Opioid Analgesics: An ED-Focused Overview

Authors: Arianna R. Moreno, MD (EM Attending); Michael J. Yoo, MD, FACEP, FAAEM (Associate Professor of Emergency Medicine, UT Health San Antonio) // Reviewed by: Jessica Pelletier, DO, MHPE (Assistant Professor of EM/APD, University of Missouri-Columbia); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

An otherwise healthy 45-year-old man presents to the emergency department (ED) with acute flank pain and hematuria. Your workup reveals a left-sided 4 mm non-infected, non-obstructive urolithiasis. You provide fluids and analgesics in the ED with significant symptomatic improvement. The patient is PO tolerant, is able to follow up closely with urology, and is requesting to be discharged with pain medications. In addition to prescribing NSAIDs, you decide to prescribe a limited quantity of opioid analgesics for breakthrough pain. Which opioid are you selecting? How long does your selected opioid last for pain control? Do you know the atypical adverse reactions of the opioid you select?

Background

Opioid prescribing in the United States has declined significantly since its peak in 2012, when over 255 million prescriptions were written.^1-3 Amid growing concerns over addiction and overdose deaths, prescriptions dropped 44% to 143 million prescriptions by 2020, or 43 prescriptions per 100 people.^1-3 In EDs specifically, there has also been an overall decline in opioid prescribing at discharge from 50.5 per 1,000 visits in 2017-2018 down to 36.4 per 1,000 in 2019-2020.⁴ However, despite this reduction, opioid-related fatalities remain high, with 81,000-82,000 deaths reported in 2022 and 2023, respectively.^1-3 Given this ongoing crisis, clinicians must understand the differences between opioids to ensure safe, effective pain management while minimizing addiction and overdose risks. Variations in potency, half-life, onset, and analgesia duration impact dosing, drug selection, and tapering strategies. For example, synthetic opioids like fentanyl are significantly more potent than natural opioids like morphine. Meanwhile, methadone and buprenorphine have distinct pharmacokinetics that make them effective for opioid use disorder (OUD) treatment. Awareness of DEA scheduling, drug interactions, and adverse effects enables clinicians to individualize opioid therapy, balancing pain relief, safety, and regulatory compliance.

Discussion

In adult patients experiencing an acute painful condition, ACEP and AAEM advocate for cautious prescribing of opioid analgesics upon discharge. ACEP specifically has Level C recommendations for the use of opioids for acute painful conditions or exacerbation of noncancer chronic pain. When using opioids, it is recommended to typically exhaust or consider nonpharmacologic and nonopioid analgesics initially, and opioids as a second-line therapy. If used, start with the lowest effective dose for the shortest time possible, with many sources recommending no more than 3 days of prescription with no refills.^5-6

Pharmacokinetics of Prescribing

Pain management is a vital component of ED patient care. When choosing the optimal opioid for each patient, it is important to consider the pharmacokinetics of the medications to be used (Table 1) and their adverse effects (Table 2). For example, many intravenous (IV) and intramuscular (IM) formulations of opioids typically have a shorter onset of action and often have a shorter duration of action. Medications like IV fentanyl have an onset of action of only 1-2 minutes, which may be helpful in those with acute, severe pain in the ED, lasting for 30-60 minutes, and may require frequent redosing. Consider using fentanyl or other short-onset opioids to bridge to longer-lasting opioids such as morphine, hydromorphone, and oxycodone, which have an onset time of 5-15 minutes. The literature is limited regarding whether one specific opioid achieves superior analgesic effects compared to other opioids for various conditions. Therefore, opioids should typically be selected based on their side effect profile and patient comorbidities.

Opiates are primarily metabolized by the liver into inactive compounds, which are then excreted by the kidneys. Lipid-soluble opiates like buprenorphine tend to redistribute into fatty tissues, leading to a prolonged half-life. In cases of liver dysfunction (e.g., cirrhosis), opiate metabolism is impaired, resulting in an extended half-life and an increased risk of toxicity—even at relatively low doses.

Synthetic opioids such as fentanyl, tramadol, and methadone may be safer in patients with renal dysfunction, as they do not produce active metabolites. In contrast, non-synthetic opioids like codeine and morphine generate active metabolites that can accumulate in renal impairment, potentially worsening adverse effects. Semi-synthetic opioids, including hydromorphone, hydrocodone, and oxycodone, also produce some active metabolites, but may be safer alternatives when used cautiously—at the lowest effective dose and with close monitoring.⁷

Co-Prescribing of Medications

The use of sedating medications should generally be avoided when prescribing opioids. Co-administration of benzodiazepines with opioids enhances the euphoric effects of opioids and significantly increases the risk of overdose and misuse.⁸ Other sedative agents, including sleep aids such as zolpidem (Ambien) and eszopiclone (Lunesta), can similarly elevate the risk of unintentional overdose.⁹

However, there are scenarios where combining medications may be beneficial. The use of non-opioid analgesics—such as NSAIDs, acetaminophen, and topical therapies—alongside opioids can improve pain control and reduce the required opioid dose.¹⁰ That said, combination opioid-acetaminophen formulations are not more effective than their individual components and can complicate appropriate dosing. They may limit the ability to titrate the non-opioid component effectively and increase the risk of liver toxicity if the patient inadvertently exceeds the recommended acetaminophen dose through combination products or concurrent monotherapy. In addition, the dosing of acetaminophen included in opioid-acetaminophen combination formulations is sub-therapeutic and is therefore unlikely to provide substantial benefit.

Additionally, naloxone prescription should be considered with all opioid prescriptions, particularly in patients at higher risk of overdose.¹¹ The initial concern that naloxone prescribing might encourage riskier opioid use has been refuted. Specifically, co-dispensing naloxone does not promote misuse and may in fact reduce opioid-related mortality. Studies have shown that approximately 9% of take-home naloxone supplies are used to reverse an overdose within three months of distribution.^12-13

Additional Considerations When Prescribing Opioids for Acute Pain

Currently, there is no evidence from human studies to suggest that specific opioids are more effective for certain types of pain (e.g., fentanyl for fractures or hydromorphone for abdominal pain). As such, the choice of opioid should instead be guided by factors such as onset and duration of action (see Table 1), as well as the side effect profile (see Table 2).

Oxycodone and hydrocodone are associated with a higher potential for euphoria and, consequently, a greater risk of misuse. In appropriate cases, consider prescribing immediate-release morphine at discharge, as it provides comparable analgesia with a potentially lower abuse potential.^14-16

Morphine has historically been avoided in patients with suspected or confirmed sphincter of Oddi dysfunction (SOD) or acute pancreatitis due to concerns about increased biliary pressure. While all opioids increase biliary pressure to some extent, morphine may cause a slightly greater increase.¹⁷ However, much of the evidence supporting this claim comes from case reports, single-center retrospective studies, and studies involving animal models or intraoperative cholangiograms.^{17 -19} To date, no outcome-driven clinical trials have demonstrated that morphine worsens outcomes in acute pancreatitis or biliary disease. Despite this, many clinicians continue to avoid morphine in such settings based on anecdotal experience and persistent clinical caution. If SOD spasm were to occur, naloxone has shown potential in reversing the spasm.²⁰

A nuanced approach to opioid selection should be taken, accounting for the other medications that a patient is prescribed and their specific medical comorbidities. Several opioid analgesics are pro-serotonergic in nature, including fentanyl, methadone, and tramadol.^21-22 These agents should be avoided in patients taking multiple pro-serotonergic agents, such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, lithium, or buspirone, given the increased risk for serotonin syndrome.²¹ Methadone is associated with QT prolongation,²³ which can lead to torsades de pointes and death;²⁴ thus, clinicians should be conscious of concomitant electrolyte derangements (i.e., hypokalemia, hypomagnesemia) or other QT-prolonging medications when prescribing methadone.

Ideally, opioids should be avoided in women who are breastfeeding, given that these medications pass into the breastmilk and can carry the risk of sedation, lethargy, and respiratory depression in the infant.²³ Tramadol and codeine should be avoided, as they are metabolized to their active forms by CYP2D6; 4-5% of the U.S. population are ultra-rapid metabolizers, which can result in high concentrations of these opioids in the breastmilk. This poses a substantial risk to the breastfeeding infant.²⁵ In situations where the use of opioids in a breastfeeding mother is unavoidable, signs of opioid toxicity in the infant should be carefully reviewed with the family (as opposed to pumping and discarding the milk).²⁶

The following tables represent various opioids that may be used for acute and chronic analgesia.^{19-20, 27-44}

Table 1. Pharmacokinetics of commonly used opioids.

Abbreviations: PO – oral; IV – intravenous; IM – intramuscular; SL – sublingual; ME – morphine equivalent; mcg – micrograms; mg – milligrams; hr: hours; DEA – Drug Enforcement Administration; IR – immediate release; ER – extended-release. *Estimations of overdose doses for opioid-naive patients.

Table 2. Adverse reactions of commonly used opioids. 

*All opioids carry a risk of respiratory depression, hypotension, nausea, and vomiting. ^All listed opioids are μ-opioid agonists; note that buprenorphine is a partial agonist.  Abbreviations: CNS – central nervous system; PO – oral; IV – intravenous; IM – intramuscular; SL – sublingual; NMDA – N-methyl-D-aspartate; SNRI – serotonin and norepinephrine reuptake inhibitor

Case Resolution

The patient has already been maximizing his use of acetaminophen, and you decide to avoid opioids combined with acetaminophen. The patient also remembers that he takes venlafaxine for his depression. You decide to also avoid prescribing tramadol due to its SNRI properties. After discussing the risks and benefits of opioid analgesics, you decide to prescribe a 3-day supply of oxycodone as a second-line for pain refractory to ibuprofen. He is able to follow up uneventfully with his urologist.

Pearls and Pitfalls

– Opioid use disorder and opioid-related deaths remain a significant public health concern. While it is essential to take patients’ pain seriously, clinicians should set clear expectations early: the goal is to help manage pain – not to eliminate it entirely.

– Opioids should be considered a second-line treatment for acute pain, and only after exhausting non-opioid medications and alternative therapies. When opioids are necessary, they should be prescribed at the lowest effective dose for the shortest possible duration – ideally, no more than three days. Clinicians must also consider the patient’s current medications and underlying medical conditions that may increase the risk of opioid toxicity.

– Co-prescribing naloxone can be a life-saving intervention, particularly for patients at higher risk of overdose or misuse.

#FOAMed:

• https://www.emdocs.net/pain-management-of-common-chief-complaints-in-the-ed/ 
• https://www.mdcalc.com/calc/10170/morphine-milligram-equivalents-mme-calculator

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