Abstract: One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update. Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The second study with 10 participants examined the addition of intravenous ketamine bolus in two different doses to ongoing morphine therapy, compared with placebo. Both of these studies reported reduction in pain intensity and reduction in morphine requirements when ketamine was added to opioid for refractory cancer pain. The new study identified by the updated search had a parallel group design and 185 participants. This placebo-controlled study examined rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids. There were no differences between groups for patient-reported pain intensity. Pooling of the data from the three included trials was not appropriate because of clinical heterogeneity. The study examining intrathecal drug administration reported no adverse events related to ketamine. In the study using intravenous bolus administration, ketamine caused hallucinations in four of 10 participants. In the rapid dose escalation/high-dose subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group, compared to the placebo group, with the most common adverse events being needle site irritation and cognitive disturbance. Two serious adverse events (bradyarrhythmia and cardiac arrest) thought to be related to ketamine were also reported in this trial. For all three studies there was an unclear risk of bias overall. Using GRADE, we judged the quality of the evidence to be very low due to study limitations and imprecision due to the small number of participants in all comparisons. Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain. The evidence was of very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is high. Rapid dose escalation of ketamine to high dose (500 mg) does not appear to have clinical benefit and may be associated with serious adverse events. More randomised controlled trials (RCTs) examining specific low-dose ketamine clinical regimens in current use are needed.

Plain-language summary: In December 2016 and January 2017, we searched for clinical trials on the addition of ketamine to morphine-like drugs for cancer pain. We found one new study, together with the two studies included in the original review. The three studies were very different, using different doses of ketamine, different routes of administration and different durations of treatment and it was not possible to combine the results of these studies. The two smallest studies reported that the addition of ketamine to morphine reduced pain intensity and morphine requirements. The third study which used high doses of ketamine reported no clinical benefit of adding ketamine to different opioids. Increased doses of ketamine in some participants caused side effects such as hallucinations. The study which examined high doses of ketamine reported two serious adverse events, which may have been related to ketamine. Although two out of three studies reported reduction in pain, this could be due to chance in such small studies. We rated the quality of the evidence using four levels: very low, low, moderate, or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. The evidence from the studies was of very low quality. There were problems with the design of some studies and there were not enough data to answer some parts of our review question.