The FDA has announced updates to the prescribing information and safety labelling for all prescription opioid medicines, including both immediate-release (IR) and extended-release/long-acting (ER/LA) formulations. These updates include the addition of a new warning regarding the risk of opioid-induced hyperalgesia (OIH), cautionary notes on the extended use of opioid products and reordering of information in the Boxed Warning [1].
Opioids Overview
Opioids are therapeutic agents commonly used for moderate to severe acute and chronic pain [2], particularly when other treatments have been ineffective.
Opioid receptors are classified into μ (Mu), δ (delta) and κ (kappa) receptors, as well as the non-classical nociception (NOP) receptor. Clinically used opioids are all μ-opioid receptor agonists, and their actions on the μ receptor lead to both desired clinical effects and significant adverse effects [2]. The μ receptor is expressed in the brain, spinal cord, and other parts of the body. Activation of this receptor produces analgesic effects and pain relief. However, it also induces tolerance, addiction, dependence, respiratory depression, and constipation [2].
FDA Updates [1]
The FDA has identified a concerning trend of opioid medicines being prescribed in excessive quantities, resulting in an increased risk of misuse and overdose. Extensive data suggests that the likelihood of an overdose rises with higher prescribed doses of opioid pain medications, and this risk exists at any stage of the treatment process.
The FDA has also discovered a link between the use of opioid medicines and opioid-induced hyperalgesia (OIH). They have documented 46 cases where hyperalgesia and allodynia were observed during the use of opioids for pain management. Among these cases, 8 involved short-term use, while 38 cases involved longer-term use. The opioids used in these cases included morphine, hydromorphone, and most commonly, fentanyl/fentanyl analogues. Cancer was the most prevalent condition being treated in these cases, and discontinuing the use of opioids improved the hyperalgesia and allodynia symptoms.
Although the exact mechanism of OIH is not yet fully understood, it is generally believed to be caused by neuroplastic changes in the peripheral and central nervous system (CNS), leading to sensitization of pronociceptive pathways [3].
The FDA has recently implemented several updates to the prescribing information for both immediate-release (IR) and extended-release/long-acting (ER/LA) opioid medicines. The key updates include:
- Clarification that the risk of overdose increases with higher doses for all opioid pain medications.
- Recommendation that opioid products should not be used for an extended period unless the pain remains severe enough to necessitate opioids and alternative treatments are inadequate. Additionally, it emphasizes that many outpatient acute pain conditions do not require opioid medications for more than a few days.
- Revision of the approved uses for ER/LA formulations to be reserved for severe and persistent pain that requires extended treatment duration with daily opioid medication when alternatives are insufficient.
- Addition of a new warning on opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid medicines, including information on differentiating OIH from opioid tolerance and withdrawal.
- Updating and reordering of information in the Boxed Warning, with an emphasis on warnings about life-threatening respiratory depression and the risks associated with the concomitant use of opioids and benzodiazepines or other central nervous system depressants.
- Various changes to sections such as Indications and Usage, Dosage and Administration, and Warning and Precautions.
The FDA will also update the existing patient Medication Guides to provide education to patients and caregivers. The Table of Key Opioid Label Updates can be found in the FDA’s Drug Safety Communication [1].
Recommendations for Healthcare Professionals [1]
The FDA encourages prescribers to assess the severity of the patient’s pain and discuss its impact on daily activities and functioning. If opioid use is warranted due to severe pain, prescribers should start with the lowest effective dose of an IR opioid for the shortest duration possible. Higher doses should only be considered when lower doses are inadequate, and the potential benefits outweigh the risks.
ER/LA formulations should be reserved for severe and persistent pain that requires long-term treatment when alternative options are insufficient. Prescribers may consider switching to an IR formulation or exploring other alternatives to optimize treatment. Regular re-evaluation of appropriate opioid use and monitoring for signs of addiction, misuse, or abuse should be conducted. Patients should also be informed about the increased risks when opioids are used with other central nervous system depressants and educated about the symptoms of respiratory depression.
If OIH is suspected in a patient, prescribers should consider reducing the dose of the current opioid medication or switching to another opioid-containing product if tolerated. Patients should be advised about the risk of OIH and the importance of not adjusting their opioid dose without consulting a healthcare professional.
Opioids in Asia [4]
The use of prescription opioid medicines in the Asia-Pacific region is not extensively studied, although limited research suggests that rates of prescription medicine misuse in this region are reportedly lower than in many Western countries.
Studies conducted in the West have shown that individuals who misuse opioids obtain their supply from various sources, including doctor-hopping, friends, families, and drug dealers. Although the sources of misused drugs are not well studied in the Asia-Pacific region, a survey of doctors in Singapore revealed that prescribers are aware that they may be prescribing to patients who could potentially abuse the drugs.
In Southeast Asia, health authorities have issued similar safety communications regarding opioid overuse and caution in the past. However, only the Drug Office in Hong Kong has issued safety communications related to this FDA safety communication [5] thus far.
References
- Centre for Drug Evaluation and Research, U.S. Food & Drug Administration. FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use. 2023 Apr; Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use (Accessed: 13 May, 2023)
- Paul AK, Smith CM, Rahmatullah M, Nissapatorn V, Wilairatana P, Spetea M, Gueven N, Dietis N. Opioid Analgesia and Opioid-Induced Adverse Effects: A Review. Pharmaceuticals. 2021; 14(11):1091. https://doi.org/10.3390/ph14111091
- Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011 Mar-Apr;14(2):145-61. PMID: 21412369.
- Chan WL, Wood DM, Dargan PI. Prescription medicine misuse in the Asia-Pacific region: An evolving issue? Br J Clin Pharmacol. 2021 Apr;87(4):1660-1667. doi: 10.1111/bcp.14638. Epub 2020 Nov 22. PMID: 33140471.
- Drug Office, Hong Kong Department of Health. FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use. 2023 Apr; Available at: https://www.drugoffice.gov.hk/eps/upload/eps_news/49332/GB/1/FDA%20updates.pdf (Accessed: 13 May, 2023)
