Objective and Rationale for the Review

Appropriate management of acute pain is an integral part of patient management in the prehospital setting. The prevalence of pain specifically in the prehospital setting varies, with estimates ranging from 20-53 percent.¹ Adequate pain relief is known to minimize anxiety and cardiac complications associated with acute pain.² However, as many as 43 percent of adults³ and 85 percent of pediatric patients⁴ have insufficient prehospital pain relief.

For patients experiencing moderate to severe traumatic injury pain, current guidelines (based on moderate quality evidence) strongly recommend initial prehospital management with a weight-based opioid, either intravenous (IV) morphine or IV/intranasal (IN) fentanyl.⁵ Complicating the appropriate use of prehospital opioids is the fear of their abuse and the resulting epidemic in the United States.^6,7 When combined with concerns of adverse events, such as vomiting and subsequent airway obstruction, respiratory depression, hypotension, and sedation,⁸ alternative analgesics have been sought. Nonopioid analgesics, including ketamine, acetaminophen (APAP), nitrous oxide/oxygen and nonsteroidal anti-inflammatory drugs (NSAIDs) (specifically ketorolac and ibuprofen) may provide adequate analgesia. This systematic review assesses the comparative effectiveness and harms of opioids compared to nonopioid analgesics for the prehospital management of acute pain (Figure A).

Figure A

Analytic framework. Abbreviations: AE=adverse event; KQ=Key Question

Data Sources

We searched MEDLINE^®, Embase^®and Cochrane Central bibliographic databases from earliest date through May 9, 2019; hand searches of references of relevant studies; www.clinicaltrials.gov and the International Controlled Trials Registry Platform. The systematic review protocol is available in the full report.

Methods

The protocol was registered in PROSPERO (CRD42018114959) and posted on the AHRQ website. The draft report will be posted for public and peer review and we will revise the report based on these comments. After input from the Technical Expert Panel (TEP), NHTSA, AHRQ and our EPC, we chose the following analgesic comparisons and outcomes upon which to formulate conclusions with graded strength of evidence (SOE): comparisons (opioids versus ketamine, opioids versus APAP, opioids versus nitrous oxide, opioids versus NSAIDs, combination opioid and ketamine versus opioids) and outcomes (pain severity, pain presence, time to analgesic effect, any adverse event, hypotension, mental status changes, and respiratory depression).

Conclusions are made in the context of clinically important differences that were established based on the input of NHTSA, AHRQ, the TEP, and our EPC. This includes 2 points on a 0 to 10 pain scale, 5 minutes for time to analgesia, 10 percent absolute difference for any adverse event and 5 percent absolute difference for hypotension, respiratory depression and mental status changes review. We judged the SOE for our conclusions in consideration of five domains: study limitations, consistency, directness, precision and reporting bias.⁹ The four levels of SOE include high (+++), moderate (++), low (+), or insufficient.

The results for analgesics comparisons and outcomes that are not graded are reported in the full report.

Results

We included 52 randomized controlled trials (RCTs) and 13 observational studies, of which 37 RCTs and 4 observational studies provided evidence for graded comparisons and outcomes (Table A).^10–74 We aimed to base conclusions on direct evidence from the prehospital setting, but this was not always possible because of a lack of studies. In the absence of sufficient prehospital evidence, we used evidence from the emergency department but downgraded strength of evidence for indirectness.

Table A

Characteristics of included studies for graded comparisons, per comparison.

Initial Analgesia

Key Questions (KQ) 1 and 2 aimed to evaluate comparative effectiveness (KQ 1) and harms (KQ 2) of initial analgesics (Table B). Conclusions are based on indirect evidence from the emergency department setting. Opioids, ketamine and NSAIDs were primarily administered IV, and for APAP this was the only route studied. The IN route was also common in studies reporting adverse event outcomes for the comparison of opioids versus ketamine.

We found no evidence of clinically important differences in pain reduction between opioids and ketamine administered primarily IV, IV APAP or NSAIDs administered primarily IV. Combining opioids and ketamine may be more effective than opioids alone, administered primarily IV.

Opioids may cause fewer adverse events than ketamine, primarily administered IN. Based on subgroup analysis, this risk may be associated with age or route of administration. Opioids may cause more adverse events than NSAIDs, administered primarily IV. Opioids may cause more side effects than APAP, both administered IV.

Table B

Summary of the comparative effectiveness and harms of initial analgesics in the prehospital setting.

Analgesia When Initial Choice Is Insufficient

KQ 3 and 4 aimed to evaluate comparative effectiveness and harms of subsequent analgesia when initial analgesia is ineffective. Giving a patient ketamine IV instead of continuing to administer morphine IV when the initial morphine IV administration does not provide the patient with pain relief may reduce pain more and may reduce pain more quickly. This is based on direct evidence from the prehospital setting. Evidence of harms was either insufficient or nonexistent.

Table C

Summary of the comparative effectiveness and harms of subsequent analgesics in the prehospital setting.

Discussion

Our review found that as an initial analgesic and primarily administered IV, opioids are no different than the nonopioid analgesics ketamine, APAP and NSAIDs in reducing pain. The combination of opioids and ketamine may be more effective in reducing pain, compared with opioids alone. When initial IV morphine is not effective, switching to IV ketamine may be better in reducing pain than continuing to administer morphine.

To put these findings in context there are key parameters concerning applicability to consider. The studies that compared the efficacy of opioids with ketamine mostly compare weight-based IV morphine 0.1mg/kg with IV ketamine (variable weight-based dosing). Some studies evaluated IN fentanyl and IN ketamine, which were prepared from the IV formulations and delivered IN via an atomizer. The IN ketamine product on the US market is not approved for pain management and is specific to management of treatment-resistant depression. The doses of ketamine varied and too few studies were available to identify associations based on dose. When ketamine was studied in combination with opioids, a single IV dose was added to the opioid regimen. How administration of more than one ketamine dose impacts outcomes is unknown. Nine of the 10 trials that compared opioids with APAP compared IV morphine 0.1 mg/kg with IV APAP 1g, thus results cannot be extrapolated to other routes or doses. There were only three studies comparing opioids with NSAIDs with a mixed representation of oral and IV dosage forms. We were unable to draw conclusions about the efficacy of opioids compared with nitrous oxide (based on a single study with limitations).

Comparative harms of specific adverse events vary among analgesics and in the absence of clinically important differences in pain reduction, can inform individualized treatment decisions. The overall frequency of total adverse events in trials that compared opioids with ketamine suggests that at least 50 percent of treated patients will experience some type of adverse event but low-strength evidence suggests that opioids may cause fewer total adverse events than ketamine. These trials studied primarily IN analgesic administration and based on our subgroup analyses, the lower overall adverse event risk with opioids may be associated with either age or route of administration. Opioids may cause more respiratory depression while ketamine causes more dizziness. In contrast to the comparison of opioids with ketamine, opioids may cause more adverse events than IV APAP or NSAIDs when used as initial analgesics. In patients who do not adequately respond to initial morphine, comparative harms of giving ketamine compared with giving additional morphine are uncertain.

The focus of this report is to synthesize existing evidence. We do not make clinical recommendations. We encourage application of this evidence toward future work generating evidence-based clinical guidelines.

The major limitation of this review is the indirectness of evidence, which may have significant implications and led to our downgrading of conclusions. We believe the single most important future research need is addressing this evidence gap with pain management studies set in the prehospital environment. In addition, research is needed to explore subgroups, including patient and drug regimen characteristics and EMS personnel training and how these characteristics may modify comparative effectiveness and harms of analgesics.

Conclusion

As initial analgesia administered primarily IV, opioids are no different than ketamine, APAP, and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Differences in specific side effects vary between analgesics and can further inform treatment decisions. Combined administration of an opioid and ketamine may reduce acute pain more than an opioid alone but comparative harms are uncertain. When initial morphine is inadequate in reducing pain, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, strength of evidence is generally low, and future research in the prehospital setting is needed.

References

1.

McLean SA, Maio RF, Domeier RM. The epidemiology of pain in the prehospital setting. J Emerg Med. 2002;6(4):402–405. PMID: 12385606. [PubMed: 12385606]

2.

Thomas SH, Shewakramani S. Prehospital trauma analgesia. J Emerg Med. 2008 Jul:35(1):47–57. PMID: 17997072. [PubMed: 17997072]

3.

Albrecht E, Taffe P, Yersin B, et al. Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study. Br J Anaesth. 2013 Jan;110 (1):96–106. PMID: 23059961. [PubMed: 23059961]

4.

Izsak E, Moore JL, Stringfellow K, Oswanski MF, Kindstrom DA, Stombaugh HA. Prehospital pain assessment in pediatric trauma. Prehosp Emerg Care 2008;12:182–6. PMID 18379914. [PubMed: 18379914]

5.

Gausche-Hill M, Brown KM, Oliver ZJ, et al. An evidence-based guideline for prehospital analgesia in trauma. Prehosp Emerg Care. 2014;18: Suppl 1:25–34. PMID: 24279813. [PubMed: 24279813]

6.

Clark DJ, Schumacher MA. America’s opioid epidemic: supply and demand considerations. Anesth Analg. 2017 Nov;125(5):1667–1674. PMID: 29049112. [PubMed: 29049112]

7.

Hoppe JA, Nelson LS, Perrone J, et al. Opioid prescribing in the cross section of US emergency departments. Ann Emerg Med. 2015 Sep;66(3):253–259. PMID: 25952503. [PMC free article: PMC4550521] [PubMed: 25952503]

8.

Benyamin R AND Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008 Mar;11:(2 Suppl):S105–S120. PMID: 18443635. [PubMed: 18443635]

9.

Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update, 2013. In: Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville MD: Agency for Healthcare Research and Quality; 2014. Chapters available at www​.effectivehealthcare.ahrq.gov.

10.

Deaton T, Auten J, 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):791–795. PMID: 25840767. [PubMed: 25840767]

11.

Farahmand S, Shiralizadeh S, Talebian MT, 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):1011–1015. PMID: 25027194. [PubMed: 25027194]

12.

Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emerg Med Austral. 2009 Jun;21(3):203–209. PMID: 19527280. [PubMed: 19527280]

13.

Sub-dissociative ketamine for the management of acute pediatric pain. NCT01951963. https://clinicaltrials.gov/ct2/show/NCT01951963?term=NCT01951963&rank=1. Accessed 11 March, 2019.

14.

Galinski M, Dolveck F, Combes X, et al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med. 2007 May;25(4):385–390. PMID: 17499654. [PubMed: 17499654]

15.

Jalili M, Mozaffarpour Noori A, Sedaghat M, Safaie A. Efficacy of intravenous paracetamol versus intravenous morphine in acute limb trauma. Trauma Mon. 2016 Feb;21(1):e19649. [PMC free article: PMC4869432] [PubMed: 27218042]

16.

Tran KP, Nguyen Q, Truong XN, et al. A comparison of ketamine and morphine analgesia in prehospital trauma care: a cluster randomized clinical trial in rural Quang Tri province, Vietnam. Prehosp Emerg Care. 2014 Apr-Jun;18(2):257–264. PMID: 24400915. [PubMed: 24400915]

17.

Verki MM, Mozafari J, Tirandaz F, Motamed H, Khazaeli A. Efficacy of nebulized fentanyl and low dose ketamine for pain control of patients with long bone fractures: a randomized, double-blind, clinical trial. African Journal of Emergency Medicine. 2019; 10.1016/j.afjem.2019.02.003. [Epub ahead of print]. [PMC free article: PMC6742599] [PubMed: 31528528] [CrossRef]

18.

Quinn K, Kriss S, Drapkin J, et al. Analgesic efficacy of intranasal ketamine versus intranasal fentanyl for moderate to severe pain in children: a prospective, randomized, double-blind study. Pediatr Emerg Care. 2018 Jul 24; doi: 10.1097/PEC.0000000000001556. [Epub ahead of print]. PMID: 30045355. [PubMed: 30045355] [CrossRef]

19.

Frey TM, Florin TA, Caruso M, et al. Effect of intranasal ketamine vs fentanyl on pain reduction for extremity injuries in children: the PRIME randomized clinical trial. JAMA Pediatr. 2019 Feb;173(2):140–146. PMID: 30592476. [PMC free article: PMC6439599] [PubMed: 30592476]

20.

Reynolds SL, Bryant KK, Studnek JR, et al. Randomized controlled feasibility trial of intranasal ketamine compared to intranasal fentanyl for analgesia in children with suspected extremity fractures. Acad Emerg Med. 2017 Dec;24(12):1430–1440. PMID: 28926159. [PubMed: 28926159]

21.

Graudins A, Meek R, Egerton-Warburton D, Oakley E. The PICHFORK (Pain in Children Fentanyl or Ketamine) Trial: a randomized controlled trial comparing intranasal ketamine and fentanyl in children with limb injuries. Ann Emerg Med 2015;65:248–254. PMID: 25447557. [PubMed: 25447557]

22.

Shimonovich S, Gigi R, Shapira A, et al. Intranasal ketamine for acute traumatic pain in the emergency department: a prospective, randomized clinical trial of efficacy and safety. BMC Emerg Med. 2016 Cov;16(1):43. PMID: 27829367. [PMC free article: PMC5103427] [PubMed: 27829367]

23.

Farnia MR, Jalali A, Vahidi E, et al. Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic. AM J Emerg Med. 2017 Mar;35(3):434–437. PMID: 27931762. [PubMed: 27931762]

24.

Motov S, Mann S, Drapkin J, et al. Intravenous subdissociative-dose ketamine versus morphine for acute geriatric pain in the emergency department: a randomized controlled trial. Am J Emerg Med. 2019 Feb;37(2):220–227. PMID: 29807629. [PubMed: 29807629]

25.

Mahshidfar B, Mofidi M, Fattahi M, et al. Acute pain management in emergency department, low dose ketamine versus morphine, a randomized clinical trial. Anesth Pain Med. 2017 Dec;7(6):e60561. PMID: 29696126. [PMC free article: PMC5903386] [PubMed: 29696126]

26.

Motov S, Rockoff B, Cohen V, et al. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: a randomized controlled trial. Ann Emerg Med. 2015 Sep;66(3):222–229. PMID: 25817884. [PubMed: 25817884]

27.

Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402–8. PMID: 25624076. [PubMed: 25624076]

28.

Majidinejad S, Esmailian M, Emadi M. Comparison of intravenous ketamine with morphine in pain relief of long bones fractures: a double blind randomized clinical trial. Emerg (Tehran). 2014 Spring;2(2):77–80. PMID: 26495351. [PMC free article: PMC4614583] [PubMed: 26495351]

29.

Jahanian F, Hosseininejad SM, Amini Ahidashti H, et al. Efficacy and safety of morphine and low dose ketamine for pain control of patients with long bone fractures: a randomized, double-blind, clinical trial. Bull Emerg Trauma. 2018 Jan;6(1):31–36. PMID: 29379807. [PMC free article: PMC5787361] [PubMed: 29379807]

30.

Bronsky ES, Koola C, Orlando A, et al. Intravenous low-dose ketamine provides greater pain control compared to fentanyl in a civilian prehospital trauma system: a propensity matched analysis. Prehosp Emerg Care. 2018 May;1–8. doi: 10.1080/10903127.2018.1469704. [Epub ahead of print]. PMID: 29775117. [PubMed: 29775117] [CrossRef]

31.

Schauer SG, Mora AG, MAddry JK, Bebarta VS. Multicenter, prospective study of prehospital administration of analgesia in the U.S. combat theater of Afghanistan. Prehosp Emerg Care. 2017 Nov-Dec;21(6):744–749. PMID: 28829661. [PubMed: 28829661]

32.

Schackelford SA, Fowler M, Schultz K, et al. Prehospital pain medication use by U.S. forces in Afghanistan. Mil Med. 2015 Mar;180(3):304–309.PMID: 25735021. [PubMed: 25735021]

33.

Jennings PA, Cameron P, Bernard S, et al. Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial. Ann Emerg Med. 2012 Jun;59(6):497–503. PMID: 22243959. [PubMed: 22243959]

34.

Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med. 2009 Nov;17:61. PMID: 19943920. [PMC free article: PMC2789038] [PubMed: 19943920]

35.

Clark E, Plint AC, Correll R, et al. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007 Mar;119(3):460–467. PMID: 17332198. [PubMed: 17332198]

36.

Oberholzer N, Kaserer A, Albrecht R, et al. Factors influencing quality of pain management in a physician staffed helicopter emergency medical service. Anesth Analg. 2017 Jul;125(1):200–209. PMID: 28489643. [PubMed: 28489643]

37.

Hosseininejad SM, Jahanian F, Erfanian Irankar S, et al. Comparing the analgesic efficacy of morphine plus ketamine versus morphine plus placebo in patients with acute renal colic: a double-blinded randomized controlled trial. Am J Emerg Med. 2018 Sep 3. pii: S0735-6757(18)30733-2. doi: 10.1016/j.ajem.2018.09.004. [Epub ahead of print]. PMID: 30201237. [PubMed: 30201237] [CrossRef]

38.

Sin B, Tatunchak T, Paryavi M, et al. The use of ketamine for acute treatment of pain: a randomized, double-blind, placebo-controlled trial. J Emger Med. 2017 May;52(5):601–608. PMID: 28279542. [PubMed: 28279542]

39.

Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193–1202. PMID: 25377395. [PubMed: 25377395]

40.

Abbasi S, Bidi N, Mahshidfar B, et al. Can low-dose of ketamine reduce the need for morphine in renal colic? A double-blind randomized clinical trial. Am J Emerg Med. 2018 Mar;36(3):376–379. PMID: 28821365. [PubMed: 28821365]

41.

Mohammadshahi A, Abdolrazaghnejad A, Nikzamir H, Safaie A. Intranasal ketamine administration for narcotic dose decrement in patients suffering from acute limb trauma in emergency department: a double-blind randomized placebo-controlled trial. Adv J Emerg Med. 2018;2(3):e30. [PMC free article: PMC6549208] [PubMed: 31172093]

42.

Vahdati S, Morteza Baghi HR, Ghobadi J, et al. Comparison of paracetamol (apotel®) and morphine in reducing post pure head trauma headache. Anesth Pain Med. 2014 Jun;4(3):e14903. PMID: 25237630. [PMC free article: PMC4164985] [PubMed: 25237630]

43.

Pathan SA, Mitra B, Straney LD, et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial. Lancet. 2016 May;387(10032):1999–2007. PMID: 26993881. [PubMed: 26993881]

44.

Sotoodehnia M, Farmahini-Farahani M, Safaie A, Rasooli F, Baratloo A. Low-dose intravenous ketamine versus intravenous ketorolac in pain control in patients with acute renal colic in an emergency setting: a double-blind randomized clinical trial. Korean J Pain 2019;32:97–104. PMID: 31091508. [PMC free article: PMC6549592] [PubMed: 31091508]

45.

Serinken M, Eken C, Gungor F, et al. Comparison of intravenous morphine versus paracetamol in sciatica: a randomized placebo controlled trial. Acad Emerg Med. 2016 Jun;23(6):674–678. PMID: 26938140. [PubMed: 26938140]

46.

Eken C, Serinken M, Elicabuk H, et al. Intravenous pracetamol vesus dexketoprofen versus morphine in acute mechanical low back pain in the emergency department: a randomised double-blind controlled trial. Emerg Med J. 2014 Mar;31(3):177–181. PMID: 23407378. [PubMed: 23407378]

47.

Serinken M, Eken C, Turkcuer I, et al. Intravenous paracetamol versus morphine for renal colic in the emergency department: a randomised double-blind controlled trial. Emerg Med J. 2012 Nov;29(11):902–905. PMID: 22186009. [PubMed: 22186009]

48.

Craig M, Jeavons R, Probert J, Benger J. Randomised comparison of intravenous paracetamol and intravenous morphine for acute traumatic limb pain in the emergency department. Emerg Med J. 2012 Jan;29(1):37–39. PMID: 21362724. [PubMed: 21362724]

49.

Al B, Sunar MM, Zengin S, et al. Comparison of IV dexketoprofen trometamol, fentanyl, and paracetamol in the treatment of renal colic in the ED: a randomized controlled trial. Am J Emerg Med. 2018 Apr;36(4):571–576. PMID: 29029797. [PubMed: 29029797]

50.

Mollaei M, Esmailian M, Heydari F. Comparing the effect of intravenous acetaminophen (Apotel®) and intravenous morphine in controlling the pain of forearm and leg fractures in adults. J Isfahan Med Sch. 2016;34(376):293–298.

51.

Masoumi K, Forouzan A, Asgari Darian A, et al. Comparison of clinical efficacy of intravenous acetaminophen with intravenous morphine in acute renal colic: a randomized, double-blind, controlled trial. Emerg Med Int. 2014;2014:571326. PMID: 25197573. [PMC free article: PMC4147290] [PubMed: 25197573]

52.

Masoumi B, Farzaneh B, Ahmadi O, Heidari F. Effect of intravenous morphine and ketorolac on pain control in long bones fractures. Adv Biomed Res. 2017 Jul;6:91. PMID: 28828342. [PMC free article: PMC5549551] [PubMed: 28828342]

53.

Safdar B, Degutis LC, Landry K, et al. Intravenous morphine plus ketorolac is superior to either drug alone for treatment of acute renal colic. Ann Emerg Med. 2006 Aug;48(2):173–181. PMID: 16953530. [PubMed: 16953530]

54.

Le May S, Ali S, Plint AC, et al. Oral analgesics utilization for children with musculoskeletal injury (OUCH Trial): an RCT. Pediatrics. 2017 Nov;140(5): pii: e20170186. doi: 10.1542/peds.2017-0186. Epub 2017 Oct 11. PMID: 29021235. [PubMed: 29021235] [CrossRef]

55.

Cenker E, Serinken M, Uyanik E. Intravenous paracetamol vs ibuprofen in renal colic: a randomised, double-blind, controlled clinical trial. Urolithiasis. 2018 Aug;46(4):369–373. PMID: 28681267. [PubMed: 28681267]

56.

Cozzi G, Zanchi C, Chiaretti A, et al. Adminsitering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency room. Acta Paediatr. 2019 Jan;108(1):143–148. PMID: 30043434. [PubMed: 30043434]

57.

Weldon ER, Ariano RE, Grierson RA. Comparison of fentanyl and morphine in the prehospital treatment of ischemic type chest pain. Prehosp Emerg Care. 2016;20(1):45–51. PMID: 26727338. [PubMed: 26727338]

58.

Smith MD, Wang Y, Cudnik M, et al. The effectiveness and adverse events of morphine versus fentanyl on a physician-staffed helicopter. J Emerg Med. 2012 Jul;43(1):69–75. PMID: 21689900. [PubMed: 21689900]

59.

Rickard C, O’Meara P, McGrail M, et al. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med. 2007 Oct;25(8):911–917. PMID: 17920976. [PubMed: 17920976]

60.

Galinski M, Dolveck F, Borron SW, et al. A randomized, double-blind study comparing morphine with fentanyl in prehospital analgesia. Am J Emerg Med. 2005 Mar;23(2):114–119. PMID: 15765326. [PubMed: 15765326]

61.

Farahmand S, Shiralizadeh S, Talebian MT, 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):1011–1015. PMID: 25027194. [PubMed: 25027194]

62.

Mahar PJ, Rana JA, Kennedy CS, Christopher NC. A randomized clinical trial of oral transmucosal fentanyl citrate versus intravenous morphine sulfate for initial control of pain in children with extremity injuries. Pediatr Emerg Care. 2007 Aug;23(8):544–548. PMID: 17726413. [PubMed: 17726413]

63.

Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007 Mar;49(3):335–340. PMID: 17067720. [PubMed: 17067720]

64.

Younge PA, Nicol MF, Kendall JM, et al. A prospective randomized pilot comparison of intranasal fentanyl and intramuscular morphine for analgesia in children presenting to the emergency department with clinical fractures. Emerg Med. 1999;11:90–94.

65.

Scharonow M, Alberding T, Oltmanns W, Weilbach C. Project for the introduction of prehospital analgesia with fentanyl and morphine administering by specially trained paramedics in a rural service area in Germany. J Pain Res. 2017 Nov;10:2595–2599. PMID: 29158691. [PMC free article: PMC5683795] [PubMed: 29158691]

66.

Daoust R, Paguet J, Lavigne G, et al. Impact of age, sex and route of administration on adverse events after opioid treatment in the emergency department: a retrospective study. Pain Res Manag. 2015 Jan-Feb;20(1):23–28. PMID: 25664538. [PMC free article: PMC4325886] [PubMed: 25664538]

67.

Schacherer NM, Erikson Ramirez D, Frazier SB, Perkins AM. Expedited delivery of pain medication for long-bone fractures using an intranasal fentanyl clinical pathway. Pediatr Emerg Care. 2015 Aug;31(8):560–563. PMID: 25875994. [PubMed: 25875994]

68.

Wenderoth BR, Kaneda ET, Amini A, et al. Morphine versus fentanyl for pain due to traumatic injury in the emergency department. J Trauma Nurs. 2013 Jan-Mar;20(1):10–15. PMID: 23459426. [PubMed: 23459426]

69.

Bendall JC, Simpson PM, Middleton PM. Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients. Prehosp Emerg Care. 2011 Apr-Jun;15(2):158–165. PMID: 21294628. [PubMed: 21294628]

70.

Garrick JF, Kidane S, Pointer JE, et al. Analysis of the paramedic administration of fentanyl. J Opioid Manag. 2011 May-Jun;7(3):229–234. PMID: 21823553. [PubMed: 21823553]

71.

Fleischman RJ, Frazer DJ, Daya M, et al. Effectiveness and safety of fentanyl compared with morphine for out-of-hospital analgesia. Prehosp Emerg Care. 2010 Apr-Jun;14(2):167–175. PMID: 20199230. [PMC free article: PMC2924527] [PubMed: 20199230]

72.

Vahedi HSM, Hajebi H, Vahidi E, Nejati A, Saeedi M. Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury. World J Emerg Med 2019;10:27–32. PMID: 30598715. [PMC free article: PMC6264977] [PubMed: 30598715]

73.

Griffioen MA, Ziegler ML, O’Toole RV, Dorsey SG, Renn CL. Change in pain score after administration of analgesics for lower extremity fracture pain during hospitalization. Pain Management Nursing 2019;20:158–163. PMID: 30442567. [PubMed: 30442567]

74.

Zhang M, Cowan T, Smiles JP, et al. Prehospital analgesic choice in injured patient does not impact on rates of vomiting: experience from a New South Wales primary retrieval service. Emerg Med Australas. 2018 Jun;30(3):406–411. PMID: 29205811. [PubMed: 29205811]