[fmichael]

Jim Broatch of the RSDSA just forwarded a press release, dated October 3, 2007, in which this work was referred to as meeting "The Holy Grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, coordination, or other vital functions of the nervous system," by the director of the National Institute of Neurological Disorders and Stroke (NINDS) at NIH:

TREATMENT BLOCKS PAIN WITHOUT DISRUPTING OTHER FUNCTIONS

A combination of two drugs can selectively block pain- sensing neurons in rats without impairing movement or other sensations such as touch, according to a new study by National Institutes of Health (NIH)-supported investigators. The finding suggests an improved way to treat pain from childbirth and surgical procedures. It may also lead to new treatments to help the millions of Americans who suffer from chronic pain. The study used a combination of capsaicin -- the substance that makes chili peppers hot -- and a drug called QX-314. This combination exploits a characteristic unique to pain-sensing neurons, also called nociceptors, in order to block their activity without impairing signals from other cells. In contrast, most pain relievers used for surgical procedures block activity in all types of neurons. This can cause numbness, paralysis and other nervous system disturbances.

"The Holy Grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, coordination, or other vital functions of the nervous system. This finding shows that a specific combination of two molecules can block only pain- related neurons. It holds the promise of major future breakthroughs for the millions of persons who suffer with disabling pain," says Story C. Landis, Ph.D., director of the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH, which funds the investigators' research along with the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS). The study appears in the October 4, 2007, issue of "Nature".[1]

Lidocaine, the most commonly used local anesthetic, relieves pain by blocking electric currents in all nerve cells. Although it is a lidocaine derivative, QX-314alone cannot get through cell membranes to block their electrical activity. That's where capsaicin comes in. It opens large pores called TRPV1 channels -- found only within the cell membrane of pain-sensing neurons. With these channels propped open by capsaicin, QX-314 can pass through and selectively block the cells' activity. The research team, led by Clifford J. Woolf, M.D., Ph.D., of Massachusetts General Hospital and Harvard Medical School and Bruce Bean, Ph.D., at Harvard Medical School, tested the combination of capsaicin and QX-314 in neurons isolated in Petri dishes and found that it blocked pain-sensing neurons without affecting other nerve cells. They then injected the drugs into the paws of rats and found that the treated animals could tolerate much more heat than usual. They also injected the two drugs near the sciatic nerve that runs down the hind leg. The treated rats did not show any signs of pain, and five of the six animals continued to move and behave normally. This showed that the drugs could block pain without impairing motor neurons that control movement. The drug combination took half an hour to fully block pain in the rats. However, once it began, the pain relief lasted for several hours.

"Current nerve blocks cause paralysis and total numbness," Dr. Woolf says. "This new strategy could profoundly change pain treatment in the perioperative setting."

The treatment tested in this study is unique in that it uses a type of ion channel (TRPV1 channels) as an avenue to deliver medication. Ion channels are pores in the cell membrane that control the flow of electrically charged ions in and out of cells. "I'm not aware of any other strategy that uses a channel within cells to deliver a drug to a select set of cells," Dr. Woolf says. The strategy builds on research done since the 1970's, largely supported by NIH, that shows how electrical signaling in the nervous system results from expression of dozens of different types of ion channels. Some of these ion channels are found only in specific types of neurons. "This project is a nice illustration of how research trying to understand very basic biological principles can have practical applications," says Dr. Bean. This type of treatment has great potential to improve pain treatment during childbirth, dental procedures, and surgery, the researchers say. "Surgical pain is the obvious first application for this type of treatment," Dr. Woolf says. However, similar therapies might eventually be useful for treating chronic pain, he adds. Chronic pain continues for weeks, months, or even years and can cause severe problems, and is often resistant to standard medical treatments. While the researchers focused on finding a treatment for pain, this strategy might also be useful for treating itch from eczema, poison ivy rashes, and other conditions, Dr. Woolf says. Like pain sensations, itch signals come from nociceptors. One problem with the combination treatment is that the capsaicin can cause unpleasant burning sensations until the QX-314 takes effect, Dr. Woolf says. Administering the QX-314 ten minutes before the capsaicin minimized this problem in rats. The investigators are now looking for ways to open the TRPV1 channels without the burning sensations, perhaps by finding an alternative to capsaicin. They also hope to find ways of prolonging the pain relief. Eventually, they might be able to develop pills that will stop pain signals without requiring injections, Dr. Woolf adds.

[1]Binshtok AM, Bean BP, Woolf CJ. "Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers." "Nature", October 4, 2007, Vol. 449, No. 7162, pp. 607-610.

[fmichael]

From The Independent (U.K.)

Drug derived from chillis is hailed as a breakthrough in pain relief

By Steve Connor, Science Editor
Published: 04 October 2007

A substance found in chilli peppers has been used to create a painkiller which prevents suffering without the usual side-effects of conventional anaesthetics, such as unconsciousness and paralysis. The new drug can be targeted against only those nerves involved in sending pain signals to the brain, making pain relief far more effective and safer than existing anaesthetics, researchers believe.

They also think the new analgesic could benefit people suffering from so-called pathological pain – long-term discomfort which is not caused by any obvious injury – as well as chronic itching which can seriously affect quality of life.

A painkiller that blocks only pain neurons – the nerve cells leading to the central nervous system – could allow women to give birth painlessly using an epidural which does not paralyse the lower body, or allow a patient to have open-heart surgery while remaining conscious.

"Current nerve-blocks cause paralysis and total numbness. We're offering a targeted approach to pain management that avoids these problems. This new strategy could profoundly change pain treatment," said Clifford Woolf, of the Massachusetts General Hospital in Boston, who led the study with Bruce Bean, of Harvard Medical School.

"Eventually, this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis. In fact, the possibilities seem endless," Dr Woolf added.

"I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones."

The new painkiller is based on combining two molecules. One is normally an inactive ingredient of the local anaesthetic lidocaine, called QX-314, and the other is capsaicin, the chemical in chilli peppers that makes them taste spicy or feel hot when rubbed on the skin.

When combined, the two molecules create an analgesic that works only on pain-sensitive nerves and leaves other types of nerves unaffected, the scientists found. Their study, published in the journal Nature, found it to be effective in laboratory tests on rats. When injected into the animals' paws, the drug anaesthetised the rodents against heat and pain but their movements and other normal bodily functions were unaffected. The effects lasted for up to two hours.

Further work is needed before tests can begin on humans but Dr Woolf believes the drug will work. He said: "We are optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions."

The secret of how the two molecules combine to kill pain lies in how they target a molecule "pore" which exists only in the membrane of nerve cells involved in pain detection. By blocking the opening of the pore, the scientists, in effect, disconnected pain-sensitive nerve cells.

"We introduced a local anaesthetic selectively into specific populations of neurons," said Professor Bean. "Now we can block the activity of pain-sensing neurons without disrupting other kinds of neurons that control movements or non-painful sensations."

Story Landis, of the US National Institute of Neurological Disorders and Stroke, which funded the research, said it could be a landmark in the development of new painkillers.

"The holy grail in pain science is to eliminate pathologic pain without impairing thinking, alertness, co-ordination, or other vital functions of the nervous system," Dr Landis said.

"This finding holds the promise of major future breakthroughs for millions of people who suffer with disabling pain."

How it works

Conventional painkillers work by blocking the tiny channels in nerve cell membranes, which are essential for a cell to function properly. However, as well as blocking pain, anaesthetics also block anything to do with movement or non-pain sensations, causing paralysis, numbness or unconsciousness. The new drug works specifically against a type of channel called TRPV1, which exists only in the membrane of pain cells. The drug has two active ingredients which work together in unison. The capsaicin molecule from chilli peppers opens the TRPV1 channel and allows it to act as a gate through which the second molecule, derived from the anaesthetic lidocaine, enters pain-sensitive cells.

[tayla4me]

Hi Mike,

I tried Capsaicin about 4 years ago and had crossed it off my useful list as I developed one heck of a rash from it, but after reading your posts I reckon it may well be worth another try!

Cheers Tayla

[Auberon]

Hi Mike,
this certainly is interesting & although I have read many times as also stated in this article that topical application of capsaicin is an extreme irritant to some rsd sufferers, this is certainly promising.
Basically, I see it as a potential quantum leap in the right direction: almost an active vector that goes beyond the role of a catalyst & vector & plays a role in moderating the affected cell......wow!

This combination might just carry it deep enough (just ever so sub-Q) to help as a cream. Other more efficacious methods of admin could increase drug efficacy too. This sort of work sets the mind racing in a positive way.
The mind boggles to the heddy heights of drug delivery by nonobes...now that would be something.

Complementary polypharmacy with targeting nanobes...who would have thought?

Mssrs Woolf & Bean certainly have a good rep.

This I will watch closely.

Thanks heaps for the post.
Auberon

Dear Mike,

This sounds wonderful, I hope I am not dreaming. I am wondering if a person could get a cream made up at a compound pharmacy. Much Love, Roz xxx