Comparative Effectiveness of Analgesics to Reduce Acute Pain in the Prehospital Setting

Figures & data

Figure 1. Identification and screening of citations. Abbreviations: ED = emergency department; OBS = observational; RCT = randomized controlled trial.

Table 1. Conclusions and strength of evidence for the comparison of opioids vs. ketamine as initial analgesics

Outcome	Study Design and Sample Size	Conclusions (Setting: Supporting Effect Estimates)	Strength of Evidence (Limitations)
Pain severity – 15 min	12 RCTs (24, 27–37) (n = 1128)	There is no evidence of a clinically important difference between opioids and ketamine in the change of pain scores in 15 min. ED: Meta-analysis of 12 RCTs found MD 0.35 (−0.36 to 1.06) at 15 min	Low (Inconsistent, indirect)
Pain severity –30 min	12 RCTs (24, 27–36, 38) (n = 1153)	There is no evidence of a clinically important difference between opioids and ketamine in the change of pain scores in 30 min. ED: Meta-analysis of 12 RCTs found MD 0.26 (−0.23 to 0.75) at 30 min	Low (Inconsistent, indirect)
Pain severity – 60 min	12 RCTs (24, 25, 27–31, 33–36, 38) (n = 1409) 1 OBS (62) (n = 158)	There is no evidence of a clinically important difference between opioids and ketamine in the change of pain scores in 60 min. EMS: One trial (25) over prehospital period, MD −0.4 (−0.8 to 0.09). One observational study (62) favored ketamine vs. morphine over the prehospital period [−5.5(3.1) vs. −2.5 (2.4), p < 0.001] ED: Meta-analysis of 11 RCTs (24, 27–31, 33–36, 38) found MD −0.36 (−0.94 to 0.23) at 60 min.	Low (Inconsistent, indirect)
Any adverse event	8 RCTs (24, 27, 28, 30, 32, 33, 35, 36) (n = 398)	Opioids may cause fewer total adverse events than ketamine. ED: Meta-analysis of 6 RCTs (24, 27, 28, 30, 32, 36) over the study period found AR 50.0% vs. 82.4%; RD −30% (−56 to −4). Two RCTs (33, 35) reported AEs at 15 and at 30 min are generally in agreement.	Low (Inconsistent, indirect, imprecise)
Mental status changes - dizziness	9 RCTs (n = 723) (27, 28, 30, 31–36)	Opioids cause less dizziness than ketamine. ED: Meta-analysis of 7 RCTs (27, 28, 30, 31, 32, 34, 36) over the study period found AR 25.4% vs. 43.5%; RD −29% (−52 to −6). Two RCTs (33, 35) reported dizziness at 15 and 30 min and are generally in agreement.	Low (Inconsistent, indirect)
Respiratory depression	4 RCTs (24, 33, 34, 36) (n = 491) 1 OBS (62) (n = 158)	Opioids may cause more respiratory depression than ketamine. EMS: One OBS study (62) found 2 vs. 0 cases of respiratory compromise that needed oxygen supplementation – insufficient data, conclusion based on ED data ED: Meta-analysis of 4 RCTs (24, 33, 34, 36) over the study period found AR 11.5% vs. 2.4%, RD 4% (−2 to 11)	Low (Inconsistent, indirect, imprecise)

Abbreviations: AR = absolute risk; ED = emergency department; EMS = emergency medical services; IM = intramuscular; IN = intranasal; IV = intravenous; MD = mean difference; min = minutes; OBS = observational; RCT = randomized controlled trial; RD = risk difference.

Table 2. Conclusions and strength of evidence for the comparison of opioids vs. ketamine in patients with inadequate response to initial analgesia

Outcome	Study Design and Sample Size	Conclusions (Setting: Supporting Effect Estimates)	Strength of Evidence (Limitations)
Pain severity	2 RCT (39, 40) (n = 162)	Giving ketamine may reduce pain more than giving additional opioids. EMS: Meta-analysis of 2 RCTs found MD 1.99 (0.95 to 3.03) over the prehospital period.	Low (Medium study limitations, imprecise)
Time to analgesic effect	1 RCT (39) (n = 135)	Giving ketamine may be quicker to reduce pain to a clinically important difference compared to giving additional opioids. EMS: 1 RCT found the median difference in the change of pain score per minute to be −2.5 points per minute (−3.9 to −1.1) in favor of ketamine compared to opioids.	Low (Medium study limitations, unknown consistency)

Abbreviations: EMS = emergency medical services; MD = mean difference; OBS = observational; RCT = randomized controlled trial.

Table 3. Conclusions and strength of evidence for the comparison of combining an opioid and ketamine vs. an opioid

Outcome	Study Design and Sample Size	Conclusions (Setting: Supporting Effect Estimates)	Strength of Evidence (Limitations)
Pain severity – 15 min	4 RCT (41, 43, 45, 46) (n = 336)	Combining an opioid and ketamine may reduce pain more than an opioid alone at 15 min. EMS: 1 RCT (41) found MD −1.3 (−2.6 to 0.02) at 15 min. ED: Meta-analysis of 3 RCT (43, 45, 46) found MD −1.04 (−2.55 to 0.47).	Low (Inconsistent, indirect, imprecise)
Pain severity –30 min	5 RCT (41–43, 45, 46) (n = 545)	Combining an opioid and ketamine may reduce pain more than an opioid alone at 30 min. EMS: 1 RCT (41) found mean difference in the change of pain scores to be MD −1 (−2.2 to 0.2) at 30 min. ED: Meta-analysis of 4 RCT (42, 43, 45, 46) found MD −0.59 (−2.24 to 1.06).	Low (Inconsistent, indirect, imprecise)
Pain severity – 60 min	3 RCT (43, 45, 46) (n = 241)	There is no evidence of a clinically important difference between combining opioid and ketamine and opioid alone in the change of pain scores in 60 min. ED: Meta-analysis of 3 RCT found MD −0.07 (−1.14 to 1.00).	Low (Inconsistent, indirect)

Abbreviations: ED = emergency department; EMS = emergency medical services; MD = mean difference; NR = not reported; OBS = observational; RCT = randomized controlled trial.

Table 4. Conclusions and strength of evidence for the comparison of opioids vs. acetaminophen

Outcome	Study Design and Sample Size	Conclusions (Setting: Supporting Effect Estimates)	Strength of Evidence (Limitations)
Pain severity – 15 min	7 RCT (47,48,50–53,56) (n = 647)	There is no evidence of a clinically important difference between IV opioids and IV APAP in the change of pain scores in 15 min. ED: Meta-analysis of 7 RCTs found MD 0.18 (−1.06 to 1.42).	Low (Inconsistent, indirect)
Pain severity –30 min	9 RCT (47–53, 55, 56) (n = 1795)	There is no evidence of a clinically important difference between IV opioids and IV APAP in the change of pain scores in 30 min. ED: Meta-analysis of 9 RCTs found MD 0.30 (−0.84 to 1.44).	Low (Inconsistent, indirect)
Pain severity – 60 min	3 RCT (49, 53, 56) (n = 1260)	There is no evidence of a clinically important difference between IV opioids and IV APAP in the change of pain scores in 60 min. ED: Meta-analysis of 3 RCT found MD 0.40 (−1.01 to 1.81).	Low (Inconsistent, indirect)
Time to analgesic effect	1 RCT (49) (n = 1097)	There is no evidence of a clinically important difference in the time to analgesia with IV opioids compared with IV APAP. ED: Median time to NRS < 2 was 60 min in both arms, IQR 30 to 90 min.	Low (Unknown consistency, indirect)
Any adverse event	6 RCTs (47, 49, 51–53, 56) (n = 1,484)	Opioids may cause more adverse events than APAP. ED: Meta-analysis of 5 RCTs (47, 51–53, 56) over the study period found AR 35.4% vs. 5.6%, RD 30% (−1 to 62). 1 RCT (49) reporting total AEs “during acute” management found 3.5% vs. 1.3%, RD 2% (0.4 to 4).	Low (Inconsistent, indirect, imprecise)
Hypotension	5 RCTs (47, 50–52, 54) (n = 624)	There is no evidence of a clinically important difference in hypotension with opioids compared to APAP. ED: Meta-analysis of 5 RCTs found AR 2.6% vs. 0%, RD 2% (0.00 to 4%).	Low (Indirect, imprecise)
Mental status changes - dizziness	6 RCTs (47, 48, 51, 52, 54, 55) (n = 539)	Opioids cause more dizziness than APAP. ED: Meta-analysis of 6 RCTs found, AR 7.8% vs. 0.3%, RD 7% (5 to 9)	Moderate (Indirect)

Abbreviations: ED = emergency department; IQR = interquartile range; MD = mean difference; min = minutes; NRS = Numeric Rating Scale; RCT = randomized controlled trial; RD = risk difference.

Table 5. Conclusions and strength of evidence for the comparison of opioids vs. nonsteroidal anti-inflammatory drugs

Outcome	Study Design and Sample Size	Conclusions (Setting: Supporting Effect Estimates)	Strength of Evidence (Limitations)
Pain severity –30 min	3 RCT (58–60) (n = 453)	There is no evidence of a clinically important difference between opioids and NSAIDs in the change of pain scores in 30 min. ED: Meta-analysis of 3 RCT found MD 0.01 (−0.29 to 0.32)	Moderate (Indirect)
Pain severity – 60 min	3 RCT (58–60) (n = 453)	There is no evidence of a clinically important difference between opioids and NSAIDs in the change of pain scores in 60 min. ED: Meta-analysis of 3 RCT found MD 0.21 (–0.10 to 0.51)	Moderate (Indirect)
Any adverse event	2 RCT (58, 60) (n = 367)	Opioids may cause more adverse events than NSAIDs. ED: Meta-analysis of 2 RCTs found AR 24.6% vs. 7.4%, RD 21% (4 to 38)	Low (Inconsistent, indirect, imprecise)
Mental status changes – drowsiness	2 RCT (58, 60) (n = 367)	Opioids may cause more drowsiness than NSAIDs. ED: Meta-analysis of 2 RCTs found AR 3.9% vs. 0.7%, RD 3% (0 to 6%)	Low (indirect, imprecise)

Abbreviations: ED = emergency department; MD = mean difference; NSAIDs = nonsteroidal anti-inflammatory drugs; RCT = randomized controlled trial; RD = risk difference.

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