Objective:

To assess comparative effectiveness and harms of opioid and nonopioid analgesics administered by emergency medical services for treatment of moderate to severe acute pain in the prehospital setting.

Data sources:

MEDLINE^®, Embase^®, and Cochrane Central from earliest date through May 9, 2019; hand searches of references of relevant studies and study registries.

Review methods:

Two investigators screened abstracts, reviewed full-text files, abstracted data, and assessed study-level risk of bias. We performed meta-analyses when appropriate and graded the strength of evidence (SOE) upon which conclusions were made for a priori determined comparisons and outcomes. We defined the following as clinically important differences: 2 points on a 0 to 10 pain scale; time to analgesia of 5 minutes; 10-percent absolute risk difference for any adverse event; and 5-percent absolute risk difference for hypotension, respiratory depression, and mental status changes.

Results:

We included 52 randomized controlled trials and 13 observational studies. Due to the absence or insufficiency of prehospital evidence we based conclusions for initial analgesia on indirect evidence from the emergency department setting. As initial analgesics, we found no evidence of a clinically important difference in the change of pain scores with opioids versus ketamine administered primarily intravenously (IV) (low SOE), IV acetaminophen (APAP) (low SOE), or nonsteroidal anti-inflammatory drugs (NSAIDs) administered primarily IV (moderate SOE). The combined use of an opioid and ketamine, administered primarily IV, may reduce pain more than an opioid alone at 15 and 30 minutes (low SOE), but we found no evidence of a clinically important difference at 60 minutes (low SOE). We found no evidence of a clinically important difference in time to analgesia with opioids compared with APAP, both administered IV. Opioids may cause fewer adverse events than ketamine (low SOE), primarily administered intranasally. Opioids cause less dizziness than ketamine (low SOE) but may increase the risk of respiratory depression compared with ketamine (low SOE), primarily administered IV. Opioids cause more dizziness (moderate SOE) and may cause more adverse events than APAP (low SOE), both administered IV, but we found no evidence of a clinically important difference in hypotension (low SOE). Opioids may cause more adverse events and more drowsiness than NSAIDs (low SOE), administered primarily IV. Evidence on comparative effects of nitrous oxide and on harms of combined opioid and ketamine is insufficient.

For patients whose pain is not adequately reduced by IV morphine initially, we found that giving IV ketamine may reduce pain more and may be quicker than giving additional IV morphine (low SOE, insufficient evidence to determine comparative harms).

Conclusion:

As initial analgesia administered primarily IV, opioids are no different than ketamine, APAP, and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Differences in specific side effects vary between analgesics and can further inform treatment decisions. Combined administration of an opioid and ketamine may reduce acute pain more than an opioid alone, but comparative harms are uncertain. When initial morphine is inadequate in reducing pain, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, SOE is generally low, and future research in the prehospital setting is needed.