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

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, [mu]-opioid receptor agonist and diffuse across bloodbrain barrier rapidly. (7) Its equilibration t V is about six minutes and fentanyl is 100-fold more potent than morphine. (8) Fentanyl metabolized in the liver. (9, 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

To data collecting for this review, we searched 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. The following keywords were used: fentanyl; emergency department and pain management. The search was further limited by age group to adults, moreover, the duration of pain and the articles evaluating patients with chronic pain were excluded. Moreover, articles with duplicated 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 conducted between 2010 to 2016 were recruited and totally 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. The 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(Table 1). Moreover, Table 2 shows the number of the participants in each trials, the dose of administered drugs, the level of pain reduction etiology of pain and possible adverse effect of treatments (Table 2).

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 [micro]g/ 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 [micro]g/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 surveys evaluated in this review by Middleton compared two analgesics including morphine and methoxyflurane with fentanyl and demonstrated that IV morphine and intranasal fentanyl was more effective than methoxyflurane regarding the pain relief among the out patients. Moreover, in comparison between fentanyl and morphine, they proved that morphine was more effective than fentanyl. While IN 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. that 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 patients' satisfaction (24). Three of practices were conducted by the authors as cohort study and compared the pain score before and after fentanyl administration. Wedmore et al. in 2012 studied the effectiveness and safety of 286 out hospital patients that were treated with oral transmucosal fentanyl citrate (OTFC) and revealed a significant difference between pain score before and 15, 30 minutes after treatment. Moreover, they emphasized that fentanyl is safe, however, in high dose administration, nausea, hypoventilation and O2 saturation less than 90% may occur (25).

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 articles. 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 that whether fentanyl is a useful agent in the patients with chronic pain such as patients with cancers other painful chronic diseases.

CONCLUSION

In summary, the studies proved that fentanyl significantly decreases the acute pain intensity and 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 and increased the level of patients' satisfaction. A review by Downey et al. indicated that pain reduction increases satisfaction and function of patients, moreover they emphasized that pain relief improves patients doctor communication (26). 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. Finally, we concluded that fentanyl significantly decreases the pain intensity in patients referring with acute pain to the emergency department. Moreover, it is more effective than morphine and methoxyflurane in the most of the patients.

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

REFERENCES

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(7.) Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology. 1985;62(3):234-241. [PubMed]

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(11.) Food and Drug Administration. FDA warns of potential serious side effects with breakthrough cancer pain drug [press release]. Silver Spring (MD): FDA; September 26, 2007. Available from: http://www. fda.gov/ NewsEvents/ Newsroom/ PressAnnouncements/ 2007/ ucm108994.htm. Accessed June 1, 2011.

(12.) Knill R, Cosgrove JF, Olley PM, Levison H. Components of respiratory depression after narcotic premedication in adolescents. Can Anaesth Soc J. 1976;23(5):449-458. [PubMed]

(13.) Rigg JR, Goldsmith CH. Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man. Can Anaesth Soc J. 1976;23:370-382.

(14.) Cephalon. ACTIQ[R] (oral transmucosal fentanyl citrate) [package insert]. Salt Lake City: Cephalon, Inc.; 2011.

(15.) Hansen MS, Dahl JB.Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting--a systematic review. Dan Med J 2013;60(1):A4563. [PubMed]

(16.) Borland M, Milsom S, Esson A. Equivalency of two concentrationsof fentanyl administered by the intranasal route for acute analgesia inchildren in a paediatric emergency department: a randomizedcontrolled trial. Emerg Med Australas. 2011;23(2):202208. doi: 10.1111/j.17426723.2011.01391.x[PubMed]

(17.) Holdgate A, Cao A, Lo KM. The implementation of intranasal fentanyl for children in a mixed adult and pediatric emergency department reduces time to analgesic administration. Acad Emerg Med.2010;17(2):214217. doi: 10.1111/j.15532712.2009.00636.x[PubMed]

(18.) Ziegler DK."Opioids in headache treatment: is there a role?"Neurologic Clinics, vol. 15, no. 1, pp. 199-207, 1997.

(19.) Deaton T, Auten JD, Darracq MA.Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial. Am J Emerg Med. 2015 Jun;33(6):791-5. doi: 10.1016/j. ajem.2015.03.046. Epub 2015 Mar 25. [PubMed]

(20.) Farahmand S, Shiralizadeh S, Talebian MT, Bagheri-Hariri S, Arbab M, Basirghafouri H, et al. Nebulized fentanyl vs intravenous morphine for ED patients with acute limb pain: a randomized clinical trial. Am J Emerg Med. 2014 Sep;32(9):1011-5. doi: 10.1016/j.ajem.2014.05.051. Epub 2014 Jun 12. [PubMed]

(21.) Wenderoth BR, Kaneda E , Amini A, Amini R, Patanwala AE.Morphine versus fentanyl for pain due to traumatic injury in the emergency department. J Trauma Nurs. 2013 Jan-Mar;20(1):10-5. doi: 10.1097/ JTN.0b013e31828660b5. [PubMed]

(22.) Fleischman RJ, Frazer DG, Daya M, Jui J, Newgard CD.Effectiveness and Safety of Fentanyl Compared with Morphine for Out-of-Hospital An algesia. 2010; 14(2):167-175 doi: 10.3109/10903120903572301 [Pub Med][Free full text]

(23.) Johnston S, Wilkes GJ, Thompson JA, Ziman M, brightwell R. Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service. Emerg Med J. 2011;28(1):57-63. doi: 10.1136/ emj.2009.078717 [PubMed]

(24.) Middleton PM, Simpson PM, Sinclair G, Dobbins T, Math B, Bendal JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care. 2010;14:439-47. doi: 10.3109/10903127.2010.497896. [PubMed]

(25.) Taylor D, Galan V, Weinstein SM, Reyes E, Pupo-Araya AR, Rauck R. Fentanyl Pectin Nasal Spray in Breakthrough Cancer Pain .J Support Oncol 2010;8(4):184-190. [PubMed]

(26.) Wedmore IS, Kotwal RS, McManus JG, Pennardt A, Talbot TS, Fowler M, et al. Safety and efficacy of oral transmucosal fentanyl citrate for prehospital pain control on the battlefield. J Trauma Acute Care Surg. 2012 Dec;73(6 Suppl 5):S490-5. doi: 10.1097/ TA.0b013e3182754674. [PubMed]

(27.) DowneyLA, Zun LS.Pain management in the emergency department and its relationship to patient satisfaction J Emerg Trauma Shock. 2010 Oct-Dec;3(4): 326-330. doi: 10.4103/0974-2700.70749. [PubMed][Free full text]

Sara Payami

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

Correspondence: Sara Payami

Department of Emergency Medicine, Imam Reza Hospital, Kermanshah University of Medical Science, Kermanshah, Iran; Phone: 00989121466649, 00988334276326; E-mail: payami.sara@gmail.com

Received: 4 Mar 2018

Reviewed: 22 May 2018

Corrected: 30 May 2018

Accepted: 2 Jun 2018
Table 1: Characteristics of the trials

Authors      Year      Setting          Route of      Type of study
                                     administration

Middleton    2010    No blinding,    IN fentanyl vs   Retrospective,
et al.                    no         IV morphine vs    comparative,
                    randomization    methoxyflurane   observational
                     (N=42, 844)

Taylor       2010    Randomized,        Fentanyl       Prospective
et al.                 placebo-       pectin nasal      randomized
                     controlled,      spray (FPNS)
                     double-blind
                       (n=114)

Fleischman   2010   No blinding no   IV Fentanyl vs   Retrospective,
                    randomization       Morphine       comparative
                       (n=718)

Johnston     2011   No blinding no   IN fentanyl vs   Retrospective,
et al.              randomization    methoxyflurane    comparative,
                       (n=1024)                       observational

Wedmore      2012   No control, no        Oral         Prospective
et al.              randomization,    transmucosal        Cohort
                     no blinding        fentanyl
                       (N=197)       citrate (OTFC)
                                        Fentanyl
                                       (different
                                         doses)

Wenderoth    2013   No control, no   IV Fentanyl vs   Retrospective
et al.              randomization,      morphine       comparative
                          no
                       blinding
                       (N=168)

Farahmand    2014      Placebo-        Nebulized        Controlled
                     controlled,      fentanyl vs         trial
                    double-blind,     intravenous
                     randomized,        morphine
                       clinical
                    trial. (N=90)

Deaton       2015    Randomized,       Nebulized        Controlled
                       double-        fentanyl vs         trial
                       blinded,       intravenous
                       double-          morphine
                       placebo-
                      controlled
                     trial (N=40)

Table 2: The number of the participants, dose, level and etiology of
pain and possible adverse effects

Author (Year)      Number of Patients           Dose of analgesic

Middleton       42844 patients; Morphine        Morphine 0.5 mg/
et al.          (12955), Fentanyl (3778),        kg, IN fentanyl
(2010)           Methoxyflurane (19235),           90 [micro]g
                 Combination (morphine,
                      fentanyl, or
                 methoxyflurane) (6876).

Taylor et al.    114 (FPNS and placebo)         BTCP: 7 episodes
(2010)                                         for case and 3 for
                                                     placebo

Fleischman       718 (355 morphine, 363        Morphine IV 2--5
(2010)                  fentanyl)                mg, maximum 20
                                            mg. Fentanyl 50-[micro]g
                                                IV dose, maximum
                                                  200 [micro]g.

Johnston        1024;MTX (465), INF(393),     INF (15-180 [micro]g
et al.                 both (162)             first, 15-60 [micro]g
(2011)                                       second dose), MTX (3 ml
                                              at a concentration of
                                                   0.2%-0.4%)

Wedmore          197(156 received OTFC)            OTFC (962.4
et al.                                          (452.7) [micro]g
(2010)

Wenderoth        168 (84 in fentanyl and        morphine 4 mg IV,
et al.            84 in morphine group)     fentanyl 50 [micro]g IV.
(2013)

Farahmand       90 patients (47 nebulized     nebulized fentanyl (4
et al.           fentanyl, 43 morphine)        [micro]g/kg) and IV
(2014)                                      normal saline as placebo.
                                             IV morphine (0.1 mg/kg)
                                              and nebulized normal
                                                saline as placebo

Deaton,            40 (20 NF, 20 IVM)            IVM = 0.1 mg/kg
et al.                                        5, NF= 2 [micro]g/kg
(2015)

Author (Year)         Pain score *              Etiology of pain
                      at admission
                     [right arrow]
                     after treatment

Middleton                8.4-3.9             Pain in abdomen, back,
et al.                                         respiratory, chest,
(2010)                                             obstetrics

Taylor et al.    Two point discretion in             cancer
(2010)               pain intensity

Fleischman        morphine (8.3 [right       Extremity and hip pain,
(2010)            arrow] 5.4), fentanyl         burns Atraumatic
                  (8.1 [right arrow] 5)       abdominal and pelvic
                                              pain, ischemic chest
                                             pain, Back pain, Other
                                            chest pain, Head and neck
                                                      pain

Johnston          MTX (8 [right arrow]      visceral pain(abdominal,
et al.            5.5), INF (7.6 [right          cardiac, renal)
(2011)           arrow] 4.4), both (8.8
                   [right arrow] 5.4)

Wedmore            8 [right arrow] 3.2        Gun shot, orthopedic
et al.                                        injuries, laceration
(2010)

Wenderoth         fentanyl = 10 [right         All types of trauma
et al.           arrow] 8, morphine = 8
(2013)               [right arrow] 6

Farahmand         fentanyl (8.7 [right        Wound and soft tissue
et al.            arrow] 3.5), morphine        injuries Fractures
(2014)           (8.4 [right arrow] 3.8)       Sprains and strains

Deaton,          IVM =7.5, [right arrow]        undifferentiated
et al.          5.9 NF= 6.6 [right arrow]        abdominal pain
(2015)                     2.8

Author (Year)         Side effects

Middleton             Not reported
et al.
(2010)

Taylor et al.     Patients with adverse
(2010)            events were excluded

Fleischman         Nausea, Hypotension
(2010)

Johnston               Not report
et al.
(2011)

Wedmore             nausea, pruritus,
et al.            drowsiness, dizziness
(2010)

Wenderoth       In fentanyl: hypotension,
et al.           respiratory depression,
(2013)             oxygen desaturation

Farahmand           Nausea, vomiting
et al.           Lightheaded-ness, loss
(2014)              of consciousness

Deaton,               Not reported
et al.
(2015)

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

* NRS (1-10)
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Author:Payami, Sara
Publication:Anaesthesia, Pain & Intensive Care
Article Type:Report
Date:Apr 1, 2018
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