Opioid Toxicity Associated With Tirzepatide in a Patient on Chronic Oral Morphine

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist, delays gastric emptying and can alter the pharmacokinetics of coadministered oral medications, particularly those with narrow therapeutic indices. We report the first case of life-threatening opioid toxicity precipitated by tirzepatide initiation in a patient on chronic oral sustained-action opioid therapy. A 53-year-old man with primary progressive multiple sclerosis complicated by quadriplegia, maintained on oral sustained-action morphine sulfate 180 mg/day for 13 years without incident, presented with opioid-induced respiratory failure six weeks after starting tirzepatide 2.5 mg weekly (escalated to 5 mg at week 4). He required 12 mg of intranasal naloxone for reversal. Concurrent findings included acute kidney injury (creatinine 1.04 mg/dL from a baseline of 0.5-0.6 mg/dL), hemoconcentration, metabolic acidosis, and ketonuria consistent with tirzepatide-associated dehydration. His caregiver had prospectively noted recurrent somnolence after each weekly injection. Two complementary mechanisms likely converged: tirzepatide-mediated delayed gastric emptying disrupting the release profile of sustained-action morphine and dehydration-induced kidney injury impairing renal clearance of morphine-6-glucuronide, the active opioid metabolite. Concurrent use of other renally cleared CNS depressants likely amplified toxicity. A prior hospitalization for sepsis with similar renal impairment, before tirzepatide initiation, did not produce opioid toxicity, offering a useful, though imperfect, point of comparison. Morphine was reduced to 60 mg/day; at follow-up, the patient reported equivalent pain control on one-third of his prior dose. This case highlights a previously unrecognized, clinically significant drug interaction with urgent implications as GLP-1-based therapies are increasingly co-prescribed with chronic opioid therapy, underscoring the need for clinician vigilance and formal pharmacokinetic study.