Prehospital Pharmacology: FENTANYL

A 39-year-old male hiker was walking with his two daughters on the evening of February 18, 2007, when the snow along a hillside gave way under their weight and all three slid 300-400 feet down a steep 45° hillside in Limerick Township, PA. The male became entangled in a patch of trees along the hillside, while his daughters escaped without injury. Arriving fire and EMS resources found all three initially inaccessible due to the terrain.

Once Limerick and New Hanover Fire Departments established a rope and pulley system to safely access the scene, Trappe Fire Department ambulance personnel were lowered to the patients. The male hiker was precariously positioned and at risk for sliding further down into the ravine. Therefore, he was secured to the tree with safety rope, then backboarded and packaged in a Reeves stretcher for extrication from the hillside. He complained of severe lower back pain secondary to what was eventually diagnosed as an L1 burst fracture, initial inability to move his lower extremities (which had now resolved), and he had an obviously deformed mid-shaft right femur. However, he remained alert and oriented with a stable blood pressure and heart rate. Ten mg morphine was readily available and administered intramuscularly, since initial attempts at IV access were unsuccessful secondary to venous vasoconstriction from the cold ambient temperature and his positioning on the hill.

Extrication from the hillside took just over an hour. Once the patient was loaded in the ambulance, IV access was established. Secondary survey revealed a grossly deformed and angulated femur fracture, a rapidly expanding hematoma and palpable pedal pulses. The Trappe Fire Department EMS physician who responded to the scene decided to reduce the fracture for purposes of pain management and to facilitate placement of skeletal traction prior to loading the patient into a medical helicopter for transport to a central Philadelphia trauma center.

The patient was placed on continuous ETCO₂ and SpO₂ monitoring, then 10 mg of etomidate and 100 mcg of fentanyl were administered intravenously. The fracture was reduced under manual traction and placed into a Hare traction splint. The patient tolerated the procedure well. ETCO2 remained 40-44 mmHg, and the patient did not desaturate. He noted marked improvement in pain after the reduction. Another 80 mcg of fentanyl was administered for continued back pain en route to the landing zone. The flight was uneventful, and the patient sustained no spinal cord or neurological injury.

Introduction
     Fentanyl is a synthetic narcotic first synthesized by Janssen Pharmaceutica in Belgium in the 1950s. It is an extremely potent medication that has an analgesic effect approximately 50-100 times greater than that of morphine. It was initially used for intravenous anesthesia and analgesia in the 1960s and is a mainstay of intra-operative and peri-operative analgesia and both conscious and deep sedation in the in-hospital setting.

Pharmacology
     Fentanyl is a DEA Schedule II narcotic that has an almost-immediate onset of action when given intravenously. Peak analgesic effects last from 30-60 minutes. When given intramuscularly, the time to onset is about eight minutes and the duration of action may extend as long as two hours. The characteristics of ultrashort onset of action and short duration of action make fentanyl an ideal agent to be used in the out-of-hospital setting for analgesia and pain management.

The potency of narcotic pain medications is always compared to morphine, since this pharmaceutical is considered the original medicinal agent for pain control. However, it is critically important to note that fentanyl is dosed in micrograms (mcg), whereas morphine is dosed in milligrams (mg). In the metric system, the prefix milli- refers to one thousandth and the prefix micro- refers to one millionth. Also note that potency and dosage are not comparable terms. Thus, a 100 mcg dose of fentanyl has roughly the same analgesic effect as 10 mg of morphine, despite the fact that fentanyl is 50-100 times stronger in terms of its analgesic effect than that of morphine.

Fentanyl is dosed at 1-2 micrograms per kilogram (1 mcg/kg) actual body weight when given parenterally. Thus, the common adult dose of fentanyl is 50-200 mcg IV or IM. Frequently, the typical starting dose for a healthy 70 kg adult who requires analgesia is either 50 mcg or 100 mcg rather than 70 mcg for the following reason: Fentanyl is supplied in ampoules of varying sizes, which all have a concentration of 50 mcg/ml. Most emergency departments and ambulances stock ampoules of 100 mcg or 250 mcg, which are both multiples of 50. Thus, it is easier to calculate increments of 50 mcg when drawing up the medication in a syringe. If repeated doses are required, they can be given at 10 minute intervals. The maximum recommended dose is 150 mcg per hour in a patient who is not tolerant of the effects of narcotics. Patients who are in extreme pain and those who have a history of intravenous drug abuse may require larger doses.

Use of fentanyl in the pediatric population is reserved for children over age two. The dosing regimen is 2-3 mcg/kg. Prehospital use of fentanyl for children has historically been limited to aeromedical crews (presumably due to higher training and the presence of a nurse or physician on board). Fentanyl lollipops are often used in hospitals when children undergo painful procedures, such as suturing. The time to onset of action is about five minutes for the oral route.

Fentanyl is manufactured as a powder, but is commonly available in liquid form and is packaged as 50 mcg per one milliliter of solution, regardless of the size of the ampoule. For administration, it is diluted to a volume of 5 cc using either D5W or normal saline infused slowly over one minute (see adverse drug effects for the reasoning behind this method of infusion). Fentanyl is also marketed as a transdermal patch, a lollipop and a newly created oral pill, but none of these formulations are routinely used in the emergency medicine or EMS settings. Fentanyl is stable at room temperature, but should be protected from light.

Opinions from the Einstein Division of EMS and Disaster Medicine
     Morphine was the first agent commonly used on ambulances for prehospital pain management. Commonly heard on the series Emergency! when Gage and DeSoto spoke of "MS" (morphine sulfate), morphine has been the quintessential narcotic analgesic in the pharmacy of virtually every advanced life support EMS agency since their inception in the late 1960s and early 1970s. The primary reason that this drug has lasted in the EMS pharmacopeia for so long is that there was not much other choice. Thus, many paramedics have become comfortable with the medication. As with any attempt to implement change in an organization, introduction of fentanyl may cause trepidation among the rank and file, so it is incumbent upon the EMS medical director to ensure that appropriate training and strict quality assurance measures accompany the rollout of this medication.

The medical literature, coupled with field experiences, clearly demonstrates the superiority of fentanyl as an analgesic medication for use in the EMS environment. Fentanyl does not affect hemodynamics, oxygen saturation or GCS when used appropriately. It is fast-acting, short-acting and causes less histamine release than other narcotics. Traditionally, its use has been limited to critical care ambulances or air medical services, but many leaders in EMS are advocating that fentanyl become the primary narcotic analgesic in the field, because it causes less hypotension, respiratory sedation and mental status depression than morphine or meperidine. Also, its short duration of action would appear to be ideal for agencies that still have difficulty with emergency physicians who chastise use of narcotics that may mask symptoms of pain and hide illness or injury despite the overwhelming scientific opinion in the peer-reviewed medical literature that this is a myth.

Indications
     Indications for the use of fentanyl in the prehospital setting are identical to those of morphine. Specifically, there are three primary indications: non-cardiac pain management (which accounts for the vast majority of administrations across EMS systems), chest pain of presumed ischemic origin, and as a third-line agent in the management of a patient with acute pulmonary edema. Although our case vignette demonstrates the use of fentanyl as part of a drug cocktail to induce deep sedation, this procedure is not routinely permitted outside the hospital for ground EMS crews, with the rare exception of EMS physician scene response for difficult patient scenarios in which this may be necessary.

One myth that we have heard frequently in the Philadelphia area (and which is probably universal) is that fentanyl is not an adequate replacement for morphine in the cardiac chest pain protocol, i.e., that morphine has some special benefit for patients who suffer from ischemic chest pain or acute MI. This is completely false. It is likely that paramedics tend to believe this simply because morphine has been the only prehospital narcotic available for routine use since Demerol was cast aside in the medical literature in the latter 1990s, and because morphine has been around in EMS drug caches since the early days of advanced life support. The utility of narcotics in the setting of ischemic chest pain is that of an anxiolytic, which ultimately aids in the reduction of myocardial wall stress and heart rate. Thus, any narcotic will do.

Contraindications
     As with any pharmaceutical, the primary contraindication to use of a medication is a known or suspected allergy, which is rare. Interestingly, unlike other medication classes, fentanyl has very few contraindications. A relative contraindication to its use would be inability to reverse the analgesic effect in the event respiratory depression occurred. However, since naloxone is universally available and contained in virtually every ALS system's protocols, this is unlikely. Fentanyl is a Category C medication in pregnancy, which means there are inadequate studies to recommend routine use in humans. However, based on animal evidence, it is unlikely that a single use would lead to birth defects. Similarly, it is not known whether the drug is excreted in human milk. Again, given the rapid breakdown of the drug, it is unlikely that emergency doses would have an adverse effect on an infant.

Adverse Drug Reactions
     There are extremely few adverse drug reactions reported with fentanyl. The most likely adverse event would be secondary to unintentional overdose, in which the medical practitioner exceeds recommended dosing without precautionary measures in place to predict obtundation and respiratory depression. Our case vignette exhibits the national standard of care in emergency medicine for critical care monitoring whenever larger than normal doses of narcotics are being administered or conscious, or deep sedation is implemented.

Other potential adverse effects include bradycardia, more rapid and significant ventilation impairment in patients with COPD and prolonged clinical effects in patients with hepatic or renal impairment. Finally, there is a rare but recognized phenomenon in which severe muscular rigidity develops in patients administered large doses (to induce anesthesia) of fentanyl very rapidly. Thus, the recommendation is that fentanyl be given via slow IV push.

One notable adverse drug reaction that does not occur much in comparison with morphine is histamine release. This phenomenon is the cause of a variety of side effects related to morphine use, which have varying clinical significance, ranging from pain and hives at the injection site to nausea/vomiting from mucosal edema in the GI tract and hypotension from vascular effects. The authors have personally witnessed these effects in the field, as well as in the ED. The transient hypotension is enough to cause worry in any emergency medicine practitioner. The urticaria from histamine release occasionally necessitates administration of Benadryl as an antihistamine.

Support For Fentanyl In The Emergency Medicine Literature
     Pain management has been one of the most talked about topics in EMS practice within the last five years. Numerous national experts have clearly stated that pain management being provided to patients in the prehospital environment is inadequate, and the National Association of EMS Physicians has echoed its call for standardization in the approach to the EMS patient with acute pain in a position paper on the subject.¹

A review of the safety profile of fentanyl and a comparison with other narcotic analgesics used in emergency medicine practice can be found in the May 2005 issue of Emergency Medicine Clinics of North America.² A multitude of peer-reviewed emergency medicine journal articles summarizing the evidence that fentanyl can be used successfully in the EMS environment and that adverse drug effects are rare are referenced in an article on aeromedical use of fentanyl that appeared in the American Journal of Emergency Medicine in May 2006.³

One recent study of fentanyl in the prehospital environment deserves special attention because of its focus and attempts to measure the potential for adverse drug effects as a marker for safety and effectiveness. Kanowitz et al performed a retrospective chart review of more than 2,100 patients who received fentanyl from paramedics in the Denver area during 2002-2003.⁴ In a subgroup analysis of patients for whom both EMS and ED charts were available for review, only one (0.2%) of the 611 patients had a vital sign abnormality that necessitated a recovery intervention. Furthermore, the authors showed a statistically significant improvement in subjective pain scale scores, and they did not identify any admissions to the hospital or patient deaths attributed to fentanyl use. Their data set appears to demonstrate that fentanyl was effective in decreasing pain scores without causing significant hypotension, respiratory depression, hypoxemia or sedation.

Potential For Abuse
     According to the DEA, abuse of fentanyl in the medical community first appeared in the 1970s. Since then, 12 different analogs of fentanyl have been identified in U.S. drug traffic. It is increasingly being mixed into other street drugs like cocaine and heroin, and multiple deaths in large cities have recently been attributed to these admixtures.

Given the well-described phenomenon of narcotic abuse by medical personnel through the centuries and the inherent problems with security and accountability of narcotics in EMS systems, it is not surprising that fentanyl has been at the forefront of EMS drug thefts recently. One such theft to support a paramedic's drug habit was prosecuted several months ago in our region of Pennsylvania.⁵ While this is not sufficient reason to avoid placing the medication in an EMS formulary, it is wise for EMS administrators and their medical directors to review practices related to the storage, use and accountability of all narcotics at least annually.

Conclusion
     The decision to use fentanyl remains the responsibility of individual EMS medical directors in conjunction with the administrative and operations personnel who will have to implement it in a given system. Given its potential for abuse, supplies must be safe-guarded and use must be monitored carefully. However, we support it as the agent of choice for out-of-hospital analgesia. It is likely that we will continue to see more U.S. EMS systems advocate fentanyl over morphine.

References

1. Alonso-Serra HM, Wesley K. Prehospital pain management. Prehosp Emerg Care 7:482-488, 2003.

2. Innes GD, Zed PJ. Basic pharmacology and advances in emergency medicine. Emerg Med Clin N Am 23:433-465, 2005.

3. Frakes MA, Lord WR, Kociszewski C, Wedel S. Efficacy of fentanyl analgesia for trauma in critical care transport. Am J Emerg Med 24:286-289, 2006.

4. Kanowitz A, Dunn TM, Kanowitz EM, et al. Safety and effectiveness of fentanyl administration for prehospital pain management. Prehosp Emerg Care 10(1):1-7, 2006.

5. kyw1060.com/print_page.php?contentId=228947&contentType=4

David Jaslow, MD, MPH, EMT-P, FAAEM, is chief of the Division of EMS and Disaster Medicine and director of the EMS Special Operations and Disaster Medicine Fellowship program within the Department of Emergency Medicine at Albert Einstein Medical Center in Philadelphia. He is a firefighter/paramedic, assistant chief and EMS medical director at Bryn Athyn Fire Company in suburban Philadelphia and serves as medical editorial consultant for EMS Magazine.

Anne Klimke, MD, EMT-B, a PGY-2 emergency medicine resident at Albert Einstein Medical Center, is the first resident to enter into the newly created track for the EMS Special Operations and Disaster Medicine fellowship program, in which both programs are completed in five years. As such, she functions as assistant medical director for Bryn Athyn Fire Company.

Peter Cunnius, MS, RN(c), NREMT-P, is program manager for the Center for Special Operations Training at Albert Einstein Medical Center and a lieutenant with Pottstown, PA, Fire Dept. EMS.

David Neubert, MD, EMT-P, is assistant chief of the Division of EMS and Disaster Medicine and medical director for its Center for Special Operations Training at Einstein. He is also the EMS medical director for Trappe Fire Company in suburban Philadelphia.