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Controlling Intractable Pain Resistant to Opiates

Eastman, Peggy

doi: 10.1097/01.COT.0000416577.87137.82

BETHESDA, MD—At a meeting on the grounds of the National Institutes of Health here, researchers presented new approaches to controlling intractable pain in patients for whom opiates are not adequate to bring relief. The presentations were part of the NIH Pain Consortium's 7th Annual Symposium on Advances in Pain Research.

Speakers agreed that new therapies for the estimated 100 million Americans in chronic pain are urgently needed. About 40 to 70 percent of patients in pain are not properly managed, and the prevalence of pain in the United States is increasing, said Nora D. Volkow, MD, Director of the National Institute on Drug Abuse and a member of the executive committee of the Consortium.

“Our challenge is translating knowledge into practice,” added Roger B. Fillingham, PhD, President of the American Pain Society, Professor at the University of Florida College of Dentistry, and Director of the University of Florida Pain Research and Intervention Center of Excellence (PRICE).

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Gene Transfer with NP2

Based on promising results of a small Phase I trial in 10 terminal cancer patients with intractable pain—the first clinical trial of gene transfer as a pain treatment—a Phase II trial has been launched in cancer patients with severe pain, said the principal investigator, David J. Fink, MD, the Robert Brear Professor and Chair of the Department of Neurology at the University of Michigan.

This new gene therapy approach uses NP2, a replication-defective herpes simplex virus (HSV), as a vector to express the gene for human preproenkephalin. As an agonist for the delta opioid receptor, the endogenous peptide enkephalin is a natural analgesic that blunts chronic pain, he explained.

The fully enrolled Phase II trial, a placebo-controlled, double-blind and randomized study at 18 U.S. sites, is expected to yield results by the end of this summer. “Assuming Phase II is promising, the company would want to start a Phase III trial as soon as possible,” he said. The gene therapy is being developed for clinical use by Diamyd Medical (a Swedish company in which he has no financial interest).

“This is the first gene transfer approach to try to treat focal pain,” he said. The 10 patients in the Phase I NP2 enkephalin trial had different types of cancer, as do the 32 subjects in the Phase II trial. Fink said the replication-defective HSV vector is injected into the skin and is carried to dorsal root ganglia (DRG)—where it establishes a persistent state.

HSV is especially well suited to this mode of gene transfer therapy, he explained, since the virus used to make the replication-defective vector naturally targets DRG neurons from skin infection to establish a life-long, latent state. To date, there have been no serious adverse effects from NP2 enkephalin, and patients on higher doses of the therapy reported significant pain relief (reduction of pain from 7 on a scale of 1 to 10 to less than 2).

About 75 to 80 percent of urban dwellers have been exposed to HSV, Fink noted. Asked by a meeting attendee if this prior exposure could present a problem in use of this gene transfer therapy for pain control, Fink replied that because there is no viral replication with the vector, the expectation is that this will not be a problem.

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Prostatic Acid Phosphatase

A second approach to using an endogenous substance to control opiate-unresponsive pain is being studied by Mark J. Zylka, PhD, Associate Professor in the Department of Cell and Molecular Physiology and the UNC Neuroscience Center at the University of North Carolina. This substance is prostatic acid phosphatase (PAP), an enzyme expressed in nociceptive neurons.



PAP has long-lasting anti-nociceptive effects, he explained, describing how he and his colleagues have injected PAP into acupuncture points in rodents in an animal model, a technique he has termed “PAPupuncture.” When PAP is injected into the acupuncture points, it generates adenosine from AMP.

He noted that adenosine is known to provide pain relief. In terms of pain management, “this technique lasts 100 times longer than acupuncture, which lasts only a few hours.”

The next step in his research would be taking a form of PAP into a clinical trial. “The idea is to use the enzyme as a drug,” he said, noting that because PAP injections into the spinal cord would be invasive for humans, he and his colleagues had the idea of studying acupuncture points—even though he has never formally studied acupuncture.

“We now know there are at least three enzymes involved in pain,” said Zylka, who is also studying the enzyme ecto-5'-nucleotidase (NT5E, CD73)—which, like PAP, is expressed in pain-sensing neurons.

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Yet another non-opiate approach to pain control is being studied by Douglas A. Lappi, PhD, founder, President, and Chief Scientific Officer of Advanced Targeting Systems, Inc. (a reagent supply corporation), a former visiting scientist at the National Cancer Institute in Milan, and a former researcher at the Salk Institute.

Lappi said he expects to begin clinical trials next year in advanced-cancer patients of a novel, potential pain-targeting drug, a conjugate between saporin and the neuropeptide Substance P. Saporin is a protein from the plant Saponaria officinalis. Lappi, who has received NIH funding—including money from the National Cancer Institute—noted that in animal models the new compound, SP-SAP, blunts chronic pain and has a long-lasting effect (up to 45 days).

“In 2013 we do plan to go into the clinic in humans; we're making our way to that point…We are now looking at clinical trial protocols,” he said. “Remember, this is not a cancer cure, this is for cancer pain.”

The fact that NCI is helping to fund the research, he said, “shows the concern the National Cancer Institute has for cancer pain.”

Lappi said SP-SAP has shown a significant pain-reduction benefit in dogs. He showed a video of a companion dog with an osteosarcoma; the dog was limping markedly. Ten weeks after an SP-SAP treatment, the dog was walking normally; at 20 weeks post-treatment, the dog was jumping—even though the osteosarcoma had grown.

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Finally, H. Ralph Snodgrass, PhD, President, Chief Scientific Officer, and Director of VistaGen Therapeutics, Inc., presented data on a new compound, AV-101, which blocks neuropathic pain by altering neuronal networks at the spinal level.

Snodgrass, a former member of the Lineberger Comprehensive Cancer Center at the University of North Carolina (Chapel Hill) School of Medicine, said this novel compound has shown activity in three models of pain. A Phase Ia clinical study of AV-101 has been completed, and a Phase Ib one is ongoing. No serious adverse events have been reported, he said, and several patients reported feelings of well-being.

Asked by a symposium attendee to comment on the importance of exercising caution in clinical trials with a treatment that alters neuronal networks, Snodgrass said, “I agree with you completely.”

© 2012 Lippincott Williams & Wilkins, Inc.
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