Donezepil is a cholinesterase inhibitor of the M2 variety.
Central pain can be divided into three types, spontaneous burning, intermittent (usually lancinating) and evoked (usually more intense burning). When burning is intermitten, it may probably represent less severe central pain, which only becomes a problem when evocation brings it out. Such individuals avoid feeling spontaneous or constant ongoing burning for unknown reasons. Such pain is not normally termed intermittent CP, although in fact it is. Rather it is often termed evoked dysesthesia.
Muscle pains can be quite elaborated and variable, but can be identified as neuropathic when there is burning or when such pain occurs with activity which should not result in painful muscles. Simply laying on a mattress can feel like being on a bed of rocks when muscle pain is part of the CP. It is not easy to know if your muscle pain is due to nerve injury unless it has the burning quality which typifies the skin.
Visceral central pain nearly always feels like the pain overdistention would cause, whether it is in the bladder, gut, or rectum.
These pains may also be classed as to whether they travel upward in the anterior cord (very difficult to treat) or posterior cord (usually treatable). Visceral central pain is thought to travel in the posterior cord. The more untreatable your pain is, the more likely it is to travel in the spinothalamic tracts of the anterior cord.
It is presumed, but not known, that strokes and other injuries in and around the thalamus can also be similarly subdivided based on the tracts passing through, but this is a presumption only. Some radiologists feel that stroke NEAR the thalamus is more likely to cause CP than stroke in the actual thalamus. The thalamus may not activate on PET scans in central pain because it merely passes such signal on through as it would any other signal. The insular cortex nearly always lights up in CP on PET scans.
Stroke pain is nearly always unilateral, while SCI pain is usually bilateral. There are many mechanical pains associated with SCI. Disuse, atrophy, and changes in musculoskeletal padding or cartilage can cause nerves to generate pain. Only dysfunction in the chemical transmission of pain in the injured nerve can generate nerve injury pain.
All of the neuropathic pains of SCI feel “bizarre”, or different in quality from normal mechanical pain. They are not really describable, although they may be compared to nociceptive (normal) pain. If you had ever, or could have ever felt a given precise pain BEFORE your injury, it is probably not neuropathic. Neuropathic pain has a “bizarre” or indescribable quality. That a pain gets better with anticonvulsants is NOT a guarantee that it is neuropathic, since even normal pains may decrease if there is general quieting of the central nervous. The QUALITY of the pain is the most reliable indicator of nerve injury.
Patients in pain are not inclined to become philosophically interested in the precise nature of their pain and this confusion of mechanical and nerve injury pains is reflected in the pain literature. Patients are so poor at describing pain quality, it was not even known that there were TWO types of pain until the 1950′s, when Ron Tasker first noted it.
People had experienced pain and consulted therapists for thousands of years, but physicians had never picked up on the difference because there is no vocabulary for the central pains. Now that scientists know where to look for it, skilled examiners can usually readily diagnose central pain from the history. Any unusual burning pain, “like acid under the skin” following injury to the central nervous system, is almost certain to be central pain. The massive workup which typically follows the suspicion of CP usually does not add anything to the diagnosis. The history alone is paramount.
Anesthesiologists are finally beginning to join the hunt for cures for nerve injury pain. Perhaps this is due to the marked increase in participation in pain clinics by anesthesiologists.
At painonline, we recently reviewed acetyl choline, done so because ACV1, by Metabolic Pharmaceuticals is likely to hit the market before long. This drug is one of the nicotinic AChR drugs. (see using SEARCH). You may recall that when a nerve fires the nicotinic receptors are responsible for the initial depolarization (rapid excitatory post synaptic potential EPSP) while the Muscarinic 2 receptor is responsible for the following hyperpolarization (which makes it more difficult to fire again).
Then, Muscarinic 1 receptors, which actually are predominant in the nervous system, are responsible for the slow excitatory postsynaptic potential (EPSP) which follows. Considering the play nicotinic receptor agonists (mimics) have gotten lately, it is surprising, even to us, that now the muscarinic Acetyl Choline drugs are being suggested for pain relief. This is true because 1) M2 blockers are mostly new in concept 2) the muscarinic receptors being exploited are the type 2 which have traditionally been assoicated with the heart, not the nervous system.
So far, ACh is considered to subserve part of an inhibitory wing of the pain system, but suprisingly little is known publicly about ACh and pain, because it is one area drug companies conceal in their patent applications.
Cholinesterase breaks down acetyl choline (ACh) so it can be reabsorbed, reconstituted and recycled at the synaptic ends of the neurons. Other synaptic transmitters may act similarly. For example, in the past, serotonin reuptake inhibitors have been used for depression. ACh is a neurotransmitter and you can read the physiologic review of nicotinic vs. muscarinic actions of ACh in the earlier review at this site.
The idea of a muscarinic cholinesterase inhibitor for pain had been knocked around before, but the gastrointestinal side effects of such compounds was so great that no further work was done. By targeting ONLY the M2 receptors, the GI tract tolerates the drugs much better. The M2 receptor can be selectively attacked in such a way as to avoid GI side effects, it now appears.
The new drug, donezepil, has been shown to be effective against an animal model of PERIPHERAL nerve injury pain. Clayton, et al writing in Anesthesiology. 2007 May;106(5):1019-1025 have shown that ORAL donezepil reduces hypersensitization after nerve injury via a Muscarinic 2 inhibition of cholinesterase.
Another interesting thing is that this M2 cholinesterase inhibitor acts at the SPINAL level, not in the brain. This makes us suspect its use for CP, if any, would be for evoked pain, which involves some stimulus being applied peripherally. Evoked pain is much more severe than spontaneous pain.
Anesthesiologists spend a lot of time worrying about cholinesterase because some people hereditarily cannot degrade anesthetics and occasionally die in recovery room because cholinesterase abnormalities prevent the anesthetic from wearing off.
And so, they are quite trustworthy as observers of drugs in that area. Donzepil may be helpful. We hope this work continues.