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Sunday, July 27, 2025

Fentanyl


Fentanyl is a synthetic opioid analgesic that is significantly more potent than morphine and is primarily used in the management of severe pain, particularly in patients who are opioid-tolerant or in cancer-related pain. It is also employed during anesthesia for its rapid onset and short duration of action. Due to its high potency and narrow therapeutic index, fentanyl requires careful dosing and monitoring. Its misuse, particularly in illicit forms, has become a major public health concern worldwide due to its association with respiratory depression and fatal overdoses.

Pharmacological Classification

  • Class: Synthetic opioid analgesic

  • DEA Schedule (U.S.): Schedule II controlled substance

  • ATC Code: N01AH01

  • Chemical class: Phenylpiperidine derivative

Mechanism of Action

Fentanyl is a full agonist at the μ-opioid receptors (MOR) located in the central nervous system (CNS). Activation of these receptors results in:

  • Inhibition of ascending pain pathways

  • Alteration of the perception of and emotional response to pain

  • Increased pain threshold

  • Sedation and euphoria

  • Respiratory depression through depression of brainstem respiratory centers

Fentanyl does not have a ceiling effect like partial agonists; increasing the dose continues to enhance its pharmacodynamic effects, including analgesia and respiratory depression.

Formulations and Routes of Administration

Fentanyl is available in a wide variety of formulations, both for medical use and abuse, including:

  • Injectable solution (IV, IM)

  • Transdermal patches (e.g., Duragesic®): designed for chronic pain control

  • Transmucosal (e.g., lozenges, buccal tablets, sublingual tablets/sprays): typically used in cancer breakthrough pain

  • Nasal spray

  • Sublingual spray

  • Oral film (buccal)

Illicit fentanyl is often found as powder, counterfeit tablets, or mixed with heroin, cocaine, or methamphetamine.

Clinical Uses

Approved Indications

  • Severe chronic pain (e.g., in cancer patients)

  • Post-operative pain management

  • Breakthrough pain in opioid-tolerant patients

  • Adjunct to general anesthesia

  • Sedation in ICU (e.g., continuous infusion)

  • Epidural analgesia during labor or surgery

Unapproved/Off-label Uses

  • Refractory dyspnea in palliative care

  • Sedation in procedural settings

Dosing Guidelines

Parenteral (IV/IM)

  • Initial: 50–100 mcg/dose (adjusted per clinical response)

  • Continuous infusion: 1–2 mcg/kg/hr (ICU sedation or mechanical ventilation)

Transdermal Patch

  • Dosages: 12, 25, 50, 75, 100 mcg/hour (changed every 72 hours)

  • Indicated only for opioid-tolerant patients

  • Delayed onset: analgesic effect begins ~12 hours after application

Transmucosal/Buccal/Sublingual

  • Used for breakthrough cancer pain in opioid-tolerant patients

  • Doses individualized based on titration (e.g., 100–800 mcg per episode)

Pharmacokinetics

  • Absorption: Highly variable depending on the route (rapid onset IV/sublingual, delayed onset patch)

  • Distribution: Highly lipophilic; wide distribution into fatty tissues

  • Metabolism: Primarily hepatic via CYP3A4 to inactive norfentanyl

  • Elimination half-life:

    • IV: ~3–7 hours

    • Patch: 17 hours (after removal)

  • Excretion: Primarily via urine as metabolites

Contraindications

  • Acute or postoperative pain not suitable for opioid therapy

  • Respiratory depression or significant pulmonary compromise

  • Paralytic ileus or acute abdomen

  • Use in opioid-naïve individuals (especially with long-acting formulations)

  • Known hypersensitivity to fentanyl or formulation components

Precautions and Warnings

  • Respiratory depression: Major risk, especially with high doses or in combination with other CNS depressants

  • Abuse, misuse, and addiction potential: High; monitor patients closely

  • Accidental exposure (especially children) to patches or oral forms can be fatal

  • Hyperalgesia: Paradoxical increase in pain with long-term use

  • Tolerance and physical dependence with prolonged use

  • Serotonin syndrome: Risk when used with serotonergic drugs

  • Adrenal insufficiency and hypogonadism: Rare, but possible with chronic use

  • Withdrawal symptoms: Can occur with abrupt cessation

Adverse Effects

Common (1–10%)

  • Constipation

  • Nausea, vomiting

  • Sedation

  • Dizziness, confusion

  • Headache

  • Dry mouth

  • Sweating

  • Urinary retention

  • Pruritus

Serious (Rare)

  • Respiratory depression

  • Apnea

  • Bradycardia

  • Serotonin syndrome

  • Severe hypotension

  • Addiction, misuse, overdose

  • Death (especially with illicit use or improper dosing)

Drug Interactions

CYP3A4 Inhibitors (↑ fentanyl levels, risk of toxicity)

  • Ketoconazole, itraconazole

  • Clarithromycin, erythromycin

  • Ritonavir, cobicistat

  • Verapamil, diltiazem

  • Grapefruit juice

CYP3A4 Inducers (↓ fentanyl levels, reduced efficacy)

  • Rifampicin

  • Carbamazepine

  • Phenytoin

  • St. John's Wort

Other Significant Interactions

  • CNS depressants (benzodiazepines, alcohol, antihistamines): ↑ risk of sedation, respiratory depression

  • MAO inhibitors: contraindicated within 14 days; may lead to serotonin syndrome

  • Serotonergic agents (SSRIs, SNRIs, TCAs, triptans): ↑ serotonin syndrome risk

  • Muscle relaxants: additive hypotension or sedation

Monitoring Parameters

  • Respiratory rate and oxygen saturation

  • Sedation level

  • Pain control and functional improvement

  • Signs of misuse or dependence

  • Blood pressure and heart rate

  • Signs of withdrawal or tolerance

Withdrawal Symptoms

Abrupt discontinuation or a rapid taper in a physically dependent person can result in:

  • Anxiety

  • Irritability

  • Rhinorrhea

  • Mydriasis

  • Yawning

  • Chills, goosebumps

  • Muscle aches

  • Insomnia

  • Nausea, vomiting, diarrhea

Managed by gradual dose reduction or opioid rotation.

Overdose and Antidote

Symptoms

  • Severe respiratory depression

  • Cyanosis

  • Hypotension

  • Coma

  • Bradycardia

  • Pinpoint pupils

Treatment

  • Naloxone (opioid antagonist): IV or IM, repeated doses may be required due to fentanyl’s potency

  • Mechanical ventilation may be necessary

Illicit Use and Public Health Concerns

  • Fentanyl analogs (e.g., carfentanil, acetylfentanyl) have emerged in illicit opioid markets

  • Extremely potent (carfentanil is 100 times more potent than fentanyl)

  • Commonly mixed with heroin or counterfeit tablets

  • Responsible for thousands of overdose deaths globally

  • Urine drug screens may not detect fentanyl without specific assays

Patient Counseling Points

  • Take exactly as prescribed; do not increase dose or frequency without medical advice

  • Do not share medication due to high risk of fatal overdose

  • Avoid alcohol and sedatives while on fentanyl

  • Proper use and disposal of transdermal patches (fold and flush or use take-back programs)

  • Do not apply heat to patch site; increases absorption and overdose risk

  • Store securely to prevent misuse or accidental exposure

Brand Names

  • Duragesic® (transdermal patch)

  • Actiq® (oral transmucosal lozenge)

  • Fentora® (buccal tablet)

  • Sublimaze® (injectable, hospital use)

  • Lazanda® (nasal spray)

  • Subsys® (sublingual spray)

  • Abstral®, Onsolis®, Instanyl®




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