The Search for the Killer Painkiller

NY Times ^ | February 15, 2005 | ANDREW POLLACK

[neverdem]

Despite all the advances of modern medicine, the main drugs used to fight pain today are essentially the same as those used in ancient times.

Hippocrates wrote about the pain-soothing effects of willow bark and leaves as early as 400 B.C. Opium was cultivated long before that. Aspirin and morphine, based on the active ingredients in these traditional remedies, were isolated in the 1800's and helped form the foundation of the modern pharmaceutical industry.

But scientists are now trying to find new ways of fighting pain. The effort has been given new impetus by the recent withdrawal of Vioxx and the questions surrounding the safety of similar pills like Celebrex and Bextra. Those concerns come on top of the problems of abuse of narcotic painkillers like OxyContin. "There's a huge void, and no one is filling it," said Remi Barbier, chief executive of Pain Therapeutics, a company in South San Francisco, Calif.

But Dr. Barbier's company and dozens of others are trying. And some new treatments may come from things in nature that soothe or sting, like marijuana, hot chili peppers, nicotine and deadly toxins of snails and fish.

While the withdrawal of Vioxx leaves more room for newcomers, it also makes their challenge harder. Not only have opioids and aspirin been hard to beat, but the Food and Drug Administration is now expected to demand more evidence that drugs are safe before approving them.

But what scientists have going for them now is a more detailed, though still not complete, understanding of the molecular mechanisms by which pain is perceived. The goal is to create drugs that block specific parts of the mechanism while avoiding the side effects that have plagued opioids and anti-inflammatory drugs like aspirin.

Tens of millions of Americans suffer from chronic pain, according to various surveys, and millions more suffer acute pain from an illness or injury each year. Specialists say pain has received inadequate attention and treatment.

"Pain has historically been viewed as a symptom of other things that are more important," said Dr. Russell Portenoy, chairman of pain management and palliative care at Beth Israel Medical Center in New York. But now, he said, there is a growing realization that "chronic pain is itself an illness, and it's a complex illness."

Normal pain - from touching a hot stove, for example - is a beneficial warning system. After an injury nerves can become extra sensitive to pain. A warm shower can be painful on a sunburned back. That, too, is protective, said Dr. Clifford J. Woolf, a professor of anesthesia research at Harvard and Massachusetts General Hospital. The sensitivity forces a person to protect an injured area so it can heal.

But in some cases this nerve hypersensitivity continues well after the stimulus is gone, like an alarm frozen in the "on" position. The pain takes on a life of its own.

"Persistent pain is not just long-term acute pain," said Dr. Allan I. Basbaum, a professor of anatomy at the University of California, San Francisco and editor of the journal Pain. "The nervous system has changed."

Doctors classify pain into various categories, but there are two main types of persistent pain. One, sometimes called nociceptive pain, results from damage to tissues, as from arthritis or a burn. The other, called neuropathic pain, results from damage to the nerves themselves and is often set off by diseases like diabetes or shingles.

Opioids, like morphine or OxyContin, are used for more severe tissue-type pain. But the drugs have side effects, including constipation and a slowdown in breathing. Users can become tolerant, meaning that they need increasingly higher doses, or they become addicted to the drugs.

Aspirin and similar drugs like naproxen (sold under names like Aleve and Naprosyn) and ibuprofen (Advil and Motrin) are called nonsteroidal anti-inflammatory drugs or Nsaid's and are used for less serious pain. They block certain chemicals that contribute to inflammation, but they can also cause stomach ulcers and bleeding.

Vioxx, Celebrex and Bextra are newer types of Nsaid's called cox-2 inhibitors, which were intended to cause fewer gastrointestinal problems. But Vioxx was found to raise the risk of heart attacks and stroke, and there is concern the other cox-2 inhibitors may do so as well.

Nsaids don't work for neuropathic pain, specialists say, and there is disagreement on how effective opioids are. Doctors often use epilepsy drugs like Pfizer's Neurontin, which calm overexcited nerves that can cause seizures. Certain antidepressants are also used, most recently Eli Lilly's Cymbalta, which is also approved as a treatment for diabetic neuropathic pain.

Some efforts to develop better pain relievers focus on variations of the existing treatments.

For example, DOV Pharmaceutical, based in Hackensack, N.J., is in the final stages of testing a drug, bicifadine, for lower back pain. Like some antidepressants, it helps prolong the action of two brain chemicals, serotonin and norepinephrine.

Pain Therapeutics is in the final stages of testing a combination of an opioid with a small amount of a drug that counteracts the opioid's effect. The theory is that this will stop the buildup of tolerance, allowing opioids to be used more effectively.

NicOx, a French company, is testing a drug that breaks down in the body into naproxen and a chemical that releases nitric oxide. Nitric oxide plays many roles in the body, including dilating blood vessels and spurring mucus formation in the gastrointestinal tract. Some early trials suggest, though not definitively, that the drug may have lower gastrointestinal and cardiovascular risks than other Nsaid's.

But experts say there is also a need for totally new categories of pain relievers, ones that work in entirely different ways.

One such drug, called Prialt, was approved by the F.D.A. in December. It is a synthetic version of a toxin that a South Pacific marine snail uses to paralyze its prey. The drug impedes the transmission of pain signals through the nerves by blocking channels through which calcium ions flow into nerve cells.

"This is really the first new analgesic in two decades," said Lars Ekman, head of research and development at Elan, the Irish company that developed the drug. He said the drug was nonaddictive and 1,000 times as potent as morphine.

Potent, yes, but also problematic. To minimize side effects as diverse as heart rhythm disturbances and hallucinations, the drug must be injected directly into the fluid surrounding the spinal cord with a catheter and implanted pump. That will limit its use, as will the F.D.A. approval, which is only for severe pain that is not responsive to other analgesics.

Neuromed Technologies of Vancouver, British Columbia, says it has a calcium channel blocker that is safe enough to be taken orally. But the drug is only in the first stage of clinical trials, so there is no real proof yet that it is safe and effective.

Another approach is to block sodium channels. This is how local anesthetics like those given by dentists work. Wex Pharmaceuticals of Vancouver is testing tiny amounts of a toxin from the fugu, or puffer fish, a dangerous delicacy in Japan.

Chili peppers are less deadly, but their main ingredient, capsaicin, can cause intense pain when put in the mouth or rubbed on skin. Exposure desensitizes and temporarily damages the pain sensors.

Some over-the-counter pain ointments contain capsaicin. NeurogesX of San Carlos, Calif., is developing a patch containing highly concentrated capsaicin to be put on the skin for an hour in a doctor's office. A local anesthetic would be used to blunt the pain of the treatment itself. But after the patch is removed, pain in that area is diminished for weeks, the company's studies have shown. AlgoRx of Secaucus, N.J., is developing a capsaicin formulation that can be injected into joints or spread on surfaces exposed during surgery.

A different approach would be to block the sensors on nerve cells activated by capsaicin, called the TRPV1 or VR-1. That would theoretically provide pain relief without the initial pain. The drug giant Merck and tiny Neurogen of Branford, Conn., are working together on drugs to block this receptor, as are other companies like Amgen and GlaxoSmithKline.

Derivatives of marijuana are also being looked at. "Certainly with marijuana there's thousands of years of human experience that in addition to the psychoactive effects there are also medicinal effects," said Dr. James E. Shipley, senior vice president for clinical development and medical affairs at Indevus Pharmaceuticals in Lexington, Mass. "The problem heretofore is that you can't have one without the other."

Indevus is testing a drug based on a chemical, tetrahydrocannabinol-11-oic acid, that THC, the main ingredient in marijuana, turns into in the body. In healthy volunteers, Dr. Shipley said, the drug caused no psychoactive effects. But there has been only one small trial showing that the drug provided better pain relief than a placebo.

GW Pharmaceuticals, a British company, is further ahead. It says it is close to getting approval from Canada to sell a mouth spray derived from marijuana as a treatment for neuropathic pain in patients with multiple sclerosis. Nicotine, the poisonous substance in tobacco, also has soothing effects. Companies like Abbott Laboratories and Targacept, which was once part of cigarette maker R. J. Reynolds, are in early testing of drugs designed to bind to some of the same receptors in the body as nicotine but not be addictive.

Rinat Neuroscience of Palo Alto, Calif., and Genentech are working together on an antibody that blocks nerve growth factor, a protein made by the body that stimulates the growth of nerve cells.

Genentech initially tested the growth factor to see if it would reverse nerve damage from diabetes. But patients getting the drug experienced severe pain. It turns out that nerve growth factor has a second role: it is released after an injury and helps activate the pain pathway. So the companies figure that blocking it will stop pain.

Experts like Dr. Basbaum and Dr. Woolf, who consult for various pharmaceutical companies, say that controlling pain may require a combination of drugs hitting different mechanisms, just as cancer is treated with combinations. Ultimately, they say, the goal will be to tailor drug therapy to each patient based on the mechanisms underlying that person's pain.

New drugs are not expected to reach the market for a few years, and many may fail or have unacceptable side effects. Still, the void left by Vioxx has buoyed companies like NicOx, which two years ago faced a bleak future when a big drug company it was working with decided not to pursue its drug.

"You're standing on a rock surrounded by water," said Vaughn Kailian, a director of NicOx, "and just when you think you're going to vanish under the waves, the water recedes and you're standing on a mountain."

[neverdem]

Susan Farley for The New York Times

Joan Klopfer, 54 | Bronx, nurse
I used to be a nurse at Sloan-Kettering Cancer Center. In late 1997, I was lifting a heavy patient in the I.C.U. when I felt pain shooting down both my legs.

I knew right away I was in trouble. I had two herniated disks as a result and had to undergo spinal fusion. I woke up in the recovery room in the most excruciating pain you could imagine. It was worse than natural childbirth. They gave me morphine, which wasn't really enough.

I went home with a prescription for Percocet. It would offer me some relief for maybe an hour, then this awful pain would start again. Eventually, they put me on OxyContin, and I would take oxycodone as a "rescue dose" whenever I experienced terrible breakthrough pain.

Now, seven years later, I'm in constant pain, and this is as good as it's going to be. I'm permanently disabled. I probably will never work again.

My life is altered tremendously as a result of the pain.

Marty Katz for The New York Times
Farrell Fitch, 59 | Chevy Chase, Md., agency worker
I have nerve damage on the left side of my face, a result of shingles. At first, I thought I'd be fine and could get through it. But I couldn't. It feels like a branding iron pressed against my head.

What's discouraging is that you lose faith in the medicine. It takes the edge off the pain, but can never really take it away.

My doctor started me on hydrocodone and an antidepressant. After about two years, I wasn't getting any better so I tried other things. I tried acupuncture, massage therapy, even Chinese herbs. Eventually, I went to a pain specialist and one of the first things he had me do was to try methadone. It was a catastrophe. It just made me incredibly sick.

I got better when I combined Neurontin and Vicodin; something just clicked. Three years later, I had another crushing episode. I had to stop working and go on disability.

The pain is a large part of my life now. I struggle with it.

Frances Roberts for The New York Times

Steve Feldman, 52 | Manhattan, advertising
I was diagnosed with Lyme disease about seven years ago, and a side effect of it is arthritis. It's affected my hips, my hands and my fingers. The only time it bothers me is when the Lyme disease kicks in, which inflames everything.

When it first started, I asked my doctor what I could take besides aspirin or Motrin. All those things really have no effect on it at all.

We tried one of the arthritis medications, Vioxx, and the sides effects were awful. I suffered nausea and stomach pains and stopped taking it.

Then my doctor suggested some nutritional alternatives that had worked for some of his other patients. I said, "Sure, anything to get rid of the aches."

So I started taking glucosamine, fish oils and a product that's an oil made from macadamia nuts. I actually started feeling the aches going away after a couple weeks.

My doctor also said don't stagnate. In other words, walk. Use the joints. That helps me because it gets the muscles and the tendons around the joints used to working.

[neverdem]

FReepmail me if you want on or off my health and science ping list.

[zencat]

I'm with you. Have abnormal large congenital cysts in my C-T region and many more in the L region. Several of the cysts are over 1cm in the T region and cause unimaginable pain and numbness down my arms. Have a pretty good doc that cool with narcotics, but most people can't understand that it's just not "back pain". Duh! You've freaking cysts around the nerve root push on the nerve itself. It doesn't only hurt at times, just an indescribable feelings of numbness, pain. It's still not all about the narcotics, but does help the same way antibiotics help strep throat or pneumonia.

[John Valentine]

The authors failed to mention this one, perhaps the most promising of new therapies for neuropathic pain:

ACV1

Metabolic's novel compound ACV1, was discovered by Associate Professor Bruce Livett and fellow scientists associated with the University of Melbourne. ACV1 is a peptide compound discovered in the venom of the Australian marine cone snail, Conus Victoriae, which has been found to have profound analgesic properties. Owing to the success and advanced stage of efficacy testing already performed on the compound, Metabolic will accelerate the commencement of a pre-clinical toxicity program. Metabolic has acquired from the inventors the exclusive worldwide license to commercialise ACV1, in return for milestone and royalty payments.

Cone snails have evolved a rich cocktail of peptides in their venom, which together act by a variety of mechanisms in the nervous system to quickly immobilize or kill their prey. The potential of cone snail venoms as a source of new therapies has been recognised for many years, and the first such compound to be commercialised is the analgesic Ziconotide being developed by Elan Pharmaceuticals. Ziconotide acts by blocking a component of the central nervous system called the N-type calcium channel and must be injected into the spine (directly into the central nervous system) so as to avoid adverse reductions in blood pressure which would otherwise occur. ACV1 acts by an entirely novel mechanism, specifically blocking a subtype of a broad class of receptors in the peripheral nervous system called neuronal nicotinic acetylcholine receptors (nAChR). Unlike other cone snail venoms, ACV1 is effective and without apparent adverse effects when administered by convenient routes such as subcutaneous injection, providing substantial pain relief in models of nerve pain. Nerve (neuropathic) pain is the category of pain having the greatest need for improved drugs. An additional unique feature is that ACV1 also appears from the animal data to accelerate the functional recovery of injured nerves.

More here: http://www.metabolic.com.au/

[corkoman]

Very good article. The withdrawal of Vioxx and Celeb are forcing all new drugs to be compared with the opiodes. Other than the dependancy issue and constipation they are remarkably well-tolerated for chronic use over decades. Being compared to opiates is unfair - with their high safety profile any new drug is going to have to jump through hoops of fire to get approved.

Pain is nature's fire alarm but the Maker didnt give us a very good way to turn that alarm klaxon off.

[St.Mark]

Sciatica, pain down my right leg all the times. Some days are worse than others. Right now I am on Vicoden but my tolerance for the drug has gone up and so has the pain. It hurts so bad sometimes I cry and I am a 50 year old man that never cried a day in his adult life.

[xJones]

I took my cousin to a chronic pain care center. She has very bad daily migraine headaches and she'd done all the pain meds plus alternative meds, herbals, and acupuncture.

While I waited for her, I talked to the other people and everyone else was there for chronic back pain. I don't what they got, but my cousin had cortisone shots to both sides of her neck. It only eases things for about 3 months. Any migraine help would be appreciated.

[afnamvet]

Having just been released from the hospital for a partial bowel obstruction (Crohn's disease), I can attest to the effectiveness of morphine. 2-4mg every four hours for level 7-8 pain. I don't recall the alternative pain med name that was available.

[Goodgirlinred]

I just want my Viox back until they come up with something just as good to replace it. I had forgotten how bad the pain was until I had to go off of it and it got out of my system. Now I have to take OTC Ibuprophen in high doses and experience stomach upset. :(

[steve86]

Have your tried acupuncture? It stopped my mother's sciatica in its tracks, instantly, after several unproductive visits to conventional physicians. And my wife had the experience of sinus clearing while actually receiving the acupuncture.

I am 50 also and went through the crying thing in the 90s. Embarrassing when you know the neighbors can hear it. My pain left on its own -- so might yours.

[steve86]

Maybe some acupuncturists are better than others.

[John Valentine]

ACV1 is targeted at precisely your type of pain. See above.

Problem is, it's four years away from the market.

[unixfox]

Oh man how I feel your pain! I have sciatica as well and it has to be the worst pain you can get. My leg has gone so numb that I couldn't walk.

I cannot tolerate codeine or any derivative thereof. I have learned to actually pop my back to alleviate the pressure. The problem with painkillers is that they only trick your brain into thinking the pain is gone. When what they should really do is attack the affected area.

[Graybeard58]

Having just been released from the hospital for a partial bowel obstruction

My colon ruptured and the pain was intense. Two years after that surgery, scar tissue obstructed my bowels. THAT pain made the original pain seem like a picnic.

On vacation, lying on a couch in a motel lobby waiting for an ambulance to come through a snow storm. A cop got there before the ambulance and I layed there wondering if I could get his gun some how and end that pain.

I am 59 years old and that was the first and only time I had ever given a thought to suicide.

[St.Mark]

Bear Wash- I hope it does leave like what happened to you. The Doc's say surgery is my only option besides drugs. The success rate stinks with back surgery. I have to apologize for the whining it's hurting bad tonight and I know I won't be able to sleep. Enough said, thanks for listening and understanding, sometimes a man can feel so damn alone with a problem.

[St.Mark]

I wish there was a cure too Unixfox I REALLY do!

[afnamvet]

I am 59 years old and that was the first and only time I had ever given a thought to suicide.

I'm 57 and have had those thoughts countless times. March 15th is the surgery date for either bowel resection (will be my 6th surgery) or multiple stricture plasty. Quality of life isn't too promising but who knows until after this is over. Good health to you and yours.

Roger

[neverdem]

Triptan nonresponder studies: implications for clinical practice.

Birth contol pills can cause migraines. Good luck

[not_apathetic_anymore]

bookmark

[KingNo155]

Did she see a good dentist? I only ask because my brother suffered from migraines for years and Doctors and dentists could not find any reason. To cut it short... he went to a new dentist who found a hairline crack inside his tooth next to the nerve, the tooth was removed and now he no longer has migraines.