Fentanyl

Opioid analgesic – synthetic μ-opioid receptor agonist

ATC code: N02AB03

Updated 12 Aug 2026 · Methodology

Indications

Moderate-to-severe chronic pain

Second line

Transdermal fentanyl is used in stable chronic pain in opioid-tolerant patients who do not manage on oral opioids or have intake problems. NCCN Adult Cancer Pain 2024 and 2018 do not prescribe the patch to opioid-naive patients or for acute pain. Starting dose 25 mcg/h with patch change every 72 hours. Peak concentration is reached at 17–48 hours after the first patch – a short-acting opioid is needed in this window for breakthrough pain.

Only in opioid-tolerant patients with stable chronic pain.

Sources

ICD-10: R52.2 · ICD-11: MG30

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

Mild to moderate pain in adults

Not recommended

Transdermal fentanyl is not used in acute pain – unsuitable pharmacokinetics (slow onset, long elimination), disproportionate risk of fatal respiratory depression in opioid-naive patients. Sublingual and buccal forms (Abstral, Effentora) are approved only for breakthrough pain in cancer patients on stable baseline opioid therapy – not for general acute pain. Per TIRF REMS data, a million off-label prescriptions led to hundreds of deaths in the US.

Sources

AEMPS: Ficha técnica de Fentanilo (2024)

ICD-10: R52 · ICD-11: MG31

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

A highly selective full μ-opioid agonist with 50–100× the affinity of morphine. Analgesia from 100 mcg fentanyl matches 10 mg morphine. High lipophilicity gives rapid CNS entry (IV onset 1–2 minutes) and enables transdermal and sublingual use. CYP3A4-metabolized to inactive metabolites. IV half-life is short (1–2 hours); after patch removal, half-life reaches 17 hours (skin depot).

Safety

Boxed warning

FDA boxed warning: high addiction and abuse risk; fatal respiratory depression in opioid-naive patients on the patch; accidental exposure in children has been fatal; combination with benzodiazepines or other CNS depressants carries risk of profound sedation, respiratory depression, coma, and death; CYP3A4 interactions can dangerously raise fentanyl levels.

Contraindications

Fentanyl hypersensitivity
Opioid-naive patients (transdermal)
Acute pain, postoperative pain with available alternatives
Severe respiratory failure
Acute bronchospasm
Paralytic ileus
Concurrent MAO inhibitors or within 14 days of stopping

Serious adverse effects

Severe respiratory depression (especially in opioid-naive and with benzodiazepines, alcohol, gabapentinoids)
Serotonin syndrome with SSRIs/SNRIs
Physical dependence and withdrawal
Adrenal insufficiency with long-term use
Hypoglycemia
QT prolongation

Common adverse effects

Nausea and vomiting
Constipation
Drowsiness
Confusion
Itching
Dry mouth
Patch site reactions

Pregnancy: can you take Fentanyl?

Long-term T3 use causes neonatal abstinence syndrome. In pregnant patients with severe chronic pain, decisions are made with the obstetrician; non-opioid alternatives are first-line.

Breastfeeding: can you take Fentanyl?

Fentanyl passes into milk. Lactation use is possible in patients on stable opioid therapy under monitoring of infant sedation, weight gain, and activity.

Calculate RID Full profile on NIH LactMed ↗

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Common myths

Myth: «the fentanyl patch is weaker than morphine injections, safe to start at any pain.» Fact: 25 mcg/h patch equals 50–60 mg oral morphine per day – a dose opioid-naive patients cannot tolerate. Patch use in opioid-naive patients is among the most common causes of fatal fentanyl overdose in outpatient practice ( boxed warning 2007, updated 2023). Myth: «with fever or exercise the patch works as usual.» Fact: skin temperature above 40 °C raises fentanyl release by 30–50%; hot showers, heating pads, saunas, and fever are real causes of overdose in patch users.

Drug–nutrient interactions

Grapefruit juice

Fentanyl is cleared by CYP3A4. The Effentora SmPC (buccal fentanyl) names grapefruit juice among moderate inhibitors of this enzyme that can raise fentanyl levels. Excess fentanyl causes deep drowsiness, pinpoint pupils and slow breathing, which can be fatal. The SmPC asks for close, prolonged monitoring when fentanyl is combined with these inhibitors. The safest course is to skip grapefruit juice.

Source: EMA: Ficha técnica de Effentora 100 microgramos comprimidos bucales (fentanilo) (2026)

Label mentions68 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

MajorAmiodarone
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
Majorbenzodiazepinasclass named in the label
«Depresión respiratoria: El uso concomitante de Fentanilo Matrix Normon con medicamentos sedantes como las benzodiazepinas o medicamentos relacionados, alcohol o medicamentos narcóticos depresores del…»
AEMPS, section 4.4 · Open on CIMA
MajorClarithromycin
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorDiltiazem
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorErythromycin
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorFluconazole
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorGabapentin
«El empleo concomitante de Fentanilo Matrix Normon con otros depresores del sistema nervioso central (incluidos benzodiazepinas y otros sedantes/hipnóticos, opioides, anestésicos generales…»
AEMPS, section 4.5 · Open on CIMA
MajorIMAOclass named in the label
«Inhibidores de la Monoamino-oxidasa (IMAOs): No se recomienda el empleo de Fentanilo Matrix Normon en pacientes que requieren la administración concomitante de un IMAO. Se han notificado…»
AEMPS, section 4.5 · Open on CIMA
Majorinhibidores del CYP3A4class named in the label
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorItraconazole
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorKetoconazole
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorMAO inhibitorsclass named in the label
«DRUG INTERACTIONS: Intervention: The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.»
FDA, section 7 · Open on DailyMed
MajorPregabalin
«El empleo concomitante de Fentanilo Matrix Normon con otros depresores del sistema nervioso central (incluidos benzodiazepinas y otros sedantes/hipnóticos, opioides, anestésicos generales…»
AEMPS, section 4.5 · Open on CIMA
Majorrelajantes muscularesclass named in the label
«El empleo concomitante de Fentanilo Matrix Normon con otros depresores del sistema nervioso central (incluidos benzodiazepinas y otros sedantes/hipnóticos, opioides, anestésicos generales…»
AEMPS, section 4.5 · Open on CIMA
MajorRitonavir
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorVerapamil
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
MajorVoriconazole
«Inhibidores del citocromo P450 3A4 CYP3A4: El empleo concomitante de Fentanilo Matrix Normon con inhibidores del citocromo P450 3A4 (CYP3A4) puede producir un aumento de las concentraciones…»
AEMPS, section 4.5 · Open on CIMA
Moderateantihistamínicosclass named in the label
«El empleo concomitante de Fentanilo Matrix Normon con otros depresores del sistema nervioso central (incluidos benzodiazepinas y otros sedantes/hipnóticos, opioides, anestésicos generales…»
AEMPS, section 4.5 · Open on CIMA
ModerateCarbamazepine
«Inductores del citocromo P450 3A4 CYP3A4: El uso concomitante de fentanilo transdérmico con inductores del CYP3A4 puede resultar en una disminución de las concentraciones plasmáticas de fentanilo y…»
AEMPS, section 4.5 · Open on CIMA
ModerateCYP3A4 inducersclass named in the label
«DRUG INTERACTIONS: Intervention: If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Evaluate for signs of opioid…»
FDA, section 7 · Open on DailyMed
ModerateCYP3A4 inhibitorsclass named in the label
«DRUG INTERACTIONS: Intervention: If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Evaluate patients at frequent…»
FDA, section 7 · Open on DailyMed
Moderateinductores del CYP3A4class named in the label
«Inductores del citocromo P450 3A4 CYP3A4: El uso concomitante de fentanilo transdérmico con inductores del CYP3A4 puede resultar en una disminución de las concentraciones plasmáticas de fentanilo y…»
AEMPS, section 4.5 · Open on CIMA
ModerateISRSclass named in the label
«Medicamentos serotoninérgicos: La administración conjunta de fentanilo con fármacos serotoninérgicos, tales como un Inhibidor Selectivo de la Recaptación de Serotonina (ISRS) o un Inhibidor de la…»
AEMPS, section 4.5 · Open on CIMA
Moderatemuscle relaxantsclass named in the label
«DRUG INTERACTIONS: Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. Due…»
FDA, section 7 · Open on DailyMed
ModeratePhenobarbital
«Inductores del citocromo P450 3A4 CYP3A4: El uso concomitante de fentanilo transdérmico con inductores del CYP3A4 puede resultar en una disminución de las concentraciones plasmáticas de fentanilo y…»
AEMPS, section 4.5 · Open on CIMA
ModeratePhenytoin
«Inductores del citocromo P450 3A4 CYP3A4: El uso concomitante de fentanilo transdérmico con inductores del CYP3A4 puede resultar en una disminución de las concentraciones plasmáticas de fentanilo y…»
AEMPS, section 4.5 · Open on CIMA
ModerateRifampicin
«Inductores del citocromo P450 3A4 CYP3A4: El uso concomitante de fentanilo transdérmico con inductores del CYP3A4 puede resultar en una disminución de las concentraciones plasmáticas de fentanilo y…»
AEMPS, section 4.5 · Open on CIMA

From other drugs’ labels

MajorParoxetine
«Fármacos serotoninérgicos: Se aconseja precaución y un estrecho control del paciente cuando se combinan fármacos con actividad serotoninérgica (incluyendo L-triptófano, triptanes, tramadol…»
AEMPS, section 4.5 · Open on CIMA
ModerateCobicistat
«Established and Other Potentially Significant Interactions: fentanyl ↑ fentanyl Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression)…»
FDA, section 7 · Open on DailyMed
ModerateDarunavir
«ANALGÉSICOS NARCÓTICOS / TRATAMIENTO DE LA DEPENDENCIA A LOS OPIÁCEOS: Fentanilo Oxicodona Tramadol»
AEMPS, section 4.5 · Open on CIMA
ModerateDarunavir
«Established and Other Potentially Significant Drug Interactions: Narcotic analgesics metabolized by CYP3A: e.g. fentanyl, oxycodone  fentanyl  oxycodone Careful monitoring of therapeutic…»
FDA, section 7 · Open on DailyMed
ModerateFluconazole
«Fentanilo: Se ha notificado un caso mortal de intoxicación por fentanilo debido a la posible interacción del fentanilo y fluconazol. Además, en un estudio con voluntarios sanos, se ha evidenciado que…»
AEMPS, section 4.5 · Open on CIMA
ModerateMoclobemide
«En los animales, la moclobemida potencia los efectos de los opiáceos. Por tanto, puede ser necesario un ajuste de la dosis con los siguientes opiáceos: morfina, fentanilo y codeína.»
AEMPS, section 4.5 · Open on CIMA
ModerateRitonavir
«Analgésicos: Ritonavir dosificado como potenciador farmacocinético o como agente antirretroviral inhibe CYP3A4 y como resultado se espera un aumento de las concentraciones plasmáticas de fentanilo…»
AEMPS, section 4.5 · Open on CIMA
ModerateRitonavir
«Established and Other Potentially Significant Drug Interactions: Analgesics, Opioid: tramadol, propoxyphene, methadone, fentanyl ↑ analgesics ↓ methadone ↑ fentanyl A dose decrease may be needed for…»
FDA, section 7 · Open on DailyMed
ModerateSertraline
«Se recomienda tener precaución con el uso de fentanilo (utilizado en anestesia general o en el tratamiento del dolor crónico), otros medicamentos serotoninérgicos (incluyendo otros antidepresivos…»
AEMPS, section 4.5 · Open on CIMA
ModerateTranylcypromine
«Clinically-Significant Drug Interactions: Fentanyl Use with caution SS»
FDA, section 7 · Open on DailyMed
ModerateVoriconazole
«Opioides: Se debe considerar una reducci ó n de la dosis de alfentanilo, de fentanilo y de otros opi á ceos de acci ó n corta de estructura similar al fentanilo y que se metabolizan por el CYP3A4 (p…»
AEMPS, section 4.5 · Open on CIMA
ModerateVoriconazole
«DRUG INTERACTIONS: Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with…»
FDA, section 7 · Open on DailyMed
Alprazolam
«Drugs Having Clinically Important Interactions with Alprazolam: Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine…»
FDA, section 7 · Open on DailyMed

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Frequently asked

What is Fentanyl used for?

Fentanyl is evaluated for the following indications with varying evidence strength: Moderate-to-severe chronic pain (evidence tier A), Mild to moderate pain in adults (evidence tier D). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Fentanyl?

Common side effects of Fentanyl (≥ 1 in 100): Nausea and vomiting, Constipation, Drowsiness, Confusion, Itching, Dry mouth. See the Safety section for uncommon and serious reactions.

Is Fentanyl safe during pregnancy?

Long-term T3 use causes neonatal abstinence syndrome. In pregnant patients with severe chronic pain, decisions are made with the obstetrician; non-opioid alternatives are first-line.

Is Fentanyl compatible with breastfeeding?

Fentanyl passes into milk. Lactation use is possible in patients on stable opioid therapy under monitoring of infant sedation, weight gain, and activity.

Who should not take Fentanyl?

Fentanyl is contraindicated in: Fentanyl hypersensitivity; Opioid-naive patients (transdermal); Acute pain, postoperative pain with available alternatives; Severe respiratory failure; Acute bronchospasm. Full list in the Safety section.

Does Fentanyl carry an FDA boxed warning?

Official sources

Direct links to regulator labels. Open in a new tab.

AEMPS / CIMALabel dated 04/04/2025
EMALabel dated 04/04/2008
FDA / DailyMedLabel dated 04/07/2026

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