A 2018 consensus guideline published by the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists addressed use of intravenous (IV) ketamine infusions for acute pain management. Specific to patient controlled IV ketamine analgesia (IV-PCA) in acute medical and postoperative pain settings, the Panel concluded that evidence is limited regarding benefit when IV-PCA delivered ketamine is used as the sole analgesic (grade C recommendation, low certainty of evidence). Conversely, the Panel concluded that moderate evidence supports the benefit of the addition of ketamine to an opioid-based IV-PCA protocol for acute and perioperative pain management (grade B recommendation, moderate level of certainty). Evidence to support these recommendations is limited to that which was published prior to 2018; in this context, use of ketamine as a sole IV-PCA analgesic was limited to a single case report, pediatric case series, and small uncontrolled observational study. No supporting evidence from a randomized controlled trial was available for assessment. However, evidence to support addition of ketamine to an opioid in an IV-PCA regimen was assessed via pooled data in meta-analyses, which found benefit for 24-hour pain intensity, immediate postoperative nausea and vomiting (PONV), and reduction of opioid consumption. [1]
A 2016 systematic review and meta-analysis included 19 randomized controlled trials to evaluate the effects of adding ketamine to opioids in PCA devices for postoperative pain management. The analysis included 1,349 adults and 104 children and aimed to assess whether ketamine could decrease pain intensity by at least 25%, reduce cumulative opioid consumption by 30% or more, diminish the risk of PONV by 30%, lower the incidence of respiratory adverse events by 50%, and limit the increase in hallucination risk to less than two-fold. The trials varied in ketamine regimens and the analysis included outcomes such as: pain intensity at rest at 24 hours, opioid consumption in the first 24 hours post-surgery, and the incidence of side effects like PONV and hallucinations. Results from the review indicated that ketamine added to opioids reduced pain intensity at rest by 32% (p<0.001) and cumulative 24-hour morphine consumption by 28% (p= 0.002). Furthermore, the incidence of PONV was reduced by 44% (p<0.001) when ketamine was included. Interestingly, there was no significant difference in the incidence of respiratory adverse events or hallucinations, suggesting that ketamine may offer analgesic and antiemetic benefits without exacerbating these particular risks. However, due to the heterogeneity in study methodologies and the varied ketamine regimens used, uncertainty remains regarding the dose-responsiveness. Trial sequential analyses supported the significant benefits of ketamine on reducing pain intensity, opioid use, and PONV, while also indicating that ketamine did not double the risk of hallucinations. The study highlighted the need for additional research to clarify ketamine's effects on respiratory adverse events and to establish optimal dosing strategies. [2]
A 2016 systematic review and meta-analysis examined the effects of adding ketamine to morphine or hydromorphone PCA for acute postoperative pain management in adults. The comprehensive analysis included 36 randomized controlled trials encompassing 2,502 patients, of which 22 trials were identified as having a low risk of bias. The primary objective was to determine whether ketamine, when combined with morphine or hydromorphone PCA, provides significant reductions in postoperative pain, opioid consumption, and adverse events compared to morphine or hydromorphone PCA alone. Adding ketamine to PCA resulted in modest yet statistically significant reductions in postoperative pain at various intervals post-surgery, with pain reduction ranging from 0.6 cm to 1.3 cm on a 10-cm visual analogue scale. Furthermore, cumulative morphine consumption decreased by approximately 5 to 20 mg over 24 to 72 hours, while PONV were significantly reduced with ketamine addition, resulting in a relative risk reduction of 29%. No significant differences in patient satisfaction scores at 24 and 48 hours were observed, and there was no increase in other adverse effects such as hallucinations or vivid dreams, although adverse events were possibly underreported. The findings suggest that ketamine adjunct to opioid PCA offers a small improvement in analgesia while decreasing opioid requirements and certain opioid-related side effects. [3]
Another review article undertook a comprehensive analysis of randomized, double-blinded clinical trials to evaluate the efficacy and safety of adding ketamine to morphine for intravenous PCA in managing acute postoperative pain. The review included a total of 11 studies encompassing 887 patients that met the inclusion criteria. Results from six studies showed significant improvement in postoperative analgesia with ketamine use in comparison to morphine alone, particularly in thoracic surgeries, where the addition of ketamine resulted in notable reductions in pain scores, cumulative morphine consumption, and postoperative desaturation. However, four studies reported no significant pain improvement with ketamine. Three studies found a statistically shorter duration of PCA use in the ketamine group. In seven studies, opioid-related side effects were statistically significantly higher in the morphine group compared with the ketamine group. The review highlighted the lack of clarity on the benefits of adding ketamine in orthopedic or abdominal surgeries, attributing the conflicting results to heterogeneity and small sample sizes among the studies. Despite these discrepancies, the analysis confirmed the safety of ketamine at subanaesthetic doses, aligning with prior reviews. [4]
A 2012 review analyzed the effectiveness and safety of adding ketamine to morphine PCA in post-operative pain management following thoracic surgery. The review included nine articles, comprising randomized controlled trials, meta-analyses, and cohort studies, which provided comparative data on pain scores, morphine consumption, and side effects when ketamine was added to morphine PCA versus morphine alone. The synthesis of evidence revealed that the inclusion of ketamine resulted in significantly lower pain scores for thoracic surgery patients, as demonstrated in all five thoracic surgery-specific studies with a sample size of 243 patients. These studies reported reduced morphine requirements, improved oxygen saturations, and enhanced respiratory outcomes, such as decreased nocturnal desaturation and improved PaCO2 levels. The safety profile of ketamine, as assessed in a 2004 meta-analysis conducted by Subramaniam et al., indicated a slightly higher incidence of central nervous system side effects with a relative risk of 1.27, although this was statistically non-significant compared to morphine alone. Another study by Sveticic et al., 2005, involving 1026 patients, reported a 2.9% incidence of hallucinations requiring intervention. Despite these concerns, no hallucinations or psychological side effects were observed in the controlled trials specific to thoracic surgery. The gathered evidence supports the routine use of ketamine in combination with morphine PCA for managing post-thoracotomy pain, offering better pain control and improved patient satisfaction without a significant increase in adverse side effects. [5]