Matt Friedman, MD, FACEP, DABEMS
Associate Medical Director of Prehospital Care
Director, EMS Clerkship
Department of Emergency Medicine
Maimonides Medical Center
Analgesia in the prehospital setting is often suboptimally delivered. (Gausche-Hill 2014, Samuel 2015) This has been demonstrated not only in the United States, but also in Australia, Germany and France. (Thomas 2008) Pain is a common reason to request EMS; (Policy Statement 2016) and acute pain is experienced by 35 – 70% of trauma patients. (Jennings 2010, Chambers 1993) However, administering analgesia in the prehospital environment is a relatively new paradigm; until the 1990s, most EMS systems did not have regional protocols to treat pain other than in patients with suspected acute coronary syndromes. (Paris 1996) Guidelines now recommend analgesia for most prehospital trauma patients, regardless of transport times, (Gausche-Hill 2014) and encourage relief of severe acute pain to be a priority for every EMS system. (Alonso-Serra 2003)
In calling for EMS systems to align care around best practices, the Institute of Medicine has advocated for a national approach to prehospital evidence-based guidelines and protocols. (IOM 2006) It has been repeatedly demonstrated that prehospitally administered analgesia reduces discomfort substantially faster than waiting for administration in the ED. (Abbuhl 2003, Dong 2012, Swor 2005) The American College of Emergency Physicians recommends that advanced life support (ALS) EMS systems should provide analgesia and sedation as appropriate with close physician oversight and continuous quality improvement programs in place. (Policy Statement 2016) Concerns that providing analgesia to patients with severe acute abdominal pain may hinder the physical exam or diagnosis have been disproven and in fact appropriate pain control may produce a more reliable physical examination. (Vermeulen 1999, LoVecchio 1997, Pace 1996)
Alongside stabilizing the patient’s injuries and addressing dangerous conditions, treating pain is a central EMS objective. In addition to reducing suffering as a primary goal of healthcare, adequate analgesia has other important benefits. Elevations in heart rate and blood pressure that frequently accompany pain can be a diagnostic impediment, and the catecholaminergic state of patients with insufficiently controlled pain may aggravate conditions such as myocardial ischemia and traumatic brain injuries, in addition to inducing cardiac dysrhythmias (Thomas 2008) and possibly other untoward effects on clinical outcomes. (Gausche-Hill 2014)
The ideal prehospital analgesic agent would have rapid onset of action, relative ease of administration, be highly effective with a wide therapeutic index, and rarely cause adverse events. It would maintain hemodynamic stability and airway reflexes, as well as having low inter-patient pharmacokinetic variability and arguably an anxiolytic or even amnestic effect. (Lee & Kent) No such medication presently exists.
Simple and Non-Pharmacologic Analgesia
NSAIDs and acetaminophen are well studied, effective, safe, and have an opioid-sparing effect. (Policy Statement 2016) Although prehospital care is focused on analgesic drugs to alleviate pain, there is a range of non-pharmacological options that play an important role. Splinting/immobilization of the injured extremity is a quick, effective, and universally available method to reduce pain.
Other non-pharmacological approaches to relieve pain and anxiety include psychological interventions such as distraction, especially for children, stress management, and other cognitive behavioral interventions. (Pak 2015) Therapeutic communication is an underutilized technique that can be very effective in the early phase of injury or illness. This involves reassurance, distraction, and a professional demeanor that conveys compassion and competence. (Alonso-Serra 2003) Parents should be permitted to ride with pediatric patients in the ambulance when possible.
Transcutaneous electrical nerve stimulation has been demonstrated to be safe and effective in the prehospital environment (Simpson 2014) as well as physiotherapy, massage, and application of heating and cooling techniques. (Pak 2015)
Opioids have been used by the American military since the American Civil War. (Wilson 1946) Until more recently, however, adequate pain control was considered detrimental to injury diagnosis. A 1981 paper on civilian prehospital analgesia stated, “Any agent that interferes with the patient’s normal pain response may frustrate the physician attempting to make a diagnosis.” (Amey 1981) It continues “…a suitable agent…should be quick-acting and short lived in order to preserve the pain response for diagnostic purposes in the ED.” US Army physicians minimized analgesia use during World War II concluding that severe wounds in critical trauma patients “are often associated with surprisingly little pain.” (Beecher 1946)
The use of parenteral opioids for patients who have severe pain in the prehospital setting is in most cases safe, effective, and appropriate. (Park 2010) Morphine and fentanyl are well tolerated and result in quantifiable decreases in subjective and objective pain scores. (Gausche-Hill 2014, Smith 2012) The use of intravenous fentanyl 1 μg/kg or intravenous morphine 0.1 mg/kg is comparably effective with similar low rates of adverse events. (Galinski 2005, Smith 2012)
A prehospital review encompassing 6,000 civilian and military patients with acute traumatic and medical conditions found that opioids achieved adequate pain reduction with acceptable efficacy and safety. (Park 2010) The data do not support a preferential IV opioid or specific dose to treat acute pain in trauma patients. (Lee) However guidelines do recommend withholding opioids in the following clinical scenarios associated with severe acute pain: GCS less than 15, hypoxia with supplemental oxygen therapy unless mechanically ventilated, signs of hypoventilation, hypotension, or allergy to the candidate class of drug. (Gausche-Hill 2014)
Morphine, the most commonly used prehospital analgesic (Thomas 2008), also has sedative and anxiolytic properties. It may cause euphoria, dysphoria, hallucinations, respiratory depression, and cough suppression. Morphine induces histamine release via mast cells resulting in urticaria, pruritus, bronchospasm, and hypotension which may be reversed by naloxone. (Trivedi 2007) There is no analgesic ceiling except that imposed by adverse effects; respiratory depression (and analgesia) is also reversed by naloxone. Parenteral morphine is rapidly effective and its effect lasts longer than an equivalent dose of fentanyl. When vascular access has been established, 5 mg IV or IO morphine may be administered to healthy non-elderly adults, every 10 minutes as needed, with careful monitoring for respiratory depression. IM morphine is not recommended as a first line medication due to its highly variable absorption and efficacy, as well as the potential for overdose when multiple doses are administered awaiting the onset of analgesia, which is typically slow by the IM route. (Wedmore 2017) However, absent alternatives, a single IM dose of morphine may be appropriate for patients without vascular access who have severe acute pain.
Fentanyl is a highly lipid soluble synthetic opioid with a more rapid onset of action than morphine and 100-fold greater potency (i.e., 50 mcg IV fentanyl is roughly equivalent to 5 mg IV morphine). [see opioid table] (Alonso-Serra 2003) It can be administered transmucosally, intranasally (IN), intravenously, and via nebulization for rapid pain relief. Fentanyl’s onset of action can be as short as 90 seconds after intravenous administration, with a maximum effect apparent within 10-15 minutes, and duration of approximately 1 hour. (Prommer 2011) Fentanyl produces less histamine release compared with morphine and is therefore less likely to cause hypotension, which favors its use in polytrauma patients [see trauma chapter]. However, patients dependent on sympathetic tone to maintain blood pressure will develop relative hypotension with fentanyl. (Blackburn 2000, Thomas 2008) Additionally, fentanyl is effective when administered IN, in circumstances when IV access is unobtainable or undesirable, as in pediatric patients. A total dose of 1.5-2 μg/kg IN has been effective in the pediatric ED setting and may be a favorable route for prehospital pain relief. (Borland 2002) Fentanyl can also be administered via nebulization at doses of 3 to 4 mcg/kg to patients with acute severe pain, to good effect. (Motov 2016)
The N-methyl-D-aspartate (NMDA) antagonist ketamine, first synthesized in the 1960s from phencyclidine, was initially used in dissociative doses (>1 mg/kg IV) to effect a state of sensory isolation where the patient does not perceive external stimuli, while cardiorespiratory tone and airway reflexes are maintained. In low dose (approximately one-tenth the dissociative dose), ketamine is a highly effective analgesic, providing pain relief prehospitally as monotherapy or in combination with reduced-dose morphine or nitrous oxide. (Jennings 2011, Bansal 2020, Andolfatto 2019) Compared to morphine, ketamine used for prehospital analgesia delivered equivalent reduction in pain scores with a lower associated risk of emesis. However, there is a higher rate of psychoperceptual effects, which are often perceived as dizziness or feelings of unreality, and can make some patients uncomfortable. (Tran 2014, Sandberg 2020) The concomitant administration of ketamine and morphine provides superior analgesia than morphine alone, though dosing adjustments are required.
Historical concerns that ketamine increases intracranial pressure (ICP) or intraocular pressure (IOP), and the concern that ketamine may precipitate persistent perceptual disturbances or psychosis have been disproven. (Filanovsky 2010, Halstead 2012, McGhee 2008) Ketamine preserves airway reflexes and augments blood pressure and heart rate, lending it an advantageous safety profile among prehospital analgesics. In 1,030 prehospital clinical encounters, there were no episodes of hypoxia or need for airway management related to analgesic-dose ketamine administration. (Bredmose 2009)
Inhalable analgesics have been proven to be safe and effective for prehospital use. (Johnson 1991, Donen 1982) The United Kingdom employs Entonox, a 50/50 mixture of oxygen and nitrous oxide. (Lee) Nitrous oxide (N2O) is inexpensive and hemodynamically stable; however concerns around hepatotoxicity, nephrotoxicity, teratogenicity and abuse have impeded the prehospital use of inhalational anesthetics in the United States and Canada. N2O can worsen pneumothoraces or air emboli, and should be avoided in patients known or at high risk to have these conditions.
Methoxyflurane is an inhalational anesthetic first used in the 1960s, though its use was discontinued due to nephrotoxicity at high anesthetic doses. Methoxyflurane has analgesic properties at low doses and is widely used in Australia and New Zealand under the trade name Penthrox where it is self-administered through a disposable inhaler colloquially known as a “green whistle.” Low-dose methoxyflurane is safe, with no reports of nephro- or hepatotoxicity; mild dizziness and somnolence are the most commonly reported adverse effects. Methoxyflurane’s self-contained, portable delivery system is well suited to prehospital use and is an attractive non-opioid option for moderate to severe pain, though it is likely less effective than IV morphine or IN fentanyl. (Middleton 2010, Borobia 2020, Porter 2018)
Regional Nerve Blocks
Prehospital regional analgesia can be rapidly performed in patients with traumatic extremity injuries to significantly reduce pain intensity and severity. (Buttner 2018, Dochez 2014) Ultrasound-guided regional analgesia provides substantial pain relief, reduces systemic analgesia requirements, increases patient satisfaction, and decreases resource utilization. (Motov 2016) Studies demonstrated that either 1% lidocaine or 0.25% bupivacaine for patients with extremity trauma or infections demonstrated significant pain control, total muscle relaxation, successful completion of procedures, and decreased need for rescue analgesia. (Motov 2016) Prehospital use of regional nerve blocks has an evolving role in systems with longer transport times.
Route of administration
The ideal route of administration for prehospital analgesia is more controversial than the ideal agent, with lack of IV access identified as a barrier to effective analgesia. (Turturro 2002, Borland 2002) Obtaining IV access on-scene prolongs the prehospital interval, which may be detrimental in clinical conditions where expedient transport to the hospital is important. Conversely, obtaining IV access en route to the hospital is inherently challenging due to the confinement restrictions of the ambulance and turbulent ride. Additionally, intravenous attempts are associated with harm to healthcare providers. Needlestick exposures in EMS providers occur 145 times per 1000 employee-years. (Hochreiter 1988) This risk is likely compounded in combative patients, explaining why most prehospital protocols initially call for sedative medications for agitated patients to be administered intramuscularly. Expert consensus highlights the need to study analgesia provision via non-intravenous routes. (Borland 2002)
Intramuscular administration avoids the need to start an IV but is painful and IM medications are erratically absorbed, especially in obese patients. Intranasal delivery offers a safe, effective, and convenient alternative to traditional routes of administration. A randomized, controlled trial comparing IN fentanyl with IV morphine found similar efficacy. (Rickard 2007) The time, technical skills, and motionless environment required for IV line placement are not needed for IN administration, making the latter an advantageous route for medication administration by EMS providers. (Corrigan 2015) However, IN medications typically have a slower onset of effect than by IV route.
Intraosseous (IO) access is widely used in some prehospital systems when vascular access is difficult or delayed to provide critical medications and blood. While the availability of alternatives (IN, IM, nebulized, inhaled) make placing an IO line for the purpose of administering analgesia inappropriate in most scenarios, if the patient has an IO for other reasons, it is prudent to use it for analgesia as well. (Olaussen 2012) The effectiveness is generally equivalent to the IV route of administration.
Special Considerations in Prehospital Analgesia
Neurological assessment guides therapy in stroke, a generally non-painful condition, but also in patients with traumatic brain injury. Because opioids can cause somnolence, their prehospital use has been cautioned against in these patients. (Thomas 2008)
Prehospital research has inherent challenges that act as barriers to high quality analgesia studies, such as the difficulty obtaining informed consent during brief, time-sensitive encounters and patient privacy restrictions limiting retrieval of hospital outcome data. Additionally, pediatric patients are underrepresented in the prehospital literature, attributed to relatively infrequent pediatric patient transports and the exclusion of children in many studies.
Psychological and educational barriers have been identified as factors contributing to the provision of suboptimal analgesia. (Vassiliadis 2002, McGrath 1996) Male patients, initially higher pain scores, and treatment by a junior physician have been identified as increasing the likelihood of inappropriate pain treatment. (Albrecht 2013) Pediatric patients are inadequately treated at a higher rate because healthcare providers and parents often underestimate the severity of pediatric pain. (Singer 2002, Kelly 2000)
Despite decades of data and myriad trials, the preferred agent for prehospital analgesia has not been identified. Several analgesics offer equal efficacy with a similar risk profile, and the specific clinical situation should dictate the analgesic agent used. There is a preference for IV or IN routes of analgesia delivery given their shorter onset of action compared to IM and oral administration. (Tveita 2008)
Prehospital protocols should include routine and repeated assessment of the adequacy of pain control, which will improve pain management in the prehospital domain by prompting providers and normalizing attention to what is often the symptom that prompted EMS activation to begin with. (Alonso-Serra 2003)
The author reports no relevant conflicts of interest.
Alonso-Serra HM, Wesley K; National Association of EMS Physicians Standards and Clinical Practices Committee. Prehospital pain management. Prehosp Emerg Care. 2003 Oct-Dec;7(4):482-8.
Andolfatto G, Innes K, Dick W, Jenneson S, Willman E, Stenstrom R, Zed PJ, Benoit G. Prehospital Analgesia With Intranasal Ketamine (PAIN-K): A Randomized Double-Blind Trial in Adults. Ann Emerg Med. 2019 Aug;74(2):241-250. doi: 10.1016/j.annemergmed.2019.01.048. Epub 2019 Mar 27. PMID: 30926189.
Amey BD, Ballinger JA, Harrison EE. Prehospital administration of nitrous oxide for control of pain. Ann Emerg Med. 1981 May;10(5):247-51.
Bansal A, Miller M, Ferguson I, Burns B. Ketamine as a Prehospital Analgesic: A Systematic Review. Prehosp Disaster Med. 2020 Jun;35(3):314-321. doi: 10.1017/S1049023X20000448. Epub 2020 Apr 15. PMID: 32290881.
Beecher HK. Pain in Men Wounded in Battle. Ann Surg. 1946 Jan;123(1):96-105.
Blackburn P, Vissers R. Pharmacology of emergency department pain management and conscious sedation. Emerg Med Clin North Am. 2000 Nov;18(4):803-27.
Borland ML, Jacobs I, Geelhoed G. Intranasal fentanyl reduces acute pain in children in the emergency department: a safety and efficacy study. Emerg Med (Fremantle). 2002 Sep;14(3):275-80.
Borobia AM, Collado SG, Cardona CC, et al; InMEDIATE Investigators Group. Inhaled Methoxyflurane Provides Greater Analgesia and Faster Onset of Action Versus Standard Analgesia in Patients With Trauma Pain: InMEDIATE: A Randomized Controlled Trial in Emergency Departments. Ann Emerg Med. 2020 Mar;75(3):315-328.
Bredmose PP, Lockey DJ, Grier G, Watts B, Davies G. Pre-hospital use of ketamine for analgesia and procedural sedation. Emerg Med J. 2009 Jan;26(1):62-4.
Büttner B, Mansur A, Kalmbach M, Hinz J, Volk T, Szalai K, Roessler M, Bergmann I. Prehospital ultrasound-guided nerve blocks improve reduction-feasibility of dislocated extremity injuries compared to systemic analgesia. A randomized controlled trial. PLoS One. 2018 Jul 2;13(7):e0199776.
Chambers JA, Guly HR. The need for better pre-hospital analgesia. Arch Emerg Med. 1993 Sep;10(3):187-92.
Corrigan M, Wilson SS, Hampton J. Safety and efficacy of intranasally administered medications in the emergency department and prehospital settings. Am J Health Syst Pharm. 2015 Sep 15;72(18):1544-54.
Dochez E, van Geffen GJ, Bruhn J, Hoogerwerf N, van de Pas H, Scheffer G. Prehospital administered fascia iliaca compartment block by emergency medical service nurses, a feasibility study. Scand J Trauma Resusc Emerg Med. 2014 Jun 23;22:38.
Donen N, Tweed WA, White D, Guttormson B, Enns J. Pre-hospital analgesia with Entonox. Can Anaesth Soc J. 1982 May;29(3):275-9.
Dong L, Donaldson A, Metzger R, Keenan H. Analgesic administration in the emergency department for children requiring hospitalization for long-bone fracture. Pediatr Emerg Care. 2012 Feb;28(2):109-14.
Filanovsky Y, Miller P, Kao J. Myth: Ketamine should not be used as an induction agent for intubation in patients with head injury. CJEM. 2010 Mar;12(2):154-7.
Galinski M, Dolveck F, Borron SW, Tual L, Van Laer V, Lardeur JY, Lapostolle F, Adnet F. A randomized, double-blind study comparing morphine with fentanyl in prehospital analgesia. Am J Emerg Med. 2005 Mar;23(2):114-9.
Gausche-Hill M, Brown KM, Oliver ZJ, Sasson C, Dayan PS, Eschmann NM, Weik TS, Lawner BJ, Sahni R, Falck-Ytter Y, Wright JL, Todd K, Lang ES. An Evidence-based Guideline for prehospital analgesia in trauma. Prehosp Emerg Care. 2014;18 Suppl 1:25-34.
Halstead SM, Deakyne SJ, Bajaj L, Enzenauer R, Roosevelt GE. The effect of ketamine on intraocular pressure in pediatric patients during procedural sedation. Acad Emerg Med. 2012 Oct;19(10):1145-50.
Hochreiter MC, Barton LL. Epidemiology of needlestick injury in emergency medical service personnel. J Emerg Med. 1988 Jan-Feb;6(1):9-12.
Institute of Medicine Committee on the Future of Emergency Care in the U.S. Health System. The future of emergency care in the United States health system. Ann Emerg Med. 2006 Aug;48(2):115-20.
Jennings PA, Cameron P, Bernard S. Ketamine as an analgesic in the pre-hospital setting: a systematic review. Acta Anaesthesiol Scand. 2011 Jul;55(6):638-43.
Johnson JC, Atherton GL. Effectiveness of nitrous oxide in a rural EMS system. J Emerg Med. 1991 Jan-Apr;9(1-2):45-53.
Kelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med. 1998 Nov;5(11):1086-90.
Lee M, Kent M, Small CS, Park CL, et all. Prehospital Analgesia. Combat Anesthesia: The First 24 Hours. pp 267-274.
LoVecchio F, Oster N, Sturmann K, Nelson LS, Flashner S, Finger R. The use of analgesics in patients with acute abdominal pain. J Emerg Med. 1997 Nov-Dec;15(6):775-9.
McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The correlation between ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008 Feb;64(2 Suppl):S195-8; Discussion S197-8.
McGrath PJ, Frager G. Psychological barriers to optimal pain management in infants and children. Clin J Pain. 1996 Jun;12(2):135-41.
Middleton PM, Simpson PM, Sinclair G, Dobbins TA, Math B, Bendall JC. Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting. Prehosp Emerg Care. 2010 Oct-Dec;14(4):439-47.
Motov SM, Nelson LS. Advanced Concepts and Controversies in Emergency Department Pain Management. Anesthesiol Clin. 2016 Jun;34(2):271-85.
Olaussen A, Williams B. Intraosseous access in the prehospital setting: literature review. Prehosp Disaster Med. 2012 Oct;27(5):468-72.
Out-of-Hospital Use of Analgesia and Sedation. Ann Emerg Med. 2016 Feb;67(2):305-6.
Pace S, Burke TF. Intravenous morphine for early pain relief in patients with acute abdominal pain. Acad Emerg Med. 1996 Dec;3(12):1086-92.
Pak SC, Micalos PS, Maria SJ, Lord B. Nonpharmacological interventions for pain management in paramedicine and the emergency setting: a review of the literature. Evid Based Complement Alternat Med. 2015;2015:873039.
Paris PM. Prehospital analgesia. In: Paris PM, Roth R, Verdile V (eds). Prehospital Medicine: The Art of On-Line Medical Command. St. Louis, MO: Mosby Life- time, 1996, pp 85-90.
Park CL, Roberts DE, Aldington DJ, Moore RA. Prehospital analgesia: systematic review of evidence. J R Army Med Corps. 2010 Dec;156(4 Suppl 1):295-300.
Porter KM, Dayan AD, Dickerson S, Middleton PM. The role of inhaled methoxyflurane in acute pain management. Open Access Emerg Med. 2018;10:149–164. Published 2018 Oct 18.
Prommer E, Thompson L. Intranasal fentanyl for pain control: current status with a focus on patient considerations. Patient Prefer Adherence. 2011 Mar 18;5:157-64.
Rickard C, O’Meara P, McGrail M, Garner D, McLean A, Le Lievre P. A randomized controlled trial of intranasal fentanyl vs intravenous morphine for analgesia in the prehospital setting. Am J Emerg Med. 2007 Oct;25(8):911-7.
Sandberg M, Hyldmo PK, Kongstad P, Dahl Friesgaard K, Raatiniemi L, Larsen R, Magnusson V, Rognås L, Kurola J, Rehn M, Vist GE. Ketamine for the treatment of prehospital acute pain: a systematic review of benefit and harm. BMJ Open. 2020 Nov 24;10(11):e038134.
Samuel N, Steiner IP, Shavit I. Prehospital pain management of injured children: a systematic review of current evidence. Am J Emerg Med. 2015 Mar;33(3):451-4.
Simpson PM, Fouche PF, Thomas RE, Bendall JC. Transcutaneous electrical nerve stimulation for relieving acute pain in the prehospital setting: a systematic review and meta-analysis of randomized-controlled trials. Eur J Emerg Med. 2014 Feb;21(1):10-7.
Singer AJ, Gulla J, Thode HC Jr. Parents and practitioners are poor judges of young children’s pain severity. Acad Emerg Med. 2002 Jun;9(6):609-12.
Smith MD, Wang Y, Cudnik M, Smith DA, Pakiela J, Emerman CL. The effectiveness and adverse events of morphine versus fentanyl on a physician-staffed helicopter. J Emerg Med. 2012 Jul;43(1):69-75.
Swor R, McEachin CM, Seguin D, Grall KH. Prehospital pain management in children suffering traumatic injury. Prehosp Emerg Care. 2005 Jan-Mar;9(1):40-3.
Thomas SH, Shewakramani S. Prehospital trauma analgesia. J Emerg Med. 2008 Jul;35(1):47-57.
Tran KP, Nguyen Q, Truong XN, Le V, Le VP, Mai N, Husum H, Losvik OK. 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):257-64.
Trivedi M, Shaikh S, Gwinnut C. Pharmacology of Opioids. Update in Anaesthesia. 2007, pp 118-124.
Turturro MA. Pain, priorities, and prehospital care. Prehosp Emerg Care. 2002 Oct-Dec;6(4):486-8.
Tveita T, Thoner J, Klepstad P, Dale O, Jystad A, Borchgrevink PC. A controlled comparison between single doses of intravenous and intramuscular morphine with respect to analgesic effects and patient safety. Acta Anaesthesiol Scand. 2008 Aug;52(7):920-5.
Vassiliadis J, Hitos K, Hill CT. Factors influencing prehospital and emergency department analgesia administration to patients with femoral neck fractures. Emerg Med (Fremantle). 2002 Sep;14(3):261-6.
Vermeulen B, Morabia A, Unger PF, Goehring C, Grangier C, Skljarov I, Terrier F. Acute appendicitis: influence of early pain relief on the accuracy of clinical and US findings in the decision to operate–a randomized trial. Radiology. 1999 Mar;210(3):639-43.
Wedmore IS, Butler FK Jr. Battlefield Analgesia in Tactical Combat Casualty Care. Wilderness Environ Med. 2017 Jun;28(2S):S109-S116.
WILSON. Military aspects of early analgesia and anesthesia. Curr Res Anesth Analg. 1946 Jan-Feb;25:10-21.