Saturday, September 07, 2013

Update on Ketamine in Palliative Care Settings


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.


Further Reading

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?


Footnotes

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.


References

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”

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7 Comments:

At September 09, 2013 10:34 AM, Blogger Neuroskeptic said...

Good post.

Perhaps ketamine could be added to a next-generation Brompton Cocktail.

 
At September 09, 2013 11:12 AM, Blogger The Neurocritic said...

Thanks.

I did find a paper on use of the Kosish Cocktail in India. It's "a mixture of ketamine, midazolam, pentazocine lactate, and other adjuvants for use in the domiciliary set-up as intermittent subcutaneous injections in a morphine-naïve community."

 
At September 12, 2013 10:29 AM, Blogger Christian Sinclair said...

Thanks so much for linking to Pallimed. We appreciate the link love. Excellent post. I found it actually via Research Blogging's Twitter Feed. Will be looking here more often for palliative care content.

For many doctors, there is little experience in working with ketamine outside of ERs and ORs and maybe ICUs. The medication has been often given a special status where you may only prescribe it on certain floors or only if you have had hospital specific training in its use. Even in palliative care settings many HPM fellows do not get consistent exposure to situations where prescribing ketamine may be an option. It will be interesting to see if more research brings down some of these self-imposed cultural barriers to appropriate use of ketamine.

My condolences on your father. It is great that you can combine your advocacy and concern for him with the education of more people. One of the great special powers of blogs.

 
At September 12, 2013 1:36 PM, Blogger Bruce Scott said...

There is some evidence for use of ketamine in complex regional pain syndrome. http://www.ncbi.nlm.nih.gov/pubmed/19604642 I had an opportunity to use it in about 10 patients in a previous job. Pretty good results. My results in the couple of cancer pain patients was disappointing.

There is some (mostly anecdotal) evidence for use in sickle cell pain crisis as well. I haven't yet convinced my hospital to allow me to use it for this purpose in our particularly difficult cases.

Some docs are using it orally (compounded from the IV solution). My compounding costs were surprisingly high when I checked, so this wasn't an option the couple times I wanted to prescribe it.

My interest in use of ketamine for depression would mostly center on use in elderly patients (who didn't improve with more traditional antidepressants + cognitive therapy if available), yet couldn't get ECT because of lack of availability in my area. I've had a couple of candidates in mind, but once again my hospital will not permit it. (Despite the fact that ketamine is so -relatively- safe that it is on the WHO list of essential medications in 3rd world countries...for surgeries without a full operating theater. And despite the fact that I'm fellowship-trained and boarded, and experienced in use.) I've not yet been convinced that the evidence for maintenance oral use is strong enough to try to fight the battle at nursing home. I'd love to see more data.

 
At September 13, 2013 2:21 AM, Blogger The Neurocritic said...

Thanks for relaying your clinical experiences with different uses for ketamine (and for the kind words).

 
At October 20, 2013 12:15 PM, Anonymous Anonymous said...

If only 8 patients completed the Ketamine trial, it is insufficient to claim "but all showed at least 30% improvement in symptoms." How much is 30% in "hard data"?

For example, let's hypothetically place 8 patients in a depression trial, where the initial BDS (Beck Depression Scale) ranged from 1 (completely disabled by the illness) to 10 (in full remission and even describing oneself as "happy"), with 5 indicating partial remission (improvement in mood but without approaching "normalcy" and with no apparent improvement in functioning). All 8 patients began at 0 on the scale. A 30% improvement from 0 to 3 may be a slight improvement on paper but the patient as an individual has not improved substantially. Or let's say the only patients who reached a "7 to 8" level on the BDI were patients who had started at 4 to 5 at the beginning of the study. They were mildly depressed, and their depression improved to nearly a full remission. Terrific, right? But the same sample bias you attack Dr. Carl Hart for is exactly what you're doing here. Is it a good beginning for a pilot study? Can Ketamine and MDMA therapy ever be tested in a lab where "set and setting" were utterly discarded? I don't know. I do know that I take a MAOI+an amphetamine (for only the most extreme treatment-resistant patients), have endured ECT and found it kept me chained to being a "professional patient" even before it stopped helping, and I believe that it's time for innovative thinking. But let's ALL keep our biases in check.

[I watched my father die of metastatic liver cancer. It was so traumatic I went into complicated grief/post-traumatic shock for 2 and 1/2 years and am only now improving, more than 3 years later. I would have injected him with a mixture of diacetylmorphine (heroin) and diazepam (Valium) myself or strapped fentanyl patches all over his body because I know that despite the Dilaudid, fentanyl, morphine, oxycodone, lorazepam, etc. they gave him at the hospice to "keep him comfortable," even they said "he medically should be dead but he's refusing to let go." I gave him my permission at the very end, told him to fly away and be free. Maybe that's what he was so desperately waiting for. I will never know. I do know that even if Ketamine would have provided some placebo peace-of-mind (because it's very hard to experience a true blinded placebo response in a Ketamine clinical trial, I'd imagine) ... I'd tell them to do it. But it's not the media's fault for taking pilot studies and making them into definitive conclusions about medicine ... We do it, too. (Hey, have you heard Oreos are as addictive as cocaine?)

 
At October 20, 2013 12:24 PM, Blogger The Neurocritic said...

I'm very sorry about your father and your treatment-resistant status. But I'm not sure I understand your point, or why Dr. Carl Hart is relevant here.

 

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