Fentanyl side effects and how to avoid them

Up to 29% of patients who are prescribed opioids misuse them. Fentanyl high, withdrawal, and overdose are possible fentanyl side effects.

By Georgia C. Yalanis, MD | Jun. 17, 2021 Medically reviewed by Irene Xue, Pharm.D.

Fentanyl is a powerful, synthetic opioid analgesic that is similar to morphine but is 50 to 100 times more potent. Opioid or opiate drugs are medications that act on the opioid receptors in the central nervous system to produce morphine-like effects. Opioids are commonly prescribed by healthcare professionals to provide pain relief.

RELATED: List of opioids

When is fentanyl prescribed?

Fentanyl is often used to treat severe, acute pain including the pain following surgery. Fentanyl is available in a variety of forms and has several brand names, which vary according to the preparation. In a hospital or acute care setting, fentanyl citrate may be administered intramuscularly (IM) or intravenously (IV). Fentanyl is the first medication to be FDA-approved to treat cancer breakthrough pain, and the fentanyl patch is approved to treat chronic pain associated with malignant and non-malignant conditions.

The U.S. Food and Drug Administration (FDA) has categorized certain medications that use fentanyl to augment cancer pain as TIRF (transmucosal immediate-release fentanyl) medications. These preparations allow fentanyl to be absorbed through the nasal and oral mucous membranes and include:

Actiq (fentanyl citrate) oral transmucosal lozenge and its generic equivalent
Fentora (fentanyl citrate) buccal tablet and its generic equivalents
Lazanda (fentanyl) nasal spray
Onsolis (fentanyl) buccal soluble film
Subsys (fentanyl) sublingual spray
Fentanyl citrate sublingual tablets

Fentanyl preparations are not over-the-counter medications. They are prescription drugs with potentially life-threatening side effects and should only be taken when following medical advice. This article will discuss the side effects associated with fentanyl use and abuse, important warnings, and drug interactions, as well as provide tips for how to avoid any adverse effects.

Note: The fentanyl transdermal patch sold under the brand name Duragesic and manufactured by Janssen has been discontinued in the U.S. as of April 1, 2020. The last batch released expires on July 31, 2021. If you have been prescribed the Duragesic/fentanyl transdermal system, speak with your healthcare provider about whether you should continue using this medication or begin a new one.

Common side effects of fentanyl

As with any medication, fentanyl use is associated with some very common, non-serious side effects. If any common side effects become worrisome, individuals should notify their healthcare provider or seek medical care.

Gastrointestinal side effects including stomach pain, nausea, vomiting, diarrhea, and constipation
Sleep disturbances including somnolence or drowsiness, sleepiness or tiredness, sleep apnea, and insomnia
General feelings of malaise, headache, dizziness, lightheadedness, fatigue, confusion, weakness, and lack of energy
Skin problems such as rash, pruritus or itching, and redness of the skin where the sticky side of the patch is placed
Psychiatric effects including anxiety, depression, hallucinations, euphoria, and nervousness
Autonomic nervous system effects including hyperhidrosis or excessive sweating, xerostomia or dry mouth, urinary retention, tremor, and heart palpitations
Peripheral nervous system effects including cold sensations, muscle spasms, and paresthesia or numbness
Peripheral edema
Loss of appetite
Bradycardia or low heart rate
Dyspnea or shortness of breath

Serious side effects of fentanyl

Individuals who use fentanyl preparations may experience severe adverse effects. Drug abuse or overuse could result in death. If prescribed a fentanyl preparation, it should be used only as prescribed and for the individual it was prescribed for. Notify your healthcare provider or seek medical treatment if you experience any serious side effects of fentanyl listed below.

Hypersensitivity reaction including anaphylaxis
Respiratory depression, respiratory arrest, shallow breathing, trouble breathing, or severe breathing problems of any kind
Central sleep apnea and sleep-related hypoxemia (low oxygen levels)
Central nervous system (CNS) depression
Severe hypotension or low blood pressure
Severe bradycardia or slow heart rate, and other cardiac arrhythmias
Cardiac arrest and chest pain
Circulatory collapse
Seizures
Delirium
Sedation
Paralytic ileus or intestinal blockage
Biliary spasm (spasm of the biliary tract)
Laryngospasm (spasm of the vocal cords)
Bronchoconstriction (airway constriction)
Severe muscle rigidity and chest wall rigidity known as “wooden chest syndrome”
Adrenal insufficiency
Opioid-induced androgen deficiency with long-term use
Brain injury with long-term use or abuse
Serotonin syndrome when used with other medications that increase serotonin
Dependency and drug abuse
Withdrawal symptoms with abrupt discontinuation of treatment, including neonatal opioid withdrawal syndrome

How long do fentanyl side effects last?

Fentanyl is often prescribed to treat severe pain as it is rapidly absorbed by the body and will begin working within a few minutes. Because of the way the body metabolizes fentanyl, the analgesic effects from one dose of fentanyl do not last longer than several hours, but transdermal fentanyl patches can be worn for up to 72 hours to provide long-lasting pain relief.

The majority of common side effects associated with using fentanyl are self-limiting (they go away on their own) within several hours to several days of discontinuing the use of the medication. However, there are several long-term side effects and complications associated with long-term fentanyl use or abuse.

Opioids exert much of their effects on the CNS, especially the brain, so they can have severe and lasting effects on health over time. Some common long-term side effects include chronic depression, sensitivity to pain, tolerance to pain medications, and anhedonia—the inability to experience pleasure. These effects may continue for years after using fentanyl for a long period of time.

Some other complications are irreversible. Irreversible effects are usually the result of opioid misuse and include death, side effects from non-fatal overdose such as toxic brain injury, and the decline of functioning leading to difficulties in managing the activities of daily living. ]

Fentanyl contraindications and warnings

Opioids like fentanyl have black box warnings on their labels. Black box warnings are the FDA’s most stringent warning for drugs. A black box warning is meant to provide important drug information to the public and healthcare professionals related to serious side effects such as injury or death.

The black box warning for fentanyl includes:

Addiction, abuse, and misuse: Fentanyl exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Risk should be assessed before prescribing and individuals monitored for these behaviors and conditions.
Life-threatening respiratory depression: Monitor individuals closely, especially upon initiation or following a dose increase.
Liver enzyme interactions: Concomitant use with liver enzyme inhibitor drugs (or discontinuation of inducer drugs) can result in a fatal overdose of fentanyl.
Concomitant use with benzodiazepines or other CNS depressants, including alcohol: This interaction may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant use for individuals for whom alternative treatment options are inadequate; limit dosage and durations to the minimum required, and follow individuals for signs and symptoms of respiratory depression and sedation.

Fentanyl should also be avoided or used with caution in patients with asthma and other lung diseases, gastrointestinal obstruction, head injury, cardiac disease, and liver and kidney problems due to an increased risk of side effects, including respiratory depression.

Fentanyl high and withdrawal

Opioid medications like fentanyl are highly addictive. With prolonged use, it may take higher and higher doses to achieve adequate pain relief and pain can actually become worse. In these conditions, individuals could develop a dependence on the drug in order to function “normally.”

Fentanyl is very potent, which contributes to its high abuse potential. By binding to the opioid receptors in the brain, fentanyl not only reduces pain sensations but also elevates feelings of pleasure. This combination leads to a euphoric feeling or feeling “high.” Since fentanyl has such a short onset, individuals desiring to continue those feelings of pleasure and euphoria require more frequent and higher doses to achieve them. As this cycle continues, dependence can eventually become an addiction.

For individuals trying to get out of this cycle, or who are unable to maintain it, abrupt discontinuation of opioid medications can cause withdrawal, making it difficult, or even painful, to stop taking the medications. Withdrawal symptoms can be severe and life-threatening, usually beginning within 12 to 30 hours after the last dose and increasing in severity for the first few days afterward. Withdrawal symptoms are usually over in seven to 10 days. If you experience any of the withdrawal symptoms below, it is important to seek emergency medical care as opioid withdrawal can be life-threatening and should be done under medical supervision with a slow removal of the drug over a period of time.

Early withdrawal symptoms:

Agitation
Anxiety
Muscle aches
Increased tearing
Insomnia
Runny nose
Sweating
Yawning

Late withdrawal symptoms:

Abdominal cramping
Diarrhea
Dilated pupils
Goosebumps
Nausea
Vomiting

Treatment for withdrawal usually includes medications, counseling, and other support as needed. Withdrawal can be done at home, in dedicated facilities, or in a hospital setting. Several different types of medications can be used including methadone, buprenorphine, and clonidine to help with withdrawal symptoms, and other medications to help with sleep and nausea or vomiting.

Overdose

Opioid overdose usually occurs in a non-clinical setting. Individuals at the highest risk for overdose are those already taking high doses, those with a history of substance abuse, or individuals taking other sedatives. The maximum amount of fentanyl used for pain management after surgery in a clinical setting is generally 100 mcg IV or IM. In clinical trials, the transdermal patch has been studied at very high doses of 600 mcg per hour in cancer patients.

According to the NIH National Institute on Drug Abuse, approximately 21% to 29% of patients prescribed opioids for chronic pain misuse them. Opioid overdose can occur when individuals misuse the medication or obtain the medication from illicit manufacturers or providers. Most of the research studies available do not include information about illicitly manufactured opioids, but they are widely considered to be responsible for the substantial increase in fentanyl overdose deaths seen in the U.S. in the last five years.

Fentanyl overdose is usually treated with a medication called Narcan (naloxone).

Individuals who are worried about misusing opioids and need help can call a local or national hotline to receive addiction assistance. There is effective treatment available at low- to no cost.

Restrictions

Children

The FDA has issued several disclaimers to warn about the accidental exposure to fentanyl patches which can lead to death in children. Fentanyl patches should be stored, used, and disposed of according to the package insert and away from children. Fentanyl preparations in pediatric doses are approved for children 2 years of age and older.

Pregnancy

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome and other negative outcomes such as poor fetal growth. According to the FDA, fentanyl is not recommended for use in labor, when other analgesics are more appropriate.

Breastfeeding

Fentanyl is present in breastmilk. There is limited data to determine the effects of fentanyl on breastfed infants. Use should take into consideration the health benefits of breastfeeding and the mother’s clinical need for fentanyl.

Opioid naive

Fentanyl should not be used in opioid-naive patients who do not use opioids on a regular basis. Fentanyl patches and transmucosal preparations should only be given to patients who have used opioids before and demonstrated tolerance to the therapy, and they are not indicated for short-term or mild pain.

Fentanyl interactions

Fentanyl is contraindicated for use with the following medications:

Mifepristone
Naltrexone
Safinamide

CYP3A4 inhibitors

CYP3A4 is a liver enzyme that aids in the removal of drugs from the body. Fentanyl should not be administered with CYP3A4 inhibitors such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), as well as grapefruit juice. These medications and foods may increase plasma concentrations of fentanyl and prolong opioid adverse reactions, which may exacerbate respiratory depression. This interaction is especially harmful when an inhibitor is added after a stable dose of fentanyl is reached.

Benzodiazepines and CNS depressants

Benzodiazepines and other sedatives, anti-anxiety medications, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol should be avoided while taking fentanyl due to the increased risk of respiratory depression.

How to avoid fentanyl side effects

It is important to follow medical advice while taking this medication. Take only the dose prescribed by a healthcare professional. Do not take more medication and do not take less. Take all of the doses how and when they are prescribed. If you miss a dose, take the next dose as soon as you remember.
Patients should disclose a full medication list, health history, and allergies before taking fentanyl. This includes all medications and supplements, any medical conditions the patient has, or any allergic reactions they have had to medications in the past.
Store and dispose of the medication correctly and away from children. Fentanyl preparations should be stored at room temperature (68 to 77 degrees Fahrenheit). Improper storage and disposal of the medication could potentially expose children to the medication.
Use the medication preparation exactly as it was prepared. Do not modify it in any way.
Avoid grapefruit, alcohol, illegal drugs, other CNS depressants, and medications with known interactions while taking fentanyl. Fentanyl is known to cause severe respiratory depression and should not be taken with any medications that could exacerbate this effect.
Avoid external heat while using the fentanyl patch. Exposure to heat increases fentanyl absorption and may lead to an overdose.
Be informed and aware about access to and availability of treatment for substance use disorders. There are many resources available for individuals who may be living with opioid addiction. Getting help early could save lives.
Intervene early. Patients should immediately seek medical care if they experience any type of allergic reaction to this medication or any evidence of overdose or withdrawal.