Modified-release opioids

In this step, Dr Jane Quinlan, Consultant in Anaesthesia and Pain Medicine at Oxford University Hospitals and Honorary Senior Lecturer at Oxford University, discusses why modified-release opioids are no longer recommended for routine use in acute postoperative pain.

How do modified release preparations work?

Modified-release (MR) opioid formulations (also known as slow-release, sustained-release, controlled-release or long-acting formulations) are medicinal products which are designed to prolong opioid absorption from the gut, resulting in a steady-state plasma concentration over a prolonged period.

Their dosing schedules are usually 12-hourly. MST Continus (an MR formulation of morphine), for example, reaches a peak at 3 hours, with a sustained effect lasting approximately 12 hours. OxyContin (MR oxycodone), notably, has an unusual biphasic release pattern, with approximately 40% of the dose release within 37 minutes, and the remainder having an absorption half-life of 6 hours [1].

Fentanyl and buprenorphine are also available as transdermal drug delivery systems, which similarly produce sustained plasma opioid concentrations. Their absorption profile is even slower, with a slow build-up to a steady-state concentration around the third day, and wide inter-individual variation in the plasma concentrations achieved.

Much of the evidence for the efficacy and safety profile for these preparations was carried out in cancer pain and chronic non-cancer pain populations. Despite this, since they were introduced in the 1990s, the use of MR opioids became a widespread and integral part of many enhanced recovery pathways. They have been found to account for more than a third of all opioids prescribed after surgery in some settings [2].

This practice became accepted in the belief that MR opioids were safer (as the lower peak concentration was supposed to be less rewarding and therefore cause less risk of opioid use disorder), providing better analgesia (as the trough concentration was supposed to be within the therapeutic window), as well as reducing nursing workload.

Although there were some studies which backed these claims, most have been discredited either as frankly fraudulent or as being methodologically flawed [1-2].

Current evidence suggests that the use of these MR formulations is not as safe or effective as initially thought. The use of MR opioids (even when combined with immediate-release [IR] opioids) is associated with worse postoperative analgesia and leads to higher cumulative doses being used.

It is also associated with an increased risk of opioid-related adverse drug events (ORADEs), including opioid-induced ventilatory impairment (OIVI). When they occur, such events last longer than they would with IR formulations due to their slow onset and offset. MR opioids are also associated with longer length of stay, and there is strong evidence that their use is one of the main risk factors for PPOU [3].

As a result, a number of international guidelines and position statements now advise against the use of MR and transdermal opioids in the management of acute postoperative pain [4-5].

Your turn now

Use the comments section below to share your thoughts and experiences.
What do you think about the changing role of modified-release opioids in postoperative pain management? Have you seen these formulations used in this setting?
Have you seen any patients sustain adverse events as a result of the use of modified-release formulations?

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References

_{1. Quinlan J, Levy N, Lobo DN, et al. No place for routine use of modified-release opioids in postoperative pain management. Br J Anaesth 2022;129:290–3.}

_{2. Liu S, Athar A, Quach D, et al. Risks and benefits of oral modified-release compared with oral immediate-release opioid use after surgery: a systematic review and meta-analysis. Anaesthesia 2023;78:1225–36.}

_{3. Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use-United States, 2006-2015. Morb Mortal Wkly Rep 2017;66:265–269.}

_{4. Wilkinson P, Srivastava D. Surgery and Opioids: Best Practice Guidelines 2021. Faculty of Pain Medicine, London (2021).}

_{5. Australian and New Zealand College of Anaesthetists. Statement on the Use of Slow-Release Opioid Preparations in the Treatment of Acute Pain. ANZCA Bull 2018;01:15–6.}