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Ketamine offered no clinical benefit in pain management of cancer
Researchers who conducted a randomized, phase 3 trial designed to evaluate pain management in a cohort of patients with cancer observed no difference between ketamine and placebo.
Ketamine, an anesthetic, often is used to treat cancer-related pain but evidence to support its use in this setting, according to researchers.
The researchers conducted this multisite, double blind, trial to evaluate whether ketamine was more effective for management of chronic uncontrolled pain than placebo when used in conjunction with opioids and standard adjuvant therapy.
Outcome measures included a clinically relevant improvement in pain with limited breakthrough analgesia and an acceptable toxicity profile.
The trial included 185 participants. They were randomly assigned to ketamine (n=93) or placebo (n=92) subcutaneously for 3 to 5 days.
The researchers observed no significant difference between the proportion of positive outcomes between the two study arms (0.04; 95% CI, −0.1 to 0.18). The response rate was 31% for ketamine and 27% for placebo.
Pain type — nociceptive vs. neuropathic — did not predict response.
After 1 day of treatment, adverse events nearly doubled from baseline in the ketamine group (incidence rate ratio=1.95; 95% CI, 1.46-2.61). This trend continued throughout the study.
The OR for a severe-grade adverse event per day was increased in the ketamine group (OR=1.09; 95% CI, 1.00-1.18).
Twenty-five patients needed to be treated with ketamine for one additional patient to have a positive outcome (95% CI, 6-infinity), according to researchers.
“The number needed to harm, because of toxicity-related withdrawal, was six (95% CI, 4-13),” the researchers wrote.
They concluded that there is no clinical benefit of ketamine when used as an adjunct to opioids and standard coanalgesics.
Perspective
Back to TopThis is an interesting study looking at ketamine in addition to more standard treatments for uncontrolled cancer pain. It may be difficult to draw wide-reaching conclusions based on these results, but there are a few points of note. The first thing is that ketamine was administered subcutaneously. We typically administer ketamine as a continuous IV infusion because ketamine has a relatively narrow therapeutic window, and it can be difficult to balance good analgesia and untoward side effects. Secondly, while the abstract notes that the patients had uncontrolled pain, it does not report the opioid doses required by the patients in the two arms of the study. We typically utilize ketamine in patients who have poor analgesic results on relatively high doses of opioids (greater than 200 mg to 300 mg morphine equivalents per day). It makes it difficult to generalize what “uncontrolled” means. Have these patients not been aggressively titrated on opioids and adjuvant pain medications, or is it uncontrolled even with optimization of standard therapy? It is not clear. Lastly, it would be important to know the primary source of pain in the patients enrolled in the study.
Cancer pain often involves a combination of somatic, visceral, inflammatory and neuropathic pain, but the predominant cause of pain often dictates the potential success of treatment. Our experience with ketamine has been much more positive for patients with predominantly neuropathic or visceral/pleuritic pain who have failed an aggressive opioid titration with the addition of standard adjuvant pain medications. Regarding adverse events, these results are in line with what we see. Ketamine does have side effects that often are dose limiting. Adding a medication like ketamine to a patient’s regimen increases their risk of adverse reactions, such as hallucinations, bad dreams and general dysphoria. We attempt to limit the extent of these adverse reactions by utilizing continuous ketamine intravenous infusions rather than intermittent dosing. To generalize that ketamine doesn’t have clinical benefit when used as an adjuvant to opioids may depend on the patient, the predominant source of pain, and their tolerance of opioids and opioid side effects.
We have had good experiences with ketamine, particularly among patients with a significant neuropathic pain component, who have failed aggressive opioid titration or who have exhibited signs of opioid-induced hyperalgesia with high-dose opioid therapy. As for how these results may impact the average hematology-oncology clinician, we need to look a little closer at ketamine to define its place in cancer-pain management. This drug is generally used in patients with severe cancer-related pain who have failed standard therapy, often times in the palliative care setting. Ketamine will not likely be a medication used for routine cases of difficult-to-treat cancer-related pain. It is probably prudent to consult a pain specialist when patients have failed standard opioid and adjuvant pain medication therapy, because those patients may benefit from more aggressive pain therapy, which can involve more aggressive medical therapy, neurolytic blocks, intrathecal drug therapy, or other interventional pain treatment modalities. We continue to use ketamine in selective cases, and it is something that should be in the armamentarium for severe cancer-related pain, especially for those with end-stage disease or opioid induced hyperalgesia.