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.

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