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Fentanyl Interactions and Contraindications

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Fentanyl is a potent opioid that is most often found illicitly but can be obtained in some forms with a prescription. It’s been known to interact with many prescription drugs, including benzodiazepines, antidepressants, and other opioids. It may also interact with over-the-counter medicines, herbal supplements, illegal substances, and alcohol. Fentanyl is contraindicated (not recommended) for those with certain conditions, including respiratory depression, paralytic ileus, or hypersensitivity to the drug. (1)

If you or a loved one is using fentanyl for legitimate medical purposes or recreationally, it’s important to understand that it’s an extremely dangerous drug, even when used independently, and mixing it with other substances can increase the risk of severe side effects, life-threatening complications, and overdose. Fentanyl use and misuse, especially in excessive amounts or over a prolonged period, can also rapidly lead to dependence. Contact Guardian Recovery today for more information about the dangers and risks of fentanyl and how we can help you overcome addiction.

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Medications That Should Not Be Used With Fentanyl

Fentanyl is a potent opioid that is 50 times more powerful than heroin, and when used medically, it can be effective at managing severe pain. Some medications can interact with fentanyl and cause dangerous side effects.

Medications Not To Be Used With Fentanyl Include:

  • Other opioids, such as oxycodone (Oxycontin), morphine, codeine, hydrocodone, etc., can increase the risk of respiratory depression and overdose.
  • Benzodiazepines, including alprazolam (Xanax), diazepam, or lorazepam, can also cause respiratory depression and overdose.
  • Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), such as sertraline, and monoamine oxidase inhibitors (MAOIs), such as selegiline, can cause serotonin syndrome, a potentially life-threatening condition.
  • Muscle relaxants, including carisoprodol, cyclobenzaprine, or tizanidine, as they can increase the sedative effects of fentanyl.
  • Some antidepressants, such as fluoxetine and paroxetine, can increase the concentration of fentanyl in the body, which can lead to respiratory depression and other adverse effects.

It is important to always inform your healthcare provider of all medications and substances you are taking, including over-the-counter medications, vitamin and mineral supplements, and recreational drugs, to avoid potential interactions.

Fentanyl Interactions With Alcohol

Because alcohol is a central nervous system depressant, it can interact with fentanyl’s sedative properties and cause dangerous effects.

Ways Alcohol Can Interact With Fentanyl Include:

  • Both fentanyl and alcohol can cause sedation, dizziness, and impaired coordination. When used together, these effects can intensify and result in serious complications.
  • Fentanyl and alcohol can both cause slow, shallow breathing, and taking them in combination can increase the risk of life-threatening respiratory depression.
  • Both fentanyl and alcohol can impair judgment and increase impulsivity, and mixing them may be more likely to lead to poor decision-making, impaired driving, or other dangerous behaviors.

As a powerful opioid, fentanyl can adversely affect the liver, and using it with alcohol can increase the risk of liver damage, especially in those who already have liver issues. (2)(3)

Avoiding Grapefruit Juice When Administering Fentanyl

It is recommended to avoid consuming grapefruit or grapefruit juice while using fentanyl, as it can increase the levels of the drug in the bloodstream, leading to potential side effects such as respiratory depression and overdose. This is because grapefruits contain compounds called furanocoumarins that can inhibit the activity of an enzyme called CYP3A4 in the liver and intestines. (4) This enzyme plays an integral role in breaking down fentanyl and other drugs, and when inhibited, levels of fentanyl in the bloodstream can increase significantly.

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What Are the Possible Risks & Side Effects of Fentanyl?

Fentanyl is a potent opioid medication that has many risks and side effects, some related to interactions with other substances.

Potential Risks & Side Effects Include:

  • Sedation—Fentanyl can cause sedation, drowsiness, and impaired coordination. When combined with other sedatives, such as benzodiazepines or muscle relaxants, it can increase the overall tranquilizing effects, leading to impaired judgment and coordination.
  • Cardiovascular Effects—Fentanyl can cause changes in blood pressure, heart rate, and cardiac output. When combined with medications such as beta-blockers or calcium channel blockers, the risk of cardiovascular side effects can increase.
  • Serotonin Syndrome—Fentanyl can interact with certain antidepressant medications that increase serotonin levels in the brain, leading to serotonin syndrome, a potentially lethal condition marked by fever, agitation, confusion, and muscle rigidity. (5)
  • Respiratory Depression—Fentanyl is a potent central nervous system depressant, which means it can impede breathing and cause it to become shallow and slow. When combined with other depressants, such as alcohol, benzodiazepines, or other opioids, this can increase the risk of life-threatening respiratory depression.
  • Liver Toxicity—Fentanyl is broken down in the liver, and certain medications, such as erythromycin or ketoconazole, can inhibit the liver enzyme activity, leading to increased levels of fentanyl in the bloodstream and potential toxicity.

Fentanyl Side Effects Include:

  • Slowed breathing and heart rate.
  • Nausea and vomiting.
  • Dizziness and drowsiness.
  • Constipation.
  • Confusion and disorientation.
  • Itching and rash.
  • Tolerance, dependence, and addiction.
  • Withdrawal symptoms.

Fentanyl Overdose Symptoms Include:

  • Slow, shallow, or stopped breathing.
  • Weak pulse.
  • Constricted pupils.
  • Confusion and disorientation.
  • Blue or gray lips and nails (cyanosis).
  • Cold and clammy skin.
  • Extreme drowsiness or unconsciousness.
  • Coma.

A fentanyl overdose is a life-threatening emergency that requires immediate medical attention. If someone you know is showing signs of an overdose, you are urged to call 911 as soon as possible.

Fentanyl Disease Interactions & Contraindications

Fentanyl should not be used by people who have certain diseases due to the dangers involved, which include complications that can be severe or life-threatening.

Fentanyl Disease Interactions & Contraindications Include:

  • Respiratory Disease—Fentanyl can further compromise respiratory function In people with asthma, chronic obstructive pulmonary disease (COPD), or sleep apnea, potentially leading to respiratory failure.
  • Liver Disease—People who have impaired liver function, such as with cirrhosis or hepatitis, can experience increased levels of fentanyl in their bloodstream and potential liver toxicity.
  • Kidney Disease—People with renal disease, such as chronic kidney disease or failure, may experience decreased elimination of fentanyl and potential accumulation in the body.
  • Cardiovascular Disease—In people with cardiovascular disease, such as coronary artery disease or heart failure, fentanyl can worsen these conditions, leading to potential cardiovascular complications.
  • Seizure Disorder—In people with a history of seizure disorder, fentanyl can increase the risk of seizures.
  • Fentanyl Hypersensitivity—People who are allergic to or sensitive to the drug should not use fentanyl.
  • Paralytic Ileus—Because opioids such as fentanyl impair intestinal motility, the drug should not be used by people with this condition, in which the intestinal muscles are paralyzed and cannot move food and waste through the digestive tract. (6)

Brain Function—Fentanyl can cause respiratory depression and decreased blood pressure, which can further compromise brain function in people with head injuries or increased intracranial pressure.

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Fentanyl is considered relatively safe and effective when used precisely as prescribed by a doctor, although it may still result in dependence and withdrawal symptoms when discontinued. When used illicitly, fentanyl is considerably more dangerous because these forms vary in terms of potency and are not subject to any standards or regulations. Any person who is misusing fentanyl is in imminent danger of suffering a life-threatening overdose and is urged to seek professional help right away.

If you or a loved one needs help breaking free from fentanyl misuse, contact Guardian Recovery today. You can speak to an experienced, empathetic Treatment Advisor and learn about our streamlined admissions process and multiple levels of care. We also provide free, no-obligation health benefits checks and can answer any questions you have about our individualized programs and treatment plans. We are dedicated to helping our clients overcome drug and alcohol addiction and cultivate healthier, more fulfilling lives.


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Disclaimer: Does not guarantee specific treatment outcomes, as individual results may vary. Our services are not a substitute for professional medical advice or diagnosis; please consult a qualified healthcare provider for such matters.

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Reviewed professionally for accuracy by:

Ryan Soave


Ryan Soave brings deep experience as a Licensed Mental Health Counselor, certified trauma therapist, program developer, and research consultant for Huberman Lab at Stanford University Department of Neurobiology. Post-graduation from Wake Forest University, Ryan quickly discovered his acumen for the business world. After almost a decade of successful entrepreneurship and world traveling, he encountered a wave of personal and spiritual challenges; he felt a calling for something more. Ryan returned to school and completed his Master’s Degree in Mental Health Counseling. When he started working with those suffering from addiction and PTSD, he found his passion. He has never looked back.

Written by:

Cayla Clark

Cayla Clark

Cayla Clark grew up in Santa Barbara, CA and graduated from UCLA with a degree in playwriting. Since then she has been writing on addiction recovery and psychology full-time, and has found a home as part of the Guardian Recovery team.

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