Can Glucagon-like peptide-1 (GLP-1) receptor agonists interact with oxycodone in patients with type 2 diabetes?

GLP-1 Receptor Agonists and Oxycodone: Drug Interaction Assessment

GLP-1 receptor agonists do not have direct pharmacokinetic or pharmacodynamic drug interactions with oxycodone, but their combined use creates a clinically significant additive risk for delayed gastric emptying and aspiration, particularly in perioperative settings. 1

Mechanism of Interaction

The interaction is indirect and mechanistic rather than a traditional drug-drug interaction:

• GLP-1 receptor agonists delay gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, mediated through the vagus nerves 1
• Opioids like oxycodone independently delay gastric emptying through mu-opioid receptor activation in the gastrointestinal tract 1
• When combined, these medications create additive gastric stasis that significantly increases aspiration risk, even with extended fasting periods 1

Clinical Implications and Risk Stratification

The primary concern is perioperative aspiration risk, not systemic drug interactions:

• Retained gastric contents are documented in 24.2% of GLP-1 receptor agonist users versus 5.1% of controls, despite 10-14 day discontinuation and 12-hour fasting 1
• Cases of regurgitation or aspiration during general anesthesia have been reported in patients on GLP-1 receptor agonists who also received opioids perioperatively 1
• Co-prescription of opioids and GLP-1 receptor agonists should be documented as a high-risk factor for delayed gastric emptying 1

Practical Management Recommendations

For patients on both medications requiring procedures or surgery:

• Document both medications as co-prescribed drugs that delay gastric emptying 1
• For weight loss patients (non-diabetic), discontinue GLP-1 receptor agonist for at least 3 weeks (three half-lives for semaglutide) before elective procedures 1
• For diabetic patients, consult endocrinology regarding risks and benefits of holding GLP-1 receptor agonist, considering bridging therapy 1
• Consider gastric ultrasound pre-operatively to assess residual gastric contents in all patients on this combination 1
• Use rapid-sequence intubation to reduce aspiration risk if both medications cannot be discontinued 1

Non-Perioperative Settings

In outpatient chronic pain management:

• No dose adjustments of either medication are required based on pharmacokinetic interactions 2, 3
• Monitor for enhanced gastrointestinal side effects, particularly nausea, which occurs in 17-44% of GLP-1 receptor agonist users and is also common with opioids 4, 2
• The glucose-dependent mechanism of GLP-1 receptor agonists means no increased hypoglycemia risk when combined with oxycodone 3, 5
• Constipation from oxycodone may partially offset diarrhea from GLP-1 receptor agonists (occurring in 12-32% of users), though this is not a therapeutic strategy 4

Common Pitfalls to Avoid

• Do not assume standard fasting periods are adequate for patients on both medications—extended fasting does not eliminate aspiration risk 1
• Do not overlook this combination when assessing perioperative risk—it requires specific documentation and risk mitigation strategies 1
• Do not discontinue GLP-1 receptor agonists in diabetic patients without endocrinology consultation, as glycemic control benefits may outweigh aspiration risks in some cases 1