The Safety And Efficacy Of Morphine Vs. Fentanyl In The Pre-Hospital Setting: A Critically Appraised Topic
By Dan Piquette, AEMCA, PCP Peel Regional Paramedic Services Brampton
Introduction and Clinical Question
Acute pain is a significant consequence of many medical conditions and is a common reason for ambulance system activation in many countries (1). In fact, in 2014 it was the number one reason for emergency depart-ment visits in the United States (2). There are many medications available for treating pain, however according to the American College of Emergency Physicians, opioids are preferred as they are “the mainstay of hospital and out-of-hospital analgesia” (3).
Paramedics in many Canadian jurisdictions can treat pain with Morphine or Fentanyl. In some of them it is not specified which of these opioid analgesics should be administered and when (4). Although not formally documented, we noted in a 2017 Advanced Care Paramedic training program in Ontario, Canada that educators viewed fentanyl as being a more effec-tive and safer analgesic agent than morphine, with morphine having a theoretical risk of causing hypotension. Indeed, the literature would suggest that physicians view fentanyl as having a more favourable hemodynamic profile perhaps making it more suitable (3). Therefore, our goal in this review is to answer the following questions: in patients presenting to paramedics with acute pain, is morphine or fentanyl more effective at reducing pain using a quantitative measurement scale? Secondly, which drug has less reported adverse effects?
A literature search was conducted using Google Scholar to identify experimen-tal studies comparing the two medications against each other. Search terms included were “morphine AND fentanyl AND prehospi-tal,” and “morphine AND fentanyl AND out of hospital.” Articles were eligible for inclu-sion only if they met the following criteria: 1. Contains all search terms; 2. Involves prehos-pital medical care; 3. Involves patients in acute pain; 4. Involves a systematic review, random-ized controlled trial or a well-conducted obser-vational study; 5. Published within the last 10 years; and 6. Involves adult patients only. The search yielded 5 articles for full review which included two observational studies (6,7), two randomized controlled trials (8,9) and one systematic review (10). The systematic review was subsequently rejected after full review of the article as its scope differed too widely from Canadian paramedic practice to be applicable. To assess methodological rigor, the random-ized controlled trials were appraised using the CONSORT statement checklist (11), while the observational studies were appraised using the STROBE statement checklist (12). Results were summarized and analyzed for evidence.
Weldon et al. conducted a double-blind, randomized controlled trial (RCT) in 2015 comparing morphine and fentanyl adminis-tered by Winnipeg paramedics for ischemic-type chest pain (6). Their results showed no significant difference in adverse effects between narcotics (Heart rate reduction: 95% CI fentanyl -5.5 +/- 6.7, morphine – 8.1 +/- 27.3, p=0.81; Respiratory rate reduction: 95% CI fentanyl -2.0 +/- 2.8, morphine – 2.7 +/- 4.3, p=0.74; MAP reduction: 95% CI fentanyl -7.1 +/- 17, morphine -9.6 +/- 8.0, p=0.87) nor did they show a significant difference in pain reduc-tion measured on a visual analog scale (p=0.47)(6).
Rickard et al conducted a randomized, controlled, open-label trial in 2006 comparing intranasal fentanyl and intravenous morphine administered by Australian paramedics for patients in severe pain (7). Their results showed no statistically significant difference in pain reduction on a verbal rating scale (Morphine 95% CI 3.10-4.03, fentanyl 95% CI 3.74-4.7, p=0.08). Intranasal fentanyl had a higher proportion of adverse effects than intravenous morphine (27% versus 15%) but the authors deemed this to be statistically insignificant (relative risk 2.09, 95% CI 0.92-4.78, p=0.07)(7).
Fleischman et al conducted a retrospec-tive (observational) before and after study of a protocol change from morphine to fentanyl administered by Oregon paramedics for patients experiencing pain due to cardiac ischemia, burns, and extremity injuries (8). The study was conducted between 2006 and 2007. Both drugs showed similar decreases in pain scores for morphine (2.9, 95% CI 2.5 to 3.2) versus for fentanyl (3.1, 95% CI 2.8 to 3.4). There were no significant differences in rates of adverse effects (23.1% for morphine, 23.8% for fentanyl; 95% CI for the difference -6.9% to 5.5%). Of note was that the dosage of fentanyl used for this trial was a higher narcotic equivalent dose (8).
Middleton et al. conducted a retrospective observational study between 2004 and 2006 comparing administration of IV morphine, IN fentanyl and methoxyflurane given by Austra-lian paramedics for patients experiencing pain (9). There was no difference in pain score reduc-tion between morphine (4.5, 95% CI 4.5-4.6) a
nd fentanyl (4.5, 95% CI 4.4-4.6). The relationship between drug and rates of adverse effects were not explored in this study (9).
It is relevant from a number of perspec-tives to compare opioids such as fentanyl and morphine since superficially they seem similar. There are obvious advantages to agents like fentanyl that can be administered cheaply and safely through the intranasal route (9). Although morphine and fentanyl have similar overall costs (13), it is logical to assume that costs to stock and provide both drugs in an EMS system are greater than stocking one of them. There is therefore a specific advantage to examine the efficacy and safety of morphine and fentanyl in the prehospital system for patients presenting with acute pain. That is to say, if one drug is more effective or safer, then an EMS system might benefit from stocking only that drug. If both drugs are clinically similar, then it might be cheaper for an EMS system to stock only a single drug instead of carrying both.
The articles examined in this review provided nearly unanimous consensus that there is no statistical difference in the efficacy of fentanyl versus morphine with respect to objective measures such as visual analog p
ain scale score reduction. There is consensus that although both drugs are associated with predictable rates of adverse effects, neither drug has a statisti-cally significant difference in the rate of adverse effect occurrence.
The question of morphine versus fentanyl use in prehospital care is important to paramedic practice. As mentioned above, some EMS systems stock only a single opioid analge-sics while others stock both morphine and fentanyl. When provided with multiple choices for opioid analgesia, paramedics should be guided by clinical practice and expert research to choose which drug should be adminis-tered to a particular patient. It is important for practitioners to note the results of this analysis since available research indicates that neither drug is more effective or safer than the other. There are cost implications to ambulance services for providing and maintaining stock of two different medications (13) that must also be considered. Lastly, if both analgesic agents are equivalent in effect and have similar incidences of adverse effects, there are questions left to the clinician to answer regarding which medication to choose to administer at any given time. The available research does not provide answers to those questions. Of course, if only a single opioid medication is utilized, this clinical judgment is no longer required since practi-tioners only have a single drug to choose from.
It is important to note that each of the studies referenced here suffered from limita-tions that affect the generalizability of the results to paramedic practice in Canada. Two of the studies were retrospective observational studies (8,9), and studies using this method-ology are comparatively more vulnerable to confounding. The authors acknowledge this in both cases. Both of the RCTs (6,7) suffered from low recruitment that affected the statisti-cal test power, and one was an open-label trial (7) that likely introduced bias from the clini-cians administering the drug. Neither RCT was placebo-controlled. Unfortunately, due to the difficulties in data collection in many of these studies, along with ethical concerns regarding withholding analgesia, it is unlikely that the objectives posed herein will be examined using a prospective, placebo-controlled randomized trial of fentanyl versus morphine for acute pain in the prehospital setting. Of significant impor-tance was that none of the trials reported their sources of funding or sponsorship. The trials were conducted using medications, and since ambulance services can be constrained in their purchasing of medications by specific munic-ipal guidelines regarding costs and preferred suppliers, it is important to declare sponsorship, funding and supply of the drugs. This trans-parency would address any potential bias or conflict of interest.
According to Pasternak and Pan, “patients can have markedly different responses to mu opioids” (14). It is possible that morphine and fentanyl create different, non-quantifiable subjective effects in patients who receive them. These effects may not correlate with measur-able scales such as the visual analog pain scale. A patient who receives one drug or the other may not objectively have more pain reduction, but may qualitatively feel better due to the unpredictable or unknown mu receptor effects of that drug. At present, this effect appears to be impossible to quantify but may contribute to overall success of one drug over the other in managing the overall condition of pain as opposed to purely reducing quantitative pain scores. As an example, one drug may be superior to the other in reducing the anxiety and sympa-thetic nervous system response associated with pain, but there are no available research trials to empirically conclude this.
Morphine and fentanyl are two opioid analgesics that are widely used by paramedics in Canada. Available research shows that neither drug is more effective than the other in terms of pain reduction or rate of adverse effects. Both drugs appear to be a similarly effective method for controlling pain in the prehospital environ-ment. Fentanyl has a unique advantage of being able to be administered intranasally, eliminat-ing the need for IV access. Future large-power RCT’s may find evidence that one drug is more favourable than the other, and future qualitative research may be an effective method for explor-ing the secondary effects of each drug (such as relief of anxiety) and how these effects contrib-ute to pain relief. Objectively, the available liter-ature indicates that morphine and fentanyl have similar abilities to relieve pain and have similar rates of adverse effects. Extending this concept, it is safe and effective for the clinician to utilize either drug to manage acute pain, and neither drug is safer nor provides objectively superior analgesia than the other.
(1) Moller et al. Why and when citizens call for emergency help: an observational study of 211,193 medical emergency calls. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 2015;23(88). doi: https://doi.org/10.1186/s13049-
(2) Chang H, Daubresse M, Kruszewski S, Alexander G. Prevalance and treatment of pain in EDs in the United States, 2000 to 2010. American Journal of Emergency Medicine. 2014;32(5):
421- 431. doi: 10.1016/j.ajem.2014.01.015
(3) American College of Emergency Physicians. Policy statement: out-of-hospital use of analgesia and sedation. Annals of Emergency Medicine. 2016(67):305-306. Available from http://www.annemergmed.com/article/S0196-0644(15)01604-2/pdf
(4) Ministry of Health and Long-Term Care. ALS PCS Version 3.0. Queen’s Printer for Ontario. Toronto: The Queen’s Printer for Ontario; 2011
(5) Ministry of Health and Long-Term Care. ALS PCS Versio 3.3. Queen’s Printer for Ontario. Toronto: The Queen’s Printer for Ontario; 2015.
(6) Weldon E, Ariano R, Grierson R. Comparison of fentanyl and morphine in the prehospital treatment of ischemic type chest pain. Prehospital Emergency Care, 2016 (20):45-51. doi: 10.3109/10903127.2015.1056893
(7) Rickard C, O’Meara P, McGrail M, Garner D, McLean A, La Lievre
- A randomized controlled trial of intranasal fentanyl vs intra-venous morphine for analgesia in the prehospital setting. The American Journal of Emergency Medicine. 2007(25):911-917. doi: 10.1016/j.ajem.2007.02.027
(8) Fleischman R, Frazer D, Daya M, Jui J, Newgard C. Effectiveness and safety of fentanyl compared with morphine for out-of-hospi-tal analgesia. Prehospital Emergency Care, 2010 (14):167-175. doi: 10.3109/10903120903572301
(9) Middleton P, Simpson P, Sinclair G, Dobbins T, Bendall J. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehospital Emergency Care, 2010 (14):439-
- doi: 10.3109/10903127.2010.497896
(10) Wolf R, Aune D, Truyers C, Hernandez A, Misso K, Riemsma R, Kleijnen J. Systematic review of efficacy and safety of buprenor-phine versus fentanyl or morphine in patients with chronic moderate to severe pain. Current Medical Research & Opinion, 2012; 28 (5):833-845. doi: 10.1185/03007995.2012.678938
(11) Shulz K, Altman D, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. BMJ. 2010(340). doi: 10.1136/bmj.c332
(12) Strengthening the Reporting of Observational Studies in Epidemi-ology. STROBE Checklist. Strobe-Statement.org. Available from https://www.strobe-statement.org/fileadmin/Strobe/uploads/ checklists/STROBE_checklist_v4_combined.pdf
(13) Palmer P, Lemus B, DiDonato K, House J. Cost of delivering intra-veneous opioid analgesia in emergency departments in the United States. ISPOR 21st Annual International Meeting. 2016. Available from http://www.acelrx.com/technology/publications/arx04/ISPOR%202016%2 0ER%20IV%20MS%20Poster%20 5%209%2016.pdf
(14) Pasternak G, Pan Y. Mu opioid receptors in pain management. Acta Anaesthesiologica Taiwanica. 2010;49(1):21-25. Doi: https://doi.org/10.1016/j.aat.2010.12.008
ABOUT THE AUTHOR
Dan Piquette has been working as a Primary Care Paramedic with Peel Regional Paramedic Services in Ontario, Canada since 2006. He is currently attending the Advanced Care Paramedic program with Humber College and is also completing a Bachelor of Health Sciences Degree. In his spare time he is the chief steward of his workplace union. When not pursuing academic endeavors, he can be found on local roadways running and cycling.