Reflex Sympathetic Dystrophy Syndrome
Complex Regional Pain Syndrome
New discoveries and treatments offer hope
Pain has an element of blank;
It cannot recollect
When it began or if there were
A time when it was not.
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
(MTC) 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 (PFE) impotence
Celebrex is only the first of a wave of novel analgesics before the FDA. A similar
Cox-2 treatment, Merck & Co.'s (MRK) Vioxx, is expected to win approval in May,
while Algos Pharmaceutical Corp. (ALGO) 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 (ABT) 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 (WLA) 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
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
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
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. (NSTA) 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 (GLX) 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. (LLY) 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
Pain has an element of blank;
It cannot recollect
When it began or if there were
A time when it was not.