Mounjaro and Opioids (Oxycodone, Hydrocodone, Tramadol): Interaction Guide

What the Mounjaro label says about other oral medicines

Section 7.2 of the Mounjaro label states that tirzepatide delays gastric emptying and therefore has the potential to affect the absorption of oral medicines taken at the same time. It advises caution and says to monitor patients on oral drugs that depend on threshold concentrations for efficacy, and those with a narrow therapeutic index, naming warfarin as its example [1]. Section 7.1 covers insulin and insulin secretagogues, where the concern is hypoglycemia and a lower secretagogue dose may be needed [1]. Neither section names an opioid.

Mounjaro is labeled for type 2 diabetes in adults and children 10 years and older, and for reducing major cardiovascular events in adults with type 2 diabetes at high risk. It is not labeled for weight loss [1].

The two possible routes of interaction

The first is liver enzymes. Tirzepatide is broken down by proteolytic cleavage of its peptide backbone, beta-oxidation of its fatty diacid and amide hydrolysis rather than by CYP enzymes, and it has low in vitro potential to inhibit or induce CYP enzymes [1].

The opioids here are cleared differently. In a healthy-volunteer oxycodone study, CYP3A-mediated N-demethylation accounted for 45% ± 21% of the dose and CYP2D6-mediated conversion accounted for 11% ± 6% [5]. Tramadol is converted to M1, its main analgesic metabolite, by CYP2D6 [4].

The second route is absorption, and that is the one the Mounjaro label addresses.

How large is the absorption effect? The acetaminophen numbers

The label's own pharmacokinetic work gives a sense of scale. After a first 5 mg dose of tirzepatide, acetaminophen peak concentration (Cmax) was 55% lower and peak time (Tmax) was about 1 hour later. At week 6, on 15 mg, there was no meaningful effect on acetaminophen Cmax or Tmax, and total exposure (AUC) was not changed [1]. The label states separately that the gastric-emptying delay is largest after the first dose and diminishes over time [1].

The drug measured was acetaminophen, not an opioid. These results do not show what happens to oxycodone, hydrocodone or tramadol.

Oxycodone

Oxycodone's visible effects follow the parent drug. In the healthy-volunteer study, the time course of pupil constriction was fully explained by plasma oxycodone; the metabolites added little because of low potency, low circulating amounts or poor entry into the brain [5].

The GI side effects are the more predictable overlap. In Mounjaro's placebo-controlled trials in adults with type 2 diabetes, nausea was 12%, 15% and 18% at 5, 10 and 15 mg versus 4% on placebo, and constipation was 6%, 6% and 7% versus 1% [1]. Opioids cause both as well, and opioid-induced bowel dysfunction includes constipation, decreased gastric emptying, delayed transit and bloating [6].

Hydrocodone

The Mounjaro label reports an acetaminophen absorption study, but it did not measure hydrocodone or a hydrocodone/acetaminophen tablet [1]. The measured pattern was a smaller, later acetaminophen peak after the first dose and no meaningful difference by week 6 on 15 mg [1].

Tramadol

Tramadol differs from the other two. It acts at mu opioid receptors, but it also inhibits serotonin and norepinephrine reuptake [4]. Its main analgesic metabolite, M1, is formed by CYP2D6 [4].

Tirzepatide has low in vitro potential to inhibit or induce CYP enzymes [1]. Because it delays gastric emptying, it may change the timing of absorption of oral tramadol [1].

Nausea, vomiting and constipation

Mounjaro and opioids can each cause nausea and constipation, so these symptoms may be a concern when they are used together [1][6]. Mounjaro's trial rates for vomiting were 5%, 5% and 9% at 5, 10 and 15 mg versus 2% on placebo, and diarrhea 12%, 13% and 17% versus 9% [1]. Severe GI reactions were reported in 1.3%, 0.4% and 1.2% of Mounjaro patients versus 0.9% on placebo, and the label says Mounjaro is not recommended in people with severe gastroparesis [1]. Up to 40% of patients taking opioids develop constipation [2]. Opioid-induced bowel dysfunction can lead some patients to alter or abandon opioid treatment, potentially reducing pain relief [6].

Sedation, drowsiness and breathing

Opioid labels carry a class boxed warning: combining an opioid with benzodiazepines or other CNS depressants, including alcohol, can cause profound sedation, respiratory depression, coma and death. FDA required that warning, with patient medication guides, on nearly 400 opioid and benzodiazepine products in August 2016 [3]. The signs FDA lists are unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, coma and death [3].

The Mounjaro label lists fatigue as an adverse reaction, reported in 10% of the 6,647 adults in its cardiovascular outcomes trial [1].

What changes over the first weeks

Mounjaro starts at 2.5 mg once weekly, with increases of 2.5 mg after at least 4 weeks on the current dose, to a maximum of 15 mg weekly in adults and 10 mg in children 10 and older [1]. The label says the gastric-emptying delay is largest after the first dose and diminishes over time, and that most nausea, vomiting and diarrhea occurred during dose escalation and decreased over time [1].