What Drugs Interact With Morphine? Understanding Key Drug Interactions

October 11, 2025 •

4 min read

According to the National Institute on Drug Abuse, combining opioids like morphine with other CNS depressants is a major contributor to overdose deaths. Understanding what drugs interact with morphine is crucial for patient safety, as many common medications and substances can cause serious adverse reactions when taken concurrently.

Quick Summary

This article explains critical drug interactions involving morphine, detailing how specific drug classes can cause additive central nervous system depression, serotonin syndrome, or precipitated withdrawal. It identifies medications and substances to avoid and emphasizes monitoring for adverse effects.

Key Points

Additive CNS Depression: Combining morphine with other central nervous system depressants, like benzodiazepines, alcohol, or other opioids, significantly increases the risk of respiratory depression, coma, and death.
Avoid MAOIs: Monoamine oxidase inhibitors (MAOIs) should not be taken with morphine due to the high risk of serotonin syndrome or opioid toxicity; a 14-day washout period is required.
Risk of Serotonin Syndrome: Other serotonergic medications, including SSRIs, SNRIs, and triptans, can also cause serotonin syndrome when combined with morphine and require careful monitoring.
Precipitation of Withdrawal: Mixed agonist/antagonist or partial agonist opioids, such as buprenorphine, can block the effects of morphine and cause withdrawal symptoms in dependent individuals.
Monitor for Constipation: Anticholinergic drugs and other constipating agents can increase the risk of severe constipation and ileus when taken with morphine.
Tell Your Doctor Everything: To ensure safety, always inform your healthcare provider about all prescription drugs, over-the-counter medications, herbal products, and supplements before starting or changing morphine therapy.

Morphine is a powerful opioid analgesic used to treat moderate to severe pain. Its effectiveness comes from its interaction with opioid receptors in the brain and nervous system. However, this potent action also makes it susceptible to serious drug interactions, which can increase side effects, diminish efficacy, or lead to life-threatening complications. Many interactions involve the central nervous system (CNS) or affect the body's metabolic processes. Patients must inform their healthcare provider of all medications and supplements they are taking to avoid potentially dangerous combinations.

Central Nervous System (CNS) Depressants

Perhaps the most critical interaction with morphine involves other CNS depressants. These substances amplify the sedative and respiratory depressant effects of morphine, which can lead to profound sedation, respiratory arrest, coma, and death. This additive effect is particularly dangerous and often cited as a cause of fatal overdose.

Benzodiazepines: Anti-anxiety and sedative medications like alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan) are extremely dangerous when combined with morphine. Concomitant use should be reserved only for cases where alternatives are inadequate and should involve a reduced dosage and close patient monitoring.
Other Opioid Painkillers: Taking morphine with other opioids, such as hydrocodone, oxycodone (OxyContin), or codeine, significantly increases the risk of overdose and severe CNS depression.
Alcohol: Alcohol has an additive CNS depressant effect with morphine and should be strictly avoided. It increases the risk of confusion, drowsiness, and serious breathing problems.
Muscle Relaxants: Medications like cyclobenzaprine (Flexeril) and carisoprodol (Soma) enhance the CNS depressant effects of morphine.
Sedatives and Hypnotics: Sleep medications such as zolpidem (Ambien) or eszopiclone can lead to dangerous levels of sedation when combined with morphine.
First-Generation Antihistamines: Certain antihistamines, like promethazine and diphenhydramine, can cause drowsiness and contribute to the additive sedative effects.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are a class of antidepressants that pose a severe and life-threatening risk when combined with morphine. The interaction can lead to serotonin syndrome or opioid toxicity, which can be fatal. A washout period of at least 14 days is required between discontinuing an MAOI and starting morphine.

Examples: Isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate) are classic MAOIs to avoid.
Other Agents: Certain other drugs, including the antibiotic linezolid and the injectable dye methylene blue, also have MAOI properties and should be avoided.

Serotonergic Drugs

Concomitant use of morphine with other medications that increase serotonin levels can lead to serotonin syndrome, a potentially life-threatening condition caused by excessive nerve cell activity. Patients should be closely monitored for symptoms such as agitation, hallucinations, rapid heartbeat, and fever.

Examples: Selective Serotonin Reuptake Inhibitors (SSRIs) such as sertraline (Zoloft) and fluoxetine (Prozac); Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) like duloxetine (Cymbalta); and triptans used for migraine headaches.

Mixed Agonist/Antagonist Opioids

Combining morphine, a pure opioid agonist, with mixed agonist/antagonist or partial agonist opioids is contraindicated. These drugs work differently on opioid receptors and can displace morphine, leading to reduced pain relief and potentially triggering withdrawal symptoms in a physically dependent patient.

Examples: Butorphanol, pentazocine, nalbuphine, and buprenorphine.

Metabolism-Affecting Drugs

Some medications can influence the body's processing of morphine, altering its concentration in the bloodstream and increasing the risk of adverse effects.

P-Glycoprotein (P-gp) Inhibitors: Drugs that inhibit the P-gp transport protein can increase morphine's absorption and exposure, significantly enhancing its CNS effects. Quinidine is a known P-gp inhibitor that can increase morphine exposure by about two-fold.
Cimetidine: This histamine blocker has been anecdotally reported to precipitate apnea and confusion when co-administered with morphine.

Comparison of Key Morphine Interactions


Interacting Drug Class	Mechanism of Interaction	Potential Risk	Key Examples
CNS Depressants	Additive CNS depression	Severe sedation, respiratory depression, coma, death	Benzodiazepines, alcohol, other opioids, muscle relaxants
MAOIs	Potentiates morphine, affects serotonin	Serotonin syndrome, opioid toxicity	Isocarboxazid, phenelzine, linezolid
Serotonergic Drugs	Increases serotonin levels	Serotonin syndrome	SSRIs, SNRIs, triptans
Mixed Agonist Opioids	Displaces morphine from receptors	Reduced pain relief, precipitated withdrawal	Buprenorphine, pentazocine
P-gp Inhibitors	Increases morphine absorption/exposure	Enhanced CNS effects, increased side effects	Quinidine

Conclusion

Given the wide array of potential drug interactions, exercising extreme caution when taking morphine is paramount. Many interactions, particularly those with CNS depressants and MAOIs, can lead to serious and life-threatening complications. Always disclose all medications, including over-the-counter and herbal supplements, to your doctor or pharmacist. Healthcare providers should carefully evaluate the patient's full medication regimen to avoid dangerous combinations and adjust dosages as necessary. Patient education regarding the risks, especially with alcohol and illicit substances, is a vital part of safe pain management while on morphine therapy.

Visit MedlinePlus for comprehensive drug information and warnings.

Frequently Asked Questions

No, you should not drink alcohol while taking morphine. Alcohol is a CNS depressant and combining it with morphine can cause life-threatening respiratory depression, extreme sedation, and coma.

You should not take morphine with other opioid painkillers like hydrocodone or codeine, as this greatly increases the risk of severe side effects, overdose, and death. However, it is generally safe to take morphine with over-the-counter painkillers like paracetamol (acetaminophen) or ibuprofen.

Combining morphine with benzodiazepines, such as Xanax or Valium, can lead to dangerously enhanced CNS depression, increasing the risk of profound sedation, severe respiratory depression, and death.

It depends on the type of antidepressant. Combining morphine with Monoamine Oxidase Inhibitors (MAOIs) is extremely dangerous and can cause serotonin syndrome or opioid toxicity. Other serotonergic antidepressants, like SSRIs and SNRIs, also increase the risk of serotonin syndrome.

Precipitated withdrawal is a severe and sudden withdrawal syndrome that occurs when a mixed agonist/antagonist opioid (like buprenorphine) is given to a person who is physically dependent on a full opioid agonist (like morphine). The mixed agonist displaces the morphine, causing immediate withdrawal.

Yes, some herbal supplements can interact with morphine. For example, St. John's wort and tryptophan are known to have potential interactions. Always discuss any herbal remedies or supplements with your doctor or pharmacist before using them with morphine.

The most effective way to reduce risk is to provide a complete and accurate list of all medications and supplements you are taking to your healthcare provider. Adhere strictly to the prescribed dosage, avoid alcohol, and be vigilant for any unusual symptoms.