Fentanyl

Synthetic drug that has been one of the most commonly used opioid analgesics for more than 50 years. Fentanyl is 100 times more potent than morphine and is primarily used for the treatment of acute and chronic pain. In addition to its analgesic use, fentanyl is also suitable as a narcotic in higher doses (Stanley TH 2014). Fentanyl falls under the German and Swiss Narcotics Act and the Austrian Narcotics Act.

Opioid analgesics act via so-called opioid receptors. The lipophilic fentanyl binds primarily to the μ-opioid receptor on cell surfaces. Because this type of receptor is found at many sites in the body, fentanyl exhibits both a central and a peripheral effect.

In the periphery, it prevents the formation or transmission of excitations at sensory nerve terminals. At the spinal and supraspinal levels, it interferes with pain pathways and modulates, among other things, the sensation of pain. Via opioid receptors in the brain, fentanyl is also sedative, and in high doses comatose. Because fentanyl can easily cross the blood-brain barrier, it has a euphoric effect and a high potential for addiction. Due to the wide distribution of μ-opioid receptors in the body, the active substance has a broad spectrum of side effects.

Fentanyl can be administered orally, sublingually, transdermally, as a nasal spray or intravenously. The duration of action depends on the form of administration.

Intravenous use: When administered intravenously, a central effect occurs as early as 5 minutes after application. The distribution half-life is about 10 minutes, the half-life 3 to 12 H.

Transdermal application: In this case, the serum level rises slowly and reaches a sufficient level after 12 to 24 hours. This level remains relatively constant for about 72 hours. The half-life is 17 hours.

Approximately 80% of the active ingredient is bound to plasma proteins, regardless of the dosage form. Fentanyl is metabolized to norfentanyl predominantly in the liver via the enzyme CYP3A4. Norfentanyl has no opioid effect. Excretion is predominantly renal with only a small percentage excreted in the stool. Much of the drug is stored in the lungs during the first passage. Subsequently, the content increases in less well perfused tissues and subsequently accumulates mainly in fatty and muscle tissue.

Fentanyl is commonly used as fentanyl dihydrogen citrate. Four forms of administration are common.

• intravenous administration (e.g. in anaesthesia or emergency medicine)
• transdermal application (i.e. as a membrane patch adhered to the skin, which then releases the active ingredient (at either 12.5/ 25/ 37.5/ 50/ 75 or 100 micrograms per hour) in a controlled manner for absorption through the skin
• oral-transmucosal application: rapid release formulation (oral-transmucosal therapeutic system, used for breakthrough pain as a lozenge containing 200 to 1600 µg of active ingredient with an integrated applicator on the oral mucosa, or as a buccal tablet containing 100 to 800 µg of active ingredient or as a sublingual tablet containing 50 to 800 µg of fentanyl.
• nasal application: fentanyl nasal spray

Treatment of severe to very severe pain when non-opioid painkillers or weakly acting opioids show no or only insufficient effect. This applies to tumour pain or traumatic pain after accidents and operations. Fentanyl is not indicated for the long-term treatment of chronic pain.

Fentanyl must not be used during pregnancy because fentanyl can cross the placental barrier and animal studies have shown a reproductive toxic effect.

The potential risk to humans is not known; there are insufficient data when used in pregnant women. There is a risk of withdrawal symptoms in the neonate with prolonged use.

Use during childbirth (including cesarean section) is not recommended because fentanyl may cause respiratory depression in the fetus/newborn.

Fentanyl passes into breast milk and thus may cause sedation and/or respiratory depression in the breastfed infant. Therefore, women should not breastfeed until at least 24 hours after the last intravenous application, for at least 72 hours after removal of a patch, and for at least 5 days after the last buccal application of fentanyl. A benefit-risk analysis of breastfeeding after use of fentanyl should be considered.

The dosage of fentanyl is individually adjusted to the patient's age, weight, general condition, concomitant diseases, concomitant medication and indication.

The side effects depend on the form of application (e.g. transdermal or intravenous). Exact details on the respective form of administration can be found in the technical information.

Very common: somnolence, headache, dizziness, nausea, vomiting, constipation, sweating, pruritus.

Frequent: xerostomia, dyspepsia, skin reactions at application site with transdermal administration.

Sedation, nervousness, loss of appetite

Occasional: tachycardia, bradycardia, tremor, paresthesia, speech disorders, dyspnea, hypoventilation, diarrhea, urinary retention, hypertension/hypotension, hallucinations, euphoria, amnesia, agitation, cough (Chen R et al. 2020; Ai Q et al. 2010).

Furthermore: exanthema, contact allergic reactions to fentanyl patches (Rojas-Pérez-Ezquerra P et al. 2019).

Rare: arrhythmia, hiccups, vasodilation, edema, cold sensation, amblyopia.

Very rare: Ataxia, seizures (including clinical and grand mal seizures), respiratory depression, apnea, painful flatulence, ileus, cystalgia, oliguria, anaphylaxis (Dewachter Pet al. (2009), delusions, agitation, disturbance of sexual function.

Side effects of unknown frequency: habituation, physical and psychological dependence, withdrawal symptoms (e.g. nausea, vomiting, diarrhea, anxiety, chills).

Interactions such as respiratory depression may be expected with the following drugs or agents: barbiturates, benzodiazepines, opiates, neuroleptics, halogenated inhalation gases and substances with non-specific central depressant effects (e.g. alcohol).

Additional depressant effects, hypoventilation, hypotension and significant sedation or coma may occur in combination with the following substances or classes of substances: anxiolytics and tranquilizers, hypnotics, general anesthetics, phenothiazines, muscle relaxants, sedative antihistamines, alcohol.

Effects on duration of action are possible due to similar degradation enzymes or enzyme inhibition with: erythromycin, itraconazole, ketoconazole, diltiazem, cimetidine, ritonavir, some macrolide antibiotics.

Other substances that may interact: nitrous oxide or even small doses of diazepam: impairment of cardiovascular function.

midazolam: hypotension

Neuroleptics: hypotension, hypertension, reduced pulmonary artery pressure, tremor, restlessness, postoperative episodes with hallucinations

MAO inhibitors within the last 14 days: life-threatening interactions on central nervous system, respiratory and circulatory functions.

cimetidine: increased plasma levels of fentanyl

Buprenorphine, nalbuphine, and pentazocine: antagonization of analgesic effect and risk of withdrawal symptoms

Drugs affecting serotonergic neurotransmitter systems: risk of serotonin syndrome.

hypersensitivity to fentanyl or other opioids and other components of the dosage form but also hydrogenated rosin, soy and peanut

severe impairment of the central nervous system

Abstral®; Allomedic Sublingual Tablets®; Durogesic SMAT®, Actiq®, Effentora®, PecFent®, Instanyl®.

Fentanyl belongs to the group of narcotics and falls under the Narcotics Act. According to the Drug Commission of the German Medical Profession, the strictest criteria must be applied when prescribing and using the active ingredient, as there are repeated reports of serious side effects and deaths in connection with the improper administration of fentanyl. In recent years, fentanyl derivatives have increasingly appeared on the drug market. The number of addicts of these substances has also increased worldwide.

Effect on ability to drive and operate machinery: Patients receiving intravenous fentanyl should not participate in road traffic, operate machinery or work without a safe stop. For further information, please refer to the relevant product information.

1. Ai Q et al. (2010) Pentazocine pretreatment suppresses fentanyl-induced cough. Pharmacol Rep 62: 747-750.
2. Chen R et al (2020) Mechanism and management of fentanyl-induced cough. Front Pharmacol11:584177.
3. Dewachter Pet al (2009) An anaphylactic reaction to transdermally delivered fentanyl. Acta Anaesthesiol Scand 53:1092-1093.
4. Pergolizzi J et al. (2008) Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract 8:287-313.
5. Rojas-Pérez-Ezquerra Pet al. (2019) Allergic Contact Dermatitis to Fentanyl TTS with Good Tolerance to Systemic Fentanyl. Recent Pat Inflamm Allergy Drug Discov 13:66-68.
6. Stanley TH (2014) The fentanyl story. J Pain 15:1215-1226.