Wednesday, October 30, 2013

New Wrinkle for Old Drug It’s not just for smoothing laugh lines. Botulinum toxin may have the potential to ease OA pain.| Arthritis Today Magazine

Widely used by doctors to soften forehead wrinkles and reduce uncontrollably sweaty armpits, researchers now are exploring botulinum toxin as a potential therapy for osteoarthritis (OA) pain.

Although botulinum toxin (Botox, Dysport, Myobloc) has been studied since the 1950s, recent studies on its use in osteoarthritis pain suggest it could be a new analgesic option for a group of patients that's been hard to treat.

"The Botox story is very intriguing," says David Felson, MD, professor of medicine and epidemiology at Boston University. "It isn't just muscles. It can paralyze nerves. Just like celebrities injecting it into wrinkles, it could have the same effect on a hip muscle. Botox could paralyze the muscle that is transmitting pain."

A powerful neurotoxin produced by a bacterium that can cause deadly botulism poisoning at higher doses, botulinum toxin has an anticholinergic effect, meaning it can block the delivery of the neurotransmitter acetylcholine to the central nervous system, an action which can cause the body to produce chronic pain signals. The substance can temporarily paralyze muscles for a few months, easing painful spasms and tightness in muscles around OA-affected joints. It can also have an antinociceptive effect, meaning it can block nociceptors, or pain receptors, from sending a pain signal up the spinal cord to the brain.

This toxin may eventually be used to treat OA patients whose pain is not sufficiently controlled by traditional medicines like NSAIDs or analgesics, and for patients who may experience adverse effects from those medicines, says Dr. Felson.

Blocks Pain Signals

In the same action that botulinum toxin flattens wrinkles for up to six months, the substance "blocks the neuromuscular junction, so the nerve can't transmit signals to the muscle and it prevents contraction," says Eric Hsu, MD, a pain specialist at Ronald Reagan-UCLA Medical Center in Los Angeles.

These early, small studies on the pain-fighting potential of botulinum toxin are promising for people who have chronic osteoarthritis pain due to muscle spasms and tightness, or myofascial pain, says Dr. Hsu. Doctors don't know why some people have this type of chronic muscular pain that never shuts off, he notes. "It's still a controversial issue and we can't pinpoint the reason, but there is a theory that chronic inflammation can trigger primary or secondary muscle spasm. This induces the neurotransmitters to be consistently aroused, and it triggers the central nervous system" to send continuous pain signals to the joint.

Botulinum toxin, which can block the transmission of these neurotransmitters for several months at a time, might be a useful treatment for this type of pain, says Dr. Hsu.

Although the studies conducted so far are small and look at short-term results, the results of these recent studies are "impressive," says Dr. Felson. "A lot of [current treatments for OA pain] don't work, and this one may actually work."

He points to a Minneapolis-based study published in the Journal of Rheumatologyin 2010 that looked at 54 patients experiencing chronic pain after total knee arthroplasty. Some were given an intraarticular injection of 100 units of botulinum toxin type-A and some were given an identical placebo. The results were significant: 71 percent of those injected with botulinum toxin achieved clinically meaningful reduction in pain and improved, measurable physical function in the joint compared to 35 percent of those receiving the placebo shot.

Even surgical replacement of a hip or knee joint eroded by OA may not eliminate pain and mobility issues, says Dr. Felson.

"No one is quite sure of the reason for pain after knee arthroplasty, but a significant percentage of patients have pain after surgery," he says.

Traditional medications to treat OA pain include NSAIDs or corticosteroids, which target inflammation, and analgesics, which act on the central nervous system to block pain signals. Botulinum toxin could be a welcome alternative, says Dr. Hsu, because it appears that the localized injections do not cause the type of systemic side effects of NSAIDs or corticosteroids, or the dependence issues of narcotic analgesics.

"If it does get widespread use at some point, then I anticipate people would get maintenance injections every three to four months or so," he notes. Some studies are exploring the use of the toxin in conditions like hip and knee OA and frozen shoulder, or adhesive capsulitis, the inflammation of connective tissue in the shoulder joint capsule. Dr. Hsu sees botulinum toxin as a potential auxiliary treatment for OA patients with uncontrolled pain. "I cannot predict that this will be the only treatment people with osteoarthritis will get, but for people with advanced disease, people who feel hopeless, this may provide hope that something can be done" to treat their pain.

Pain Results Promising

Recently published studies explore the use of botulinum toxin in different joints and in patients who have either had total joint replacement or not. Another study has raised further interest by suggesting that botulinum toxin might someday be used to treat inflammation as well.

An Italian study published in the Journal of Rehabilitative Medicine in 2010 looked at the efficacy of botulinum toxin type-A injections in the thigh muscles of patients experiencing pain due to hip OA. Each subject received two injections of the solution for a total of 400 units: 250 units in the adductor longus muscle and 150 units in the adductor magnus muscle of the thigh on the same side of the body as the affected hip. Results were equally promising. The patients were evaluated to measure hip function, pain, and overall well-being and quality of life before the study, and all saw improvements in these areas in follow-up evaluations at two, four and 12 weeks after the injections.

Another study conducted by University of Wisconsin researchers published in the journal Biochemistry in 2011 explored a future use of botulinum toxin: Treating chronic inflammation, not just temporarily relieving pain. Felix Yeh, PhD, who led the study and is now working in the private sector in San Francisco, said the focus of the study was to learn how toxins get into neurons, something he calls "a Trojan horse strategy."

Using botulinum toxin type B, a relatively new product on the market, on laboratory mice, Yeh and his colleagues showed that the neurotoxin could be retargeted to inhibit the release of tumor necrosis factor alpha, a key cytokine that is one of the possible causes of inflammation in autoimmune diseases like rheumatoid arthritis.

"Toxins cannot naturally get into non-neural cells," says Yeh. "But we found if we coated our toxins with antibodies, we could drive them through." The re-engineered toxins could enter cells and cleave to SNAREs, key proteins that play a role in the secretion of inflammation-causing substances. In their mouse study, the researchers measured about a 50-percent decrease in TNF-alpha release after treating the tissue with the engineered toxin, without significantly affecting other cells. "Since we were able to inhibit its secretion, we were able to lower overall inflammatory phenotypes," says Yeh. "We saw the potential for all toxins. All of these could be retargeted to non-neural cells for therapeutic use."

Physicians treating patients with serious chronic joint pain see botulinum toxin as potentially useful, but urge caution at this point. Although studies haven't shown serious adverse effects, Dr. Felson speculates that injecting it into large muscles supporting weight-bearing joints, such as the thigh, might impair one's ability to walk, for example.

So far, the results look promising, so Dr. Hsu is hopeful. "I think things like this, which do not cause the systemic, multi-organ side effects of other treatments, are potentially an option for us to help our patients."