Hardy, J., Quinn, S., Fazekas, B., Plummer, J., Eckermann, S., Agar, M., … Currow, D.C. (2012). Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. Journal of Clinical Oncology, 30, 3611–3617.

To determine whether ketamine, delivered subcutaneously with dose titration over five days, has greater clinical benefit than placebo when used in conjunction with opioids and standard adjuvant therapy in the management of cancer pain

• Patients received either a continuous subcutaneous infusion of ketamine on a five-day, escalating-dose schedule (100 mg, 300 mg, and 500 mg over 24 hours) or placebo (normal saline) given over five days. 
• Patients were assessed every 24 hours for pain (least, average or best)  using the Brief Pain Inventory (BPI). No dose change occurred if 80% of ketamine was delivered, pain improvement was greater than 2, and no more than four breakthrough pain doses were needed.
• Dose reductions occurred if toxicity was unacceptable. The drug was discontinued at 500 mg if no response to pain occurred or toxicity became intolerable.

• The study reported on 149 patients with a mean age of 63.
• The sample was 55% male and 45% female.
• Patients had refractory pain secondary to cancer or its treatment.
• For 48 hours prior to beginning the study, participants could have no change in baseline opioid dosing. 
• Patients were excluded if they had received ketamine within the past six months, had radiotherapy to a site of pain within two weeks, or received any other procedure that may affect pain.

This was a multisite, inpatient study conducted in Australia.

• Patients were in the late effects and survivorship phase of care.
• This study has clinical applicability for palliative care.

This was a randomized, double-blinded, placebo-control study.

• The Common Terminology Criteria for Adverse Events v 3.0, Clinician-Administered Dissociative States Scale, and BPI were used.
• A positive response was defined as a clinically relevant improvement in pain.

• Findings showed no significant differences between study groups. Pain declined somewhat over time in both groups. The decline in worst pain ratings was lower in the ketamine group (p = 0.034). No differences were found between groups in use of rescue medication.
• More patients withdrew from the ketamine arm. The incidence of adverse events was higher with ketamine.
• The most common events were light headedness, hypoxia, and somnolence. Psychotoxicity significantly increased each day, and, by day 3, the odds of psychotoxicity development were significantly higher in the ketamine group (OR = 2.53; 95% CI [1.11, 5.78]; p = 0.027).

Ketamine was only associated with improvement in worse pain compared to placebo, and it was associated with more adverse events and psychotoxicity.

• A risk of bias exists because of the sample characteristics.
• The findings are not generalizable.
• Entry inclusion criteria included an average pain score of 3 or more on BPI. This may not reflect clinically acceptable pain of 3 or 4. 
• Concerns exist regarding the aggressive dosing and short duration of the study. The short duration of the study over five days with rapid escalation of ketamine may have been overly aggressive. A question exists around whether more careful titration of ketamine may have altered results.

Ketamine as an adjunct to opioids to manage chronic refractory cancer pain only appeared to affect worst pain rating and may cause adverse effects and increase psychotoxicity. Incidence of adverse events with ketamine infusion adjunctively with opioids in the management of refractory pain should be reevaluated when considering the patient population of advanced cancer.