Benefit and harm of adding ketamine to an opioid in a patient-controlled analgesia device for the control of postoperative pain: systematic review and meta-analyses of randomized controlled trials with trial sequential analyses

Abstract

Ketamine is often added to opioids in patient-controlled analgesia devices. We tested whether in surgical patients, ketamine added to an opioid patient-controlled analgesia decreased pain intensity by ≥25%, cumulative opioid consumption by ≥30%, the risk of postoperative nausea and vomiting by ≥30%, the risk of respiratory adverse effects by ≥50%, and increased the risk of hallucination not more than 2-fold. In addition, we searched for evidence of dose-responsiveness. Nineteen randomized trials (1349 adults, 104 children) testing different ketamine regimens added to various opioids were identified through searches in databases and bibliographies (to 04.2016). In 9 trials (595 patients), pain intensity at rest at 24 hours was decreased by 32% with ketamine (weighted mean difference -1.1 cm on the 0-10 cm visual analog scale [98% CI, -1.8 to -0.39], P < 0.001). In 7 trials (495 patients), cumulative 24 hours morphine consumption was decreased by 28% with ketamine (weighted mean difference -12.9 mg [-22.4 to -3.35], P = 0.002). In 7 trials (435 patients), the incidence of postoperative nausea and vomiting was decreased by 44% with ketamine (risk ratio 0.56 [0.40 to 0.78], P < 0.001). There was no evidence of a difference in the incidence of respiratory adverse events (9 trials, 871 patients; risk ratio 0.31 [0.06 to 1.51], P = 0.08) or hallucination (7 trials, 690 patients; odds ratio 1.16 [0.47 to 2.79], P = 0.70). Trial sequential analyses confirmed the significant benefit of ketamine on pain intensity, cumulative morphine consumption, and postoperative nausea and vomiting and its inability to double the risk of hallucination. The available data did not allow us to make a conclusion on respiratory adverse events or to establish dose-responsiveness.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

“…Rationale: Ketamine, because of its N-methyl-d-aspartate (NMDA) receptor-blocking properties and potential to reduce the risk for opioid hyperalgesia, has been evaluated in postoperative adults as a strategy to improve pain relief while reducing opioid requirements in two non-ICU systematic reviews (93,94). In a single-center, double-blind RCT of 93 postabdominal surgery ICU patients, adjunctive ketamine (0.5 mg/kg IV push, 2 μg/ kg/min infusion × 24 hr followed by 1 μg/kg/min × 24 hr) was associated with reduced morphine consumption (MD, -22 mg; 95% CI, -30 to -14; low quality) but no difference in patients' self-reported pain intensity (95).…”

“…Based on this generally positive ICU RCT, the panel made a conditional recommendation for the use of low-dose ketamine as an adjunct to opioids to optimize acute postoperative pain management in critically ill adults once the benefits and harms of its use have been considered by clinicians. Because this single available ICU RCT had a high risk of bias and was also limited to postoperative abdominal surgery patients, the panel also considered indirect evidence from RCTs involving non-ICU patients that, overall, suggested benefit with ketamine use (93,94).…”

Ketamine for pain management

“…A search of PubMed on February 23, 2018, using the terms “ketamine” AND “postoperative pain” and the filter “systematic reviews” yielded 56 hits, 11 of which were systematic reviews addressing perioperative ketamine for acute or chronic postoperative pain 4 , 8 , 16 , 21 , 30 , 36 , 42 , 55 , 59 , 60 , 63 (Table 3 ). A recently completed Cochrane review, 14 currently under review, has also been included.…”

Quo Vadis PCA? A Review on Current Concepts, Economic Considerations, Patient-Related Aspects, and Future Development with respect to Patient-Controlled Analgesia

“…For intravenous administration, common opioids like morphine, fentanyl, hydromorphone, oxycodone, or tramadol are used. Research is conducted to what extend drug combinations, for example, with ketamine [32], have positive aspects and whether it may be beneficial to add antiemetics [33,34]. For regional techniques, a combination of opioids and longacting local anaesthetics (e.g., bupivacaine and ropivacaine) provide high efficacy, and additional additives like clonidine or dexmedetomidine are added to prolong the effect of local anaesthetics [35].…”