Fentanyl Injection

Fentanyl, a potent opioid agonist, was developed in the 1950s to fill a need for strong and rapid analgesia. Because of these characteristics, fentanyl is commonly used to treat chronic cancer pain or in anesthesia. Fentanyl is related to other opioids like morphine and oxycodone.

Fentanyl's high potency has also made it a common adulterant in illicit drugs, especially heroin. In 2017, 47600 overdose deaths in the United States involved some opioid (over 2/3 of all overdose deaths). Opioid overdoses kill an average of 11 Canadians daily.

Fentanyl is an opioid analgesic used in anesthesia, for breakthrough cancer pain, or round the clock pain management.

Fentanyl intravenous or intramuscular injections are indicated for short term analgesia during induction, maintenance, and recovery from general or regional anesthesia. These injections are also used with a neuroleptic for premedication, induction, and as an adjunct to maintenance of anesthesia. Finally, fentanyl intravenous or intramuscular injections are used with oxygen for anesthesia in high risk patients.

Fentanyl sublingual tablets, transmucosal lozenges, buccal tablets, sublingual sprays, transdermal systems, and nasal sprays are indicated for the management of breakthrough pain in opioid tolerant cancer patients who require around the clock pain management.

• Cancer Related Pain (Breakthrough Pain)
• Severe
• Chronic Pain
• Anesthetic premedication therapy
• Anesthetics Agent
• General Anesthesia
• Induction of anesthesia therapy
• Maintenance of anesthesia therapy
• Regional Anesthesia
• Preanesthetic medication therapy

Fentanyl produces strong analgesia through its activation of opioid receptors. It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids. Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines.

Fentanyl binds to opioid receptors, especially the mu opioid receptor, which are coupled to G-proteins. Activation of opioid receptors causes GTP to be exchanged for GDP on the G-proteins which in turn down regulates adenylate cyclase, reducing concentrations of cAMP. Reduced cAMP decreases cAMP dependant influx of calcium ions into the cell. The exchange of GTP for GDP results in hyperpolarization of the cell and inhibition of nerve activity.

Fentanyl sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable).

Fentanyl transmucosal lozenges reach a C_max of 0.4±0.1ng/mL for a 200µg dose and 2.5±0.6ng/mL for a 1600µg dose with a T_max of 20-40 minutes. The AUC was 172±96ng*min/mL for a 200µg dose and 1508±1360ng*min/mL for a 1600µg dose.

Fentanyl sublingual spray reached a C_max of 0.20±0.06ng/mL for a 100µg dose and 1.61±0.60ng/mL for an 800µg dose with a T_max of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng*h/mL for a 100µg dose and 10.38±3.70ng*h/mL for a 800µg dose.

Fentanyl transdermal systems reached a C_max of 0.24±0.20ng/mL with a T_max of 3.6±1.3h for a 25µg/h dose. The AUC was 0.42±0.35ng/mL*h.

Fentanyl nasal spray reaches a C_max of 815±301pg/mL with a T_max of less than 1 hour for a 200µg/100µL dose. The AUC was 3772pg*h/mL.

The intravenous volume of distribution is 4L/kg (3-8L/kg). The oral volume of distribution is 25.4L/kg. In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8L/kg.

Fentanyl crosses the blood brain barrier and the placenta.

Fentanyl is 80-85% bound to plasma proteins. In one study, a 0.1µg/L solution of fentanyl was 77.9±1.1% bound to human serum albumin and 12.0±5.4% bound to α-1 acid glycoprotein. A 0.1µg/L solution of norfentanyl, the primary metabolite of fentanyl, was 7.62±1.2% bound to human serum albumin and 7.24±1.9% bound to α-1 acid glycoprotein.

Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with Label,15,19

The half life of fentanyl is 7 hours. The half life of fentanyl sublingual spray is 5-12 hours.

Total plasma clearance of fentanyl is 0.5L/hr/kg (0.3-0.7L/hr/kg) or 42L/hr. Following an intravenous dose, surgical patients displayed a clearance of 27-75L/h, hepatically impaired patients displayed a clearance of 3-80L/h, and renally impaired patients displayed a clearance of 30-78L/h.

Fentanyl has an intravenous LD₅₀ of 2.91mg/kg in rats, an oral LD₅₀ of 18mg/kg in rats and 368mg/kg in mice. The LD50 in humans is not known.

Symptoms of overdose include respiratory depression, somnolence, stupor, coma, skeletal muscle flaccidity, cold and clammy skin, pupillary constriction, pulmonary edema, bradycardia, hypotension, airway obstruction, atypical snoring, and death. In case of overdose, patients should receive naloxone or nalmefene to reverse the action of the opioids as well as supportive measures to maintain the airway or advanced life support in the case of cardiac arrest.

• Avoid alcohol.

• Starting Dose: The initial dose of Fentanyl should be 100 mcg.
• Re-dosing patients within a single episode:  Dosing may be repeated once during a single episode of breakthrough pain if pain is not adequately relieved by one Fentanyl dose. Re-dosing may occur 30 minutes after the start of administration of Fentanyl and the same dosage strength should be used.
• Increasing the dose:  Titration should be initiated using multiples of the 100 mcg Fentanyl tablet. Patients require to titrate above 100 mcg can be instructed to use two 100 mcg tablets (one on each side of the mouth in the buccal cavity). If this dose is not successful in controlling the breakthrough pain episode, the patient may be instructed to place two 100 mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate above 400 mcg by 200 mcg increments bearing in mind using more than 4 tablets simultaneously has not been studied and it is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. To reduce the risk of overdose during titration, patients should have only one strength of Fentanyl tablet available at any one time.
• Dosage Adjustment: Generally, the dose of Fentanyl should be increased when patients require more than one dose per breakthrough pain episode for several consecutive episodes.

• Fentanyl injection can be administered intravenously either as a bolus or by infusion & by intramuscular route also. The dose of fentanyl should be individualized according to age, body weight, physical status, underlying pathological condition, use of other drugs and type of surgery and anesthesia.

• Doses in excess of 200mcg are for use in anesthesia only. As a premedicant, 1-2 ml fentanyl may be given intramuscularly 45 minutes before induction of anesthesia. After IV administration in unpremedicated adult patients, 2ml fentanyl may be expected to provide sufficient analgesia for 10-20 minutes in surgical procedures involving low pain intensity. 10 ml fentanyl injected as a bolus gives analgesia lasting about one hour. The analgesia produced is sufficient for surgery involving moderately painful procedures. Giving a dose of 50mcglkg fentanyl will provide intense analgesia for some four to six hours, for intensely stimulating surgery.

• Fentanyl may also be given as an infusion. In ventilated patients, a loading dose of fentanyl may be given as a fast infusion of approximately 1 mcg/kg/min for the first 10 minutes followed by an infusion of approximately 0.1 mcg/kg/min. Alternatively the loading dose of fentanyl may be given as a bolus. Infusion rates should be titrated to individual patient response; lower infusion rates may be adequate. Unless it is planned to ventilate post operatively, the infusion should be terminated at about 40 minutes before the end of surgery.

• Lower infusion rates, e.g. 0.05-0.08 mcg/kg/min. are necessary if spontaneous ventilation .is to be maintained. Higher infusion rates (up to 3 mcg/kg/min) have been used in cardiac surgery. Fentanyl is chemically incompatible with the induction agents thiopentone & methohexitone because of wide differences in pH

• Use in elderly and debilitated patients: It is wise to reduce the dosage in the elderly and debilitated patients. The effect of the initial dose should be taken into account in determining supplemental doses.

• Adult: Patches deliver fentanyl in doses that range from: 12-100 mcg/hr. Doses should be individually titrated based on previous use of opioids. Opioid-naive patients: Initially, ≤25 mcg/hr; it is recommended to initially titrate w/ low doses of short-acting opioids before starting fentanyl patches. Patients receiving a strong opioid analgesic: Initial dose should be based on the previous 24-hr opioid requirements. During transfer to fentanyl patches, previous opioid treatment should be phased out gradually. If patient requires doses >100 mcg/hr, >1 patch may be used; consider alternative or additional therapy if doses >300 mcg/hr are required. Replace patch every 72 hr and apply the new patch to a different site; avoid using the same area of skin for a few days.
• Elderly: Dose reduction may be needed.