Calling time on the use of modified‐release opioids for acute pain

The first modified‐release (MR) formulation of oxycodone was approved for the management of pain in 1995 and aggressively marketed (with false claims of a low addiction risk) primarily for the management of chronic non‐cancer pain.1 In many high income countries, including Australia,2 prescription of MR oxycodone for the management of acute pain, especially post‐operative pain, then became commonplace.1 This occurred despite no evidence at the time showing that MR oxycodone was better — in terms of analgesia and/or adverse effects — than immediate‐release (IR) oxycodone alone (as explained below).1,3,4 A survey of Australian public and private hospital pharmacists showed that MR opioids were commonly prescribed to opioid‐naïve patients with acute pain in more than 70% of hospitals — both as an inpatient and at discharge.2

Guidelines reflecting the current evidence base and aiming to improve the safety of opioid use for acute pain management in Australia have recently been introduced.5,6 These strongly recommend against the initiation of MR opioids for acute pain in opioid‐naïve patients. Opioids remain an important part of multimodal acute pain analgesic regimens, with guidelines indicating how to use IR opioids more safely and effectively, while not limiting appropriate access and dosing for patients who require them.

Calling time on initiating MR opioids for acute pain is a key recommendation of these guidelines and aims to reduce opioid risk in two key areas: in‐hospital morbidity and mortality, and inadvertent persistent post‐discharge opioid use (PPOU), which comes with its own list of potential adverse effects.7

Recent changes to opioid‐prescribing guidelines in Australia

In 2000, regulatory changes made by the Australian Therapeutics Goods Administration were designed to decrease the risk of harm from prescription opioids.8 Included in the changes were that MR opioids should not be used for the management of severe pain unless the pain is opioid‐responsive and “requires daily, continuous, long term treatment” (thus excluding acute pain).8 In 2022, the Australian Commission on Safety and Quality in Health Care published their Opioid Analgesic Stewardship in Acute Pain Clinical Care Standards, which advised that MR opioid use for the management of acute pain “should be exceptional and not routine”.5 In the same year, a new Choosing Wisely Australia statement said “Avoid routine prescription of slow‐release (SR) opioids in the management of acute pain, in hospital and community settings, unless there is a demonstrated need, close monitoring is available, and a cessation plan is in place”.9 A 2023 publication from the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine contains similar recommendations,6 which are consistent with other Australian10,11 and international guidelines.7,12,13,14

Although most of the literature on the topic involves acute pain management in inpatients, there is no reason to think that MR opioids would be any more effective or safer when used for non‐surgical acute pain, or acute pain in the community when appropriate and reliable monitoring is not available. Two Australian guidelines do not specify the acute pain setting when advising that MR opioids not be used.9,11

The most recent Australian guidance documents recommend that, if an opioid is indicated for the management of acute pain, an IR and not MR opioid should be commenced. This does not mean that IR opioid regimens are without risk of patient harm; however, risks can be mitigated through appropriate dosing and safer monitoring practices.

Benefits and risks of immediate‐release compared with modified‐release opioids

Despite the popularity of MR opioid prescription for the management of acute pain, there are few head‐to‐head trials comparing IR and MR opioids (especially the same opioid).15

In some countries, but not Australia, IR oxycodone is available as a tablet containing both oxycodone and paracetamol. This combination tablet limits the amount of oxycodone that can be given because of recommended maximum daily doses of paracetamol. Therefore, MR oxycodone should be compared with oxycodone alone. There was no good evidence to support the idea that MR oxycodone was superior to IR oxycodone alone when prescribing of MR oxycodone for acute pain started to become common practice.3,16 One study reporting significantly better pain relief and fewer adverse effects associated with the use of MR compared with IR oxycodone alone was retracted a decade later because of scientific fraud.17

Recent Australian publications show that, compared with IR opioids, use of MR formulations (with or without additional IR opioid as needed) for the management of acute post‐operative pain actually leads to less effective pain relief, higher opioid dose requirements, an increased risk of opioid‐related adverse events, increased lengths of hospital stay, and higher 28‐day readmission rates.3,4,15,18 The risk of falls is also increased.4 Older patients may be at particular risk because of age, comorbid conditions, or concurrent medications.19 MR opioid formulations have also been associated with more frequent opioid‐related adverse events after hospital discharge.20

The risk of PPOU, where opioids are continued for longer than 30 days after initial prescription for acute pain, is higher in patients given MR compared with IR opioids.6,7 Estimates of new long term opioid use after opioids have been prescribed for post‐operative pain vary from less than 1% to 13%; however, the risks may be greater the longer the duration of initial use and with higher doses.12 An Australian study reported a fivefold greater risk of PPOU in opioid‐naïve patients discharged with MR + IR (5%) compared with IR opioids only (1%).21

Compared with IR opioids, the risk of opioid‐induced ventilatory impairment (OIVI) is also increased when MR opioids are prescribed for the management of acute pain.7

Marketing of MR opioids promoted the ideas of easy 12‐hourly dosing schedules and constant plasma concentrations leading to sustained pain relief.22 However, acute pain is not constant and the slow onset and offset of MR opioids means doses cannot be rapidly and safely titrated for each patient — neither up‐titrated to better cover severe episodes of acute pain associated with activity, nor down‐titrated as opioid requirements decrease as the patient recovers or if the patient has severe opioid‐related adverse effects.19,22

The aim of good acute pain management is to assist with recovery and return of patient function. The faster onset and shorter duration of action of IR opioid formulations enables more rapid and safer titration of opioid doses to better match patient needs.19 That is, titration of IR opioids can more rapidly cover the considerable and often rapid variations in pain intensity that may be experienced by patients with acute pain.22 Regular use of non‐sedating analgesia agents, including simple analgesics, and local anaesthetic techniques, where indicated, provides a sustained and opioid‐sparing background level of analgesia.

Improving the effectiveness and safety of immediate‐release opioid regimens

Concerns about opioid use should not lead to underprescription for patients with acute pain where there is an appropriate need. There needs to be an evidence‐based move towards maximising safety and efficacy in prescribing, by limiting commencement of MR opioids while advocating for appropriate dosing of IR opioids.

Just as MR opioid regimens fail to enable adequate titration in a patient with acute pain, so do some IR opioid regimens, especially when prescribed doses are inappropriate (including underdosing) or dose intervals are too long. There is, unfortunately, a lack of good evidence to support the best way to use IR opioids in the acute pain setting. However, a number of consensus‐based Australian guidelines have been published and should be considered for use.6,10,11,23

For IR opioid regimens to be as safe and effective as possible, they need to be titrated to individual patient needs. A “one size fits all” prescription will not be appropriate for all patients, and inadequate monitoring and a lack of individual dose titration, as well as a failure to intervene quickly should the patient show signs of OIVI, can lead to patient harm. Suggested requirements for individualised opioid titration regimens are described in the Box.

Atypical opioids (meaning their analgesic effect does not only result from μ‐opioid‐receptor activation), including tapentadol, tramadol and buprenorphine, are increasingly prescribed in the acute pain setting. At equianalgesic doses, the risks of OIVI from IR tapentadol and tramadol are less compared with conventional μ‐agonist opioids such as oxycodone.19 There is no difference in the incidence of OIVI in patients given parenteral or sublingual buprenorphine compared with conventional opioids.19 Coprescription of more than one opioid increases the risk of OIVI; this includes coprescription of a conventional and atypical opioid (eg, tapentadol and oxycodone).7 A dosing interval for one opioid makes little sense in the context of coprescription of more than one opioid where there is no guidance about intervals between them.

Conclusions

The widespread use of MR opioids in acute pain occurred despite the lack of any good evidence of benefit compared with IR opioids. Patients should be prescribed adequate initial age‐ and condition‐appropriate IR doses that are then titrated to the variable levels of pain that occur throughout the acute pain period, with close monitoring, particularly for excessive sedation. The literature clearly shows that MR opioid use in acute pain is associated with less effective pain relief and a greater risk of patient harm. Although continuing pre‐operative long term MR opioids is good practice, MR opioids should no longer be routinely initiated for management of acute pain.