Posts tagged neuropathic pain

Researchers at the School of Medicine have identified a subset of nerve cells that mediates a form of chronic, touch-evoked pain called tactile allodynia, a condition that is resistant to conventional pain medication.

The discovery could point researchers to more fruitful efforts to develop effective drugs for the condition.

Touch-evoked pain occurs as part of a larger neuropathic pain condition arising from damage or disruption of nerve-cell circuits or signals caused by disorders such as alcoholism, diabetes, shingles and AIDS, or procedures such as spine surgery and chemotherapy. For patients with tactile allodynia, the slightest touch — a gentle caress or the brush of shirt against skin — can cause excruciating pain because changes in nerve-cell signals or networks trick the brain into mistaking touch for pain.

The study, published online Feb. 27 in Neuron, found that these “touch” neurons are different from the usual “pain” neurons that respond to stimuli such as cuts or bruises.

Unlike pain caused by such wounds, neuropathic pain is difficult to manage because little can be done to repair nerve damage. Managing it may require strong painkillers or combinations of treatments.

Common painkillers such as morphine have little effect on touch-evoked pain, possibly because they don’t target the touch neurons, the authors say. Morphine binds to specific protein-binding sites on pain neurons called mu opioid receptors, or MORs, and cuts off the their signals so that the brain can no longer sense pain.

However, the touch neurons do not carry MORs, which is why morphine cannot bind to them and block the pain. Instead, they carry delta opioid receptors, or DORs, whose role in pain control has been unclear until recently.

"That’s been the problem so far; any type of severe pain you have, you go into the clinic and very likely you will be treated with morphine-like opioids," said Gregory Scherrer, PharmD, PhD, the senior author of the study and an assistant professor of anesthesia. "You can give some of these patients as much morphine as you want; it won’t work if the mu opioid receptor is not present on the neurons that underlie that type of pain."

There are currently no Food and Drug Administration-approved pain-control drugs that target DORs. Previous attempts at developing DOR-targeting drugs haven’t succeeded because researchers didn’t know what type of pain such drugs would be useful for, Scherrer said.

Two DOR-binding drugs developed for knee pain by Adolor Corp., a biotechnology firm, for instance, probably failed because there is no compelling evidence that DOR was present or involved. AstraZeneca, another pharmaceutical firm, also had a DOR program but recently stopped its research efforts, Scherrer added.

"Now that we have provided a rationale and mechanism supporting the utility of DOR agonists for cutaneous pain and tactile allodynia, these companies will be able to design trials more carefully to evaluate specifically the drugs’ efficacy against touch-evoked pain," he said.

Earlier studies by Scherrer and others hinted at the presence of special nerve fibers on the skin that might contribute to touch-evoked pain.

In the current study, Scherrer and colleagues used fluorescent mouse models to isolate these neurons and identify how they control touch-evoked pain. They found that DOR can play an inhibitory role in these neurons: When proteins bind to DOR, they cut off communication to the spinal cord, through which sensory signals travel to the brain.
DOR-carrying “touch” neurons pervade the skin and could easily be targeted by drugs in the form of skin patches or topical creams, Scherrer suggested.

"By contrast, most MOR-carrying neurons penetrate internal organs," he said. "That’s why morphine is effective in treating post-surgery pain, for example."

Scherrer and fellow researchers tested two different DOR-binding compounds individually on mice and found that both reduced the mice’s sensitivity to touch-evoked pain.

Preliminary studies also indicate that DOR-targeting drugs might not cause dramatic side effects like morphine does, especially if they can be used topically, Scherrer said.

"Morphine and other MOR-targeting drugs have myriad deleterious side effects — including addiction, respiratory depression, constipation, nausea and vomiting — that further limits their utility for chronic pain management," he said.

The next step is to determine whether DOR could be a target for other types of pain, such as arthritis pain, pain from bone cancer and muscle pain, Scherrer added.

The findings also suggest that the body’s opioid system — normally associated with pain and addiction — may also respond to other stimuli such as touch.

"We may have underestimated the importance of the opioid system and what can be achieved with drugs targeting other subtypes of opioid receptors," Scherrer said.

(Source: med.stanford.edu)

Neuropathic pain — pain that results from a malfunction in the nervous system — is a daily reality for millions of Americans. Unlike normal pain, it doesn’t go away after the stimulus that provoked it ends, and it also behaves in a variety of other unusual and disturbing ways. Someone suffering from neuropathic pain might experience intense discomfort from a light touch, for example, or feel as though he or she were freezing in response to a slight change in temperature.

A major part of the answer to the problem of neuropathic pain, scientists believe, is found in spinal nerve cells that release a signaling chemical known as GABA. These GABA neurons act as a sort of brake on pain impulses; it’s thought that when they die or are disabled the pain system goes out of control. If GABA neurons could be kept alive and healthy after peripheral nerve or tissue injury, it’s possible that neuropathic pain could be averted.

Now, University of Texas Medical Branch at Galveston researchers have found a way to, at least partially, accomplish this objective. The key, they determined, is stemming the biochemical assault by reactive oxygen species that are generated in the wake of nerve injury.

"GABA neurons are particularly susceptible to oxidative stress, and we hypothesized that reactive oxygen species contribute to neuropathic sensitization by promoting the loss of GABA neurons as well as hindering GABA functions," said UTMB professor Jin Mo Chung, senior author of a paper on the research now online in the journal Pain.

To test this hypothesis — and determine whether GABA neurons could be saved — the researchers conducted a series of experiments in mice that had been surgically altered to simulate the conditions of neuropathic pain. In one key experiment, mice treated with an antioxidant compound for a week after surgery were compared with untreated mice. The antioxidant mice showed less pain-associated behavior and were found to have far more GABA neurons than the untreated mice.

"So by giving the antioxidant we lowered the pain behavior, and when we look at the spinal cords we see the GABA neuron population is almost the same as normal," Chung said. "That suggested we prevented those neurons from dying, which is a big thing."

One complication, Chung noted, is a “moderate quantitative mismatch” between the behavioral data and the GABA-neuron counts. While the anti-oxidant mice displayed less pain behavior, their behavioral improvement wasn’t as substantial as their high number of GABA neurons would suggest. One possibility is that the surviving neurons were somehow impaired — a hypothesis supported by electrophysiological data.

Although no clinical trials are planned in the immediate future, Chung believes anti-oxidants have great potential as a treatment for neuropathic pain. “If this is true and it works in humans — well, any time you can salvage neurons, it’s a good thing,” he said. “Neuropathic pain is very difficult to treat, and I think this is a possibility, a good possibility.”

(Source: eurekalert.org)

For many patients with difficult-to-treat neuropathic pain, deep brain stimulation (DBS) can lead to long-term improvement in pain scores and other outcomes, according to a study in the February issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

About two-thirds of eligible patients who undergo DBS achieve significant and lasting benefits in terms of pain, quality of life, and overall health, according to the report by Sandra G.J. Boccard, PhD, and colleagues of University of Oxford, led by Tipu Aziz FMedSci and Alex Green, MD. Some outcomes show continued improvement after the first year, according to the new report, which is one of the largest studies of DBS for neuropathic pain performed to date.

Most Patients Benefit from DBS for Neuropathic Pain

The authors reviewed their 12-year experience with DBS for neuropathic pain. Neuropathic pain is a common and difficult-to-treat type of pain caused by nerve damage, seen in patients with trauma, diabetes, and other conditions. Phantom limb pain after amputation is an example of neuropathic pain.

In DBS, a small electrode is surgically placed in a precise location in the brain. A mild electrical current is delivered to stimulate that area of the brain, with the goal of interrupting abnormal activity. Deep brain stimulation has become a standard and effective treatment for movement disorders such as Parkinson’s disease. Although DBS has also been used to treat various types of chronic pain, its role in patients with neuropathic pain remains unclear.

Between 1999 and 2011, that authors’ program evaluated 197 patients with chronic neuropathic pain for eligibility for DBS. Of these, 85 patients proceeded to DBS treatment. The remaining patients did not receive DBS—most commonly because they were unable to secure funding from the U.K. National Health Service or decided not to undergo electrode placement surgery.

The patients who underwent DBS were 60 men and 25 women, average age 52 years. Stroke was the most common cause of neuropathic pain, followed by head and face pain, spinal disease, amputation, and injury to nerves from the upper spinal cord (brachial plexus).

In 74 patients, a trial of DBS produced sufficient pain relief to proceed with implantation of an electrical pulse generator. Of 59 patients with sufficient follow-up data, 39 had significant improvement in their overall health status up to four years later. Thus, 66 percent of patients “gained benefit and efficacy” by undergoing DBS.

Benefits Vary by Cause; Some Outcomes Improve with Time

The benefits of DBS varied for patients with different causes of neuropathic pain. Treatment was beneficial for 89 percent for patients with amputation and 70 percent of those with stroke, compared to 50 percent of those with brachial plexus injury.

On average, scores on a 10-point pain scale (with 10 indicating the most severe pain) decreased from about 8 to 4 within the first three months, remaining about the same with longer follow-up. Continued follow-up in a small number of patients suggested further improvement in other outcomes, including quality-of-life scores.

Deep brain stimulation has long been regarded as potentially useful for patients with severe neuropathic pain that is not relieved by other treatments. However, because of the difficulties of performing studies of this highly specialized treatment, there has been relatively little research to confirm its benefits; only about 1,500 patients have been treated worldwide. The new study—accounting for about five percent of all reported patients—used up-to-date DBS technologies, imaging, and surgical techniques.

Dr. Boccard and coauthors acknowledge some important limitations of their study—especially the lack of complete patient follow-up. However, they believe their experience is sufficiently encouraging to warrant additional studies, especially with continued advances in stimulation approaches and technology. The researchers conclude, “Clinical trials retaining patients in long-term follow-up are desirable to confirm findings from prospectively assessed case series.”

(Source: eurekalert.org)