Ketamine as an adjuvant to opioids for cancer pain Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

This is an update of a review first published in 2003 and updated in 2012.

Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects.

Objectives

To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults.

Search methods

For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017.

Selection criteria

The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre‐existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial.

Data collection and analysis

Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient‐reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Main results

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.

Authors' conclusions

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.

Author(s)

Rae Frances Bell, Christopher Eccleston, Eija A Kalso

Abstract

Plain language summary

Adding ketamine to opioid for opioid‐resistant cancer pain 

Bottom line 

The benefits and harms of adding low‐dose ketamine to strong pain‐killers such as morphine for the relief of cancer pain are not yet established. High‐dose ketamine does not appear to be effective and may be associated with serious side effects.

Background 

This review is an update of a review first published in 2003 and updated in 2012.

Morphine‐like drugs (opioids) are frequently prescribed for moderate and severe cancer pain, but in some cases these drugs are not effective. Ketamine, an anaesthetic agent, is used in low doses in palliative care to improve analgesia when opioids alone are ineffective.

Study characteristics 

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.

Key results 

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.

Quality of the evidence 

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.

Author(s)

Rae Frances Bell, Christopher Eccleston, Eija A Kalso

Reviewer's Conclusions

Authors' conclusions

Implications for practice For people with refractory cancer pain treated with opioid

The evidence base for ketamine as an adjuvant to opioids for the treatment of cancer pain is insufficient to enable us to draw any conclusions. 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.

For clinicians

The evidence base for ketamine as an adjuvant to opioids for the treatment of cancer pain is insufficient to enable us to draw any conclusions. 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.

For policy makers

The evidence base for ketamine as an adjuvant to opioids for the treatment of cancer pain is insufficient to enable us to draw any conclusions. 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.

For funders of the intervention

The majority of this patient group are commonly in‐patients, due to refractory symptoms. Ketamine administered to hospitalised patients is an inexpensive treatment. However, the evidence base for ketamine as an adjuvant to opioids for the treatment of cancer pain is insufficient to enable us to draw any conclusions.

Implications for research General implications

The amount of clinical trial evidence in this review is limited. Studies investigating specific low‐dose ketamine treatment regimens commonly used for refractory cancer pain are needed.

Design

Conducting scientifically sound trials in a population of terminally ill cancer patients is a considerable challenge, and this is perhaps reflected in the small number of published trials available for this review. It is difficult to recruit large numbers of patients from this population. Cross‐over designs, as used in the two of the three included studies, may be more appropriate than placebo‐controlled parallel group studies. Where there are large trials, planned subgroup analyses should be considered.

Measurement (endpoints)

Outcomes should be clearly defined, and trial managers should also restrict study outcomes to those that are the most clinically useful, such as which route of administration, relevant dose, co‐analgesic effects with specific opioids, and the cost to the patient in terms of adverse events.

Whether ketamine is more effective in combination with specific opioids is not known, and this is an area for further research. Rapid titration of ketamine to high dose (Hardy 2012) had no clinical benefit and was associated with adverse events. Further studies examining this specific treatment regimen are not warranted. Trials with S‐ketamine as an adjuvant to opioids might be appropriate.

Other

Opioid tolerance may also be an issue. It has been suggested that pharmacological tolerance to opioid can develop early (Laulin 2002), but it is not clear how often it is a clinical problem in cancer patients. It may be difficult in this patient population to distinguish between tolerance and disease progression, both of which require an increase in opioid dose. In patients who appear to have a problem tolerating opioids, ketamine in low dose may be a treatment option. This is a topic for future research.

More information is needed on whether the route of administration of ketamine has an impact on its effectiveness as an analgesic. If ketamine is used spinally, issues of neurotoxicity should be considered (Karpinski 1997).

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