The efficacy of fentanyl for pain management in emergency department: a review

Sara Payami*

*Assistant Professor of Emergency Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, (Iran)

Correspondence: Sara Payami, Assistant Professor of Emergency Medicine, Department of Emergency Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran; Phone: 00989121466649, 00988334276326; E-mail: payami.sara@gmail.com

ABSTRACT
Fentanyl is a strong opioid and it is widely used for pain relief. In this review, we evaluated the efficacy of fentanyl in pain management in the emergency department. For this review, we searched scientific search engines including google, google scholar, Cochrane library, Medline, and PubMed and collected original articles, including randomized controlled trials, comparative studies, cohort and case series related to fentanyl and its administration in the emergency department from 2010 to 2016. In this review, 8 articles and 44493 patients were evaluated. Four articles were retrospective and 4 articles were prospective of these four articles were a randomized placebo-controlled and double-blinded. Among eight, six articles compared the efficacy and adverse events of fentanyl with other opioids. We found fentanyl significantly decreases pain intensity in the patient with acute pain in the emergency department. Moreover, it is more effective than morphine and methoxyflurane.
Keywords: Acute pain; Analgesia; Fentanyl; Pain management; Emergency department
Citation: Payami S. The efficacy of fentanyl for pain management in emergency department: a review. Anaesth Pain & Intensive Care 2018;22(2):251-255
Received – 4 Mar 2018, Reviewed – 22 May 2018, Corrected –30 May 2018, Accepted 2 Jun 2018

INTRODUCTION
Pain is the most prevalent complaint among patients referring to the emergency department.1 The previous reports revealed pain is chief complaint among 75 % of patients and it is more weakening than cancer and heart diseases.1-3 Untreated pain may elevate the level of plasma catecholamine, glucose, antidiuretic hormone, cortisol, and acute phase protein.1-3 To overcome these acute phase reactants, a diverse class of drugs and methods such as opioids, benzodiazepines, and local anesthesia are used to ameliorate the level of pain and distress.4,5 Opioids such as meperidine, morphine, hydromorphone, fentanyl, and methadone are the most common agents used for pain relief in the emergency department (ED).6 Among these drugs, the most appropriate agent regarding BMI, age, and intensity of pain should be chosen as an analgesic or sedative. Fentanyl is a highly lipophilic, µ-opioid receptor agonist and diffuse across blood-brain barrier rapidly.7 Its equilibration t ½ is about six minutes and fentanyl is 100-fold more potent than morphine.8 Fentanyl metabolized in the liver9-11 and may induce some important and life-threatening adverse effects such as hypoventilation and respiratory depression, but, they are rare. In general, like as other opioids, nausea, vomiting, pruritus, and urinary retention are the commonest adverse effect of fentanyl.12,13 The routes of administration of fentanyl include transdermal, intravenous, subcutaneous, oral transmucosal, sublingual, and neuraxial. Moreover, several formulations are accessible.14 Previous practices have reported that fentanyl is well tolerated without any serious adverse effect.15,16 Moreover, it effectively decreases the level of pain as much as other analgesics with a lower serious side effect.17 In this review, we evaluated the effectiveness and possible side effects of fentanyl for pain relief in adult patients referring to the emergency department with acute pain.

Data collection:
For this review, we searched google, google scholar, Cochrane library, Medline, PubMed and collected original articles, including randomized controlled trials, comparative studies, cohort, and case series related to fentanyl and its administration in the emergency department from 2010 to 2016. The following keywords were used: fentanyl; emergency department and pain management. The search was further limited by age group to adults; the duration of pain and the articles evaluating patients with chronic pain were excluded. Moreover, articles with duplicate records and irrelevant full text were excluded. Finally, 8 articles met the inclusion criteria and were enrolled to this review including one cohort and seven comparative studies, including three double blinded placebo controlled trials.

RESULTS
In this review, 8 articles that were published from 2010 to 2016 were recruited and a total of 44493 patients were evaluated. Four articles were retrospective and 4 articles were prospective. The later four articles were randomized placebo controlled and double blinded. Among all eight relevant articles, six of them compared the efficacy and adverse events of fentanyl with other opioids such as morphine and methoxyflurane and two of them compared the pain severity before and after fentanyl prescription. The route of administration of fentanyl in most of the experiences was intranasal but it was intravenous for morphine. Most of the articles demonstrated that fentanyl decreases pain score after administration and is more potent than morphine and methoxyflurane with lower side effects. The characteristics of the trial are summarized in Table 1. Moreover, Table 2 shows the number of the participants in each trial, the dose of administered drugs, the level of pain reduction, etiology of pain and possible adverse effect of treatments (Table 2).

Table 1: Characteristics of the trials
Authors Year Setting Route of administration Type of study
Middleton et al. 2010 No blinding, no randomization(N=42, 844) IN fentanyl vs IV morphine vs methoxyflurane Retrospective, comparative, observational
Taylor et al. 2010 Randomized, placebo-controlled, double-blind (n=114) Fentanyl pectin nasal spray (FPNS) Prospective randomized
Fleischman 2010 No blinding no randomization (n=718) IV Fentanyl vs Morphine Retrospective, comparative
Johnston et al. 2011 No blinding no randomization(n=1024) IN fentanyl vs methoxyflurane Retrospective, comparative, observational
Wedmore et al. 2012 No control, no randomization, no blinding (N=197) Oral transmucosal fentanyl citrate (OTFC) Fentanyl (different doses) Prospective Cohort
Wenderoth et al. 2013 No control, no randomization, no blinding(N=168) IV Fentanyl vs morphine Retrospective comparative
Farahmand 2014 Placebo-controlled, double-blind, randomized, clinical trial. (N=90) Nebulized fentanyl vs intravenous morphine Controlled trial
Deaton 2015 Randomized, double-blinded, double-placebo–controlled trial (N=40)  Nebulized fentanyl vs intravenous morphine Controlled trial
 

Table 2: The number of the participants in each trial, the dose of administered drugs, the level of pain reduction, etiology of pain and possible adverse effect
Author (Year)  
Number of Patients
 		 Dose of analgesic Pain score
[NRS (1-10)]
at admission→after treatment		 Etiology of pain Side effects
Middleton et al. (2010) 42844 patients; Morphine (12955), Fentanyl (3778), Methoxyflurane (19235), Combination (morphine, fentanyl, or methoxyflurane) (6876). Morphine 0.5 mg/kg, IN fentanyl 90 µ g 8.4→3.9 Pain in abdomen, back, respiratory, chest, obstetrics Not reported
Taylor et al. (2010)  114 (FPNS and placebo) BTCP: 7 episodes for case and 3 for placebo Two point discretion in pain intensity cancer Patients with adverse events were excluded
Fleischman

(2010)		 718 ( 355 morphine, 363 fentanyl) Morphine IV 2--5 mg, maximum 20 mg. Fentanyl 50-μg IV dose, maximum 200 μg. Morphine (8.3→5.4 ), fentanyl (8.1→5) Extremity and hip pain, burns Atraumatic abdominal and pelvic pain, ischemic chest pain, Back pain, Other chest pain, Head and neck pain Nausea, Hypotension
Johnston et al. (2011) 1024;MTX (465), INF(393), both (162) INF (15-180 µ g first, 15-60 µ g second dose), MTX (3 ml at a concentration of 0.2% - 0.4%) MTX (8→5.5), INF (7.6→4.4), both (8.8→5.4) visceral pain(abdominal, cardiac, renal) Not reported
Wedmore et al. (2010)

 		 197(156 received OTFC) OTFC (962.4 (452.7) µ g 8→ 3.2 Gun shot, orthopedic injuries, laceration nausea, pruritus,

drowsiness, dizziness

 
Wenderoth et al. (2013) 168 (84 in fentanyl and 84 in morphine group) morphine 4 mg IV, fentanyl 50 µ g IV. fentanyl =10→8, morphine =8→6 All types of trauma In fentanyl: hypotension, respiratory depression, oxygen desaturation

 
Farahmand et al.

(2014)		 90 patients (47 nebulized fentanyl, 43 morphine) nebulized fentanyl (4 μg/kg) and IV normal saline as placebo.

IV morphine (0.1 mg/kg) and nebulized normal saline as placebo		  fentanyl (8.7→3.5), morphine (8.4→3.8) Wound and soft tissue injuries Fractures Sprains and strains Nausea, vomiting Lightheaded-ness, loss of consciousness
Deaton, et al.

(2015)		 40 (20 NF, 20 IVM) IVM = 0.1 mg/kg 5, NF= 2 μg/kg IVM =7.5, →5.9

NF= 6.6→2.8		 undifferentiated abdominal pain Not reported
  Legend: IN = intranasal, IVM = intravenous morphine, NF = nebulized fentanyl, OTFC = oral transmucosal fentanyl citrate, MTX) = Methoxyflurane, INF: intranasal Fentanyl, Fentanyl pectin nasal spray (FPNS), breakthrough cancer pain =BTCP
 

DISCUSSION
The management of pain is a wide field and several hypotheses about the pain relief and agents that can decrease the pain are presented, but most of these guidelines and recommendations are insufficient. For instance, several opioid agonist-antagonists such as buprenorphine, butorphanol, nalbuphine, and pentazocine have been used for decades to reduce pain in patients with acute pain in the emergency department, in the ambulance or in the hospital with some useful effect but with serious complications such as dysphoria.18 In this review, we gathered the articles that were performed to evaluate the efficacy of fentanyl on pain relief in patients in the emergency department. Four studies have compared the efficacy and adverse events of fentanyl with morphine, two of these were double blinded randomized trials including; A study by Deaton et al. in 2015 that compared the effect of nebulized fentanyl (NF) (2 μg/kg) with intravenous morphine (IVM) (0.1 mg/kg) in patients with acute abdominal pain presenting to emergency departments. They revealed that the pain reduction occurred sooner in the NF group and more sustained. Moreover, the authors showed that the satisfaction of patients and doctors in fentanyl group was more than morphine group.18 Another study by Farahmand in 2014 also compared the effectiveness of nebulized fentanyl (4 μg/kg) (47 patients) with intravenous (IV) morphine (0.1 mg/kg) (43 patients) and showed no difference regarding pain reduction and patients’ satisfaction between two groups after 10 minutes, however, after 15 the pain relief in fentanyl group was significantly more than morphine.19 Moreover, one non-blinded study by Wenderoth et al.in 2013 compared the analgesic response and safety of intravenous morphine with fentanyl on adult trauma patients who referred to the emergency department (ED). The pain score reduction in two groups did not differ significantly, although the pain reduction in fentanyl occurred sooner than morphine group. The difference between two groups regarding side effects was not significant.20 Another non-blinded study by Fleischman in 2010 was conducted on 168 patients who were assigned in fentanyl (N=84) and morphine (N=84) groups. The severity of injury in fentanyl was more than morphine group. Five patients in two groups regularly used opioids before admission.

They found that morphine and fentanyl provide the comparative analgesic effect, however, the opioids consumption in fentanyl groups was higher than patients receiving morphine. On the other hand, the adverse events in morphine group was more than fentanyl group.21 Among the comparative surveys, one non-blinded study by Johnston et al. compared the pain relief effect of intranasal fentanyl with methoxyflurane and proved that fentanyl was more effective than methoxyflurane.22 Only one study among those evaluated in this review by Middleton compared two analgesics including morphine and methoxyflurane with fentanyl and demonstrated that IV morphine and intranasal fentanyl were more effective than methoxyflurane regarding the pain relief in the day case patients. Moreover, in comparison between fentanyl and morphine, they proved that morphine was more effective than fentanyl, while nasal fentanyl was more accessible and useable.23 Only one of the study was double-blinded controlled trial and compared the efficacy of fentanyl with controls conducted by Taylor et al., which confirmed fentanyl pectin nasal spray (FPNS) was an effective agent in pain relief. Additionally, they indicated that FPNS is well tolerated and leads to more patient satisfaction.24 Three of the trials were conducted by the authors as cohort studies and compared the pain score before and after fentanyl administration. Wedmore et al. in 2012 studied the effectiveness and safety of 286 outdoor patients that were treated with oral transmucosal fentanyl citrate (OTFC) and revealed a significant difference between pain score before and 15 and 30 min after treatment. Moreover, they emphasized that fentanyl is safe, however, at higher doses, nausea, hypoventilation and O2 saturation less than 90% may occur.25
In summary, the studies proved that fentanyl significantly decreases the acute pain intensity and is well tolerated by the patients. The adverse effects related to fentanyl were not serious and were transient. Pain reduction is related to function improvement in patients, increased the level of patients’ satisfaction, and also improves patient-doctor relationship.26,27 The most of the experiences reviewed in this article used fentanyl as an intranasal spray and showed this is an alternative to the traditional routes of administration such as oral administration and intravenous injection.

LIMITATIONS
Of the 8 studies included in this review, only three studies were randomized and double-blinded, which emphasizes the fact that further high quality double-blinded randomized controlled trials are required to validate results reported in these papers. Moreover, we did not enroll studies on children and all recruited practices were conducted in patients more than 16 years of age. Studies in children may lead to different results. Additionally, we could not confirm whether fentanyl was a useful agent in the patients with chronic pain, e.g. patients with cancer pain or other chronic painful conditions.

CONCLUSION
Finally, we conclude that fentanyl significantly decreases the pain intensity in patients reporting with acute pain to the emergency department and it is more effective than morphine and methoxyflurane in this regard, however, its role in management of cancer pain and chronic pain conditions needs to be assessed by larger multi-center studies.

Conflict of interest: No funding was used for the preparation of this review.

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