Table 4 The intravenous and oral analgesics analyzed in this study: Associated recommendations and rationale

1. Should morphine or fentanyl be used for acute moderate-severe pain?

4. Should hydromorphone or oxycodone be used for acute pain?

We recommend fentanyl (1 mcg/kg, then ~30 mcg q 5 min) over morphine (weak recommendation, low quality evidence)

We are unable to comment on the superiority/inferiority of either of these drugs in treating acute pain

If morphine is used to treat acute pain, we suggest giving 0.1 mg/kg, then 0.05 mg/kg at 30 min, with the maximum suggested dose of 10 mg

The only studies we identified that compared these drugs assessed the extended release forms of hydromorphone (Exalgo^®) and oxycodone Further research is needed to assess the immediate release forms of hydromorphone (e. g., Dilaudid^®) and oxycodone, and whether they have a role in treating acute pain in the emergency department

Rationale[28–30]

   • People with morphine allergies do not have allergies to fentanyl

   • Fentanyl has a shorter onset of action as well as being 100 times more potent than morphine, and thus is better suited to treat acute moderate to severe pain. (Fentany l is more lipid soluble and thus has higher bioavailability)

Rationale[34, 35]

   • There is no substantial cost difference between the two medications

   • We only identified two studies comparing hydromorphone and oxycodone. They assessed the extended release forms. Both studies suggested no difference between the drugs in either pain relief or adverse effects

   • Fentanyl is reported to be less pro-emetic than morphine and does not produce a histamine release like morphine does. This leads to less hypotension and less pruritus, facial flushing, or urticaria

   • We are unable to make recommendation about hydromorphone (PO) and oxycodone (PO) in treating acute pain. Extended release forms appear to be equal in terms of pain relief and side effect profile (when dosed in an equal analgesic way 2:5) based on two RCTs (strong recommendation, very low quality evidence).

   • Fentanyl with its 2-3 min onset and 30-60 min duration is less likely to cause prolonged sedation, and may encourage more frequent reassessment of ill patients

5. Should non-specific NSAIDs (e. g., ibuprofen) or codeine-acetaminophen be used for mild-moderate acute pain?

   • Fentanyl has less of a dose stacking risk than morphine. This is especially relevant in patients with renal failure in whom morphine's metabolite accumulates, whereas fentanyl does not.

We recommend non-COX specific NSAIDs over codeine-acetaminophen combinations

Currently the order sets have general doses of morphine at 2.5 mg or 5 mg, and fentanyl at 50 mcg. Because adults vary in weight, ED physicians may be well served to estimate the patient's weight and dose based on that For example a 70 kg patient should be given 7 mg of morphine or 70 mcg of fentanyl as an initial loading dose (assuming there is no contraindication to a high loading dose)

(weak recommendation, moderate quality evidence)

Rationale[36–38]

• The reported numbers needed to treat for naproxen and ibuprofen are 2.7 vs. 4.4 for codeine-acetaminophen

• NSAIDs have been shown to have a longer time to re-medication with a safer side effect profile. The number needed to treat for codeine-acetaminophen was 6

• NSAIDs do not have the CNS depressing effects of codeine

• Certain genotypes may not metabolize or may hyper-metabolize codeine into morphine (due to a CYP2D6 polymorphism)

2. Should hydromorphone or morphine be used for acute severe pain in the emergency department?

6. Should COX-2 specific NSAIDs (e. g., celecoxib) or codeine-acetaminophen be used for mild-moderate acute pain?

We recommend hydromorphone (0.015 mg/kg i.v.) as a comparable, potentially superior, analgesic to morphine (0.1 mg/kg i.v.) (strong recommendation, moderate quality evidence)

We recommend COX-specific NSAIDs over codeine acetaminophen combinations

(weak recommendation, moderate quality evidence)

Rationale[28, 31, 32]

Rationale[36]

   • Hydromorphone has a quicker onset of action, when compared with morphine

   • This is based on a Cochrane systematic review that compared NSAIDs and codeine-acetaminophen combinations with placebo in treating acute postoperative pain

   • Hydromorphone is comparable in cost to morphine

   • The number needed to treat for 400 mg of celecoxib was 2.5 whereas that for 600 mg/60 mg of acetaminophen/codeine was 3.9

   • Morphine, with a longer onset of action and greater risk for dose stacking, places patients at a higher risk for toxicity (in the context of renal failure) and hypoventilation or, on the other hand oligoanalgesia

   • The average time to re-medication with celecoxib was 8.4 h, whereas patients who used acetaminophen/codeine re-medicated in 4.1 h

   • Because hydromorphone is more potent, at a much smaller milligram dose, physicians may be more likely to adequately treat pain by giving a dose of 1.5 mg of hydromorphone vs. 10 mg of morphine

7. Should oxycodone-acetaminophen or codeine-acetaminophen be given to patients with acute pain in the ED?

   • Hydromorphone causes little or no histamine release, and may be safely administered to patients who report a type 2 allergy to morphine (urticaria, pruritis, and facial flushing)

We recommend oxycodone-acetaminophen as marginally superior to codeine-acetaminophen

(weak recommendation, low quality evidence)

3. Should hydromorphone 1 + 1 mg patient-driven protocol or other intravenous opioids at any dose (physician-driven protocol) be used for acute pain management?

Rationale[39–41]

We recommend a 1 mg + 1 mg patient-driven protocol over other intravenous opioids in the emergency department (weak recommendation, low quality evidence)

   • This recommendation is based on two Cochrane reviews that compared each of these drugs with placebo

This may be especially helpful for patients who are unable to clearly communicate their level of pain (acute mental status change, non-English speaking patients)

   • There are few studies that directly compare these two drugs, especially in an adult emergency department setting

Rationale[28, 31–33]

   • However, the Cochrane reviews and single studies consistently show that oxycodone with acetaminophen is slightly better at relieving pain than acetaminophen-codeine

   • Hydromorphone has a quicker onset of action compared with morphine

   • Hydromorphone is comparable in cost to morphine

   • Morphine, with a longer onset of action and greater risk for dose stacking, places patients at a higher risk for toxicity (in the context of renal failure) and hypoventilation or, on the other hand, oligoanalgesia

   • Because hydromorphone is more potent, at a much smaller milligram dose, physicians may be more likely to adequately treat pain by giving a dose of 1.5 mg of hydromorphone vs. 10 mg of morphine

   • Hydromorphone causes little or no histamine release, and may be safely administered to patients who report a type 2 allergy to morphine (urticaria, pruritis, and facial flushing)

   • This is superior to standard morphine and fentanyl dosing for a few reasons: Physicians tend to be concerned about giving patients more morphine than 5 mg and often give small doses, e. g., 2.5 mg. A 1 + 1 approach not only allows physicians to appropriately treat pain, but also requires fewer repeat orders