To the Editor:

I read the excellent article written by Hardy et al¹ in Journal of Clinical Oncology. Although the methodology and study design was of high scientific quality, there were several points that were not discussed in this interesting article.

As Hardy et al¹ pointed out, we have little evidence from controlled studies on ketamine use in patients with cancer with pain. However, when such a powerful drug is used, it is important to titrate the dose in a careful way. In this study, the presented schedule of dose increments was conducted during 5 days. The scheme was as follows: 100, 300, and 500 mg per day in a continuous subcutaneous infusion. Because the study duration was only 5 days, this scheme seemed to be an aggressive approach, especially when the daily dose was increased from 100 to 300 mg (by 300%). Because the careful titration of opioid analgesic is recommended, it seems that more-careful ketamine dose increments (eg, from 50 to 100, 150, 200, 250, and 300 mg) may be associated with less-adverse events. This effect might also be the case when the dose is increased from 300 to 500 mg.

Another interesting point in the study by Hardy et al¹ was that patients recruited at baseline experienced pain of moderate intensity (5.43 ± 1.3 and 5.21 ± 1.4 in the ketamine and placebo arms, respectively) according to the Brief Pain Inventory pain-on-average item. All patients had been treated at entry with high opioid doses (median oral morphine equivalents) of 300 mg (range, 160 to 480 mg) and 410 mg (range, 258 to 700 mg) in the ketamine and placebo arms, respectively. One of the entry criteria was that the average pain score was 3 or more on the Brief Pain Inventory. However, in clinical practice, a score of 3 or 4 may be acceptable for many patients, especially those suffering from neuropathic pain who usually experience severe pain (score > 6). High opioid doses might have contributed to the adverse effects observed.

From our experience, the indication on the concurrent use of opioids and ketamine could be severe neuropathic pain intensity (Numerical Rating Scale ≥ 7) that does not respond to opioids and adjuvant analgesics. The starting dose of ketamine should be low and titrated carefully to achieve satisfactory analgesia and acceptable adverse effects; then, the opioid dose may be reduced. Patients should be closely monitored at specialist in-patient units.^2,3 Ketamine may also be used for painful hygienic procedures or for changing dressings in patients after major burns.⁴

Mechanisms of ketamine analgesia include N-methyl-d- aspartate–receptor blockade, decrease of central sensitization, reduction of hyperalgesia, and reverse of opioid tolerance.⁵ Results of controlled studies^1,6 have suggested a lack of efficacy and increased toxicity when ketamine and opioids were used concurrently. It seems that we need additional controlled studies with longer follow-up that could confirm or challenge these results and look for alternatives. One possibility is the use of methadone that combines the effects of the opioid agonist and N-methyl-d-aspartate–receptor antagonist. Uncontrolled reports demonstrated the efficacy and safety of small methadone doses added to other opioids, which may reduce risks associated with complex pharmacokinetics and appropriate dosing. Meanwhile, we should be grateful to Hardy et al¹ for conducting such a challenging study, and we should undertake additional controlled trials to find the best approach for patients with cancer with severe pain.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.