Background for Fast Fact #331:  Multiple formulations of transmucosal immediate-release fentanyl (TIRF) are FDA approved for rapid-onset, breakthrough cancer pain in patients ≥ 16 years of age who are tolerant of ≥ 60 mg of oral morphine equivalents per day (1).  Off-label uses include non-cancer pain and painful procedures in children (2-4). They used to be available via a variety of non-traditional routes (e.g. buccal, intranasal, sublingual); however, as of September 30, 2024, all TIRF manufacturers discontinued their production (5).  This Fact Fact compares the catalogue of oral/nasal fentanyl preparations and Fast Fact #103 has more information on fentanyl lozenges (Actiq®). However, unless drug manufacturers begin producing TIRF medicines again, they will not be available.

Pharmacology (1): Fentanyl’s marked lipophilicity and high rate of first pass metabolism renders traditional oral pill formulations relatively ineffective. Yet, these same pharmacologic properties lead to a quicker onset and duration of action for transmucosal, or intranasal fentanyl compared with other short acting oral opioids (e.g. morphine, hydromorphone, oxycodone).  Hence, they have theoretical advantages for short onset, incident pain such as cancer related bone pain elicited by ambulation. Metabolism takes place in the liver primarily by CYP 3A4 to inactive metabolites which are excreted by the kidneys. Significant drug interactions can occur when used with other CYP 3A4 active drugs.  In those with impaired liver function, many experts recommend initiate at 50% of the typical starting dose. 

Comparative effectiveness:  In comparison to traditional oral short acting opioids, transmucosal fentanyl formulations are 20-200 times more expensive.  Hence, most insurances do not cover them as a first line analgesic. Instead, they are considered if the first-line analgesic is not tolerated due to adverse effects, route issues, or an inability to control the rapid onset of breakthrough pain.  A meta-analysis for breakthrough cancer pain found a likelihood of superiority over IR oral morphine ranging between 57-68% especially during the first 30 min of treatment (6). However, other controlled, clinical studies not included in this meta-analysis, have yielded mixed results (7-13).

Formulations: There is no evidence demonstrating superiority among the TIRF formulations; rather selection is dependent on cost, preference, and insurance coverage. Other prescribing pearls include: 

• Transmucosal absorption can result in variable bioavailability depending on the formulation and the individual ingesting it. Hence, there is little dose reliability between formulations.
• If rotating from a different opioid or converting between formulations, start at the initial dose recommendation and titrate to effect as specified in the package insert, regardless of the patient’s past or current opioid requirement.
• Nasal decongestive agents may lead to lower peak plasma concentrations of intranasal formulations due to local vasoconstriction limiting bioavailability.
• Patients, prescribers, pharmacies, and distributors must register through a Risk Evaluation and Mitigation Strategy (REMS) program. REMS programs are implemented to create a framework to promote patient safety for high-risk medications.  Since no manufacturers are currently producing TIRF medicines, the FDA stopped enrolling new patients into the TIRF REMS programs (5).

Patient counseling:  Patients need specific instructions regarding:  

• Factors that may decrease absorption: reduced saliva; recent use of liquids that reduce oral pH (coffee, cola, fruit juices); placement of product on tongue or gums; chewing gum.
• Factors that may increase absorption:  mucositis or mouth ulcerations.
• Storage and disposal: because some of these formulations may be dangerous for children, patients should store in original packaging at room temperature in childproof containers. Unused medications should be disposed in water (sink, toilet). 

 

References:  

1. Brzqkala J, Leppert W.  The role of rapid onset fentanyl products in management of breakthrough pain in cancer patients. Pharmacologic Reports 2019; 71(3):438-442.
2. Schechter NL, Weisman SJ, Rosenblum M, Bernstein B, Conard PL.  The Use of Oral Transmucosal Fentanyl Citrate for Painful Procedures in Children.  Pediatrics. 1995;95(3):335-9.
3. Taylor DR, Webster LR, Chun SY, Reinking J, Stegman M, Shoemaker S, Fortner B. Impact of Breakthrough Pain on Quality of Life in Patients with Chronic, Noncancer Pain: Patient Perceptions and Effect of Treatment with Oral Transmucosal Fentanyl Citrate (OTFC®, ACTIQ®). Pain Medicine. 2007;8(3):281-8.
4. Portenoy RK, Messina J, Xie F, Peppin J.  Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: a randomized, placebo-controlled study. Current Medical Research and Opinion. 2007;23(1):223-33.
5. US Food and Drug Administration.  Transmucosal immediate-release fentanyl (TIRF) medicines. September 16, 2024.  Available at:  Transmucosal Immediate-Release Fentanyl (TIRF) Medicines | FDA. Last accessed September 23, 2024.
6. Jandhyala R, Fullarton JR, Bennett MI. Efficacy of Rapid-Onset Oral Fentanyl Formulations vs. Oral Morphine for Cancer-Related Breakthrough Pain: A Meta-Analysis of Comparative Trials. J Pain Symptom Manage. 2013;46(4):573-80.
7. Mercadante S, Villari P, Ferrera P, Casuccio A, Mangione S, Intravaia G. Transmucosal fentanyl vs intravenous morphine in doses proportional to basal opioid regimen for episodic-breakthrough pain. Br J Cancer. 2007;96:1828-33.
8. Finn J, Wright J, Fong J, Mackenzie E, Wood F, Leslie G, Gelavis A. A randomised crossover trial of patient controlled intranasal fentanyl and oral morphine for procedural wound care in adult patients with burns. Burns. 2004;30:262-8.
9. Rickard C, O’Meara P, McGrail M, Garner D, McLean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med. 2007;25:911-7.
10. Portenoy RK, Burton AW, Gabrail N, Taylor D. A multicenter, placebo-controlled, double-blind, multiple-crossover study of Fentanyl Pectin Nasal Spray (FPNS) in the treatment of breakthrough cancer pain. Pain. 2010;151:617-24.
11. Mercadante S, Adile C, Cuomo A, Aielli F, Cortegiani A, Casuccio A, Porzio G. Fentanyl Buccal Tablet vs Oral Morphine in Doses Proportional to Basal Opioid Regimen for the Management of Breakthrough Cancer Pain: A Randomized, Crossover, Comparison Study. J Pain Symptom Manage. 2015;50(5):579-86.
12. Mercadante S, Aielli F, Adile C, Contanzi A, Casuccio A. Fentanyl Pectin Nasal Spray versus Oral Morphine in Doses Proportional to Basal Opioid Regimen for the Management of Breakthrough Cancer Pain: A Comparitive Study. J Pain Symptom Manage. 2016;52(1):27-34.
13. Zecca E, Brunelli C, Centurioni F, Manzoni A, Pigni A, Caraceni A. Fentanyl Sublingual Tablets Versus Subcutaneous Morphine for the Management of Severe Cancer Pain Episodes in Patients Receiving Opioid Treatment: A Double-Blind, Randomized, Noninferiority Trial. J Clin Oncology. 2017;35(7):759-65.

Conflicts of Interest: The authors have no conflicts of interest to disclose. 
Author Affiliations: Cedars-Sinai Medical Center (KM) and MedStar Washington Hospital Center (HG) 
Version History:  Originally edited by Sean Marks MD; first electronically published March 2017. Reviewed and updated in September 2024.