Nov. 9, 2000 For those suffering from pain, scientists from UCLA and the University of Cambridge, United Kingdom, report a revolutionary advance in pain medicine that promises to deliver painkillers directly to the affected area of the body, in smaller doses and with fewer side effects.
The researchers report the first clinically suitable method using nerves as a means of safely delivering high doses of painkillers to achieve a therapeutic effect. They announced their research findings at the Society for Neuroscience conference on Nov. 8 in New Orleans, La.
UCLA neurosurgeon Aaron Filler and his colleagues used a method called "axonal transport" to deliver a pain drug to the spinal ganglia and spinal cord, using nerves as a conduit, in an animal model.
Axonal transport works like a "conveyor-belt" process, delivering pain-relieving medication to remote sensory endings in the tissues of the body. In axonal transport, the cell moves molecules from one end of the cell to the other, thus supporting their ability to communicate with other neurons. A single neuron may be more than two feet long.
Although axonal transport has played a role in thousands of research studies in the past, this is the first-ever report of a positive clinical effect with a potential human medication. The new technology uses a novel molecular structure to achieve clinically effective dosing in targeted groups of nerves, Filler said.
This work marks an important advance, because drug treatment of nervous-system disorders is often hindered and sometimes precluded when the precise site of the injury or disease cannot be reached with adequate levels of pain medicine without causing unwanted side effects. Delivery of painkillers directly to selected target sites can avoid undesired toxicity, as well as inappropriate side effects in non-target neural tissue.
Filler says that with this new method of delivering pain medication, one shot administered during surgery could alleviate the pain sensations a patient would normally feel for several days. The painkillers will go only to the nerves involved in the surgery, eliminating the negative side effects patients experience from the current method of pain treatment such as nausea, drowsiness and impaired breathing.
The researchers found that appropriately formulated substances, including drugs, are taken up by axon nerve endings and transported to the core tissues of the nervous system. Since nerves are territorial and map out particular segments of the body, this allows the selective delivery of drugs to relevant parts of the nervous system involved in pain sensation and other disease processes.
The researchers created a complex made up of an axonal transport facilitator (ATF) attached to a linker molecule bearing up to a hundred reversibly attached drug molecules. This complex was configured to deliver the drug gabapentin in a rat model of neuropathic pain to selected dorsal-root ganglia by axonal transport after injection into tissue supplied by the target nerves.
"This very complex design achieves something that, previously, was not thought possible," Filler said. "The way it works makes this the first truly 21st-century medication. These results are expected to lead to dozens of new medications that will solve difficult drug delivery problems in the treatment of conditions as varied as stroke, Alzheimer's disease, shingles and herpes."
"A single injection of the ATF drug complex caused a 50 percent reduction in the hypersensitivity to pain that lasted up to four days," says Filler. "To achieve a similar effect by the current drugs would require more than 300 times the amount of painkiller given in multiple doses."
The current method of pain treatment involves delivering painkillers into the blood stream. The pain medication then travels throughout a patient's system, affecting all areas of the body, unlike this new, targeted approach.
Clinical trials using axonal transport to treat neuropathic pain will begin in early 2002.
In addition to Filler, Dr. Andrew Lever, Dr. Raj Munglani and Dr. Garth Whiteside of the University of Cambridge; and Dr. Mark Bacon, Dr. Jonathan Clark and Dr. Peter Laing of SynGenix Ltd. all collaborated on this research.
The research was funded by SynGenix Ltd., the UK Department of Trade & Industry, and the Neuroscience Research Foundation of Atkinson Morley's Hospital.
Filler is a co-founder, consultant and significant shareholder of the pharmaceutical firm SynGenix Ltd. of Cambridge, United Kingdom, which in part funded this research, and holds the rights to the axonal transport system described.
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