- USES: Fentanyl is used for the treatment of persistent moderate to severe chronic pain (eg, cancer pain) in opioid tolerant individuals. It may also be used for anesthesia and analgesia in the mechanically ventilated patient in the intensive care unit. It is available via the following routes: parenteral, transmucosal (transmucosal lozenge, buccal soluble film), transdermal, and sublingual (spray and tablet). It has been abused, similar to other opioids. PHARMACOLOGY: Fentanyl is a pure opioid agonist of high potency (80 to 100 times more potent than morphine) with a short duration of action. It is known to be a mu-opioid receptor agonist that can produce respiratory depression. Fentanyl exerts its primary pharmacologic effects on the central nervous system (ie, depresses the respiratory centers, depresses the cough reflex, and constricts the pupils). TOXICOLOGY: Therapeutic and toxic effects are mediated by different opioid receptors. Mu 1: Supraspinal and peripheral analgesia, sedation, and euphoria. Mu 2: Spinal analgesia, respiratory depression, physical dependence, GI dysmotility, bradycardia and pruritus. Kappa 1: Spinal analgesia and miosis. Kappa 2: Dysphoria and psychotomimesis. Kappa 3: Supraspinal analgesia. Chronic opioid users develop tolerance to the analgesic and euphoric effects, but not to the respiratory depression effects. EPIDEMIOLOGY: There have been several outbreaks of fentanyl toxicity where it was injected as a street drug of abuse. In general, pharmaceutical fentanyl exposures are less common as compared to other opiates; however, deaths have been reported in both opioid tolerant and non-tolerant individuals following intentional and unintentional misuse of fentanyl (eg, transdermal). Acetyl fentanyl is an injectable fentanyl analog that has been used illicitly. MILD TO MODERATE TOXICITY: Euphoria, drowsiness, headache, anxiety, dizziness, constipation, nausea, vomiting and pinpoint pupils. SEVERE POISONING: Respiratory depression leading to apnea or respiratory arrest, hypoxia, circulatory depression, hypotension and shock. Death may result from any of these complications. ADVERSE EFFECTS: COMMON: PARENTERAL: Respiratory depression, apnea, rigidity, and bradycardia may occur with parenteral administration. Other adverse reactions include: hypertension, hypotension, dizziness, blurred vision, nausea, emesis, laryngospasm and diaphoresis. TRANSDERMAL: Titration phase: Nausea, dizziness, somnolence, vomiting, asthenia and headache may occur. Maintenance: Dyspnea, constipation, anxiety, confusion, depression, rash and insomnia may develop. BUCCAL FILM: Nausea, vomiting, dizziness, dehydration, dyspnea and somnolence may be observed. As with other opiates, tolerance and physical dependence can develop with regular use of fentanyl.
Range of Toxicity:
- TOXICITY: ADULT: INTRAVENOUS: Intentional misuse of intravenous fentanyl can result in rapid death due to respiratory depression. If a product designed for slow release (eg transdermal patch) is abused in a manner that allows rapid release of the entire dose (eg smoked, chewed, swallowed inserted rectally or vaginally, injected, insufflated), severe, potentially fatal toxicity is expected. TRANSDERMAL: Fentanyl transdermal patches have been intentionally misused via inhalation, ingestion and intravenous exposure. Deaths have been reported. An adult died after cutting apart a 7.5 mg fentanyl transdermal patch and ingesting the contents. In another case, typical opioid toxicity occurred in an adult who intentionally inserted several fentanyl patches rectally; recovery was uneventful following removal. PEDIATRIC: A 15-year-old girl survived respiratory depression and coma after applying 5 transdermal 100 mcg/hour fentanyl patches to her body that were left in place for 12 hours. SUBLINGUAL SPRAY: Sublingual spray fentanyl is not bioequivalent with other forms of fentanyl. PEDIATRIC: A 12-month-old (11 kg) died after ingesting a transdermal fentanyl patch 25 mcg/hr (4.2 mg). THERAPEUTIC DOSE: ADULT: FENTANYL CITRATE INJECTION: Adjunct to general anesthesia, doses may vary from 2 mcg/kg (minor surgical procedure) up to 20 to 50 mcg/kg (major surgical procedure). Adjunctive for Regional Anesthesia: 50 to 100 mcg IM or IV slowly over 1 to 2 minutes. Premedication: 50 to 100 mcg IM 30 to 60 minutes prior to surgery. BUCCAL SOLUBLE FILM: Initial dose: 200 mcg for the management of pain in patients who are already opioid tolerant. Titrate dose using 200 mcg film increments up to a maximum of four 200 mcg films or a single 1200 mcg film. ORAL TRANSMUCOSAL LOZENGE: Initial dose: 200 mcg/unit. Maximum dose for any breakthrough pain episode is 2 doses. Patients should wait at least 4 hrs before treating another episode of breakthrough pain. TRANSDERMAL SYSTEM: In opioid-tolerant patients, the transdermal fentanyl dosage is based on the patient’s current 24 hrs morphine requirement; replace patch every 72 hrs. PEDIATRIC: FENTANYL CITRATE INJECTION: Children 2 to 12 years of age: Induction and Maintenance of Anesthesia: A reduced dose as low as 2 to 3 mcg/kg is recommended. BUCCAL SOLUBLE FILM: Safety and efficacy have not been established in pediatric patients less than 18 years of age. TRANSMUCOSAL LOZENGE: Safety and efficacy have not been determined in children 16 years of age and less. TRANSDERMAL SYSTEM: Children 2 years and older: In opioid-tolerant patients, the transdermal fentanyl dosage is based on the patient’s current 24 hr morphine requirement; replace patch every 72 hrs.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients may only need observation. MANAGEMENT OF SEVERE TOXICITY: Administer oxygen and assist ventilation for respiratory depression. Naloxone is the antidote indicated for severe toxicity (respiratory or CNS depression). Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.
- Decontamination: PREHOSPITAL: Fentanyl is absorbed rapidly, GI decontamination is unlikely to be of benefit and may cause aspiration; it should be avoided. Search for and remove any fentanyl patches on the patient’s body. HOSPITAL: Fentanyl is absorbed rapidly, GI decontamination is unlikely to be of benefit and may cause aspiration; it should be avoided. Search for and remove any patches on the patient’s body (including rectum and vagina).
- Airway management: Administer oxygen and assist ventilation for respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone, or in patients who develop severe acute lung injury.
- Antidote: NALOXONE, an opioid antagonist, is the specific antidote. Naloxone can be given intravascularly, intramuscularly, subcutaneously, intranasally or endotracheally. The usual dose is 0.4 to 2.0 mg IV. In patients with suspected opioid dependence incremental doses of 0.2 mg IV should be administered, titrated to reversal of respiratory depression and coma, to avoid precipitating acute opioid withdrawal. Doses may be repeated every 2 to 3 minutes up to 20 mg. Very high doses are rarely needed, but may be necessary in overdoses of high potency opioids, such as fentanyl. A CONTINUOUS infusion may be necessary in patients who ingest a sustained release formulation such as a patch. A suggested starting rate is two-thirds of the dose effective for initial reversal that is administered each hour; titrate as needed. Naloxone can precipitate withdrawal in an opioid-dependent patients, which is usually not life-threatening; however it can be extremely uncomfortable for the patient.
- Seizure: Seizures are rare, but may be a result of hypoxia or due to properties of certain agents or their metabolites (eg, meperidine, tramadol, propoxyphene). Treatment includes ensuring adequate oxygenation, and administering intravenous benzodiazepines; propofol or barbiturates may be indicated, if seizures persist.
- Acute lung injury: Acute lung injury can develop in a small proportion of patients after an acute opioid overdose, and has been reported in a number of patients following intravenous overdose of fentanyl. The pathophysiology is unclear. Patients should be observed for 4 to 6 hours after overdose to evaluate for hypoxia and/or the development of acute lung injury. Continuous oxygen therapy, pulse oximetry, PEEP and mechanical ventilation may be necessary.
- Hypotensive episode: Hypotension is often reversed by naloxone. Initially treat with a saline bolus, if patient can tolerate a fluid load; then adrenergic vasopressors to raise mean arterial pressure.
- Monitoring of patient: Monitor vital signs frequently, pulse oximetry, and continuous cardiac monitoring. Monitor carefully for CNS and respiratory depression. Urine toxicology screens for opioids often do not detect synthetic opioids such as fentanyl. Plasma concentrations are available from specialty labs. They are not available rapidly and are not useful for guiding therapy, but may confirm exposure. Routine lab work is usually not indicated, unless it is helpful to exclude other causes or if the diagnosis of fentanyl toxicity is uncertain. Evaluate for pulmonary and central nervous system manifestation of toxicity or sequelae from toxicity.
- Enhanced elimination procedure: Hemodialysis and hemoperfusion are not of value because of the large volume of distribution of fentanyl.
- Intrathecal injection: Limited experience. Treat seizures (benzodiazepines, barbiturates, propofol) and support blood pressure with fluids and pressors as needed. Naloxone infusion may be useful. Intubate and ventilate as needed. Cerebrospinal fluid drainage may accelerate recovery.
- Patient disposition: HOME CRITERIA: Respiratory depression may occur at doses just above a therapeutic dose. Children should be evaluated in the hospital and observed as they are generally opioid naive and may develop respiratory depression. Adults should be evaluated by a health care professional if they have received a higher than recommended (therapeutic) dose, especially if opioid naive. OBSERVATION CRITERIA: Patients with deliberate exposures and all children with exposures should be sent to a health care facility for observation for at least 4 hours, as peak plasma concentration and symptoms will likely develop within this time period. Opioid-naive patients who have been exposed to a transdermal patch (even after patch removal) have the potential to manifest symptoms in a delayed fashion and should be observed for 8 hours, and admitted if symptoms persist. If the exposure was intravenous, the patient should be observed for 4 to 6 hours after the last naloxone dose, for recurrent CNS depression or acute lung injury. Asymptomatic children under 6 years of age should be observed in the Emergency Department for at least 8 hours following application of a transdermal fentanyl patch once patch is removed and the skin washed, as systemic absorption from the dermal depot continues after patch removal. ADMISSION CRITERIA: Patients with significant persistent central nervous depression should be admitted to the hospital. Patients needing more than 2 doses of naloxone should be admitted as he/she may need additional doses. Patients with coma, seizures, dysrhythmias, or delirium or those needing a naloxone infusion or intubated patients should be admitted to an intensive care setting. Any patient who ingests or inserts rectally or vaginally a patch should be admitted as absorption is unpredictable, and rectal, vaginal or transdermal patches should be removed. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.