Update on Nav1.7

PhysioProf commented about this back in 2006 after Alex Palazzo 's
post, href="http://scienceblogs.com/transcript/2006/12/silent_mutations_inactivates_p.php">A
silent mutation affects pain perception? That post discussed
mutations that affect pain perception.  Now, there is a bit
more information available about potential commercial developments
stemming from this line of genetic research.  

href="http://www.bloomberg.com/apps/news?pid=20601109&sid=aC2haw8NOHW0">Firewalker's
Faulty Gene May Shake Up Market for Painkillers

By Dermot Doherty

June 25 (Bloomberg)

A Pakistani boy who could walk on burning coals
propelled drugmakers on a quest for the ultimate pain treatment that
can ease an ailment as old as life itself without harmful side effects.

    

Geoffrey Woods, a geneticist at the University of Cambridge, was
studying families that had intermarried in northern Pakistan when he
heard about the boy, who felt no pangs as he performed stunts on the
street. Research on other children in the area uncovered a faulty gene
among them. They all were healthy and had a normal sense of touch...

    

...The sodium 1.7, or Nav1.7, channel is a protein found in nerve
cells. When a cell receives a stimulus, the tube-like channel opens and
sodium ions flow into it, activating the nerves. They send an
electrical signal to the spinal cord and the brain, which interprets it
as pain.

    

In people with the gene mutations found in the Pakistani children, the
sodium channel is incomplete, interrupting the chemical cascade that
leads to pain sensation.

    

Early research on the channel, first identified in the mid- 1990s, had
found gene mutations that heightened the sense of pain. Woods's work,
funded by Pfizer, the University of Cambridge and the London-based
Wellcome Trust, was the first to establish a link between loss of the
channel and an absence of distress...

It turns out that there are several types of sodium channels found in
neurons, but so far, it appears that Nav1.7 occurs primarily in the
periphery.  This is thought to be important, because it lowers
the risk of unintended or unwanted effects in the brain.



Naturally, several companies are rushing to find a way to exploit this
finding.  



The complete absence of pain in the periphery does have
consequences.  Many children with this condition end up with
serious injuries.  (Thinking about by own behavior as a
teenage boy, I probably would have ended up with all kinds of
fractures, and I wasn't particularly rambunctious.)



The article is from Bloomberg, a financial site.  So they
focus on the fact that a small pharmaceutical firm, Newron, has a new
chemical entity that is in clinical development.  

Research
& Drug Development Ralfinamide

    

Newron is developing ralfinamide, a unique New Chemical Entity that is
believed to mediate analgesic and anti-inflammatory effects through the
modulation of ion channels implicated in pain and the inhibition of
substance P.

    

Newron recently reported excellent results for its compound ralfinamide
in patients with Nerve Compression and Entrapment conditions, where
neuropathic low back pain (NLBP) represents the most common indication
and for which there are no approved drugs. Newron recently initiated a
Phase IIb/III study with Ralfinamide in patients with neuropathic low
back pain (NLBP).

title="ralfinamide"
src="http://apps.who.int/medicinedocs/index/assoc/s5407e/p103a.gif"
height="123" width="275">

 ralfinamide structure

Note that this drug has more than one mechanism of action.  In
addition to acting on the sodium channel, it blocks Substance P.
 I am extremely curious about this, because previously there
have been suggestions that Substance P antagonists might have
antidepressant effects.  I've heard that development in this
area, by at least one major pharmaceutical firm, have not panned out.
 Still, we are in a drought right now for new antidepressants
with novel mechanisms of action.  We know that antidepressants
often treat pain, so it would be interesting to see if a novel pain
drug could be used to treat depression.



So long as we are speculating, let's imagine what would happen if this
drug were to make it to market.  (Note that many drugs in
phase II or even phase III trials are never marketed.)  One
question would be: how quickly does it act?  Would we see
football players leave the field with an injury, dose up on
ralfinamide, and return to play?  Would endurance athletes
take ralfinamide to try to improve their performance?
 Would we see an increase in athletic injuries because of this
kind of thing?  Sure we would, until sports programs added it
to the list of compounds that are banned, and started to screen for it.
 



And what about drug abuse?  Would there be a black market for
an effective pain drug?  Sure.  But if it does not
produce euphoria, would this really be drug abuse, or something else?
 Would we see a huge drop in addiction to opioids?
 That is what we hope for.  If that turned out to be
the case, the societal cost of the other problems would be tiny in
comparison to the benefit.  



Of course, the new drug would be expensive.  That would put
insurance companies in the position of having to decide whether to
cover a new, nonaddictive, expensive drug, instead of a cheap, but
potentially addictive one.  What would they do?  If
it is any indication, I've seen companies that won't cover Strattera (a
nonstimulant drug for ADHD) but who do cover Adderall (an amphetamine,
also used for AHDH).