What is synthetic fentanyl?

Synthetic Fentanyl: Clinical Overview

Fentanyl is a potent synthetic opioid analgesic that is 50-100 times more potent than morphine and approximately 80 times more potent than parenteral morphine, making it one of the most powerful opioids available in clinical practice. 1, 2

Chemical and Pharmacological Properties

• Fentanyl is a semi-synthetic opioid with high lipid solubility and low molecular weight, which facilitates rapid absorption through various routes including transdermal, intravenous, and transmucosal administration 1, 3

• The drug acts as a potent μ-selective opioid receptor agonist, producing analgesia, euphoria, respiratory depression, and other typical opioid effects through central nervous system mechanisms 2

• Its molecular formula is C22H28N2O with a molecular weight of 336.5, and it has an extremely high lipophilicity with an n-octanol:water partition coefficient of 860:1 2

Clinical Pharmacokinetics

Onset and Duration

• After intravenous administration of 100 μg, fentanyl has an onset of action of 1-2 minutes with a duration of effect of 30-60 minutes 1, 3

• The typical initial IV dose is 50-100 μg, with supplemental doses of 25 μg administered every 2-5 minutes until adequate sedation or analgesia is achieved 1, 3

• With repeated dosing or continuous infusion, fentanyl accumulates in skeletal muscle and adipose tissue, which can significantly prolong its duration of effect beyond the initial short-acting profile 3

Transdermal Formulation Characteristics

• Transdermal fentanyl patches are undetectable in systemic circulation for 1-2 hours after application, with serum levels rising and analgesic effects evident within 8-16 hours 1

• Steady-state concentrations are achieved at 72 hours, with each patch designed for 3-day application 1

• An intradermal depot develops, so following patch removal, serum levels take approximately 16-17 hours to drop to 50% of peak levels 1, 2

• The mean elimination half-life is approximately 17 hours, requiring monitoring for at least 24 hours after patch removal in patients who experience serious adverse events 2

Critical Safety Considerations

Respiratory Depression

• Respiratory depression is the chief hazard of fentanyl and can persist longer than the analgesic effect, particularly with repeated dosing or in opioid-naive patients 1, 3, 2

• Serious or life-threatening hypoventilation may occur at any time, especially during the initial 24-72 hours following initiation of therapy and following dose increases 2

• A 50% or greater dose reduction is indicated in elderly patients due to prolonged effects and increased sensitivity 1, 3

Unique Adverse Effects

• In large doses, fentanyl can induce chest-wall rigidity resulting from centrally mediated generalized hypertonicity of skeletal muscle, which can make assisted ventilation extremely difficult 1, 3

• Fentanyl has relatively minimal cardiovascular effects compared to other opioids, though small reductions in arterial blood pressure and heart rate may occur 1

• Clinically significant histamine release rarely occurs with fentanyl, even at doses up to 50 mcg/kg 2

Reversal and Monitoring

• Naloxone is the opioid antagonist for fentanyl overdose, with an onset of action of 1-2 minutes but a half-life of only 30-45 minutes 1, 3

• Because naloxone's half-life is shorter than fentanyl's, additional doses or continuous infusion may be necessary, and patients require monitoring for a minimum of 2 hours to prevent resedation 1, 3

• Naloxone should be dosed at 0.2-0.4 mg (0.5-1.0 μg/kg) intravenously every 2-3 minutes until the desired response is attained 1

Clinical Applications

Appropriate Use

• Transdermal fentanyl is best reserved for patients with stable opioid requirements who cannot take oral morphine, serving as an alternative to subcutaneous infusion 1

• The 3-day duration of transdermal patches is advantageous for patients with stable pain but complicates management in those with fluctuating opioid requirements 1

• Fentanyl transdermal systems should ONLY be prescribed to opioid-tolerant patients; use in non-opioid tolerant patients may lead to fatal respiratory depression 2

Contraindications and Warnings

• Fentanyl transdermal systems should be prescribed only by clinicians knowledgeable in continuous administration of potent opioids and management of hypoventilation 2

• Patients must avoid exposing the application site to direct external heat sources (heating pads, hot tubs, saunas, hot baths, sunbathing), as heat increases fentanyl release by up to 120% in AUC values 2

• Patients with fever or increased core body temperature from strenuous exertion require monitoring for opioid side effects, as body temperature of 40°C (104°F) can theoretically increase serum fentanyl concentrations by approximately one-third 2

Public Health Crisis Context

Illicit Fentanyl Epidemic

• Starting in 2013, illicitly manufactured fentanyl (IMF) production and distribution increased to unprecedented levels, with fentanyl submissions to law enforcement increasing 426% nationally during 2013-2014 4

• The emergence of illicitly manufactured fentanyl mixed into heroin, cocaine, and counterfeit pills (often without users' knowledge) has dramatically increased fatal overdose risk 1, 5

• Fentanyl and fentanyl analogs added to or substituting for heroin are causal factors driving overdose death rates higher, with synthetic opioid deaths increasing 79% during 2013-2014 1, 4

• New York City experienced a 55% increase in fatal drug overdose rates from 2015 to 2017, with toxicology data indicating this unprecedented increase was attributable to fentanyl 5

Sources and Abuse Patterns

• There are two main sources of fentanyl on the illicit drug market: illicitly manufactured fentanyl from clandestine laboratories (most common) and diverted pharmaceutical fentanyl, especially transdermal patches 6

• Illicit fentanyl is often mixed with heroin ("fake heroin") to increase potency at low cost, or included in cocaine products and counterfeit oxycodone, hydrocodone, or alprazolam tablets 6

• Fentanyl extracted from transdermal patches can be administered intravenously, insufflated, inhaled after volatilization, applied orally/transmucosally, or inserted rectally 6

• Toxicological data indicates fentanyl use is inextricably linked with polydrug use 6

Clinical Implications

• Attempts to revive fentanyl overdose patients with naloxone may be unsuccessful due to fentanyl's rapid onset of action and high potency 6

• Fentanyl is 50 times more potent than pure heroin, cheaper to manufacture in laboratories worldwide, and easily distributed by mail and couriers 7

• The most common overdose symptoms are coma, lethargy, respiratory depression, and respiratory arrest 6

Metabolism and Detection

• Fentanyl is not used orally because it rapidly undergoes extensive first-pass metabolism in the liver 1

• Fentanyl undergoes N-dealkylation in the liver to its inactive metabolite norfentanyl 8

• Quantitation of fentanyl and norfentanyl in whole blood can be performed using liquid chromatography-tandem mass spectrometry for forensic and clinical purposes 8