Perioperative intravenous ketamine for acute postoperative pain in adults

Elina CV Brinck; Elina Tiippana; Michael Heesen; Rae Frances Bell; Sebastian Straube; R Andrew Moore; Vesa Kontinen

doi:10.1002/14651858.CD012033.pub4

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Figure 1

Study flow diagram

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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

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Analysis 1.1

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 1: Opioid consumption at 24 hours

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Analysis 1.2

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 2: Opioid consumption at 48 hours

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Analysis 1.3

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 1.4

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 4: Pain intensity during movement at 24 hours

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Analysis 1.5

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 5: Pain intensity at rest at 48 hours

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Analysis 1.6

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 6: Pain intensity during movement at 48 hours

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Analysis 1.7

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 7: Time to first request for analgesia/trigger of PCA

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Analysis 1.8

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 8: CNS adverse events ‐ all studies

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Analysis 1.9

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 9: Hyperalgesia

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Analysis 1.10

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 10: CNS adverse events ‐ studies with events

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Analysis 1.11

Comparison 1: Perioperative ketamine versus control in a non‐stratified study population, Outcome 11: Postoperative nausea and vomiting ‐ all studies

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Analysis 2.1

Comparison 2: Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population, Outcome 1: Opioid consumption at 24 hours

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Analysis 2.2

Comparison 2: Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population, Outcome 2: Opioid consumption at 48 hours

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Analysis 2.3

Comparison 2: Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population, Outcome 3: Pain intensity at 24 hours

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Analysis 2.4

Comparison 2: Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population, Outcome 4: Pain intensity at 48 hours

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Analysis 2.5

Comparison 2: Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population, Outcome 5: Time to first request for analgesia/first trigger of PCA

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Analysis 3.1

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 1: Opioid consumption at 24 hours

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Analysis 3.2

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 2: Opioid consumption at 48 hours

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Analysis 3.3

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 3.4

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 4: Pain intensity during movement at 24 hours

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Analysis 3.5

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 5: Pain intensity at rest at 48 hours

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Analysis 3.6

Comparison 3: Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population, Outcome 6: Pain intensity during movement at 48 hours

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Analysis 4.1

Comparison 4: CNS adverse events in studies with benzodiazepine premedication, Outcome 1: CNS adverse events

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Analysis 5.1

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 1: Opioid consumption at 24 hours

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Analysis 5.2

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 2: Opioid consumption at 48 hours

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Analysis 5.3

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 5.4

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 4: Pain intensity during movement at 24 hours

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Analysis 5.5

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 5: Pain intensity at rest at 48 hours

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Analysis 5.6

Comparison 5: Perioperative ketamine versus control: thoracotomy, Outcome 6: Pain intensity during movement at 48 hours

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Analysis 6.1

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 1: Opioid consumption at 24 hours

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Analysis 6.2

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 2: Opioid consumption at 48 hours

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Analysis 6.3

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 6.4

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 4: Pain intensity during movement at 24 hours

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Analysis 6.5

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 5: Pain intensity at rest at 48 hours

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Analysis 6.6

Comparison 6: Perioperative ketamine versus control: major orthopaedic surgery, Outcome 6: Pain intensity during movement at 48 hours

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Analysis 7.1

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 1: Opioid consumption at 24 hours

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Analysis 7.2

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 2: Opioid consumption at 48 hours

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Analysis 7.3

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 7.4

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 4: Pain intensity during movement at 24 hours

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Analysis 7.5

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 5: Pain intensity at rest at 48 hours

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Analysis 7.6

Comparison 7: Perioperative ketamine versus control: major abdominal surgery, Outcome 6: Pain intensity during movement at 48 hours

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Analysis 8.1

Comparison 8: Perioperative ketamine versus control: total abdominal hysterectomy, Outcome 1: Opioid consumption at 24 hours

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Analysis 8.2

Comparison 8: Perioperative ketamine versus control: total abdominal hysterectomy, Outcome 2: Opioid consumption at 48 hours

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Analysis 8.3

Comparison 8: Perioperative ketamine versus control: total abdominal hysterectomy, Outcome 3: Pain intensity at rest at 24 hours

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Analysis 9.1

Comparison 9: Perioperative ketamine versus control: laparoscopic procedures, Outcome 1: Opioid consumption at 24 hours

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Analysis 9.2

Comparison 9: Perioperative ketamine versus control: laparoscopic procedures, Outcome 2: Opioid consumption at 48 hours

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Analysis 9.3

Comparison 9: Perioperative ketamine versus control: laparoscopic procedures, Outcome 3: Pain intensity at rest at 24 hours

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Summary of findings 1. Perioperative intravenous ketamine compared to placebo for acute postoperative pain in adults

Outcomes	Details	Number of participants (studies)	Absolute values and effect of ketamine		Quality of the evidence (GRADE)
Perioperative intravenous ketamine compared to placebo for acute postoperative pain: non‐stratified analysis
Patient or population: adults undergoing any type of surgery Settings: immediate postoperative period Intervention: intravenous ketamine given before, during, or after surgery Comparison: intravenous placebo
Outcomes	Details	Number of participants (studies)	Measured values with placebo	Difference with perioperative intravenous ketamine (95% CI)	Quality of the evidence (GRADE)
Opioid consumption (mg morphine equivalents)	24 hours	4004 (65 RCTs)	Median 31 mg (mean 42 mg)	MD 7.6 mg lower (8.9 lower to 6.4 lower)	Moderate¹
Opioid consumption (mg morphine equivalents)	48 hours	2449 (37 RCTs)	Median 59 mg (mean 67 mg)	MD 12.6 mg lower (15 lower to 10 lower)	Moderate¹
Pain intensity (0‐100 mm VAS. ⁷	At rest 24 hours	5004 (82 RCTs)	Median 25 mm (mean 26 mm)	MD 5 mm (VAS) lower (6.6 lower to 3.6 lower)	High²
	On movement 24 hours	1806 (29 RCTs)	Median 43 mm (mean 42 mm)	MD 6 mm (VAS) lower (11 lower to 0.5 lower)	Moderate¹
	At rest 48 hours	2962 (49 RCTs)	Median 21 mm (mean 23 mm)	MD 5 mm (VAS) lower (6.7 lower to 3.4 lower)	High²
	On movement 48 hours	1353 (23 RCTs)	Median 37 mm (mean 37 mm)	MD 6 mm (VAS) lower (10 lower to 1.3 lower)	Low³
Time to first request for analgesia/trigger of PCA (minutes)	All data (plus analysis omitting 1 highly aberrant study reporting time of over 1000 minutes)	1678 (31 RCTs)	Median 18 minutes (mean 39 minutes)	MD 54 minutes longer (37 to 71 longer) (MD 22 minutes longer omitting aberrant study (15 to 29 longer))	Moderate⁴
Hyperalgesia (cm²)	As described, any time point	333 (7 RCTs)	Mean 15 cm²	MD 7 cm² less (12 to 2 less)	Very low⁵
CNS adverse events	All events (major and minor), as described, any time point	6538 (105 RCTs)	52 per 1000	42 per 1000 RR 1.2 (0.95 to 1.4)	High⁶
Postoperative nausea and vomiting	All studies reporting outcomes, as described, any time point	5965 (95 RCTs)	271 per 1000	230 per 1000 RR 0.88 (0.81 to 0.96 Need to treat 24 people to prevent one episode of PONV (16 to 54)	High⁶
CI: confidence interval; CNS: central nervous system; MD: mean difference; PCA: patient controlled analgesia; PONV: postoperative nausea and vomiting; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ Downgraded once for small study effect. ² Not downgraded for small study effect because no reduction in effect with larger studies. ³ Downgraded once for small study effect, and once because fewer than 1500 participants. ⁴ Downgraded once because all studies small, more than 1500 participants but not possible to test for small‐study effects. ⁵ Downgraded three times because fewer than 400 participants. ⁶ Not downgraded: consistent across large body of data. ⁷ Lower VAS means less pain.

Summary of findings 1. Perioperative intravenous ketamine compared to placebo for acute postoperative pain in adults

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Comparison 1. Perioperative ketamine versus control in a non‐stratified study population

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Opioid consumption at 24 hours Show forest plot	65	4004	Mean Difference (IV, Random, 95% CI)	‐7.63 [‐8.88, ‐6.39]

1.2 Opioid consumption at 48 hours Show forest plot	37	2449	Mean Difference (IV, Random, 95% CI)	‐12.62 [‐15.06, ‐10.18]

1.3 Pain intensity at rest at 24 hours Show forest plot	82	5004	Mean Difference (IV, Random, 95% CI)	‐5.09 [‐6.55, ‐3.64]

1.4 Pain intensity during movement at 24 hours Show forest plot	29	1806	Mean Difference (IV, Random, 95% CI)	‐5.60 [‐10.72, ‐0.48]

1.5 Pain intensity at rest at 48 hours Show forest plot	49	2962	Mean Difference (IV, Random, 95% CI)	‐5.03 [‐6.65, ‐3.40]

1.6 Pain intensity during movement at 48 hours Show forest plot	23	1353	Mean Difference (IV, Random, 95% CI)	‐5.72 [‐10.15, ‐1.29]

1.7 Time to first request for analgesia/trigger of PCA Show forest plot	31	1678	Mean Difference (IV, Random, 95% CI)	53.89 [37.00, 70.78]

1.8 CNS adverse events ‐ all studies Show forest plot	105	6538	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.95, 1.43]

1.9 Hyperalgesia Show forest plot	7	333	Mean Difference (IV, Random, 95% CI)	‐7.08 [‐11.92, ‐2.23]

1.10 CNS adverse events ‐ studies with events Show forest plot	52	3706	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.95, 1.43]

1.11 Postoperative nausea and vomiting ‐ all studies Show forest plot	95	5965	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.81, 0.96]

Comparison 1. Perioperative ketamine versus control in a non‐stratified study population

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Comparison 2. Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Opioid consumption at 24 hours Show forest plot	28	1639	Mean Difference (IV, Random, 95% CI)	‐6.26 [‐8.42, ‐4.11]

2.1.1 Pre‐incisional ketamine	19	1045	Mean Difference (IV, Random, 95% CI)	‐5.54 [‐7.95, ‐3.12]
2.1.2 Postoperative ketamine	9	594	Mean Difference (IV, Random, 95% CI)	‐8.66 [‐13.84, ‐3.49]
2.2 Opioid consumption at 48 hours Show forest plot	16	959	Mean Difference (IV, Random, 95% CI)	‐10.76 [‐14.84, ‐6.68]

2.2.1 Pre‐incisional ketamine	9	534	Mean Difference (IV, Random, 95% CI)	‐3.88 [‐7.04, ‐0.72]
2.2.2 Postoperative ketamine	7	425	Mean Difference (IV, Random, 95% CI)	‐20.81 [‐27.39, ‐14.24]
2.3 Pain intensity at 24 hours Show forest plot	29	1646	Mean Difference (IV, Random, 95% CI)	‐7.08 [‐9.56, ‐4.59]

2.3.1 Pre‐incisional ketamine	20	1075	Mean Difference (IV, Random, 95% CI)	‐6.65 [‐10.06, ‐3.24]
2.3.2 Postoperative ketamine	9	571	Mean Difference (IV, Random, 95% CI)	‐8.30 [‐12.55, ‐4.05]
2.4 Pain intensity at 48 hours Show forest plot	15	840	Mean Difference (IV, Random, 95% CI)	‐5.49 [‐7.72, ‐3.25]

2.4.1 Pre‐incisional ketamine	9	509	Mean Difference (IV, Random, 95% CI)	‐4.36 [‐7.53, ‐1.19]
2.4.2 Postoperative ketamine	6	331	Mean Difference (IV, Random, 95% CI)	‐8.02 [‐15.79, ‐0.26]
2.5 Time to first request for analgesia/first trigger of PCA Show forest plot	13	643	Mean Difference (IV, Random, 95% CI)	37.70 [20.87, 54.52]

Comparison 2. Pre‐incisional and postoperative ketamine versus control in a non‐stratified patient population

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Comparison 3. Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Opioid consumption at 24 hours Show forest plot	33	2176	Mean Difference (IV, Random, 95% CI)	‐7.31 [‐9.78, ‐4.84]

3.2 Opioid consumption at 48 hours Show forest plot	15	1110	Mean Difference (IV, Random, 95% CI)	‐14.78 [‐21.12, ‐8.44]

3.3 Pain intensity at rest at 24 hours Show forest plot	32	2053	Mean Difference (IV, Random, 95% CI)	‐8.13 [‐10.84, ‐5.42]

3.4 Pain intensity during movement at 24 hours Show forest plot	10	613	Mean Difference (IV, Random, 95% CI)	‐6.50 [‐18.97, 5.97]

3.5 Pain intensity at rest at 48 hours Show forest plot	18	1202	Mean Difference (IV, Random, 95% CI)	‐6.38 [‐9.91, ‐2.84]

3.6 Pain intensity during movement at 48 hours Show forest plot	8	523	Mean Difference (IV, Random, 95% CI)	‐4.47 [‐13.08, 4.14]

Comparison 3. Perioperative ketamine versus control co‐administered with nitrous oxide in a non‐stratified study population

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Comparison 4. CNS adverse events in studies with benzodiazepine premedication

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 CNS adverse events Show forest plot	65	3943	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.86, 1.38]

Comparison 4. CNS adverse events in studies with benzodiazepine premedication

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Comparison 5. Perioperative ketamine versus control: thoracotomy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Opioid consumption at 24 hours Show forest plot	4	241	Mean Difference (IV, Random, 95% CI)	‐5.81 [‐10.28, ‐1.35]

5.2 Opioid consumption at 48 hours Show forest plot	3	191	Mean Difference (IV, Random, 95% CI)	‐12.52 [‐18.34, ‐6.71]

5.3 Pain intensity at rest at 24 hours Show forest plot	13	782	Mean Difference (IV, Random, 95% CI)	‐3.90 [‐8.80, 1.00]

5.4 Pain intensity during movement at 24 hours Show forest plot	5	315	Mean Difference (IV, Random, 95% CI)	‐7.32 [‐20.10, 5.45]

5.5 Pain intensity at rest at 48 hours Show forest plot	9	530	Mean Difference (IV, Random, 95% CI)	‐6.86 [‐10.37, ‐3.35]

5.6 Pain intensity during movement at 48 hours Show forest plot	5	298	Mean Difference (IV, Random, 95% CI)	‐10.64 [‐15.27, ‐6.00]

Comparison 5. Perioperative ketamine versus control: thoracotomy

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Comparison 6. Perioperative ketamine versus control: major orthopaedic surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Opioid consumption at 24 hours Show forest plot	10	797	Mean Difference (IV, Random, 95% CI)	‐19.68 [‐28.55, ‐10.82]

6.2 Opioid consumption at 48 hours Show forest plot	9	557	Mean Difference (IV, Random, 95% CI)	‐18.69 [‐27.47, ‐9.90]

6.3 Pain intensity at rest at 24 hours Show forest plot	11	843	Mean Difference (IV, Random, 95% CI)	‐6.45 [‐9.86, ‐3.03]

6.4 Pain intensity during movement at 24 hours Show forest plot	4	279	Mean Difference (IV, Random, 95% CI)	‐6.73 [‐12.64, ‐0.82]

6.5 Pain intensity at rest at 48 hours Show forest plot	7	453	Mean Difference (IV, Random, 95% CI)	‐1.39 [‐4.10, 1.32]

6.6 Pain intensity during movement at 48 hours Show forest plot	4	157	Mean Difference (IV, Random, 95% CI)	‐7.36 [‐13.12, ‐1.60]

Comparison 6. Perioperative ketamine versus control: major orthopaedic surgery

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Comparison 7. Perioperative ketamine versus control: major abdominal surgery

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Opioid consumption at 24 hours Show forest plot	16	1029	Mean Difference (IV, Random, 95% CI)	‐10.26 [‐13.75, ‐6.76]

7.2 Opioid consumption at 48 hours Show forest plot	10	704	Mean Difference (IV, Random, 95% CI)	‐14.34 [‐21.21, ‐7.48]

7.3 Pain intensity at rest at 24 hours Show forest plot	18	1178	Mean Difference (IV, Random, 95% CI)	‐7.42 [‐10.63, ‐4.21]

7.4 Pain intensity during movement at 24 hours Show forest plot	9	666	Mean Difference (IV, Random, 95% CI)	‐2.80 [‐11.24, 5.65]

7.5 Pain intensity at rest at 48 hours Show forest plot	13	891	Mean Difference (IV, Random, 95% CI)	‐5.99 [‐8.89, ‐3.08]

7.6 Pain intensity during movement at 48 hours Show forest plot	9	662	Mean Difference (IV, Random, 95% CI)	‐2.91 [‐9.15, 3.34]

Comparison 7. Perioperative ketamine versus control: major abdominal surgery

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Comparison 8. Perioperative ketamine versus control: total abdominal hysterectomy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Opioid consumption at 24 hours Show forest plot	9	511	Mean Difference (IV, Random, 95% CI)	‐5.18 [‐10.77, 0.41]

8.2 Opioid consumption at 48 hours Show forest plot	5	378	Mean Difference (IV, Random, 95% CI)	‐15.32 [‐33.20, 2.56]

8.3 Pain intensity at rest at 24 hours Show forest plot	8	493	Mean Difference (IV, Random, 95% CI)	‐2.58 [‐4.64, ‐0.52]

Comparison 8. Perioperative ketamine versus control: total abdominal hysterectomy

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Comparison 9. Perioperative ketamine versus control: laparoscopic procedures

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Opioid consumption at 24 hours Show forest plot	4	199	Mean Difference (IV, Random, 95% CI)	‐2.67 [‐6.19, 0.84]

9.2 Opioid consumption at 48 hours Show forest plot	2	85	Mean Difference (IV, Random, 95% CI)	‐4.47 [‐12.21, 3.27]

9.3 Pain intensity at rest at 24 hours Show forest plot	9	484	Mean Difference (IV, Random, 95% CI)	‐2.32 [‐6.65, 2.02]

Comparison 9. Perioperative ketamine versus control: laparoscopic procedures

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