australian Modification procedure codes used to identify opioid-related adverse drug events.