Many recent headlines have heralded a new use for the old veterinary anesthetic ketamine, which can provide rapid-onset (albeit short-lived) relief for some patients with treatment-resistant depression (aan het Rot et al., 2012). This finding has been inflated into “arguably the most important discovery in half a century” by Duman and Aghajanian (2012). While finding a cure for refractory depression is undoubtedly an important research priority, might ketamine be useful for other conditions that cause profound human misery?
The care of terminally ill patients suffering from unbearable pain is not a sexy topic, and hospice and palliative medicine is not a glamorous subspecialty. You probably haven't seen the studies examining whether ketamine is effective as an add-on agent to opioid analgesics for cancer pain (Hardy et al., 2012), or as a treatment for depression and anxiety in patients receiving hospice care (Irwin et al., 2013).
Three years ago, my father died of cancer. He had been released from the palliative care unit to a hospice, suffering with uncontrolled cancer pain. It was unbearable to watch, and beyond excruciating for him. During this time, I was writing a post for the Nature Blog Focus on hallucinogenic drugs in medicine and mental health. It included a section on drugs that might alleviate pain and anxiety in cancer patients. I told him about this, and he said to “get the word out.”
As a tribute to my father, I wanted to present a brief overview of new developments in the field.
Efficacy and Toxicity of Ketamine in the Management of Cancer Pain
In 2008, BMJ published a set of clinical practice guidelines on pain control in adults with cancer. They called for further research to investigate the role of ketamine as an adjuvant analgesic – a drug with a primary indication other than pain that might have analgesic properties in some conditions.
A recent Cochrane review evaluated the state of the literature on ketamine to alleviate cancer pain (Bell et al., 2012). Three new randomized controlled trials (RCTs) were identified since 2003, and all were excluded from further analysis. Among the older studies, the adverse effects of ketamine included hallucinations (as expected, since the drug is a dissociative anesthetic used at raves), drowsiness, nausea and vomiting, dry mouth, and confusion. The authors concluded that “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.” They also noted that clinical trials were ongoing, and that data by Hardy and colleagues were awaiting assessment.
Unfortunately, the outcome of the trial conducted by Hardy et al. (2012) was not positive. In this large RCT, 185 cancer patients with refractory chronic pain were randomized to receive either ketamine or placebo as an adjunct to their regular doses of opioids and other analgesics. Ketamine was administered subcutaneously in a dose-escalating regimen over 5 days. The response rate was 31% (29 of 93) in the treatment group compared to 27% (25 of 92) for placebo, which was not significantly different (p=.55). In addition, ketamine was associated with twice the number of adverse events relative to placebo. The authors concluded that ketamine did not have a net clinical benefit when used along with standard medications to treat cancer pain.
However, Jackson and colleagues (2013) objected to this “sweeping conclusion” in a letter to the Journal of Clinical Oncology titled “Ketamine and Cancer Pain: The Reports of My Death Have Been Greatly Exaggerated”. Their major arguments were that ketamine has been used in this fashion for the last decade, and previous open-label studies were more successful. They also suggested that Hardy et al. were too quick to call ketamine a treatment failure, and too late in administering drugs to counteract any hallucinogenic side effects.1
Hardy et al. (2013) replied to the first set of objections by stating the obvious about the value of RCTs: “Open-label studies do not meet the specific scientific definition of control.” They stood by their “sweeping conclusions” that ketamine was not beneficial in this population. On the other hand, I can see why clinicians would be desperate to help their patients. The 27% placebo response in Hardy's study is quite high. So if you're a patient in terrible pain and grape Kool-Aid improves your condition, why argue with that?
Ketamine for the Treatment of Depression and Anxiety in Hospice Patients
Speaking of open-label studies, a 2010 study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.2
A more recent open-label study by Irwin et al. (2013) enrolled 14 hospice patients with depression or depression + anxiety to receive oral ketamine for 28 days. Only 8 patients completed the study, but all showed a 30% or greater improvement in their depression or anxiety scores. Four withdrew from the study at day 14 because of no response to the drug, one dropped out earlier due to unrelated rapid decline, and one withdrew at day 21 because of a change in mental status (apparently unrelated to ketamine). “Few adverse events” were noted, the most common being diarrhea, trouble sleeping, and trouble sitting still (which to me sound problematic in an extremely ill population). It seems that dissociative symptoms, hallucinations, etc. were not evaluated. The authors again call for further studies using RCT designs to evaluate whether ketamine can improve the quality of the end-of-life experience.
Although they were not entirely successful, these studies have aimed to achieve an important goal of any civil, caring society: to provide a manner of death that minimizes fear, pain, and suffering.
The entire Pallimed Blog
"Do you have something stronger than this dilaudid?" The case for opioid rotation
Limbaugh/Palin "death panels" extend the lives of terminally ill patients
Ketamine for Depression: Yay or Neigh?
1 Jackson et al. reported using low doses of haloperidol (an antipsychotic) or midazolam (a benzodiazapine) prophylactically to prevent these adverse side effects.
2 I first wrote about this in 2010.
aan het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. (2012). Ketamine for depression:where do we go from here? Biol Psychiatry 72(7):537-47.
Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012 Nov 14;11:CD003351.
Duman RS, Aghajanian GK. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science 338(6103):68-72.
Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M, Spruyt O, Rowett D, & Currow DC (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 (29), 3611-7. PMID: 22965960
Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, & Lloyd LS (2013). Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial. Journal of palliative medicine, 16 (8), 958-65. PMID: 23805864
Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.
Fig. 2 Cormie et al. (2008). WHO analgesic “ladder”