Opioids in the ED

No Comments

When the choice, dose and route matter.

Opioids are one of the most common class of analgesics administered in the emergency department (ED) and prescribed at discharge. These agents exert their clinical analgesic effect by binding to the opioid receptors (mu, delta, kappa) in the brain, spinal cord and peripheral nervous system.[1]


Parenteral opioids administered in titrated fashion and oral opioids prescribed at the lowest effective dose for the shortest duration are effective in controlling a variety of acute painful conditions of moderate to severe intensity and are generally safe. [1, 2]

A balance between the benefits and harms related to opioids should be thoughtfully considered prior to initiating opioid therapy in the ED. [3,4]

The most commonly used opioids in the ED are pure m-receptor agonists, such as morphine, hydromorphone, fentanyl, oxycodone and hydrocodone. While these agonists produce similar analgesic effect, their metabolism, bioavailability and more importantly, euphorigenic potential may differ and require a patient-specific therapeutic strategy. [1,5]


As ED clinicians, we ought to be experts in choosing optimal opioid based on: (1) indications, (2) analgesic and euphorigenic properties, (3) dosing regimen and route of administration in the ED and at discharge. [2,6]


Opioid analgesics provide rapid and effective pain relief to patients presenting to the ED with a variety of acute painful syndromes, several chronic painful syndromes and cancer-related pain syndromes (Table 1). [7-11]Opioids should be used in the ED as a part of multimodal analgesia in conjunction with non-pharmacological and non-opioid therapies when the likelihood of analgesic benefit is judged to exceed the likelihood of harm. [4]

They should not be used as a first-line analgesics (in the ED and at discharge) in managing acute back pain (with possible exception of spine fracture) [12], acute headache [13-15], acute musculoskeletal pain (with possible exception of fractures) [16] and acute dental pain [17] as the risks associated with their use (mainly, misuse, abuse and potential for overdose) is significantly higher than the marginal, if any, analgesic efficacy.


Data discussing the use of opioids in the ED for treatment of acute exacerbation of chronic, non-cancer pain demonstrates higher likelihood of harm than benefit. [18] Opioid analgesics should not be routinely used in the ED for chronic non-cancer pain with a notable exception of vaso-occlusive crisis of sickle cell disease. [10]

Choice of opioids

Pure mu-receptor agonists such as morphine, hydromorphone, fentanyl, oxycodone and hydrocodone are similar — with respect to analgesic efficacy — when administered in equianalgesic dosing regimens.

Additionally, these opioids lack an analgesic ceiling, and their doses can be titrated upwards until pain is controlled, or side effects became intolerable or dangerous. [1,2] However, these agonists significantly differ from each other with respect to their ability to induce euphoria (based on lipophilicity and penetration of blood-brain barrier) and, and consequently, to cause addiction.

ED clinicians are uniquely positioned to provide effective and safe pain management with opioid analgesics by carefully balancing analgesic and euphorigenic properties of opioids (Table 2).

Based on available literature, morphine sulfate administered either parenterally or orally (immediate release tablets) in the ED and at discharge provides better balance between pain relief and addictive potential and should be considered an opioid of choice. In the situation when morphine is contraindicated and opioid analgesia is still warranted, fentanyl (parenteral) and hydrocodone (oral) are suitable alternatives. [1,5,19].

Hydromorphone should be avoided as a first-line opioid in the ED as traditionally utilized dosing regimens of parenteral hydromorphone (1-2mg) are on average 50% higher than the dosing of morphine, which leads to higher rates of respiratory depression requiring naloxone reversal and, occasionally, respiratory arrests requiring Intubation and ICU admission. [20,21]

Furthermore, hydromorphone utilization (parenteral and oral forms) is associated with higher rates of euphoria and subsequent development of addiction. [5, 21, 22]

Therefore, hydromorphone’s administration in the ED should be reserved for multi-analgesic-refractory painful syndrome, or when morphine side effects become intolerable. (See in-depth discussion on hydromorphone in the ED at EPMonthly: https://epmonthly.wpengine.com/article/dilaudid-detail-problem-hydromorphone/)

Oxycodone lacks analgesic superiority over morphine [23] and hydrocodone. With its highest oral bioavailability among currently prescribed opioids and disproportionately higher ability to penetrate through the BBB and induce euphoria, oxycodone possesses one of the greatest potentials for misuse, diversion, overdose and the development of an opioid use disorder. [5,19,24] Therefore, oxycodone, either alone or in combination with acetaminophen, should not be routinely used in the ED and at discharge.

Tramadol should not be used in the ED and at discharge due to modest, at most, analgesic efficacy with inferior pain relief in comparison to morphine and hydrocodone, great potential for misuse and diversion due to euphoria (active metabolite M1), and numerous other adverse effects (hypoglycemia, hyponatremia, seizures, serotonergic syndrome). [5,25]

Lastly, codeine, either alone or in combination with acetaminophen) has no utility in managing pain in the ED due to sub-optimal pain relief and great genetic variability in analgesic responses. [5, 26]

Dosing ranges and routes of administration

Parenteral opioid administration via intravenous route achieves rapid, titratable and effective pain relief in the ED and serves as a preferred route of opioid delivery. When administered in the ED in equianalgesic dosing regimens, parenteral opioid providesg similar analgesic response. ( https://www.mdcalc.com/morphine-milligram-equivalents-mme-calculator#evidence).

The intravenous dosing regimens include weight-based dosing and fixed dosing that allow for patient-tailored and titratable opioid delivery. [1,2,4]

When intravascular access is not readily available or unobtainable, ED clinicians should consider utilization of subcutaneous route (less painful upon injection than intramuscular with similar analgesic efficacy) for morphine and hydromorphone administration [27-29], intranasal route via mucosal atomization device for fentanyl and hydromorphone  [30,31], inhalation (via nebulizer) route for fentanyl and morphine administration [32,33], or transmucosal route for rapidly dissolvable fentanyl tablets. [34]

Intramuscular route of opioid administration in the ED should be avoided as it is associated with severe pain at injection site, unpredictable absorption rates, soft tissue infection (aseptic and septic necrosis) and myofibrosis leading to a dose escalation and, consequently, higher rates of adverse effects. [35,36]

Oral administration of opioid in the ED should be strongly considered even though it results in poor oral bioavailability (with exception of oxycodone) and delayed onset of analgesia in the ED that limits its utility in rapid control of pain. [1,2] The commonly used routes and dosing ranges of opioids are presented in Table 3.

Take home points

  1. Always discuss benefits and risks of opioid therapy with patients.
  2. When prescribing opioids in the ED and at discharge, honor both quantitative (lowest effective dose) and qualitative (euphorigenic potential) properties of this class.
  3. Respect equianalgesic dosing conversion and titration when using parenteral opioids.
  4. Stick to three Rs when using opioids: right drug, right dose, and right route

opioids in the ed

Table 2: Clinically Important Properties of Commonly Used Opioids in the ED

Opioid Clinically important properties
Morphine Hydrophilic-slower penetration through BBB

Less euphoric, more dysphoric

Leads to Histamine release

Severely emetogenic

Active metabolites are neurotoxic (seizures) in settings of renal failure

Requires dose reduction by 50% to 75% and extended dosing intervals in patients with moderate renal insufficiency.

Contraindicated in patients with severe renal insufficiency and ESRD.

Requires dose reduction by 50% to 75% in moderate to severe hepatic insufficiency.


Hydromorphone Eight times more potent than morphine (parenteral route), 10 times more lipophilic than morphine.

Fast penetration through BBB

Severely euphoric with high potential for abuse, misuse, and diversion

Higher rates of respiratory and CNS depression with traditional dosing (1-2mg IV).

Active metabolite is neurotoxic (seizures) in settings of renal failure

Requires dose reduction by 50% to 75% and extended dosing intervals in patients with moderate-to-severe renal insufficiency.

Contraindicated in patients with ESRD

Requires dose reduction by 50% to 75% in moderate to severe hepatic insufficiency.


Fentanyl Hundred times more potent than morphine, about 600 times more lipophilic.

Fastest penetration through BBB.

Highest euphorigenic potential.

Narrow therapeutic index requires careful initial dosing and dose titration.

Requires dose reduction by 50% in patients with severe renal and hepatic insufficiency.



Highest oral bioavailability.

Fast penetration through BBB (highest among oral opioids).

Severely euphorigenic with great potential of misuse, abuse and diversion.

Requires dose reduction by 50% to 75% and extended dosing intervals in patients with severe renal and hepatic insufficiency.

Hydrocodone Prodrug, active metabolite is hydromorphone.

Euphorigenic, abuse and misuse prone.

Requires dose reduction by 50% to 75% and extended dosing intervals in patients with moderate-to-severe renal insufficiency.

Contraindicated in patients with ESRD

Requires dose reduction by 50% to 75% in moderate to severe hepatic insufficiency.


Tramadol Prodrug, active metabolite is O-desmethyltramadol (M1), which is more potent analgesic.

Dual mode of action: inhibition of re-uptake of Norepinephrine and Serotonin and mu-receptor agonism.

Euphorigenic, abuse and misuse prone

Requires dose reduction and extending dosing intervals in patients with renal and hepatic insufficiency.

Active metabolites are neurotoxic (seizures).

Numerous adverse effects.


Codeine Prodrug-morphine is one of the active metabolites.

Weak analgesic.

Great genetic variability to response based on metabolism (no response or exaggerated response).

Limited data on addictive potential.


Table 3: Dose and Routes of Commonly used Opioids in the ED.

Opioid Route Dose
Morphine Sulfate Intravenous






Inhalation (Nebulized)




Weigh-based: 0.05-0.1 mg/kg

Fixed: 4-6 mg


Weigh-based: 0.05-0.1 mg/kg

Fixed: 4-6 mg


10-20 mg (per dose)



7.5-10 mg (opioid-naïve patients)

Hydromorphone Intravenous








Intranasal (via MAD)




Weigh-based: 0.005-0.01mg/kg

Fixed: 0.5-1 mg dose


Weigh-based: 0.005-0.01mg/kg

Fixed: 1 mg


1-2 mg (per dose)



1-2 mg (opioid-naïve patients)

Fentanyl Intravenous



Inhalation (Nebulized)




Intranasal (via MAD)


Transmucosal (lollypop)-in the ED only


Buccal (rapidly dissolvable tablets)-in the ED only


Weight-based: 0.5-1 mcg/kg

Fixed: 25-75 mcg per dose


2-4 mcg/kg




1-1.5 mcg/kg


15-25 mcg



100-200 mcg



Oral 5 mg

5 mg/325mg

Hydrocodone/Acetaminophen Oral 5mg/325mg


Oral 7.5-15-30mg

7.5-15-30mg/325 mg



  1. Wightman RS, Perrone J. Opioids. In: Strayer R, Motov S, Nelson L. Pain and Procedural Sedation in Acute Care. 2018. https://painandpsa.org/opioids/
  2. Motov SM, Nelson LS. Advanced Concepts and Controversies in Emergency Department Pain Management. Anesthesiol Clin. 2016 Jun;34(2):271-85. doi: 10.1016/j.anclin.2016.01.006. PMID: 27208710.
  3. Strayer RJ, Motov SM, Nelson LS. Something for pain: Responsible opioid use in emergency medicine. Am J Emerg Med. 2017 Feb;35(2):337-341. doi: 10.1016/j.ajem.2016.10.043. Epub 2016 Oct 24. PMID: 27802876.
  4. Motov S, Strayer R, Hayes BD, Reiter M, Rosenbaum S, Richman M, Repanshek Z, Taylor S, Friedman B, Vilke G, Lasoff D. The Treatment of Acute Pain in the Emergency Department: A White Paper Position Statement Prepared for the American Academy of Emergency Medicine. J Emerg Med. 2018 May;54(5):731-736. doi: 10.1016/j.jemermed.2018.01.020. Epub 2018 Mar 6. PMID: 29523420.
  5. Connors NJ, Mazer-Amirshahi M, Motov S, Kim HK. Relative addictive potential of opioid analgesic agents. Pain Manag. 2021 Mar;11(2):201-215. doi: 10.2217/pmt-2020-0048. Epub 2020 Dec 10. PMID: 33300384.
  6. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Opioids, Hatten BW, Cantrill SV, Dubin JS, Ketcham EM, Runde DP, Wall SP, Wolf SJ. Clinical Policy: Critical Issues Related to Opioids in Adult Patients Presenting to the Emergency Department. Ann Emerg Med. 2020 Sep;76(3):e13-e39. doi: 10.1016/j.annemergmed.2020.06.049. PMID: 32828340.
  7. Gallagher EJ, Esses D, Lee C, Lahn M, Bijur PE. Randomized clinical trial of morphine in acute abdominal pain. Ann Emerg Med. 2006 Aug;48(2):150-60, 160.e1-4. doi: 10.1016/j.annemergmed.2005.11.020. PMID: 16953529.
  8. McHale PM, LoVecchio F. Narcotic analgesia in the acute abdomen–a review of prospective trials. Eur J Emerg Med. 2001 Jun;8(2):131-6. doi: 10.1097/00063110-200106000-00009. PMID: 11436909.
  9. Klein-Kremer A, Goldman RD. Opioid administration for acute abdominal pain in the pediatric emergency department. J Opioid Manag. 2007 Jan-Feb;3(1):11-4. doi: 10.5055/jom.2007.0033. PMID: 17367089.
  10. Fiocchi J, Urits I, Orhurhu V, Orhurhu MS, Giacomazzi S, Hoyt B, Kaye AD, Kaye RJ, Viswanath O. A Comprehensive Review of the Treatment and Management of Pain in Sickle Cell Disease. Curr Pain Headache Rep. 2020 Mar 21;24(5):17. doi: 10.1007/s11916-020-00854-y. PMID: 32200490.
  11. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, Ripamonti CI; ESMO Guidelines Committee. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018 Oct;29 Suppl 4:iv166-iv191. doi: 10.1093/annonc/mdy152. Epub 2020 Jan 7. PMID: 32169224.
  12. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, Bijur PE, Gallagher EJ. Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA. 2015 Oct 20;314(15):1572-80. doi: 10.1001/jama.2015.13043. PMID: 26501533.
  13. Orr SL, Friedman BW, Christie S, Minen MT, Bamford C, Kelley NE, Tepper D. Management of Adults With Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache. 2016 Jun;56(6):911-40. doi: 10.1111/head.12835. PMID: 27300483.
  14. Friedman BW, Irizarry E, Solorzano C, Latev A, Rosa K, Zias E, Vinson DR, Bijur PE, Gallagher EJ. Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine. Neurology. 2017 Nov 14;89(20):2075-2082. doi: 10.1212/WNL.0000000000004642. Epub 2017 Oct 18. PMID: 29046364; PMCID: PMC5711508.
  15. Friedman B, Monteith T. Despite Variations, Evidence Provides Clear Road Map for Adult Patients Presenting with Acute Migraine. ED Manag. 2017 Mar;29(3):31-33. PMID: 29782757
  16. Chang AK, Bijur PE, Esses D, Barnaby DP, Baer J. Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial. JAMA. 2017 Nov 7;318(17):1661-1667. doi: 10.1001/jama.2017.16190. PMID: 29114833; PMCID: PMC5818795.
  17. Patel NA, Afshar S. Addressing the high rate of opioid prescriptions for dental pain in the emergency department. Am J Emerg Med. 2018 Jan;36(1):138-139. doi: 10.1016/j.ajem.2017.07.003. Epub 2017 Jul 3. PMID: 28709712.
  18. Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH. Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA. 2018 Dec 18;320(23):2448-2460. doi: 10.1001/jama.2018.18472. PMID: 30561481; PMCID: PMC6583638.
  19. Wightman R, Perrone J, Portelli I, Nelson L. Likeability and abuse liability of commonly prescribed opioids. J Med Toxicol. 2012 Dec;8(4):335-40. doi: 10.1007/s13181-012-0263-x. PMID: 22992943; PMCID: PMC3550270.
  20. Beaudoin FL, Merchant RC, Janicki A, McKaig DM, Babu KM. Preventing iatrogenic overdose: a review of in-emergency department opioid-related adverse drug events and medication errors. Ann Emerg Med. 2015 Apr;65(4):423-31. doi: 10.1016/j.annemergmed.2014.11.016. Epub 2014 Dec 18. PMID: 25534653.
  21. Mazer-Amirshahi M, Motov S, Nelson LS. Hydromorphone use for acute pain: Misconceptions, controversies, and risks. J Opioid Manag. 2018 Jan/Feb;14(1):61-71. doi: 10.5055/jom.2018.0430. PMID: 29508897.
  22. Mazer-Amirshahi M, Ladkany D, Mullins PM, Motov S, Perrone J, Nelson LS, Pines JM. Trends in and predictors of hydromorphone administration in US emergency departments (2007-2014). J Opioid Manag. 2018 Jul/Aug;14(4):265-272. doi: 10.5055/jom.2018.0458. PMID: 30234923.
  23. Fassassi C, Dove D, Davis A, Butt M, Masoudi A, Drapkin J, Gohel A, Silver M, Likourezos A, Motov S. Analgesic efficacy of morphine sulfate immediate release vs. oxycodone/acetaminophen for acute pain in the emergency department. Am J Emerg Med. 2021 Aug;46:579-584. doi: 10.1016/j.ajem.2020.11.034. Epub 2020 Nov 20. PMID: 33341323.
  24. Remillard D, Kaye AD, McAnally H. Oxycodone’s Unparalleled Addictive Potential: Is it Time for a Moratorium? Curr Pain Headache Rep. 2019 Feb 28;23(2):15. doi: 10.1007/s11916-019-0751-7. PMID: 30820686.
  25. Dunn KE, Bergeria CL, Huhn AS, Strain EC. A systematic review of laboratory evidence for the abuse potential of tramadol in humans. Psychiatry 10, 704 (2019).
  26. Andrzejowski P, Carroll W. Codeine in paediatrics: pharmacology, prescribing and controversies. Dis. Child. Educ. Pract.Ed. 101(3), 148–151 (2016).
  27. Stoner KL, Harder H, Fallowfield LJ, Jenkins VA. Intravenous versus Subcutaneous Drug Administration. Which Do Patients Prefer? A Systematic Review. Patient. 2014.
  28. Ackerman AL, O’Connor PG, Doyle DL, Marranca SM, Haight CL, Day CE, Fogerty RL. Association of an Opioid Standard of Practice Intervention With Intravenous Opioid Exposure in Hospitalized Patients. JAMA Intern Med. 2018 Jun 1;178(6):759-763. doi: 10.1001/jamainternmed.2018.1044. PMID: 29799964; PMCID: PMC6145746.
  29. Kestenbaum MG, Vilches AO, Messersmith S, Connor SR, Fine PG, Murphy B, Davis M, Muir JC. Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Med. 2014 Jul;15(7):1129-53
  30. 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. doi: 10.2146/ajhp140630. PMID: 26346210.
  31. Bailey AM, Baum RA, Horn K, Lewis T, Morizio K, Schultz A, Weant K, Justice SN. Review of Intranasally Administered Medications for Use in the Emergency Department. J Emerg Med. 2017 Jul;53(1):38-48. doi: 10.1016/j.jemermed.2017.01.020. Epub 2017 Mar 1. PMID: 28259526.
  32. Farahmand S, Shiralizadeh S, Talebian MT, Bagheri-Hariri S, Arbab M, Basirghafouri H, Saeedi M, Sedaghat M, Mirzababai H. Nebulized fentanyl vs intravenous morphine for ED patients with acute limb pain: a randomized clinical trial. Am J Emerg Med. 2014 Sep;32(9):1011-5. doi: 10.1016/j.ajem.2014.05.051. Epub 2014 Jun 12. PMID: 25027194.
  33. Grissa MH, Boubaker H, Zorgati A, Beltaïef K, Zhani W, Msolli MA, Bzeouich N, Bouida W, Boukef R, Nouira S. Efficacy and safety of nebulized morphine given at 2 different doses compared to IV titrated morphine in trauma pain. Am J Emerg Med. 2015 Nov;33(11):1557-61. doi: 10.1016/j.ajem.2015.06.014. Epub 2015 Jun 14. PMID: 26143313.
  34. Shear ML, Adler JN, Shewakramani S, et al. Transbuccal fentanyl for rapid relief of orthopedic pain in the ED. The American Journal of Emergency Medicine. 2010;28(8):847–852
  35. Yamanaka M, Parsa FD. Compression neuropathy from muscle fibrosis induced by repeated meperidine injections. Plast Reconstr Surg. 1985 Apr;75(4):582-3. PMID: 3983261.
  36. von Kemp K, Herregodts P, Duynslaeger L, Deleu D, Bruyland M, Cham B. Muscular fibrosis due to chronic intramuscular administration of narcotic analgesics. Acta Clin Belg. 1989;44(6):383-7


Dr. Motov is an Attending Physician and Research Director in the Department of Emergency Medicine at Maimonides Medical Center with particular interest in safe and effective analgesia in the ED.

Paraskevi (Vivian) Papas, MS is a second year student at St George's University.

Ethan Kremer, BS is a second year student at NYIT College of Osteopathic Medicine (NYITCOM)

Leave A Reply