Hitting the reset button

About a month ago I went to a talk given by a well known neuroscientist and pain clinician at my local Uni (actually, I helped host his visit, but who’s counting). During his talk he brought up the idea of using ketamine to treat pain. Ketamine, for those who don’t know, is an NMDA receptor antagonist. The idea of using ketamine for pain is not new. The approach he mentioned was.

It turns out that some European pain clinics (and maybe others) have been putting intractable pain patients in ketamine comas for up to 7 days to alleviate their pain. It turns out, that in most cases, this approach has been met with much, long lasting success. Keep in mind that patients undergoing this procedure are absolutely the worst of the worst. Severe pain all the time that is refractory to any current meds. Obviously this is a big time procedure. Patients must be monitored at all times and I’m sure there are many ways in which the procedure could go terribly wrong if not done properly. All of these potential problems tell you just how desperate many of these patients are.

There are several ideas of why this works. I will only present one of the possibilities for the sake of brevity. In many ways chronic pain is very much like memory. To establish memories the current consensus among neuroscientists is that there must be a form of persistent plasticity in the way that neurons connect to one another such that information can be stored. This is commonly called synaptic plasticity. NMDA receptors, the receptors that ketamine blocks, play a crucial role in establishing memories in many brain regions. In the case of chronic pain we now know that synaptic plasticity, in pain (and fear and stress) related brain regions, contributes strongly to ongoing pain and also to what we call hyperalgesia (an increased pain in response to a noxious stimulus) and allodynia (an innocuous stimulus becomes painful). The idea behind the ketamine coma for pain control is basically this: a long-term blockade of NMDA receptors allows for the synaptic plasticity that has been established in the chronic pain condition to return to normal — long-term ketamine hits the reset button.

Great so far; however, there is a giant gaping hole in the logic of what I just told you. If ketamine can hit the reset button on synaptic plasticity, why doesn’t it also wipe out your memories? This is slightly complicated and I think fairly theoretical but I’ll try to explain why this doesn’t happen. Memory is an interesting thing. Remembering something or an event can be very easy or it can be hard work. Whichever it is, it is likely that synaptic plasticity contributes to the information storage but we all know that we don’t have to constantly remember something to be able to recall it years or decades later. Why is this? I don’t think anyone knows this exactly, but, it is clear that storing a memory involves setting some molecular events into motion that create synaptic plasticity. Once the information is stored, some early retrieval events may further establish that memory but these don’t need to be continued over the long-term in most cases. In other words, memories can create synaptic plasticity that doesn’t require a persistent input to keep them in place.

So what about pain, or chronic pain? Here the story appears to be quite different. Almost all pain originates somewhere in your body. If the painful event is strong enough or chronic enough (like a nerve injury) it can create synaptic plasticity in the brain that leads to long-term pain amplification. In most cases, the pain amplification will eventually subside after the injury is gone (note that some injuries don’t readily go away — like nerve injuries). The molecular events that lead to the synaptic plasticity are at least superficially identical to those that occur with memory (we don’t know enough about this to reach any major conclusions at this point). On the other hand, when the injury goes away, the established plasticity appears to subside. In other words, maintaining synaptic plasticity in the pain pathway requires continuous input from the periphery (the site of injury) making this type of plasticity quite different from memory.

So what is happening in patients with the ketamine coma? The correct answer is that we don’t know, but allow me to speculate… We have known for some time that in certain conditions and in certain subgroups of patients, chronic pain does not subside when the injury is gone. It is also likely that some injuries just never heal the way that they should leaving some amount of background incoming pain information for the brain to amplify. My best guess is that the ketamine coma is of sufficient strength (full blockade of NMDA receptors) and duration to shut down this incoming pain information, or other circuitry that has become maladaptive, to allow for the plasticity to return to normal. Again, basically hitting the reset button.

So, is the ketamine coma a magic treatment for intractable pain. In a word: NO. We’re in early days and full trials have not been run. On the other hand, the treatment approach is highly innovative and it fits well with our current understanding of how plasticity contributes to chronic pain conditions. I, for one, am excited to see how this idea pans out.

One final note. I am writing about this today because I saw a wonderful special on PBS about depression last night. If you have the time check it out. During the program they talked about new trails with (you guessed it) ketamine as an antidepressant. While they are not using the coma approach, the idea behind the treatment strategy is similar. Hitting the reset button on the vicious circle that is depression and depression-related thought cycles.


15 responses to “Hitting the reset button

  1. I’ve been fascinated by the ketamine-for-depression thing ever since I saw the initial poster. Unlike SSRIs and other traditional antidepressants, the effect is apparently acute. I.e., after a single dose. This reminded me of the other treatment that works acutely for depression…ECT. Definitely one of the most obvious commonalities would be a similar “reset” type of thing.

    It makes a certain sense if you think of depression as being possibly stimulus driven- normal stimuli being linked to depressive affect circuitry (if you will permit). Or perhaps an abnormal strengthening of normally-depressing stimuli with putative negative affect circuitry. If depression was being maintained by constant activity, breaking those associations temporarily might have some therapeutic effect.

  2. Bikemonkey, I completely agree and I am also fascinated by the idea. I don’t remember seeing a poster on ketamine for depression, was it SFN? Perhaps this story is older than I realize…

    The case study presented in the PBS documentary was quite fascinating. Its about an hour in, if you have the time, I suggest taking a look.

    putative negative affect circuitry

    So can there be a reset button for this as well? I suppose the opioid activity of ketamine (the major part of the pain story I omitted) might make this a bad drug for that. Other possibilities would be fascinating…

  3. You think ketamine may tap into the brain’s perception/cognition of pain somehow? I’m connecting this talk from VS Ramachandran on TED about alleviating phantom limb pain using a mirror….kicks in at approx the 10 min mark in this clip…

  4. Well, ketamine is an excellent dissociative anesthetic (although not used so much in the US) so the short answer is yes. However, in the case of the ketamine coma, the patients are quite literally in a coma so there is no perception or cognition going on. I think the ketamine is in effect neutralizing an out of control pain amplification over the long-term by shutting it off for a period of time sufficient to achieve a reversal of the amplification.

    As for the phantom pain and mirrors stuff, it is truly amazing. I believe that the first work on this was done at US VAs and in Israel, all on soldiers that had had amputations. I have no explanation for how it works but it sure appears to be effective. Whatever works.

  5. Ketamine coma ever been done to a rat with a chronic neuropathic pain (SNL, etc) ? Doesn’t seem like a terribly hard experiment…

  6. No it hasn’t; however, it already works in lower doses. I suppose the question would be does it give a complete reversal that is long-lasting. Bust out the life support equipment if you wanna give it a shot.

  7. Very interesting idea. My question is what else do you forget after a week in a coma?

    It’s interesting you bring the topic up. Coincidently, I have been experimenting with my own therapy for chronic pain – perhaps it works similarly. You might call it pain therapy. Basically it involves inducing (unrelated) repetitive acute injuries to unlearn chronic pain. Bumps and bruises of moderate severity seem to work well. What I have noticed is that my awareness (and the associated secondary psychological impacts) of chronic pain disspiates when it is distracted by pain emanating from another location. Presumably because conscious awareness can only perceive one pain source at a time, and/or higher intensity acute pain trumps chronic pain when it comes to getting our attention?

    Anyway, for lots of reasons, acute pain is a lot easier to deal with and most importantly, much less of an interference with daily life than chronic back pain is. And who knows, perhaps long-term pain therapy can do something like you think these ketamines are doing to unlearn chronic pain.

  8. Bayman,

    My question is what else do you forget after a week in a coma?

    There are no reports of any major deficits/forgetting and I’m not sure they have the right group of patients to try to figure out if there are minor deficits. I wouldn’t be surprised if there were some but this is one of those treatments that weighs the pluses and minuses against the severity of the pre-existing condition.

    Bumps and bruises of moderate severity seem to work well

    You are likely experiencing something called Diffuse Noxious Inhibitory Control (DNIC). There is a rich literature on this going back decades. Most of the pharmacology of DNIC has focused on endogenous opioids. However, I wouldn’t be surprised at all if there was a strong role for NMDA-mediated effects (and there may be evidence for this in the lit).

  9. Interesting…Thanks for the keywords…

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  11. Hi there,

    I am one of the few people in line to undergo the ketamine coma treatment. I should be going under in the next month or two- all dependent on how long it will take to raise the finaces and resources for this costly procedure. My struggle with this disease began in July 2006 from a sports injury from overtraining that severely impacted the superficial peronial nerve. It is very interesting for me to read different peoples opinions, perceptions, and research of this disease- and this extreme treatment. Especially those that aren’t afflicted by it themselves. So much is still unknown about the disease and there is much speculation out there as well. Especially considering psychosomatic or psychogenic factors.

    What I can say for certain however, is that overnight I went from an active healthy 21 year old young woman full of life, on the go all the time, zero psychological issues- to suddenly paralized by the most intense excruciating and extreme pain I had ever felt in my life. I was a personal trainer, nutritionist, and fitness instructor with a full scholarship to law school and never imagined such pain even possible. I have had my fair share of sports injuries, but never anything like this.

    It is obvious something has clearly gone wrong in the brain and CNS in severe cases. One thing that I feel was a contributing factor to the spread in my case and other severe cases, is that the origional nerve injury was overlooked and wasn’t surgically corrected for over two years. Whatever the pathophysiology and mechanisms are, I’m sure complex- one thing I know is it is a very real disease and obvious “I” or my psyche doesn’t play any role in it. I am pretty sure my bone marrow swelling, my tissue swelling, chronic vascular disruption- and now later in the disease more prominent vasoconstriction, (earlier on it was vasodialation), but constantly color changing limbs, attacks of tachycardia and hypotension seemingly unprovoked, and all the other complications I have developed from RSD are completely triggered and regulated all on there own. Where its coming from, I don’t exactly know- but I do know I have tried EVERYTHING, literally- everything possible for chronic pain, including wholistic and alternative approaches, intense PT ect.

    If you are interested in the idea of the ketamine coma, the disease its used to treat, and wether it works or not- your welcome to check out my case and others and follow along with the research study for the ketamine coma I am participating in at:


    This is my last resort and I have seen this “reset” action work MIRACLES in the lives of others. There has to be something too it, and more to this disease then we now know. I only hope that somebody figures it out so we can find an easier and simpler “cure” or even preventative treatments for RSD. I was able to take pictures and video of my symptoms & disease progression over its development. Swelling, color changes, nail changes, muscle and bone changes ect. MRI’s also document the bone changes. Many of the pics are up on my website. But hopefully, in six months I’ll be able to post pics of normal limbs- and maybe even be able to post some aboutthe coma experience itself.

    From what I have been told by Dr.’s and by other patients and families- the “emergence” phenomena is a whole other experience and mystery in itself. And it does often time take patients some time after the coma and removal of ketamine to regain memory and full cognitive functioning. I guess when you “reset” the brain it takes some time for it to “come back online.” Some patients can remember there time in the coma and others cannot- but it also does seem that even those who do the majority of memories are from the time of ketamine emergence.

  12. Anonymoustache,

    I highly doubt ketamine “taps into the brains perception or cognition of pain” somehow. Since you are in a coma in this treatment, and sustained at minimal brain function- I highly doubt theres much “perception or cognition” at all. This treatment has only been shown to succesfully treat RSD/CRPS, the ketamine coma. Ketamine in much smaller smaller doses has been used as an anasthetic to treat other kind of chronic pain, and once a study was done on its effects on depression- but the amounts used is substantially different. RSD/CRPS and the pain it causes has been specifically linked to NMDA receptors and unique to RSD it the “wind-up” phenomena because of miscommunication and misfiring maintained in both the spinal cord and brain. The ketamine coma uses enough of the drug to entirely stop and block the misfiring connections long enough for the wind up phenomena to stop and correct itself, and for the nerves to “heal” themselves.

  13. RS, Thanks for sharing your case. Unfortunately, it is one us pain researchers here all too often. I hope the ketamine coma works for you and that you are able to get on with your life afterwards.

  14. RSD/CRPS and the pain it causes has been specifically linked to NMDA receptors and unique to RSD it the “wind-up” phenomena because of miscommunication and misfiring maintained in both the spinal cord and brain.

    While it is almost certainly the case that “wind-up” occurs in CRPS, it does also occur in other types of pain and can be elicited in pain-free individuals with injections of things like capsaicin. The problem in CRPS and other types of chronic pain is that the wind-up is present at all times, presumably, and is further enhanced during noxious stimulation than what would be observed in a person that did not have pain.

    This treatment has only been shown to succesfully treat RSD/CRPS, the ketamine coma.

    This is true, but as far as I know it has not been tried in other forms of long-term pain like neuropathic pain. It would be interesting to know if it also worked for these people who, like you, get little relief from available analgesics.

    I’m curious, did you ever take benzodiazepines? Did they help at all, or maybe make the pain worse?

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