Metaxalone Drug Interactions: What to Avoid and What to Tell Your Doctor

Metaxalone (Skelaxin) is generally considered well-tolerated, but it has several important drug interactions that every patient should know about before starting treatment. The most serious of these — serotonin syndrome — can be life-threatening if Metaxalone is combined with the wrong medications. This guide covers all of Metaxalone's known interactions and gives you practical advice on what to tell your doctor and pharmacist.

Why Metaxalone Interacts With Other Drugs

Metaxalone produces two main types of interactions:

• Pharmacodynamic interactions: When Metaxalone and another drug share similar effects (like CNS depression or serotonin increase), those effects can add up to dangerous levels.
• Pharmacokinetic interactions: Metaxalone is metabolized by multiple CYP liver enzymes (CYP1A2, 2D6, 2E1, 3A4). Drugs that affect these enzymes can change how much Metaxalone is in your bloodstream.

Most Serious Interaction: Serotonin Syndrome

The most clinically significant interaction with Metaxalone is the risk of serotonin syndrome when combined with serotonergic drugs. Metaxalone appears to inhibit MAO-A, an enzyme that breaks down serotonin. When you add another drug that also increases serotonin, the levels can accumulate to dangerous — even life-threatening — concentrations.

Drugs that increase serotonin syndrome risk when combined with Metaxalone:

• SSRIs (Selective Serotonin Reuptake Inhibitors): Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), escitalopram (Lexapro), citalopram (Celexa)
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq)
• TCAs (Tricyclic Antidepressants): Amitriptyline, nortriptyline, doxepin, imipramine
• MAO Inhibitors: Phenelzine, tranylcypromine, selegiline, rasagiline — and also linezolid (an antibiotic) and intravenous methylene blue. Most MAOIs should be avoided within 2 weeks before or after Metaxalone.
• Opioids: Fentanyl, meperidine, methadone, tramadol — these opioids increase serotonin and should be used with great caution alongside Metaxalone
• Triptans: Sumatriptan (Imitrex), rizatriptan, zolmitriptan, and other migraine triptans
• Other serotonergic drugs: Mirtazapine, trazodone, buspirone, St. John's Wort, MDMA (ecstasy)

Symptoms of serotonin syndrome to watch for: agitation, hallucinations, confusion, rapid heart rate, high fever, excessive sweating, muscle twitching, stiffness, loss of coordination, nausea, vomiting, diarrhea. Seek emergency care immediately if these appear.

CNS Depressant Interactions

Metaxalone is itself a CNS depressant. Combining it with other CNS depressants produces additive effects — the combined sedation, impairment, and respiratory depression can be significantly greater than either drug alone.

Drugs that add to Metaxalone's CNS depressant effects:

• Alcohol: Even one or two drinks can significantly intensify drowsiness and impairment. Avoid alcohol entirely while taking Metaxalone.
• Benzodiazepines: Alprazolam (Xanax), diazepam (Valium), clonazepam (Klonopin), lorazepam (Ativan) — additive CNS and respiratory depression
• Opioid pain relievers: Additive CNS and respiratory depression, plus serotonin risk with certain opioids
• Sleep aids and sedatives: Zolpidem (Ambien), eszopiclone, diphenhydramine (Benadryl)
• Antihistamines: Many OTC cold and allergy medicines contain antihistamines that can add to sedation. Check labels.

Drug Interactions to Flag at the Pharmacy

When you pick up your Metaxalone prescription, proactively mention any of the following to your pharmacist:

• Any antidepressants (especially SSRIs, SNRIs, or TCAs)
• Any pain medications, especially tramadol, fentanyl, or methadone
• Any anti-anxiety medications (benzodiazepines)
• Any migraine medications (triptans)
• Any supplements, including St. John's Wort or tryptophan
• Any sleep aids, sedatives, or antihistamines

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Interactions With Specific Conditions

• Liver disease: Metaxalone is extensively metabolized by the liver. Impaired liver function can cause the drug to accumulate to higher-than-expected levels, intensifying all effects and side effects.
• Kidney disease: Metaxalone is excreted in urine. Impaired kidney function can affect clearance. Severe renal impairment is a contraindication.
• Hemolytic anemia: Metaxalone is contraindicated in patients with a tendency to drug-induced, hemolytic, or other anemias.

The Lab Test Interaction You Need to Know

Metaxalone can cause a false-positive Benedict's test — an older urine glucose test. If you need to have urine glucose tested while taking Metaxalone, make sure the lab uses a glucose-specific test (not Benedict's reagent). Tell your doctor and any lab personnel that you're taking Metaxalone.

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Bottom Line

Metaxalone's most important interaction is with serotonergic medications — the risk of serotonin syndrome is real and potentially serious. The second major concern is additive CNS depression with alcohol, benzodiazepines, and opioids. Before starting Metaxalone, give your doctor and pharmacist a complete list of everything you're taking, including OTC medications and supplements. For more on Metaxalone's side effects, see Metaxalone Side Effects: What to Expect.