Five years ago, you were considered a snob if you insisted on bringing sodium channels into a discussion of pain. Now, everyone is acting as if they knew and know about sodium channels, no problem. It is even polite to mention calcium channels, now that the role of inflammation is being identified in a huge number of diseases. Each tiny new step in pain chemistry is resisted furiously and then suddenly accepted under an overwhelming weight of evidence.
Pardon us for finding a bit of irony in seeing everyone jump on the sodium ion bandwagon, but it was less than ten years ago when scientists, or at least clinicians couldn’t have cared less about that and brushed off our complaints of terrible pain in CP as a weakness, catastrophizing, or rooted in “secondary gain”. It was a ghastly experience going to a neurologist and trying to explain burning dysesthesia. The range of ineffective treatments they slung out is truly amazing and a tribute to medicine’s willingness to lay blame on the patient when it has nothing to offer.
We know pain is invisible but certain types of doctors could really be snots when their inability to treat was about to be exposed.** People who are nearly suicidal over agonizing pain do not need to have their hearts broken by arrogant doctors who care more for their image than about listening to the patient.
Of course, the angry ignorance of the PPP’s, the “pain patient persecutors” only made more dear the genuine and determined work of physicians like Bonica, Tasker, and Wall, who KNEW patients were telling the truth and who were determined to get to the bottom of nerve injury pain. Remember Osler’s admonition to medical students at Johns Hopkins, “If you listen carefully to patients, they will tell you what is wrong with them.” In the end, the patient is trustworthy if the doctor knows how to listen, even if the topic is pain.
When the early workers on sodium channels were trying to put forward the fact that HERE was the nexus of pain transmission, sodium channels were considered too passe for clinicians, and only the PhD’s bothered.
At painonline, we have long questioned whether the medicines claimed to “treat” central pain were treating pain at all. The descriptions coming in from the surveys and personal contact with patients all sounded like central pain patients were mostly being sedated, not analgesed. The opiates were no exception to this. Those claiming pain relief from morphine, when you pinned them down, seemed actually to be describing sedation. They were talking in terms of a general quieting of the central nervous system, not a specific targeting of the pain.
Those using anticonvulsants also fit into this category. And so we found ourselves out of step with clinicians who kept insisting that PAIN was being treated. We kept on repeating that neuropathic pain patients were primarily being sedated. Fortunately, the National Institutes of Health agreed with us, and so we survived becoming an annoyance to doctors who kept telling themselves they were treating pain. Many a friendship with clinicians had to be sacrificed when we refused to give way on this point.
Eventually, the PhD’s began to find ways to block the sodium channels, although they do not yet know how to deliver enough blockade to the brain of pain pathways without stopping the heart or other vital functions. Then, the work of Bryan Hains even pinpointed WHICH sodium channel was active in Central Pain, the Nav 1.3 which was a FETAL ion channel, not seen in adults. Additional work has now been done to show that Nav 1.7 may also be active in neuropathic pain.
In view of the above, it is not surprising that scientists have now found that SSRI* drugs (serotonin reuptake inhibitors) which are antidepressants, have a synergistic effect with anticonvulsants, which block sodium channels. It is all about general quieting of the system, and pain relief is a spinoff, not the primary action. Sedation is the fundamental issue, and we need better, more specific blockade to get the job done of stopping central pain. Pain IS depressing, but blocking the depression is NOT pain relief. For that we must also block the N type calcium channel and TRPV-1.
We may have to approach CP from the backside, by finding ways to increase natural pain inhibitors like GABA or glycine. Alternatively, it may be possible to stop ion channel activity and receptors in glia so they stop pouring out the BDNF which hyperexcites neurons. It is no longer possible to pretend expertise in pain without becoming well informed on sodium channels, calcium channels, and the TRPV-1 receptor.
Recently, Than et al, writing in Neurochem Int. 2007 Jan 13, it was shown that “Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission” may have a possible use in therapy for chronic pain. The reasoning was that when SSRI drugs (antidepressants) were added to anticonvulsants, the sodium channels were impaired. Considering that so many central pain patients take antidepressants, and so many take anticonvulsants (eg. neurontin), it is surprising that no one thought to look at this before now.
Since pain chemistry is now simply the science of ion channel behavior, it seems high time we devoted the necessary funds to follow this thing out. Fortunately, because of immunochemistry, it is not hard to study these things. The technique of patch clamping and proteomics column preparation is almost routine at institutions around the world, whereas only a few years ago, it was necessary to go to someplace like Yale to learn how to do it.
One thing is certain. The day will come when NO ONE will be claiming that central pain patients are seeking after secondary gain by alleging pain. It will be just the opposite. Central Pain patients will be used to SUPPORT the proposition that ion channels are very important and capable of producing unbearable levels of agonizing pain when the chemical cascade of exciters is all wrong. This will be little satisfaction, but for those who have been through the wars with all the “experts” at least it will give us some breathing space.
We pay tribute to people such as Patrick Wall, Carl Saab, William Willis, Bryan Hains, Tony Yaksh, Clifford Wolff, Jeffrey Coull, and others who have forced rationality into the discussion of pain. When the next generation of clinicians knows what these researchers already know, we hope for a little letup on the “pain is all in your mind” idea. Pain is in the ion channels, and in the genes which manufacture them so they can embed in the cell membrane of the neuron.
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*In this day and age, we have pretty much forgotten about neurotransmitters as we realized it was really the nature of the RECEPTORS which determined what any given neurotransmitter would do. The era of the receptor has proceeded into an era of ion channels which are the active area in channels. SSRI stands for selective serotonin reuptake inhibitor. Serotonin, the darling of psychologists during its trendy era of the prior two decades, (when no other neurotransmitter beside dopamine was really known) is 5 hydroxytryptamine. Its main source in the brain is from the raphe nuclei which are distributed in the brainstem along the reticular activating system. Classical neurotransmission proceeds by release of chemicals into the synapse by “boutons” but serotonin is relased from swellings, called “varicosities”. Serotonin diffuses over a relatively wide area into the synaptic gap and is then reprocessed by reuptake. If inhibition of reuptake is performed, then presumably serotonin activity will be higher because it stays in the synaptic gap, continuing to exert its action. Tricyclic antidepressants such as amitryptaline also inhibit serotonin reuptake. With the recent discovery that serotonin is a mitogen (induces cell division) there has been curiosity whether mitogen activated protein kinase, a known pain chemical, might link to serotonin activity. (Kicked off by ATP and BNDF, MAPK activity and ERK activity go hand in glove to make for perineural acidosis, neuroinflammation and pain).
Any terms which cause confusion in this article can be further understood by using SEARCH at this site, which discusses each of these topics in detail, except for SSRI drugs, which are described in literally thousands of sites on the internet, as well as in the preceding paragraph.
** We cannot pass mention of this ridiculous era in pain management without paying homage to the various myths used to shut the pain patient up. The favorite of doctors was the “painless soldier” myth, which by our calculation corresponded directly in its repetitions with the number of patient visits. Among men of the cloth, the “Pain is God’s Will” explanation was used with equal frequency and equal invalidity. (Once general anesthesia was invented God stopped willing that people suffer during surgery. Odd, isn’t it!) Pain CURE is God’s will. Make no mistake about it. And furthermore, once those soldiers got back to the hospital nearly ALL wanted morphine and lots of it. One source states that numerically, for every soldier in WWII, thousands of morphine ampules were ordered. SOMEONE was not painless, it would appear.
