(May 19, 2023)

Executive Summary

Fentanyl is a potent opioid pain medication that is extensively used in the ED to manage severe acute pain and as premedication to intubation preparation. It is primarily administered intravenously (IV)(3).

• In the ED is usually preferred over other opioids (eg. morphine) due to its higher potency,  faster onset of action, and shorter duration of action. This makes it useful to precisely titrate dosing in the acute setting. Additionally, it has a safer hemodynamic profile than morphine, causing less hypotension or cardiac instability (1, 10).

• Other frequent indications include fentanyl as the analgesic component for analgosedation during painful procedures and mechanical ventilation. 

• ⚠ Cautions summary: 

  • High risk of respiratory depression (black box warning) and other adverse effects (6, 21); it should be used with caution, monitoring closely for respiratory depression, hypotension, sedation and other adverse effects. Providers should also be aware that alterations in respiratory rate and ventilation may last longer than the analgesic effects (8).

  • High risk of addiction and overdose (black box warning; 21): Its use should be limited to the management of short-term acute pain and critical care support (5).
    
    

Adult dose for moderate to severe pain: (7, 21)

1 mcg/kg/dose (usually 50-100 mcg) IV. 

• Repeat in 1 to 2 hours as needed (label recommendation).

• Consider repeat doses in 5-10 min in cases of excruciating pain (emergency medicine practice).

• IV TTPE*: 5 min.

• Duration of analgesia: 30-60 min.
  
  

*TTPE: time to peak effect.

• Adult dose for moderate to severe pain: (7, 21)

• Intravenous:
  1 mcg/kg/dose (usually 50-100 mcg) IV.

• Repeat in 1 to 2 hours, as needed (label recommendation).

• Consider repeat doses in 5-10 min in cases of excruciating pain (emergency medicine practice).

• A frequent approach is to start with a fixed dose of 50ug and to consider repeating the same dose after 10-15 min if the patient persists under severe pain. 

• IV TTPE: 5 min.
  
  

• Intranasal:
  1-2 mcg/kg/dose.

• Repeat in 1 to 2 hours, as needed.

• Similar analgesic efficacy compared to IV morphine (4).

• Useful in pediatrics or patients with challenging IV access.
  
  

• Nebulized:
  1.5-4 mcg/kg/dose.

• The recommended dose range across studies varies from 25 ug to 300 ug, with a weight-adjusted dose of 1.5 to 4ug/kg per dose.

• Although there are some studies that prove its efficacy and safety (9, 13), the absorption of transpulmonary fentanyl is unreliable, with a bioavailability range of 12% to 100%. 

• There is no nebulized fentanyl formulation commercially available, so the IV vial is used off label for this purpose. It is administered using the original concentration (50mcg in 1ml). It is not clear if diluting it with normal saline will improve inhaled bioavailability.  

• The duration of action and half-life of transpulmonary fentanyl are prolonged compared to those of IV fentanyl (14).
  
  

• Adult dose for premedication for RSI:
  1-3 mcg/kg IV over 30 to 60 seconds, administered 2 to 3 minutes prior to laryngoscopy for an adequate effect.

  • The usual adequate dose is 2mcg/kg IV for hemodynamically stable patients.
    
    

• Adult dose for analgosedation:
  Loading dose of 1-2 mcg/kg IV. 

  • If used for a short procedure, fentanyl can be given in addition to a short-acting hypnotic medication. Administer the dose 3 to 5 min before the procedure to reach the time to peak effect.

  • If the patient is intubated and is experiencing a painful condition, such as fractures, or will undergo a painful procedure (eg. arterial line placement), administer the same fentanyl loading dose followed by a continuous IV infusion of 1-2 mcg/kg/hr in addition to a hypnotic medication. Titrate as needed to the desired response (16).

Comments:

• Fentanyl may be used in children with moderate to severe pain; however, all forms  should be used cautiously in children. 

• ⚠ Fentanyl has not been approved by the US-FDA for use in neonates, infants, or children <2 years of age.
  
  

• Pediatric dose for moderate to severe pain:

  • Intravenous
    1-2 mcg/kg/dose IV

• Repeat in 1 to 2 hours, as needed (label recommendation).
  
  

• Intranasal:
  1-2 mcg/kg/dose

  • Repeat in 0,5 to 2 hours, as needed (label recommendation).

• Nebulized:
  1.5-4 mcg/kg/dose

  • As in adults, it is not yet US-FDA approved for nebulized use, but if used it is recommended for patients >3 years old (13).
    
    

• Pediatric dose for premedication for RSI:
  1-3 mcg/kg IV over 30 to 60 seconds, administered 2 to 3 minutes prior to laryngoscopy for an adequate effect.

  • The usual adequate dose is 2mcg/kg IV for hemodynamically stable patients.
    
    

• Pediatric dose for analgosedation: 

  • Loading dose of 1-2 mcg/kg IV. 

    • If used for a short procedure, fentanyl can be given in addition to a short-acting hypnotic medication. Administer the dose 3 to 5 min before the procedure to reach the time to peak effect.

    • If the patient is intubated and is experiencing a painful condition, such as fractures, or will undergo a painful procedure (eg. arterial line placement), administer the same fentanyl loading dose followed by a continuous IV infusion of 1-2 mcg/kg/hr in addition to a hypnotic medication. Titrate as needed to the desired response (16).

• US-FDA labeled* (10, 21)

• Short-term analgesic effect during anesthesia and immediate postoperative recovery.

• Use as a narcotic analgesic supplement in general or regional anesthesia.

• Administration with a neuroleptic for anesthetic premedication, induction, and maintenance. 

• Anesthetic agent with oxygen in high-risk patients undergoing complex surgeries (heart, neurological, orthopedic).

• Breakthrough cancer pain (sublingual spray, nasal spray, buccal tablets).
  
  

*Comment: no form of fentanyl is US-FDA approved for use in neonates, infants, or children < 2 years of age.

• Off-label

  • Acute pain management outside the perioperative period of pain or sedation.

  • Procedural sedation.

  • Palliative care or end-of-life management (not considering breakthrough cancer pain).

  • Nebulized route of administration.

Summary of adverse effects:

As an opioid, fentanyl is inherently associated with critical adverse effects that have an increased risk of frequency and severity in the emergency department setting.

• Major / critical adverse effects (21):

  • Respiratory depression (black box warning, 8).

  • Cardiovascular depression.

  • Sedation.

  • Rigid chest (wooden chest syndrome, see next section for an in-depth review).

• Minor adverse effects

  • Nausea and vomiting.

• Long term adverse effects (5, 21)

  • High risk of opiate addiction (black box warning): fentanyl use should be limited to the management of short-term acute pain and critical care support.

  • For an extensive description of every adverse effect of fentanyl, go to DailyMed - Fentanyl Injection, solution (21).

Description of adverse effects:

• Hypoventilation
  Apnea or respiratory arrest may occur in patients not taking chronic opioids, at any dose of available non-parenteral fentanyl products. Therefore, any patient receiving fentanyl should be closely monitored for the risk of respiratory depression. In case of respiratory depression, the primary management must include supportive ventilation measures such as bag-mask ventilation and oxygen, along with considering airway protection based on the individual case. Naloxone should also be considered (6, 8, 15).

  • Although fentanyl is a more potent opioid agonist than heroin, the dose of naloxone required to reverse respiratory depression is similar to that of clinically equivalent doses of other common opioids (15).

  • Opioid antagonists: 

    • Non-opioid dependent patients: naloxone 0.4 mg IV (1 vial of 0.4 mg/ml) every 2-3 minutes until the adequate spontaneous ventilation is achieved, up to a maximum of 10 mg. If the patient requires more than one dose or is at risk of further episodes of respiratory depression, an infusion can be started, or repeat doses every 1-2 hours. 

      • To determine the wake-up dose, give 2/3 of that wake-up dose per hour. (17, 15, 22)

    • Opioid dependent patients: a significantly lower dose of naloxone should be considered to reverse hypoventilation and avoid withdrawal syndrome. The recommended dose is naloxone 0.04 mg IV every 3-5 minutes, up to a maximum of 2mg (15). 

    • Naloxone infusion preparation (22):
      2 mg in 500 ml of NaCl 0.9% or DW5 (concentration of 0.004 mg/ml).
      Calculate initiation based on ⅔ of the wake-up dose per hour.

      • Example: a successful response was achieved with 0.8mg IV. Therefore, an infusion of 0.5 mg/hr IV should be started, calculated as ⅔ of the wake-up dose. The infusion can be titrated as needed. 

• Naloxone pharmacology (22): 

  • Half-life: 30-81 min.

  • TTPE: 2-5 min.
    
    

• Severe cardiovascular depression (21)

  • Fentanyl may result in severe bradycardia, hypotension (including orthostatic hypotension), and syncope. These effects may occur due to the sympatholytic and parasympathomimetic effects of opioids. 

  • There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs. 

  • In patients with circulatory shock, fentanyl may cause vasodilation that can further decrease cardiac output and blood pressure. It is of great significance to monitor these patients for signs of hypotension after initiating or titrating the dose of fentanyl.
    
    

• Sedation and coma

  • Fentanyl may cause profound sedation and coma, which is typically dose-dependent but can be exacerbated by concurrent use of CNS depressants such as benzodiazepines. 

  • In the 1960s to 1970s, opioids were commonly administered at high doses (eg. fentanyl 10-20 mcg/kg) not only for pain relief but also as a sedative or anesthetic agent. This practice is no longer recommended due to adverse effects and the emergence of safer induction medications.

• Chest wall skeletal muscle rigidity has been proposed to be caused by fentanyl binding to opioid receptors in the central nervous system and activating a dopaminergic pathway (18). 

• The resulting decrease in chest wall compliance leads to ineffective assisted and spontaneous ventilation, which can cause elevated pressures within the ventilator circuit. 

• Fentanyl is highly lipophilic, which may contribute to more reports of RC compared to other opioids (2, 18).

• RC is usually associated with rapid administration or high doses of fentanyl, but it has also been reported at doses as low as 50mcg (10). 

  • Since 2014, isolated cases of chest wall rigidity have been reported in patients receiving fentanyl via transdermal patches, nasal spray, and oromucosal routes. It is believed that these forms of administration carry a very low risk of CR.

• The management of this syndrome includes immediate cessation of fentanyl administration, considering using an opioid receptor antagonist such as naloxone, a neuromuscular blocking agent to rapidly improve lung compliance and overall supportive care (18).

Pregnancy risk classification

• AU TGA pregnancy category: C.

• US FDA pregnancy category: C.
  
  

• Comment:
  There have been no well-controlled studies conducted in pregnant women; therefore, the use of fentanyl in pregnancy should be approached with caution. 

• In animal studies, inconsistent fertility and fetal effects have been observed with fentanyl use, without any dose-dependent or species-dependent correlation. 

• Fentanyl readily crosses the placenta and its use should be justified only if the potential benefits outweigh the risks. 

• Special precautions should be taken during labor as neonates and infants are highly sensitive to respiratory depression caused by fentanyl (11).

Lactation 

• Fentanyl  is considered a drug with a very low risk for the nursing infant (20).

  • It is excreted into breast milk in undetected or non-significant amounts.

  • No problems have been reported in infants of treated mothers.

• Fentanyl has a very low oral availability. After a mother has undergone anesthesia or analgesia with fentanyl, she may breastfeed her baby as soon as her recovery and general condition permits it (12).

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7. Patanwala AE, Keim SM, Erstad BL. Intravenous opioids for severe acute pain in the emergency department. Ann Pharmacother. 2010;44(11):1800-1809. doi:10.1345/aph.1P438
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8. Vardanyan R, Hruby V; Fentanyl- related compunds and derivatives: current status and future prospects for pharmaceutical applications. Future Med Chem. 2014 Mar: 6(4): 385-412. DOI: 10.4155/fmc.13.215
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9. Farahmand S, et al; Nebulized fentanyl vs IV morphine for ED patients with acute limb pain: a randomized clinical trial. Am J Emerg Med, 2014 Sep; 32(9): 1011-5. DOI:        10.1016/j.ajem.2014.05.051
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14. Schug S and Ting S; Fentanyl Formulations in the management of pain: An Update. Drugs 2017; 77: 747-763. DOI: 10.1007/s40265-017-0727-z
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17. Volkow N, Jones E, Einstein E, Wargo E; Prevention and Treatment of Opioid Misuse and Addiction: A review. JAMA Psychiatry 2019, Feb 76 (2): 208-216. DOI:        10.1001/jamapsychiatry.2018.3126
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18. Rosal NR, Thelmo FL Jr, Tzarnas S, DiCalvo L, Tariq S, Grossman C. Wooden Chest Syndrome: A Case Report of Fentanyl-Induced Chest Wall Rigidity. J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211034036. doi: 10.1177/23247096211034036. PMID: 34301155; PMCID: PMC8312149.
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19. Brown CA, Sackles JC, Mick NW, Mosier JM, Braude DA. The Walls Manual of Emergency Airway Management. 6th edition. Philadelphia, PA. Wolters Kluwer; 2022.
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20. APILAM (Association for promotion of and cultural and scientific research into breastfeeding). e-lactancia. Fentanyl. Updated July 2022. Accessed February 29, 2023.
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21. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Fentanyl Citrate injection, solution. Updated September 2022. Accessed May 2, 2023.
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22. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Naloxone Hydrochloride Injection, Solution. Updated January 2023. Accessed May 2, 2023.
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