Channel changes Mutations in a gene
called SCN9A can cause a number of pain disorders (right). this gene carries the instructions for
an elaborate protein called nav1.7 (above) that
lets sodium ions pass into a nerve cell. Boxes
show locations where SCN9A mutations linked
to different disorders alter the protein.
Nav1.7-linked pain syndrome Examples of symptoms
Small fiber neuropathy Hypersensitivity to stimuli; red, painful extremities
Inherited erythromelalgia Extremities become red, painful and swollen
Paroxysmal extreme pain disorder Stabbing pain in the rectum, genitalia, eyes, jaw and limbs
Congenital indifference to pain An absence of the sensation of pain
SourCES: S. DIB-HAJJ E T AL/ TRENDS IN NEUROSCIENCES 2007 AnD I. MErkIES/MAAStrICHt unIv. MEDICAl CEntEr
Pain, pain, go away
The efforts of nearly two decades of
research on Nav1.7 are now bearing fruit.
London-based Convergence Pharmaceuticals has developed a compound that
blocks the channel only when nerves are
firing like crazy. Normal pain thresholds, such as those experienced when
touching a hot stove, aren’t altered by
the Nav1.7 blocker, says Simon Tate,
Convergence’s chief scientific officer.
The company’s compound is now in
Phase II clinical testing — the stage that
looks at dosage and effectiveness — for a
painful condition of the lower back and
limbs called lumbosacral radiculopathy.
Convergence has also started a Phase II
trial testing the same Nav1.7 blocker as
a treatment for trigeminal neuralgia,
a chronic pain condition that entails
recurring brief episodes of intense, stabbing facial pain.
In January the Canadian company
Xenon Pharmaceuticals reported success
with an Nav1.7 blocker for treating erythromelalgia, often referred to as “man on
fire syndrome.” And Pfizer and its subsidiary Icagen are working with Waxman
and Yale colleague Sulayman Dib-Hajj
to investigate a blocker for treating the
Some conditions under investigation — lumbosacral radiculopathy
and trigeminal neuralgia, for example — aren’t caused by inherited mutations, but appear to result from nerve
damage. If an Nav1.7 blocker works in
such cases, the target may prove useful for treating long-term debilitating
pain more broadly. Good candidates
may include the 60 to 70 percent of
people with diabetes who have nervous
system damage that can cause daily
pain. People with traumatic injuries for
which the healing time is long, such as a
severe burn, may also benefit. Studies by
Waxman and colleagues have found that
mice without working Nav1.7 channels
don’t develop the hypersensitivity to
heat that typically follows a burn injury.
Beyond offering new tricks for treating pain when it strikes, studying the
channel may also help doctors understand their patients’ personal pain
profiles. Recent research led by Woods
found that some versions of SCN9A in
people without known pain disorders
can confer increased sensitivity to pain.
Such studies may help explain why one
solider who has been shot through the
arm experiences chronic post-trauma
pain, while another soldier with the
same wound might not. Or why some
amputees have phantom limb pain and
others don’t, says Waxman.
“It’s very exciting to us,” he says.
“If you go into a room full of people
who all look normal, 30 percent may
have a lower threshold for pain and an
increased likelihood of developing pain
after nerve injury.”
As scientists continue to investigate
the nuances of Nav1.7, some are turning
to its channel brethren as well. Nav1.8
and Nav1.9, also sodium channels, are
less understood than Nav1.7. But sci-
entists do know that these channels
also play a role in generating pain, and
therefore may be promising targets too,
says Michael Costigan, a specialist in
the genetics of chronic pain at Boston
Children’s Hospital. Changes in the
behavior of Nav1.8 have been implicated
in inflammatory pain, for instance.
s C.J. Woolf. “What is this thing called
pain?” The Journal of Clinical Investigation. november 2010.