Central Pain and Cobra Venom

It appears that not only the lowly sea snail (ziconotide) but also the cobra produces a venom which is a potent neurotoxin, but an analgesic as well.

Cobra toxin (CTX) includes two neurotoxins. Both act on acetyl choline (Ach), which has only lately been known to be part of a pain inhibitory system in the human. Ach is widely distributed in synapses, but is now known to power a specific and discrete pain inhibitory humans, which is NOT routed through the periaqueductal gray. (see prior article at this site).

The short chain neurotoxin in CTX has already been studied for its analgesic effect. Now the long chain post synaptic alpha neurotoxin has also been shown to have potent analgesic impact via the cholinergic pathways. Atropine opposes cholinergics and naloxone opposes opiates. By coadministering these two drugs, individually with the long chain alpha neurotoxin, it was determined that the analgesic effect was operating through central cholingergic pathways, and NOT via opioid receptors.

This study was done by Chen et al, reported in Acta Pharmacol Sin. 2006 Apr;27(4):402-8.

The pain model was in rodents (mice and rats) and was NOT a neuropathic model–ie. it was not nerve injury pain. Pain was induced by a hot plate or by injection of acetic acid. The long chain neurotoxin stopped writing from either noxious stimulus WITHOUT impairing the mobility of the animals. The venom was injected into the periaqueductal gray without analgesic effect.

At least two snails, one in the Philippines and one in Australia, as well as bee venom and cobra venom have now been shown to have analgesic effects. While the sting of the snails is blocks pain, a presumed benefitf or the slow snail who would otherwise be pursuing a frantic prey, a cobra bite is painful, so it is not clear why analgesics should be among the components of CTX. The studies on neurotoxins have mainly been in nociceptive pain models and NOT neuropathic pain models. We are awaiting results in nerve injury pain models. Prialt, or ziconotide, is approved for humans. It is manufactured in Ireland, but the cost is very high, in the thousands of dollars per dose. The venoms often seem to work in the cholinergic pathways, although ziconotide is said to work via the N type calcium channel.

We very much hope that technology can implant more genes which manufacture the analgesics into bacteria, (recombinant DNA technique) in order that large amounts can be produced at lesser price. Pain relief is worth whatever it costs, but insurers often view these medicines as experimental. The necessity of intrathecal (into the spinal fluid) injection is also a definite drawback. Implantation of the pump device is currently running in the tens of thousands of dollars. We are grateful to Medtronic and other companies whose research has produced implantable pumps, but we are hopeful the price can come down on the devices as well.

One of the related factors seems to be that in cord injury, reparative surgery may prevent the catheter from being advanced ABOVE the level of injury. Positioning head downward may possibly still allow the medicine to circulate above the level of injury but with less efficiency. Neurosurgeons are studying the use of titanium cages, filled with hydroxyapatite, a crystalline bone-like material, for replacement of a fractured vertebral body. (The bone fills in around it later) We are not aware that this increasingly popular method would impair later catheter placement should central pain develop, but worry about follow up with MRI. Dental implants using titanium still permit MRI but introduce artifact on the image.

Other appliances made with cobalt based metals seem to allow SWIFT imaging by the MRI machine, even up to 3.0 Tesla, which is much stronger than 1.5 Tesla magnets currently approved for use by the FDA.

Central Pain does not come first in the consideration of repair devices, but certainly the possible need for a catheter intrathecally should be kept in mind in deciding whether to use titanium, cobalt, or other metals. Some mixed reports claim these cages take better than bone graft from the hip, but other studies show just the opposite. It is quite possibly true that final results depend more on other factors, such as surgical skill.

The use of steel braces with steel screws on the spine certainly concerns us in view of the expanded use of MRI, including tensor MRI to evaluate the patients over many years. Symptoms of Central Pain not uncommonly change, as do other symptoms relating to the spine, necessitating repeat MRI over the years.

We hope the neurosurgeons are cognizant of the plight of the central pain patient as they make their determinations of which applicances or devices offer the best hope for immediate healing as well as long term follow up. The metal hemostatic clips commonly used in doing spinal surgery appear not to interfere with MRI imaging, but here also, it may be worth the time to use a suture simply because we do not know how the tantalum clips will behave when the new 3.0 Tesla or even 5.0 Tesla machines are put into use. The 5.0 Tesla machine will pull a tethered wrench horizontally which is across the room. Even metals which are relatively non-magnetic may become a problem.

Central pain patients on tricyclics are famous for having the worst teeth in the world. This is because anticonvulsants such as elavil (often preferred for its low cost and relative effectiveness) cause dry mouth, and saliva is important in preventing tooth decay. Elavil also weakens the muscles of near vision (accomodation) and so the subject may be unable to see well when brushing the teeth. This will eventually become more relevant not only to spine surgery, but to dentistry as well, where gold, titanium and other metals may be too strongly attracted by a 5.0 Tesla magnet. The old dental amalgam, which has a lead base seems to to produce the least MRI interference, but lead is toxic and on cosmetic principles, other composites are increasingly used. For those using a posterior approach to the cord, some of the newer devices which expand the lamina and create more cord space, are fastened with metal parts. Bioabsorbable screws exist, but do not represent the majority of those used.

Medicine advances, but not uniformly. It may be that for now, we will have to come to grips with anticholingergic medicines injected intrathecally, but we hope for something that can be injected in the muscles or taken orally.