Fentanyl: Biological Mechanisms, Surgical Applications, and Side Effects

By March 27, 2020Uncategorized

Fentanyl is a mu-receptor stimulating opioid first synthesized in 1960.1 As a highly lipophilic molecule, it has significantly greater potency as compared to morphine and a much faster onset of action.1 Fentanyl has become increasingly common through an abundance of analogs, wherein small modifications to the core fentanyl structure (4-anilidopiperidine) can lead to much more potent forms1. Several of these forms (carfentanil and lofentanil) have been developed through modification to the central piperidine ring.1 These slight structural changes do not alter the primary mode of binding by fentanyl to the mu-opioid receptor. By binding to the mu-opioid-receptor, fentanyl can inhibit cAMP accumulation.2 Desensitization further occurs through decoupling of the mu receptors from adenylyl cyclase2. Fentanyl induces mu-opioid-receptor interactions with beta-arrestin, receptor phosphorylation, and ultimately allows for internationalization of the receptor for desensitization.3 Beyond beta-arrestin, fentanyl also impacts the ERK1/2 pathway through beta-arrestin activity.2 Furthermore, molecular dynamics modeling of fentanyl activity in the mu-opioid receptor crystalline structure (both in its active and inactive form) has demonstrated that fentanyl converges to a singular binding orientation dependent upon stable interactions between aspartate and tyrosine residues.4  


In terms of surgical applications, fentanyl was first used in neuroleptanalgesia along with butyrophenone and droperidol.5 As a potent analgesic agent with few adverse effects, fentanyl is commonly used with different intravenous supplements to produce a “balanced” anesthesia cocktail.5 When applied through an intravenous bolus, fentanyl distributes rapidly through the blood plasma to reach the heart and lungs.5 Fentanyl also has extensive abilities to diffuse through the blood brain barrier.1 After elimination from the vascular tissue, fentanyl redistributes to fat and muscle. Drug clearance from these tissues is slower than uptake, due to the highly lipophilic properties of fentanyl.5 In terms of modes of administration, fentanyl is commonly administered intravenously for postoperative anesthesia using a loading dose with a subsequent continuous infusion, a fixed background infusion with PCA pump, or with PCA pump alone.5 Furthermore, fentanyl is used to provide postoperative anesthesia for abdominal, orthopedic, spinal, thoracotomy, and cesarean section surgeries.5,6 Fentanyl can also be used in a transdermal controlled release formula to allow for sustained blood/CSF opioid concentrations to minimize peak-trough effects.5 Thus, fentanyl is an appropriate candidate for management of chronic pain symptoms.7  


Side effects of fentanyl include nausea and vomiting (in around 30-40% of patients).5 Other minor side effects include confusion, depression, diarrhea, and weakness.8 As with other mu-opioid-receptor targeting analgesics, fentanyl also produces central nervous system actions including fatigue, sedation, bradycardia, and anesthesia in higher doses regardless of the mode of administration.1 Chest wall rigidity has also been observed.1 One major area of concern is respiratory depression, as respiratory signs should be closely monitored during and following initiation of anesthesia as well as after a dose increase.1,5,8  


Beyond the side effects of fentanyl, overdose and addiction is a widely growing problem that should be monitored as well.9 Overdose of fentanyl can lead to severe respiratory depression, apnea, and death.1 The increase in overdoses has been attributed to patient misuse, inappropriate prescriptions, and increased illicit use/abuse.1  


As a whole, however, fentanyl is a potent rapid-acting opioid that is used for its minimal cardiovascular effects, short acting nature, and inexpensive/easy synthesis. Globally, fentanyl is found in both operative and post-operative contexts; particularly, drug delivery systems have allowed for fentanyl to become useful as a pain management opioid. Thus, while fentanyl has some side effects and is affiliated with overdose/misuse, it remains a highly important drug in anesthesia.  








1.Stanley, T. H. The Fentanyl Story. The Journal of Pain 15, 1215–1226 (2014). 


2.Ellis, C. R., Kruhlak, N. L., Kim, M. T., Hawkins, E. G. & Stavitskaya, L. Predicting opioid receptor binding affinity of pharmacologically unclassified designer substances using molecular docking. PLOS ONE 13, e0197734 (2018). 


3.Lipiński, P. et al. Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis. Molecules 24, 740 (2019). 


4.Lipiński, P. F. J., Jarończyk, M., Dobrowolski, J. Cz. & Sadlej, J. Molecular dynamics of fentanyl bound to μ-opioid receptor. Journal of Molecular Modeling 25, (2019). 


5.Peng, P. W. H., MBBS, FRCPC & Sandler, A. N., MBChB, MSc, FRCPC. A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults. Anesthesiology: The Journal of the American Society of Anesthesiologists 90, 576–599 (1999). 


6.D’Angelo, R., MD, Gerancher, J. C., MD, Eisenach, J. C., MD & Raphael, B. L., MD. Epidural Fentanyl Produces Labor Analgesia by a Spinal Mechanism. Anesthesiology: The Journal of the American Society of Anesthesiologists 88, 1519–1523 (1998). 


7.Payne, R. et al. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. Journal of Clinical Oncology 16, 1588–1593 (1998). 


8.Fentanyl (Rx). Medscape. https://reference.medscape.com/drug/sublimaze-fentanyl-343311 


9.Somerville, N. J. et al. Characteristics of Fentanyl Overdose — Massachusetts, 2014–2016. MMWR. Morbidity and Mortality Weekly Report 66, 382–386 (2017).