Ketamine as an adjuvant to opioids for cancer pain

The benefits and harms of adding ketamine to strong pain-killers such as morphine for the relief of cancer pain are not yet established. 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 to improve analgesia when opioids alone are ineffective. However, evidence for the effectiveness of this practice is limited. Two small studies suggest that when ketamine is given with morphine it may help to control cancer pain. However, these data are insufficient to assess the effectiveness of ketamine in this setting.

Authors' conclusions: 

Since the last version of this review three new studies were identified but excluded from the review. Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More RCTs are needed.

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Background: 

This is an update of the original review published in Issue 1, 2003. Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of cancer pain, particularly when opioids alone prove to be ineffective. Ketamine is known to have psychotomimetic (including hallucinogenic), urological and hepatic adverse effects.

Objectives: 

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

Search strategy: 

Studies were originally identified from MEDLINE (1966 to 2002), EMBASE (1980 to 2002), CancerLit (1966 to 2002), The Cochrane Library (Issue 1, 2001); by handsearching reference lists from review articles, trials, and chapters from standard textbooks on pain and palliative care. The manufacturer of ketamine (Pfizer Parke-Davis) provided search results from their in-house database, PARDLARS.

An improved and updated search of the following was performed in May 2012: CENTRAL, MEDLINE & OVID MEDLINE R, EMBASE.

Selection criteria: 

Randomized controlled trials (RCTs) of adult patients with cancer and pain being treated with an opioid, and receiving either ketamine (any dose and any route of administration) or placebo or an active control. Studies having a group size of at least 10 participants who completed the trial.

Data collection and analysis: 

Two independent review authors identified four RCTs for possible inclusion in the review, and 32 case studies/case series reports. Quality and validity assessment was performed by three independent review authors, and two RCTs were excluded because of inappropriate study design. Patient-reported pain intensity and pain relief was assessed using visual analogue scales (VAS), verbal rating scales or other validated scales, and adverse effects data were collated. For the update three RCTs were identified for possible inclusion in the review.

Main results: 

Three new studies were identified by the updated search. All three were excluded from the review. Two studies were eligible for inclusion in the original review and both concluded that ketamine improves the effectiveness of morphine in the treatment of cancer pain. However, pooling of the data was not appropriate because of the small total number of participants (30), and the presence of clinical heterogeneity. Some patients experienced hallucinations on both ketamine plus morphine and morphine alone and were treated successfully with diazepam. No other serious adverse effects were reported.