Posted by Nancy on February 21, 1999 at 10:24:36:
I hope this isn't too long for here but it is real interesting on what they are learning about pain and new types of pain med that will be coming out!!!
..........................................
It's not just that the narcotics most commonly
prescribed have a number of worrisome side effects. They don't even work
for the millions who suffer from neuropathic pain arising from damage to
the nerves, caused by disease, trauma, or chemotherapy. A breeze across
the
skin can be excruciating, and there is no pharmaceutical recourse.
Most frightening, perhaps, is that for all pain victims, the longer
they
suffer, the more intractable the problem becomes. Continuing pain
eventually rewires the nervous system until it becomes even more
sensitive
to pain--and even harder to treat.
Here's the article in its entirety: March 1, 1999 edition Business Week
pgs 103-110
----------------------------------------------
Conquering Pain -- New discoveries and treatments offer hope
File: Conquering Pain -- New discoveries and treatments offer hope ---
BW
article Mar 1, 1999.txt
Pain has an element of blank;
It cannot recollect
When it began or if there were
A time when it was not.
Emily Dickinson
Laura A. McManus is just one of the 50 million Americans who are partly
or
totally disabled by chronic pain. The 27-year-old from Mount Sinai,
N.Y.,
has a congenital spine dysfunction that became debilitating when she
pulled
her back out at age 14. Her agony has persisted through seven spinal
operations and a steady stream of ever more powerful drugs. ''I've been
on
everything: Darvoset, Percocet, Vicodin, morphine in the pump, Dilaudid
in
the pump,'' she says. All of these narcotics eventually stopped working,
and by 24 she had upped the dosage to the point where she was so drugged
she could barely function. ''I was borderline suicidal,'' she says.
Such misery is the leitmotiv of chronic-pain sufferers. The 20th century
has brought amazing breakthroughs in almost every area of medicine save
the
one that affects everyone--pain. In the 100-plus years since Dickinson
penned her sad poem, there have been only two dismal options. Patients
could take aspirin and aspirin-like non-steroidal anti-inflammatory
drugs
(NSAIDS) such as ibuprofen and Naproxen for mild-to-moderate pain or
narcotics such as morphine and codeine for severe pain. Neither approach
works for everyone or for every pain condition. Even when they do,
nsaids
and narcotics can have serious, even life-threatening, side effects
ranging
from stomach ulcers to addiction.
At last, though, chronic-pain relief is becoming more than an oxymoron.
After two decades of grueling research into the complex cellular
processes
that trigger pain, the first drugs custom-designed to block specific
pain
mechanisms are emerging from the labs. These new agents promise to
revolutionize the treatment of pain by allowing doctors to relieve the
suffering, regardless of the underlying cause. Best of all, the new
drugs
promise minimal side effects.
Such breakthroughs should translate into one of the largest drug markets
of
the next decade (page 110). ''Let's face it: The first company that
comes
up with a drug for chronic pain will take off like a rocket,'' says Dr.
Mitchell Max, coordinator of pain research at the National Institutes of
Health. Even with the suboptimal painkillers available today, the world
market for analgesics is about $7.7 billion and growing 7% a year,
estimates Credit Suisse First Boston Corp. The firm figures that drugs
coming on the market this year and next should add $1.5 billion to that
total by 2001.
Americans alone spend some $3 billion a year on over-the-counter
analgesics, and a further $750 million is doled out for narcotics
prescribed for pain. The buyers include 20 million arthritis sufferers,
40
million victims of chronic recurrent headaches, 8 million Americans
living
with cancer, and the 15% of adults with persistent back pain.
Their need could not be more dire. For most sufferers of chronic
pain--defined as persistent pain that lasts more than three months--a
life
free of agony is elusive. It's not just that the narcotics most commonly
prescribed have a number of worrisome side effects. They don't even work
for the millions who suffer from neuropathic pain arising from damage to
the nerves, caused by disease, trauma, or chemotherapy. A breeze across
the
skin can be excruciating, and there is no pharmaceutical recourse.
Most frightening, perhaps, is that for all pain victims, the longer they
suffer, the more intractable the problem becomes. Continuing pain
eventually rewires the nervous system until it becomes even more
sensitive
to pain--and even harder to treat.
Bottom line: The American Pain Society estimates that 45% of the
population
seeks medical help for persistent pain at some point in their lives.
Medical economists estimate that pain costs the U.S. some $100 billion
every year, including 515 million workdays lost and 40 million doctor
visits.
MORE FUNDING. The sufferers are beginning to be heard. In January, the
Veterans Affairs Dept. announced a new effort to reduce pain for its 3.4
million patients, instructing VA doctors and nurses to assess and record
a
patient's pain just as they would note blood pressure, pulse, and
temperature. And last year, Congress voted to allocate $102 million to
the
NIH for pain research in 1999, a 15% jump from 1998--and $3 million more
than the White House requested.
Unfortunately, science has long lagged behind demand. The last new class
of
general analgesics to hit the market were NSAIDs almost 30 years ago.
But
in December, the logjam broke when the Food & Drug Administration
approved
Monsanto Co.'s Celebrex, likely to be the first blockbuster drug for
pain.
It is the first of a class of arthritis drugs, known as Cox-2
inhibitors,
that precisely target a key pain-triggering enzyme found around inflamed
joints. The drug is no more effective at relieving pain than the
commonly
prescribed NSAIDs, but it's less likely to cause the stomach bleeding
and
ulcers experienced by about 30% of patients on the older treatments.
That
clearly counts for a lot: Celebrex was introduced in the U.S. on Jan. 19
with no consumer advertising, and a week later it had racked up almost
10,000 prescriptions, making its launch second only to that of Viagra,
Pfizer Inc.'s impotence treatment.
Celebrex is only the first of a wave of novel analgesics before the FDA.
A
similar Cox-2 treatment, Merck & Co.'s Vioxx, is expected to win
approval
in May, while Algos Pharmaceutical Corp. in Neptune, N.J., is waiting
for
action on its application, filed last August, for MorphiDex, which
increases the effectiveness of morphine without increasing side effects.
In November, the FDA approved a novel rheumatoid arthritis drug, Enbrel,
from Immunex Corp., that boosts the body's ability to stop painful
inflammation. Enbrel is also the first drug to be tested for children
with
juvenile rheumatoid arthritis and represents ''a dramatic advancement in
treatment,'' says Dr. Daniel J. Lovell of Children's Hospital Medical
Center in Cleveland. Colleen Cotter, 7, of Madison, Wis., has been
transformed by the drug from a quiet to a bubbly child. ''She's doing so
much better now,'' says her mother, Mary.
For something completely different, there's Ziconotide, the savior of
Laura
McManus. Made by Neurex Corp. in Menlo Park, Calif., the treatment is a
synthetic analog of a chemical found in the paralyzing venom of Conus
sea
snails. Ziconotide is able to home in on receptors found only on the
pain-sensing nerve cells that connect to the spinal cord, blocking their
message from going any further.
Because the drug's target is so specific, side effects are minimal.
McManus' doctor enrolled her in a clinical trial in January, 1998. ''One
month after being on Ziconotide, it was 'Wow, I was happy,''' she says.
In
the following months, she started physical therapy, began walking, lost
the
70 pounds she gained while the pain was at its worst, returned to
college,
and danced at a wedding. ''Now,'' she says, ''I can think. I can express
my
feelings. I can have children, finish school. I can have a life.''
For pain researchers, McManus' testimonial is proof of principle--the
more
tailored the drug, the more effective. Scientists have spent the past
two
decades ferreting out the cellular receptors, channels, and chemicals
involved in different types of pain and designing drugs to block them.
''For the first time, we can dissect the pain mechanisms of different
diseases,'' says Patrick W. Mantyh, director of molecular neurobiology
at
the Veterans Administration Medical Center in Minneapolis. ''And instead
of
using a general drug for all pain, [we can] come up with one specific to
symptoms.''
NEW PATHS. A number of specific treatments are already in clinical
trials.
Abbott Laboratories is testing ABT-594, based on a toxin found in the
skin
of frogs. The drug, for severe chronic pain, aims at the same cellular
mechanism that is receptive to nicotine --which smokers know can calm
nerves. Although still in early human trials, ABT-594 has proved in lab
animals to be 50 times as effective as morphine. In a more radical
approach, CytoTherapeutics of Lincoln, R.I., is in human trials with cow
adrenal cells that are implanted at the base of the spine. There, they
continuously secrete natural painkilling substances, bolstering the
body's
own defenses.
There are several clinical trials aimed at treating neuropathic diseases
of
the nervous system for which there are currently no approved treatments,
such as shingles, phantom limb pain, and the searing pain in the
extremities that affects diabetics. Myelos Neurosciences Corp. in San
Diego
is in the second phase of testing Prosaptide TX14(a), a drug that
regenerates the damaged nerves that cause the neuropathy. And there is
increasing interest in Warner-Lambert Co.'s epilepsy drug, Neurontin,
introduced five years ago, because the nerve centers that control
seizures
and those that control pain are closely linked. Two new studies report
that
Neurontin is highly effective in the treatment of diabetic neuropathy
and
shingles.
Along with new treatments, a new way of thinking about pain is emerging.
Researchers think pain should be treated as a disease in itself,
divorced
to a large degree from the underlying cause, such as cancer or a
sprained
back. Instead, pain would be classified by the cellular mechanisms that
cause the hurt, which may be the same for different diseases--or
different
for the same disease. Once a pain mechanism is identified, doctors could
hunt through an arsenal of highly targeted drugs for just the right
treatment.
Or perhaps the body could be persuaded to stop its own hurt. One of the
great mysteries of pain is the placebo effect: In almost every pain
study,
about 35% of patients on placebo feel relief. ''Even when patients just
think they're getting treatment, there is automatically some internal
release of endorphins,'' says Dr. John T. Farrar, a neurologist at the
University of Pennsylvania Medical Center. ''We have to find some way to
harness that ability of the mind to control pain.''
The remarkable progress in pain treatments can be traced to two
important
research advances in the early 1990s. Advanced imaging technologies gave
scientists the ability to observe the way pain signals travel through
the
nervous system, while biologists developed genetically altered animal
models that experience pain in the same way humans do, enabling
researchers
to test new compounds. Suddenly, a field that had been a scientific
backwater became hot. ''In the past couple of years, there has been an
exponential increase in people's interest in pain,'' says John C.
Hunter,
head of analgesic research at Roche BioScience in Palo Alto, Calif.
UNPREDICTABLE. That enthusiasm should speed progress, but science is
still
a long way from ''curing'' pain. Pain is one of the body's most complex
biological functions, and it's hardly uniform. The pain response varies
by
gender, race, and age, making it hard to predict from one person to the
next. ''The nervous system is extremely plastic,'' explains Dr. Russell
K.
Portenoy, chairman of pain medicine at Beth Israel Medical Center in New
York. ''Once an injury occurs, the pain signals can go in any number of
directions.''
Even more problematic, pain is completely subjective--each person's
physical and emotional tolerance level is different. ''That's the great
unknown in the study of pain,'' says Dr. Richard Payne, chief of the
Pain
Care Service at Memorial Sloan-Kettering Cancer Center in New York.
''How
do you account for the individual variation in perception?''
Most doctors don't try. Physicians have always considered pain a
byproduct
of injury or disease: Treat the underlying condition, and you stop the
pain. Consequently, pain itself is undertreated, and pain management is
not
taught at most medical schools. This lack of understanding has been
almost
medieval: As recently as the early 1980s, for example, it was assumed
that
infants could not feel or remember pain, and surgeons routinely operated
on
babies without anesthesia. ''Now we know that traumatic events in
infancy
can have long-term consequences, but that knowledge has only developed
in
the last 20 to 25 years,'' says Dr. Charles Berde, director of the pain
treatment center at Children's Hospital in Boston.
The modern age of pain research started in the mid-1960s, thanks to a
breakthrough by Ronald Melzack of Canada and Patrick D. Wall of Britain.
They discovered that the pain sensation does not travel directly through
the spinal cord to the brain, as had always been assumed, but is
ratcheted
up or down by a series of chemical gates in the spinal cord. Control the
gates, they figured, and you could control the pain.
Pain starts when specific nerve fibers known as nociceptors, found
throughout the body, sense a disturbance in nearby tissue. Once alerted,
they release a chemical soup of pain messengers called
neurotransmitters,
among them potassium, prostaglandin, and substance P. If the pain is
sharp
and searing, these messengers rush to the spinal cord through superfast
nerve conduits. Dull aches and throbbing travel along slower pathways.
The
chemicals collect in a part of the spinal cord called the dorsal horn
until
a ''gate'' opens, releasing them to the brain.
Pain isn't actually ''felt'' until the message hits the brain. The brain
also prods into action the body's autonomic nervous system, which
adjusts
breathing, blood flow, pulse, and digestion, and the limbic system,
which
controls emotions. In the 1970s, researchers made an important
discovery:
The pain gates can be closed by chemicals that the brain sends back down
the spinal cord. These pain-suppressing transmitters include adrenalin,
serotonin, and most important, the endorphins, peptides similar to
opium.
Because receptors for these so-called endogenous opiates can be found
throughout the nervous system, opium-based drugs such as morphine,
codeine,
and methadone are the most powerful painkillers.
But this gold standard carries a high price. Opiates can cause
constipation, nausea, drowsiness, and slow breathing. In high enough
doses,
they can lead to addiction, though this is rare in pain treatment. To
get
around the side effects, Warner-Lambert and Pfizer, among others, are
developing compounds that target specific opiate receptors coded only to
stop pain.
BOOSTER. Meanwhile, drug companies are coming up with ways to minimize
side
effects by delivering narcotics directly to the site of the pain. Anesta
Corp. in Salt Lake City is one of the first to bring this concept to
market. In November, it won FDA approval for Actiq, a crystallized form
of
fentanyl that is the first treatment for the intense flare-ups of cancer
pain that break through a patient's standard pain treatments. Patients
place the lozenge against the inside of their cheek, where it is
absorbed
quickly into the bloodstream, avoiding the gut. ''It starts to work
almost
immediately,'' says William A. Ball of Harrisburg, Pa., who has bone
cancer. The 74-year-old says he was immobilized by breakthrough pain
before
he started using Actiq. ''Now, I'm able to get out of bed easier, able
to
stand up easier. I even played a round of golf.''
Then there's an effort to trick the opiate receptors with
dextromethorphan
(DM), a common cough syrup. DM blocks a nerve receptor called NMDA from
releasing secondary pain signals that prevent opiates from working.
Algos
combined DM with morphine to create MorphiDex, a drug that doubles the
effectiveness of the narcotic without increasing the side
effects--allowing
patients to take half their usual dosage.
The most cutting-edge pain research avoids opiates altogether.
Scientists
are looking for compounds that stop pain signals before the brain gets
the
message, either by blocking the signal in the spinal cord or by keeping
it
out of the spine in the first place. Almost monthly, scientists discover
potential new targets, but the bull's eyes they'd most like to hit are
the
neurotransmitters released at the site of the hurt.
One of the most studied is substance P, a powerful chemical whose
receptors
are found on 45% of the cells that respond to pain stimuli. But
substance P
also plays a role in depression, anxiety, and nausea, making it
devilishly
hard to tackle without disrupting other systems. Several compounds have
already been abandoned because of their side effects.
Even so, evidence is emerging that substance P agents can stop pain. In
a
recently published study, an experimental Pfizer drug proved effective
at
easing pain caused by tooth extractions. Researcher Mantyh is
experimenting
in animals with a more subtle approach, using the substance P molecule
as a
Trojan horse. He couples it with a painkiller that it delivers to the
spinal cord. ''I'm basically using [substance P] as a generic platform
to
get something into the cell, be it a toxin or a gene or some other
agent,''
he says.
Each new discovery creates more buzz among researchers. ''There
continues
to be so much excitement about drugs that are receptor-targeted,'' says
Dr.
Michael Moskowitz, a neurology professor at Harvard University Medical
School. One drug can quickly lead to better treatments, he notes--as
evidenced by the rapid succession of migraine medications.
TRIPLE PLAY. For some 50 years, the best treatment for the 25 million
Americans who suffer from migraines was ergotamine, which worked only
some
of the time and could cause nausea. Then, in 1991, Glaxo Wellcome PLC
introduced Imitrex, a fast-acting, well-tolerated drug that targets one
of
15 cellular receptors for serotonin, a brain chemical that moderates
mood
and appetite as well as migraines. Two more drugs have since been
approved,
Zeneca's Zomig and Merck's Maxalt, that target the same receptor, and a
third from Pfizer is in the wings. But all of them can raise blood
pressure, so Eli Lilly & Co. is in clinical trials with a drug that
tries
to avoid this side effect by targeting a different serotonin receptor.
Three generations of drug in one decade bodes well for pain sufferers.
If
such progress continues, in the 21st century, Emily Dickinson's words
may
finally no longer ring true: There will be a time when pain is not.
By Catherine Arnst, with Ellen Licking, in New York and Amy Barrett in
Philadelphia
Copyright 1999, by The McGraw-Hill Companies Inc. All rights reserved.