Opioids in the ED

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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]


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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]


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Indications

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]


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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.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.

Oxycodone

 

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

 

 

Subcutaneous

 

 

Inhalation (Nebulized)

 

 

Oral

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

 

 

 

Subcutaneous

 

 

 

Intranasal (via MAD)

 

 

Oral

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

Oxycodone

Oxycodone/Acetaminophen

Oral 5 mg

5 mg/325mg

Hydrocodone/Acetaminophen Oral 5mg/325mg
Codeine

Codeine/Acetaminophen

Oral 7.5-15-30mg

7.5-15-30mg/325 mg

 

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ABOUT THE AUTHORS

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)

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