Archives of Academic Emergency Medicine. 2019; 7 (1): e55 REV I EW ART I C L E Pre-hospital pain management; a systematic review of proposed guidelines Mahmoud Yousefifard1, Shaghayegh Askarian-Amiri2, Arian Madani Neishaboori2, Mostafa Sadeghi3, Peyman Saberian4, Alireza Baratloo5,6∗ 1. Prevention of Cardiovascular Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Physiology Research Center, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran. 3. Department of Anesthesiology and Critical Care, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. 4. Department of Anesthesiology, Imam Khomeini Hospital Complex, Tehran university of Medical Sciences, Tehran, Iran. 5. Prehospital and Hospital Emergency Research Center, Tehran University of Medical Sciences, Tehran, Iran. 6. Department of Emergency Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. Received: August 2019; Accepted: September 2019; Published online: 6 October 2019 Abstract: Introduction: A standard guideline concerning pre-hospital pain management is still a matter of discussion. Therefore, the current umbrella review is determined to perform a comprehensive search in databases and Grey literature and collect and summarize the guidelines and protocols dealing with prehospital pain management. Methods: In the present study, all of the available guidelines and protocols concerning pre-hospital pain man- agement were reviewed. Presented guidelines are from 2010 up to present, as the majority of guidelines are considered old and become renewed after 10 years. Finally, the development quality of each guideline was evaluated using AGREE II instrument. Results: The search conducted in databases and non-indexed protocols resulted in inclusion of 12 pre-hospital pain management guidelines. The time interval of the guidelines was from 2010 to 2019. Four guidelines were designed for pain management in trauma patients and other guidelines were presented for all of the clinical conditions associated with pain. All of the 12 included guidelines presented pain management instructions in adults. Pain management in children was reported in 10 guidelines. All of the guidelines persisted on a standard method for pain evaluation. Pain management was categorized in three groups; mild, moderate and severe pain. Most of the guidelines recommend paracetamol as an optional treat- ment for management of mild pain in both adults and children. In management of moderate and severe pain, fentanyl and morphine were suggested for both adults and children. In most of the treatment guidelines fentanyl is the optional choice for children. Conclusion: The present umbrella review has summarized the current evi- dence in pre-hospital pain management for the first time via investigation of guidelines and protocols related to the matter. Based on the obtained evidence, no guideline is yet presented concerning opioid-free management of moderate and severe pain. The evidence is insufficient for using non opioid medications such as ketamine. Keywords: Pain management; practice guideline; drug therapy; Emergency Medical Services Cite this article as: Yousefifard M, Askarian-Amiri Sh, Madani Neishaboori A, Sadeghi M, Saberian P, Baratloo A. Pre-hospital pain manage- ment; a systematic review of proposed guidelines. Arch Acad Emerg Mede. 2019; 7(1): e55. 1. Introduction P ain management has been a priority for prehospital and hospital care, and a variety of guidelines have been adopted accordingly (1). Existence of moderate ∗Corresponding Author: Alireza Baratloo; Department of Emergency Medicine, Sina Hospital, Hasanabad Square, Tehran, Iran. Tel: +989122884364; Email: arbaratloo@sina.tums.ac.ir, alirezabaratloo@yahoo.com. to severe pain is one of the most important factors, which al- ternates patients’ conditions and might have a negative im- pact on their physiological parameters, which could even- tually worsen the patient’s prognosis (2, 3). Pharmacologi- cal treatment choices in prehospital pain management are quite limited, considering that in prehospital care, analgesics should not only be effective and safe, but also not interfere with patients’ transfer (1). Based on literature reviews done in recent years and different This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 2 expert panels conducted, several guidelines have been pro- posed for pain management in prehospital care (4-6). These guidelines suggest different treatment options varying from injectable opioids to intranasal non-opioid treatments. Nev- ertheless, instructions given by these protocols are usually taken from moderate to low quality studies (7), thus, there is no consensus over a single guideline. On the other hand, the majority of these guidelines only refer to a single disease or complication. In these instructions a broad range of anal- gesic drugs are proposed. Some of the guidelines suggest us- ing multiple drugs instead of a single medication; and some others suggest using opioids in lower doses (4-8). Clearly, there is not a consensus over establishing stan- dard instructions on pre-hospital pain control. Hence, the present systematic review aims to collect and summarize pre-hospital pain management guidelines and instructions by conducting an extensive research in databases. 2. Method 2.1. Study design and search strategy The current study is an umbrella review, which investigates the guidelines and protocols for pre-hospital pain manage- ment. The researchers conducted a comprehensive search in electronic databases. Appropriate keywords were defined to accomplish the study’s objectives. For this purpose, "pre- hospital emergencies" and "analgesia" related words were obtained with advice of an experienced researcher in the field. Additionally, MeSh and Emtree word trees were in- vestigated. The attained keywords were properly combined, and standard tags were adapted for each database. Sub- sequently, a comprehensive search was conducted in elec- tronic databases including: Medline, Embase, Trip Medical Database and Scopus through March 2019. Search strategy in Medline database is presented in Panel 1. In addition to sys- tematic search, manual search was also performed in Google search engine, Google scholar and references of relevant ar- ticles. 2.2. Selection criteria In the present study, guidelines and protocols concerning pre-hospital pain management, published in peer-review journals or released in valid organizations’ websites, were in- cluded. Reviews being narrative, lack of a report on the com- plete process of the guideline’s extraction, and lack of a report on the systematic review’s process were considered as exclu- sion criteria. 2.3. Data collection The data collected from databases were saved in End- note. Two independent researchers studied the records and screened titles and abstracts of relevant guidelines. After studying the full text of these guidelines, data were filed in a checklist created in Microsoft Excel. Obtained results were perused by the two researchers with the presence of a third researcher. Any disagreement was discussed and re- solved. Recorded data in the checklist consisted of name of the guideline, year of publication, studied medications, qual- ity control and patients’ conditions (trauma, etc.). In cases of non-extractable data in the articles, their authors were con- tacted. If the author did not respond to the first email, a re- minder was sent. In case of no response, second reminder email was sent within two weeks. Granted that still no re- sponse was received, the other authors were contacted via social media such as ResearchGate and LinkedIn to attain re- quired data. 2.4. Quality assessment of the articles Quality assessment of the articles was performed using AGREE II guideline (9). In order to determine the agree- ment between the two reviewers, evaluation of Inter-rater re- liability in quality assessment of the articles was done. Dis- agreements were resolved through discussion with a third re- searcher. 3. Results 3.1. Demographic characteristics of the articles Our search in databases and non-indexed guidelines came up with 5988 records. Excluding duplicate records, 4998 arti- cles were found. Reading their titles and abstracts and the full texts of these guidelines, and according to inclusion and ex- clusion criteria, 12 guidelines for pre-hospital pain manage- ment were included in this review (10-21). These guidelines were updated between 2012 and 2019 (Figure 1). Four guide- lines were designed for managing pain in trauma patients (10, 12, 20, 21) and the other guidelines were developed for all conditions accompanying pain. All of the 12 included guide- lines provided instructions on managing pain in adults, while 10 guidelines (11-20) reported pain management methods in children. Table 1 demonstrates demographic characteristics of these guidelines. All of the above-mentioned guidelines emphasize on a standard method of pain evaluation. Sug- gested tools in these guidelines for adults included numeric analog scale (NRS) and visual analog scale (VAS), and for chil- dren included The Face, Legs, Activity, Cry, CONSOL abil- ity scale (FLACC) or Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS scale), Faces Pain Scale (FPS) scale, FPS- revised, Wong Baker scale and NRS. 3.2. Pain management in adults As mentioned previously, pain management in adults was reported in all of the 12 studies. Different medications are suggested in these guidelines which include: fentanyl, This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Panel 1: Search query in medline Search terms 1- "Emergency Medical Services"[mh] OR "Emergency Health Service"[tiab] OR "Emergency Care"[tiab] OR "Prehospital Medica- tion"[tiab] OR "Prehospital Care"[tiab] OR "Prehospital"[tiab] OR "Emergency Services, Medical"[tiab] OR "Emergency Service, Med- ical"[tiab] OR "Medical Emergency Service"[tiab] OR "Medical Emergency Services"[tiab] OR "Service, Medical Emergency"[tiab] OR "Services, Medical Emergency"[tiab] OR "Medical Services, Emergency"[tiab] OR "Emergency Medical Service"[tiab] OR "Med- ical Service, Emergency"[tiab] OR "Service, Emergency Medical"[tiab] OR "Services, Emergency Medical"[tiab] OR "Prehospital Emergency Care"[tiab] OR "Emergency Care, Prehospital"[tiab] OR "Emergicenters"[tiab] OR "Emergicenter"[tiab] OR "Emergency Care"[tiab] OR "Emergency Health Services"[tiab] OR "Emergency Health Service"[tiab] OR "Health Service, Emergency"[tiab] OR "Health Services, Emergency"[tiab] OR "Service, Emergency Health"[tiab] OR "Services, Emergency Health"[tiab] 2- Patient Controlled Analgesia[tiab] OR Analgesic Drugs[tiab] OR Drugs, Analgesic[tiab] OR Anodynes[tiab] OR Analgesic Agents[tiab] OR Agents, Analgesic[tiab] OR Analgesics, Non Narcotic[tiab] OR Non-Narcotic Analgesics[tiab] OR Nonopioid Anal- gesics[tiab] OR Analgesics, Nonopioid[tiab] OR Non-Opioid Analgesics[tiab] OR Analgesics, Non-Opioid[tiab] OR Non Opioid Anal- gesics[tiab] OR Analgesics, Nonnarcotic[tiab] OR Nonnarcotic Analgesics[tiab] OR Antinociceptive Agents[tiab] OR Opioid Anal- gesics[tiab] OR Opioids[tiab] OR Partial Opioid Agonists[tiab] OR Agonists, Partial Opioid[tiab] OR Opioid Agonists, Partial[tiab] OR Opioid Partial Agonists[tiab] OR Agonists, Opioid Partial[tiab] OR Partial Agonists, Opioid[tiab] OR Full Opioid Agonists[tiab] OR Agonists, Full Opioid[tiab] OR Opioid Agonists, Full[tiab] OR Opioid Full Agonists[tiab] OR Agonists, Opioid Full[tiab] OR Full Agonists, Opioid[tiab] OR Opioid Mixed Agonist-Antagonists[tiab] OR Agonist-Antagonists, Opioid Mixed[tiab] OR Mixed Agonist- Antagonists, Opioid[tiab] OR Opioid Mixed Agonist Antagonists[tiab] OR Narcotic[tiab] OR Narcotic Analgesics[tiab] OR Analgesics, Narcotic[tiab] OR Narcotic Effect[tiab] OR Effect, Narcotic[tiab] OR Narcotic Effects[tiab] OR Effects, Narcotic[tiab] OR Antiin- flammatory Agents, Non Steroidal[tiab] OR NSAIDs[tiab] OR Non-Steroidal Anti-Inflammatory Agents[tiab] OR Non Steroidal Anti Inflammatory Agents[tiab] OR Nonsteroidal Anti-Inflammatory Agents[tiab] OR Nonsteroidal Anti Inflammatory Agents[tiab] OR Anti Inflammatory Agents, Nonsteroidal[tiab] OR Antiinflammatory Agents, Nonsteroidal[tiab] OR Nonsteroidal Antiinflammatory Agents[tiab] OR Analgesics, Anti-Inflammatory[tiab] OR Anti-Inflammatory Analgesics[tiab] OR Aspirin-Like Agents[tiab] OR Aspirin Like Agents[tiab] OR Anesthetic Drugs[tiab] OR Drugs, Anesthetic[tiab] OR Anesthetic Agents[tiab] OR Agents, Anesthetic[tiab] OR Anesthetic Effect[tiab] OR Effect, Anesthetic[tiab] OR Anesthetic Effects[tiab] OR Effects, Anesthetic[tiab] OR Morphinan[tiab] OR "Acetaminophen"[mh] OR "Adapalene"[mh] OR "Adapalene, Benzoyl Peroxide Drug Combination"[mh] OR "Amantadine"[mh] OR "Amitriptyline"[mh] OR "Ampyrone"[mh] OR "Antipyrine"[mh] OR "Apazone"[mh] OR "Aspirin"[mh] OR "Bufexamac"[mh] OR "Car- bachol"[mh] OR "Carbamazepine"[mh] OR "Celecoxib"[mh] OR "Clonixin"[mh] OR "Dexmedetomidine"[mh] OR "Diclofenac"[mh] OR "Diflunisal"[mh] OR "Dihydroergotamine"[mh] OR "Dipyrone"[mh] OR "Dronabinol"[mh] OR "Epirizole"[mh] OR "Ergo- tamine"[mh] OR "Etanercept"[mh] OR "Etodolac"[mh] OR "Etoricoxib"[mh] OR "Fenoprofen"[mh] OR "Feprazone"[mh] OR "Flur- biprofen"[mh] OR "Glafenine"[mh] OR "Ibuprofen"[mh] OR "Indomethacin"[mh] OR "Indoprofen"[mh] OR "Interleukin-2"[mh] OR "Ketoprofen"[mh] OR "Ketorolac"[mh] OR "Ketorolac Tromethamine"[mh] OR "Masoprocol"[mh] OR "Meclofenamic Acid"[mh] OR "Medetomidine"[mh] OR "Mefenamic Acid"[mh] OR "Meloxicam"[mh] OR "Mesalamine"[mh] OR "Methotrimeprazine"[mh] OR "Milnacipran"[mh] OR "Nabumetone"[mh] OR "Naproxen"[mh] OR "Nefopam"[mh] OR "Niflumic Acid"[mh] OR "Nitrous Oxide"[mh] OR "Olopatadine Hydrochloride"[mh] OR "Oxaprozin"[mh] OR "Oxyphenbutazone"[mh] OR "Phenacetin"[mh] OR "Phenylbutazone"[mh] OR "Piroxicam"[mh] OR "Pizotyline"[mh] OR "Quinine"[mh] OR "Resveratrol"[mh] OR "Salicylates"[mh] OR "Sodium Salicylate"[mh] OR "Sulfasalazine"[mh] OR "Sulindac"[mh] OR "Suprofen"[mh] OR "Tolmetin"[mh] OR "Alfentanil"[mh] OR "Alphaprodine"[mh] OR "Buprenorphine"[mh] OR "Buprenorphine, Naloxone Drug Combination"[mh] OR "Butorphanol"[mh] OR "Dextromoramide"[mh] OR "Dextropropoxyphene"[mh] OR "Dihydromorphine"[mh] OR "Diphenoxylate"[mh] OR "Ethylketocycla- zocine"[mh] OR "Ethylmorphine"[mh] OR "Etorphine"[mh] OR "Fentanyl"[mh] OR "Hydrocodone"[mh] OR "Hydromorphone"[mh] OR "Levorphanol"[mh] OR "Meperidine"[mh] OR "Meptazinol"[mh] OR "Methadone"[mh] OR "Nalbuphine"[mh] OR "Opiate Al- kaloids"[mh] OR "Opium"[mh] OR "Oxycodone"[mh] OR "Oxymorphone"[mh] OR "Pentazocine"[mh] OR "Phenazocine"[mh] OR "Phenoperidine"[mh] OR "Pirinitramide"[mh] OR "Promedol"[mh] OR "Remifentanil"[mh] OR "Sufentanil"[mh] OR "Tapenta- dol"[mh] OR "Tilidine"[mh] OR "Tramadol"[mh] 3- #1 AND #2 morphine, ketamine, paracetamol, midazolam, nitric ox- ide, ketorolac, ibuprofen, methoxyflurane, nonsteroidal anti-inflammatory drugs, codeine, tramadol and aspirin. Medication protocols are modified in these guidelines based on the severity of pain. 3.2.1 Pre-hospital management of mild pain in adults Five studies accurately proposed protocols for pre-hospital management of mild pain. Mild pain is described as a sever- ity less than 4, on a 0-10 pain scale. Based on the guidelines included in the present systematic review, management of a patient with mild or endurable pain is prescribing oral paracetamol (1000mg or 15mg/kg). One guideline recom- mends that if a patient has weighs less than 60 kg, or is older than 60 or is malnourished, the suggested dose for paracetamol should be reduced to half. Only one guideline suggests administration of ketorolac (30mg, IV/IO or 60 mg, IM) instead of paracetamol in relieving mild pain. This guideline proposes administration of nitric oxide in 50:50 dosage as an alternative treatment. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 4 Figure 1: Flow diagram of the present review. 3.2.2 Pre-hospital management of moderate pain in adults 10 guidelines proposed instructions for pre-hospital man- agement of moderate pain. Moderate pain is described as a severity between 4 and 6 on a 0-10 pain scale. Based on the guidelines included in the present systematic review, management of a patient with moderate pain is mainly done by prescribing morphine and fentanyl. However, two guidelines (15, 18) recommend administering paracetamol 1000 mg instead. Using morphine in moderate pain man- agement is mentioned unfavorable in NAEN guideline as well. Rather, it is recommended to use fentanyl (1-2 µg/kg) or paracetamol (1000 mg) IV in 5 minutes (or as oral agent). Assuming that the patient is hypovolemic or in shock, this guideline recommends using ketamine (0.25 mg/kg) and midazolam (1 mg) for pain alleviation (10). NICE guideline, recommends using morphine as the first line treatment and ketamine as the second line (21). This guideline does not clarify the dosage and route of administration (Table 2). Intravenous paracetamol (five guidelines), ketamine (three guidelines), ketorolac (one guideline) and nonsteroidal anti-inflammatory drugs (one guideline) are other recom- mended options for adults’ pain management in prehospital conditions. Although, one guideline (20) prohibits using nonsteroidal anti-inflammatory drugs in management of Trauma patients (Table 2). 3.2.3 Pre-hospital management of severe pain in adults 12 guidelines proposed instructions on pre-hospital man- agement of severe pain. Severe pain is described as a severity of more than 6 on a 0-10 pain scale. Based on the guide- lines included in the present systematic review, prescrib- ing morphine and fentanyl is the first line of treatment in pre-hospital managing severe pain. Nevertheless, guidelines show some controversy. NAEN guideline 2014 suggests us- ing fentanyl (1-2 µg/kg) infused with paracetamol (1000 mg). This guideline does not recommend using morphine. Fur- thermore, NAEN guideline indicates that using ketamine (25 mg/kg IV ) infused with midazolam (1mg, IV ) and paraceta- mol (1000 mg IV ) (10) is preferable in cases with evidence of hypovolemia or insecure airways (10). Administration of ke- tamine is recommended in four other protocols (11, 15, 16, 20) (Table 2). Intravenous paracetamol (two guidelines), nitric oxide (three guidelines), ibuprofen (three guidelines), ketorolac (two guidelines), methoxyflurane (three guidelines), non- steroidal anti-inflammatory drugs (one guideline) and di- amorphine (one guideline) are alternative options in pre- hospital management of severe pain in adults. One guide- line suggested prescription of codeine and tramadol while another one recommended aspirin prescription (Table 2). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Table 1: The characteristics of included guidelines Name of guideline Update date Target patients Age group Organization Level of evidence Reference Netherlands Associ- ation for Emergency Nurses (NAEN) Guideline 2014 Trauma patients Adults Netherlands Associa- tion for Emergency Nurses Moderate (22) Alabama Depart- ment of Public Health EMS (ADPH- EMS) Protocol 2018 Patients with severe pain Adults; Pediatrics Alabama State Emer- gency Medical Con- trol Committee Moderate (11) Douglas County Fire/EMS (Emer- gency Medical Ser- vices)(DCFEMS) Guideline 2017 Trauma patients with severe pain Adults; Pediatrics Douglas County Fire/EMS (Emer- gency Medical Ser- vices) Moderate (12) Ambulance Tasma- nia Clinical Practice (ATCP) Guidelines for Paramedics & Inten- sive Care Paramedics 2012 General pain man- agement Adults; Pediatrics Ambulance Tasma- nia High to moderate (13) North Carolina Col- lege of Emergency Physicians (NCCEP) Protocol 2019 General pain man- agement Adults; Pediatrics North Carolina Col- lege of Emergency Physicians High to moderate (14) Clinical Practice Guideline of Pre- Hospital Emer- gency Care Council (PHECC) 2018 General pain man- agement Adults; Pediatrics Pre-Hospital Emer- gency Care Council Moderate (15) Ambulance Victo- ria Clinical Practice (AVCP) Guideline 2018 General pain man- agement Adults; Pediatrics Australia Ambulance Victoria High to moderate (16) Maryland Institute for Emergency Med- ical Services System (MIEMS) Guideline 2014 General pain man- agement Adults; Pediatrics Maryland Institute for Emergency Medi- cal Services System Moderate (7) Italian Intersociety Recommendations on pain manage- ment (IIRPM) in the emergency setting 2015 General pain man- agement Adults; Pediatrics Italian Intersociety Recommendations on pain management High to moderate (18) New Mexico Pre- hospital Treatment (NMPHT) Guideline 2018 General pain man- agement Adults; Pediatrics New Mexico Depart- ment of Health Moderate (19) U.S National Associ- ation of EMS Physi- cians (NAEMSP) guideline 2014 Trauma patients Adults; Pediatrics U.S NAEMSP Medical Directors Council High to moderate (20) UK National Institute for Health and Care Excellence (NICE) guideline 2016 Trauma patients Adults UK National Institute for Health and Care Excellence High to moderate (21) 3.3. Pain management in children (under 14 years) As mentioned, pre-hospital pain management in children was reported in 10 of the included studies. In these guide- lines, different medications were proposed, which included morphine, fentanyl, ketamine, paracetamol, midazolam, nitric oxide, ketorolac, ibuprofen, methoxyflurane, codeine, tramadol and hydromorphone. In these guidelines, instruc- tions for using medications were different according to the severity of pain. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 6 Table 2: Recommendations for pre-hospital pain management in adults Guideline Pain severity Morphine Fentanyl Ketamine Paracetamol NAEN, 2014 Moderate – 1-2 µg/kg every 3 mins (titrate medica- tion on effect) If hypovolemia or shock state is present 0.25 mg/kg+ Midazo- lam 1 mg 1000 mg IV for 5 min or 1000 mg oral Severe – 1-2 µg/kg every 3 mins (titrate medica- tion on effect) If hypovolemia or shock state is present 0.25 mg/kg+ Midazo- lam 1 mg 1000 mg IV for 5 min titrate until NRS<4 ADPH-EMS, 2018 Severe 4 mg initial dose, titrate to pain relief in 2 mg every 3-5 mins, to an initial maximum dose of 10 mg cumulative maximum dose of 25 mg 1 µg/kg slow IV/IM/IN to an initial maximum dose of 50 µg. May repeat once. 0.2 mg slow IV to a maximum dose of 25 mg – OR OR 0.5 mg IM and cumu- lative maximum dose of 50 mg 0.5 mg IM to a maxi- mum dose of 50 mg DCFEMS, 2017 Severe 2-4 mg IV/IO/IM slowly titrate to pain relief to a maximum dose of 10 mg every 10 mins 25 µg IV/IO slowly OR 2 µg/kg IN, titrate to pain relief to a maxi- mum dose of 100 µg every 10 mins – – ATCP, 2012 Mild – – – 1000 mg ATCP, 2012 Moderate Up to 0.05 mg/kg IV/IO (initial maxi- mum dose of maxi- mum 5 mg), titrate to pain relief to a maximum dose of 20 mg every 5 mins Up to 0.5 µg/kg IV/IO (initial maxi- mum dose of 5 mg), titrate to pain re- lief to a maximum dose of 200 µg ev- ery 5 mins If the IV access >10 mins de- layed/unsuccessful up to 100 µg IN, titrate to pain relief to a maximum dose of 400 µg every 5 mins – 1000 mg Severe Up to 0.05 mg/kg IV/IO (initial maxi- mum dose of maxi- mum 5 mg), titrate to pain relief to a maximum dose of 20 mg every 5 mins Up to 0.5 µg/kg IV/IO (initial maximum dose of maximum 5 mg), titrate to pain relief to a maximum dose of 200 µg every 5 mins – – NCCEP, 2019 Mild – – – 15 mg/kg oral Moderate to severe 4 mg IV/IO/IM repeat 2 mg every 5 mins if required 50-75 µg IV/IO repeat 25 µg every 20 mins to a maximum 200 µg – – PHECC, 2018 Mild – – – 1000 mg oral Moderate – – – 1000 mg oral Severe 4 mg IV, repeat 2 mg to pain relief to a maximum dose of 16 mg every 2 mins 100 µg IN or 50 µg IV, repeat IN once only after 10 min if needed 0.1 mg/kg IV, repeat once only after 10 min if needed 1000 mg IV This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Table 2: Recommendations for pre-hospital pain management in adults (continue. . . ) Guideline Pain severity Morphine Fentanyl Ketamine Paracetamol AVCP, 2018 Mild – – – 1000 mg oral; 500 mg if weight < 60 kg or frail or elderly, malnourished or liver disease Moderate Up to 5 mg IV, titrate to pain relief every 5 mins (consult after 20 mg) Up to 50 µg IV, titrate to pain relief every 5 mins (consult after 200 µg) – – OR 200 µg IN repeat up to 50 µg IN every 5 min- utes (consult after 400 µg) – – Severe Up to 5 mg IV, titrate to pain relief every 5 mins (consult after 20 mg) Up to 50 µg IV, titrate to pain relief every 5 mins (consult after 200 µg) Extreme traumatic pain persists to opi- oid: – OR OR 10-20 mg IV at 5-10 min intervals; 10 mg IM, repeat 5 mg IM after 15 minutes once only if required 200 µg IN repeat up to 50 µg IN every 5 min- utes (consult after 400 µg) For severe pain 20-30 mg IV at 2 minute in- terval MIEMS, 2014 Moderate to severe 0.1 mg/kg IV/IO, repeat 0.05 mg/kg IV/IO to pain relief every 5 mins 1 µg/kg IV/IO, repeat 0.5 mg/kg IV/IO to pain relief every 5 mins – – IIRPM, 2015 Mild – – – 1000 mg Moderate – – – 1000 mg Severe 4-6 mg IV; 2-3 mg for patients aged >65 years and/or unstable patients 50-100 µg IV – – NMPHT, 2018 Moderate to severe 4-10 mg slow IV/IO, titrating 2-4 mg every 10 mins with a maxi- mum dose of 10 mg 25-100 µg IV/IO – – NAEMSP, 2014 Moderate 0.1 mg/kg IM to a maximum initial dose of 15 mg 1 µg/kg IN/IM to a maximum dose of 100 µg 0.5 mg/kg IN to a maximum initial dose of 25 mg and maximum cumu- lative dose of 100 mg 15 mg/kg oral to a maximum dose of 1000 mg Severe 0.1 mg/kg IV/IO to a maximum dose of 10 mg 1 µg/kg IV/IO to a maximum dose of 100 µg 0.25 mg/kg IM/IV/IO to a maximum ini- tial dose of 25 mg and maximum cumu- lative dose of 100 mg – NICE, 2016 Moderate to severe Yes (IV first line; dosage not reported) – Yes Second line IN – This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 8 Table 2: Recommendations for pre-hospital pain management in adults (continue. . . ) Guideline Pain severity Midazolam Nitric oxide Ketorolac Ibuprofen Methoxyflurane NSAIDs NAEN, 2014 Moderate – – – – – – Severe – – – – – – ADPH-EMS, 2018 Severe – Until pain con- trol – – – – DCFEMS, 2017 Severe – – – – – – ATCP, 2012 Mild – – – – – – Moderate – – – – – – Severe – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – NCCEP, 2019 Mild – – – – – – Moderate to severe – – – 10 mg/kg oral – – PHECC, 2018 Mild – 50:50 mix 30 mg IV/IO OR 60 mg IM (Max- imum 60 mg) – – – Moderate – – – 400 mg oral – – Severe – 50:50 mix – 600 mg oral 3 ml, repeat once only if needed – AVCP, 2018 Mild – – – – – – Moderate – – – – – – Severe – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – MIEMS, 2014 Moderate to severe – – – – – – IIRPM, 2015 Mild – – – – – – Moderate – – – – – Yes (dosage not reported) IIRPM, 2015 Severe – – – – – Yes (dosage not reported) NMPHT, 2018 Moderate to severe – – – – – – NAEMSP, 2014 Moderate – – – – – Contraindication in trauma Severe – Yes (dosage not reported) 30 mg IM once only 10 mg/kg oral to a maximum dose of 800 mg – – NICE, 2016 Moderate to severe – – 15 mg IV once only – – – 3.3.1 Pre-hospital management of mild pain in children Four guidelines precisely proposed instructions on pre- hospital management of mild pain in children. According to the guidelines, control and management of pain in a child who is having mild pain include appeasing the child’s pain or at most prescribing paracetamol in a dose of 10-20mg/kg and ibuprofen in a dose of 4-10 mg/kg (Table 3). 3.3.2 Pre-hospital management of moderate pain in chil- dren Eight guidelines provided advice on pre-hospital manage- ment of moderate pain. Different medications are recom- mended for controlling and managing moderate pain in children. Six of these guidelines suggest using intravenous (IV ), intranasal (IN) or intra-osseous (IO) fentanyl. Also, five guidelines proposed using paracetamol with a 15 mg/kg dosage, and four guidelines referred to morphine as a treat- ment option (Table 3). It is worth mentioning that only one guideline recommends intranasal ketamine in 0.5 mg/kg dosage for managing moderate pain (20). Other recom- mended drugs in moderate pain management in children include methoxyflurane (three guidelines), ketorolac (two guidelines), nitric oxide (two guidelines), ibuprofen (two guidelines), and codeine and tramadol (one guideline) (Ta- ble 3). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Table 2: Recommendations for pre-hospital pain management in adults (continue. . . ) Guideline Pain severity Codeine Tramadol hydromorphone diamorphine Aspirin NAEN, 2014 Moderate – – – – – Severe – – – – – ADPH-EMS, 2018 Severe – – – – – DCFEMS, 2017 Severe – – – – – ATCP, 2012 Mild – – – – – Moderate – – – – – Severe – – – – – NCCEP, 2019 Mild – – – – – Moderate to se- vere – – – – 324-650 mg oral PHECC, 2018 Mild – – – – – Moderate – – – – – Severe – – – – – AVCP, 2018 Mild – – – – – Moderate – – – – – Severe – – – – – MIEMS, 2014 Moderate to se- vere – – – – – IIRPM, 2015 Mild – – – – – Moderate – – – – – IIRPM, 2015 Severe 30 mg oral 37.5 mg oral – – – NMPHT, 2018 Moderate to se- vere – – – – – NAEMSP guide- line, 2014 Moderate – – – – – Severe – – – – – NICE, 2016 Moderate to se- vere – – – Yes (dosage not re- ported) – Mild to moderate – – – – – 3.3.3 Pre-hospital management of severe pain in children 10 guidelines provided instructions on pre-hospital manage- ment of severe pain in children. The first line of treatment in pre-hospital management of severe pain in children is pre- scribing morphine and fentanyl. Nine guidelines suggested using fentanyl (1-2 µg/kg IV/IN/IO or 25-50 µg IN only) for severe pain management in children. Also, eight guidelines recommended morphine (0.05-0.1 mg/kg) as a treatment op- tion. Three guidelines proposed intravenous, intranasal or intra-osseous ketamine as another option for pain manage- ment. Furthermore, a guideline suggested using intravenous ketamine (0.25 mg/kg) only when there is a severe trauma pain in the limbs, which is not responding to opioids (16). Paracetamol (one protocol), nitric oxide (one protocol only after consultation), ketorolac (two protocols), methoxyflu- rane (two protocols) and hydromorphone (one protocol) are other drugs recommended for strict pain management in children (Table 3). 3.4. Quality Control of Guidelines The overall score of the included guidelines varied from 4.5 to 6.5. Aim and scope domain rating of the guidelines varied from 88% to 100%, stakeholder involvement domain varied from 72% to 100%, rigor of development domain varied from 12% to 81%, applicability domain varied from 79% to 100% and editorial independence varied from 8% to 50%. In the domain of clarity of presentation, the score of all studies was 100% (Table 4). 4. Discussion The current systematic review summarized the existing ev- idence on pre-hospital pain management, evaluating avail- able guidelines and protocols. These guidelines provided instructions based on age groups (adults and children) and pain severity. The majority of guidelines recommended paracetamol as the medication of choice for management of mild pain in adults and children. For management of moder- ate to severe pain in pre-hospital setting, fentanyl and mor- phine are the first line choices. Fentanyl is the first line treat- ment for children. Although, some of the guidelines referred to ketamine as an alternative treatment for pain management, it seems that ke- tamine is still not the first line treatment in these conditions. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 10 Table 3: Recommendations for pre-hospital pain management in children Guideline Pain severity Morphine Fentanyl Ketamine Paracetamol ADPH-EMS, 2018 Severe 0.1 mg slow IV to a maximum dose of 5 mg 1 µg/kg slow IV/IN to a maximum dose of 50 µg 0.2 mg slow IV to a maximum dose of 25 mg – OR 0.5 mg IM to maxi- mum dose of 50 mg OR 1 mg/kg IN to a max- imum dose of 50 mg DCFEMS, 2017 Severe – 1-2 µg/kg IV/IO slowly or 1-2 µg/kg IN Titrate to pain relief to a maximum dose of 100 µg every 10 mins – – ATCP, 2012 Mild – – – 15 mg/kg oral Moderate – 25 µg IN for small child (10-24 kg) 50 µg for large child (≥25 kg) Titrate initial IN dose to pain relief (maximum 3 doses) every 5 mins – 15 mg/kg oral ATCP, 2012 Severe Last resort if pain not controlled up to 0.1 mg/kg IM (maxi- mum dose of 5 mg), single dose only 25 µg IN for small child (10-24 kg) 50 µg for large child (≥25 kg) Titrate initial IN dose to pain relief – – OR (maximum 3 doses) every 5 mins; Up to 0.05 mg/kg IV, titrate to pain relief to a maximum dose of 0.2 mg/kg every 5 mins If pain not controlled up to 0.5 µg/kg IV, re- peat a single dose to pain relief to a maxi- mum dose of 2 µg/kg after 5 min NCCEP, 2019 Moderate to severe 0.1 mg/kg IV/IO/IM repeat 0.1 mg/kg ev- ery 5 mins (maxi- mum 10 mg) 1 µg/kg IV/IO/IM/IN repeat 0.5 µg/kg ev- ery 5 mins (maxi- mum 2 µg/kg) – – PHECC, 2018 Mild – – – 20 mg/kg oral Moderate – – – 20 mg/kg oral Severe 0.3 mg/kg PO, for age≥1 year old, re- peat 0.1 mg/kg to pain relief to a max- imum dose of 0.1 mg/kg IV every 2 mins 1.5 µg/kg IN, for age≥1 year old, repeat IN once only after 10 min if needed 0.1 mg/kg IV, repeat once only after 10 min if needed If age≤1 years: 7.5 mg/kg IV If age>1 years 15 mg/kg IV AVCP, 2018 Mild – – – 15 mg/kg oral Moderate – 25 µg IN for small child (10-24 kg) 25 to 50 µg IN for medium child (18 to 39 kg) Repeat 3 doses if needed (consult after 3 doses) – 15 mg/kg oral This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 11 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Table 3: Recommendations for pre-hospital pain management in children (continue. . . ) Guideline Pain severity Morphine Fentanyl Ketamine Paracetamol AVCP, 2018 Severe 0.05 to 0.1 mg/kg IV, titrate to pain relief to a maximum dose of 0.2 mg/kg every 5-10 mins 25 µg IN for small child (10-24 kg) 25 to 50 mg IN for medium child (18 to 39 kg) Re- peat 3 doses if needed (consult after 3 doses) Extreme traumatic pain persists despite opioid prescription 0.25 mg/kg IV at 5-10 min intervals (maxi- mum 0.5 mg/kg) – MIEMS, 2014 Moderate to severe 0.1 mg/kg IV/IO, repeat 0.05 mg/kg IV/IO to pain relief every 5 mins 1 µg/kg IV/IO, repeat 0.5 mg/kg IV/IO to pain relief every 5 mins – – IIRPM, 2015 Mild – – – 10-15 mg/kg oral Moderate – – – 15 mg/kg IV Severe 0.05-0.1 mg/kg 1-2 µg/kg – – NMPHT, 2018 Moderate to severe 0.05 mg/kg IV/IO/IM 0.5 to 1 µg/kg IV/IO – – NAEMSP, 2014 Moderate 0.1 mg/kg IM to a maximum initial dose of 15 mg 1 µg/kg IN/IM to a maximum dose of 100 µg 0.5 mg/kg IN to a maximum initial dose of 25 mg and maximum cumu- lative dose of 100 mg 15 mg/kg oral to a maximum dose of 1000 mg Severe 0.1 mg/kg IV/IO to a maximum dose of 10 mg – 0.25 mg/kg IM/IV/IO to a maximum ini- tial dose of 25 mg and maximum cumu- lative dose of 100 mg – However, it appears that ketamine should be prescribed in- stead of fentanyl if the patient is hypovolemic or the airway is not secure. Overall, there is no strong evidence supporting the usage of ketamine in pain management. Only two guide- lines reported levels of evidence in detail. All of the other guidelines depicted a description regarding how the guide- line was achieved and levels of evidence. Indeed, levels of ev- idence presented in each guideline varied from the others. In general, levels of evidence presented for using fentanyl and morphine in pain management is moderate to high. In case of using ketamine, one guideline has referred to reported ev- idence as poor, and the other articles disregarded the usage of ketamine. Overall, management of mild pain was mentioned as opioid- free in guidelines, while almost all the guidelines (except for two protocols in moderate pain management section) re- ferred to fentanyl or morphine as the first line treatments for moderate to severe pain management. The two mentioned guidelines regarding management of moderate pain (15, 18) did not recommend using fentanyl and morphine and sug- gested using paracetamol with 1000 mg dosage instead. The majority of the guidelines provided single-drug proto- cols. Only in special circumstances, such as shock, hypov- olemia and unsecure airways, multidrug protocols are sug- gested. In this regard, the NAEN, 2014 guideline recom- mended that if a patient is hypovolemic or has no secure air- ways, ketamine in 0.25 mg/kg dosage with midazolam in 1 mg dosage should be administered. 5. Conclusion The present systematic review has summarized the cur- rent evidence in pre-hospital pain management for the first time via investigation of guidelines and protocols concern- ing the matter. These guidelines presented instructions in age (adults and children) and pain severity categories. Based on the obtained evidence, most of the guidelines recommend paracetamol as the treatment of choice for mild pain in both children and adults. For moderate and severe pain manage- ment, fentanyl and morphine are suggested medications for both adults and children, between these two medications, fentanyl is the treatment of choice for children. In conclu- sion, opioid-free protocols still have no place in pre-hospital management of moderate to severe pain. 6. Appendix 6.1. Acknowledgements None. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 12 Table 3: Recommendations for pre-hospital pain management in children (continue. . . ) Guideline Pain severity Midazolam Nitric oxide Ketorolac Ibuprofen Methoxyflurane NSAIDs ADPH-EMS, 2018 Severe – Consult with online medical director – – – – DCFEMS, 2017 Severe – – – – – – Severe – – – – – – ATCP, 2012 Mild – – – – – – Moderate – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – Severe – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – NCCEP, 2019 Moderate to severe – – 0.5 mg/kg IV/IO/IM (Max- imum 30 mg) – – – PHECC, 2018 Mild – – – 10 mg/kg oral – – Moderate – 50:50 mix – 10 mg/kg oral 3 ml, for age≥5 years old repeat once only if needed – Severe – – – – – – AVCP, 2018 Mild – – – – – – Moderate – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – Severe – – – – 3 ml (repeat 3 ml if required (maximum 6 ml) – MIEMS, 2014 Moderate to severe – – – – – – IIRPM, 2015 Mild – – – 4-10 mg/kg oral – – Moderate – – – – – – Severe – – – – – Contraindication in trauma NMPHT, 2018 Moderate to severe – – – – – – NAEMSP, 2014 Moderate – Yes (dosage not reported) 1 mg IM to a maximum dose of 30 mg 10 mg/kg oral to a maximum dose of 800 mg – – Severe – – 0.5 mg/kg IV with a maxi- mum dose of 15 mg – – – 6.2. Authors Contributions All authors met the four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors. Authors ORCIDs Mahmoud Yousefifard: 0000-0001-5181-4985 Shaghayegh Askarian-Amiri: 0000-0001-8247-4485 Arian Madani Neishaboori: 0000-0002-1920-9299 Mostafa Sadeghi: 0000-0001-7277-1726 Peyman Saberian: 0000-0003-1445-2756 Alireza Baratloo: 0000-0002-4383-7738 6.3. Funding Support This research has been supported by Tehran Medical Service Center grant. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 13 Archives of Academic Emergency Medicine. 2019; 7 (1): e55 Table 3: Recommendations for pre-hospital pain management in children (continue. . . ) Guideline Pain severity Codeine Tramadol hydromorphone diamorphine Aspirin ADPH-EMS, 2018 Severe – – – – – DCFEMS, 2017 Severe – – – – – ATCP, 2012 Mild – – – – – Moderate – – – – – Severe – – – – – NCCEP, 2019 Moderate to severe – – – – – PHECC, 2018 Mild – – – – – Moderate – – – – – Severe – – – – – AVCP, 2018 Mild – – – – – Moderate – – – – – Severe – – – – – MIEMS, 2014 Moderate to severe – – – – – IIRPM, 2015 Mild – – – – – Moderate 1.5 mg/kg oral 1-2 mg/kg – – – Severe – – – – – NMPHT, 2018 Moderate to severe – – – – – NAEMSP, 2014 Moderate – – – – – Severe – – 0.015 mg/kg IM/IV/IO to an initial maximum dose of 2 mg and cumulative maximum dose of 4 mg – – Table 4: Quality assessment of prehospital pain management guidelines based on AGREE II recommendation Guideline Quality score (%) Overall Quality Vote to recommend use Domain 1 Domain 2 Domain 3 Domain 4 Domain 5 Domain 6 score Yes Yes with No modification NAEN, 2014 100 100 29 100 96 33 4.5 1 1 0 ADPH-EMS, 2018 100 94 25 100 79 50 6.0 2 0 0 DCFEMS, 2017 100 89 13 100 88 42 4.5 1 1 0 ATCP, 2012 100 100 81 100 92 17 6.5 2 0 0 NCCEP, 2019 100 78 56 100 79 33 5.0 1 1 0 PHECC, 2018 100 100 77 100 100 8 6.0 2 0 0 AVCP, 2018 100 100 75 100 88 25 5.5 2 0 0 MIEMS, 2014 100 100 81 100 92 33 5.0 1 1 0 IIRPM, 2015 100 100 67 100 88 33 4.5 0 1 1 NMPHT, 2018 89 72 13 100 79 42 4.5 1 1 0 NAEMSP, 2014 94 100 83 100 96 33 6.5 2 0 0 NICE, 2016 100 100 81 100 96 33 6.5 2 0 0 Domain 1: Aim and Scope; Domain 2: Stakeholder involvement; Domain 3: Rigor of development; Domain 4: Clarity of presentation; Domain 5: Applicability; Domain 6: Editorial independence. 6.4. 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