ABSTRACT
Although narcotic analgesics and formulations containing opioids are the most commonly used agents for the treatment of moderate to severe pain, the use of exogenous drug administration on a long-term basis for chronic pain management is often not optimal owing to potentially serious or disturbing side effects, tolerance development, poor pain control, and inconvenience. Over the last two decades, the field of cellular transplantation has exploded as a potential means of providing a local and continually renewable supply of therapeutic molecules. Cell therapy that uses transplants of cells from primary tissue, such as adrenal medullary chromaffin cells, or immortalized, bioengineered cell lines that secrete pain-reducing neuroactive substances into the central nervous system (CNS), offers a feasible alternative in the long-term management of chronic pain. Similar to the more common drug pumps used for opioid delivery, cellular implants permit long-term, low, local dose delivery of antinociceptive agents into the cerebrospinal fluid (CSF), without the side effects associated with large doses or systemic administration. In addition, these biological ‘‘cellular minipumps’’ permit the delivery and utilization of molecules that have biological half-lives that are too short to allow them to be delivered by other means, such as osmotic pumps with intrathecal catheters. With continued viability, cell transplants avoid the problems of catheter-related infections, refilling, and maintenance required with the drug pumps. Although, to date, primary cells have been utilized in initial clinical pain trials, one can envision the possibilities of generating cell lines that can manufacture novel analgesic agents for specific pain indications, or respond to the physiological microenvironment by bioengineering cells to secrete agents only when they are needed, such as with periodic episodes of pain. Some of these pain-reducing neuroactive substances that could be manufactured by the cellular minipumps include opioid peptides (e.g., endorphins and enkephalins) and other peptides such as galanin, neurotensin, somatostatin, and calcitonin; neurotransmitters such as norepinephrine, epinephrine, serotonin, and γ-aminobutyric acid (GABA); neurotrophins such as brain-derived neurotrophic factor (BDNF); cytokines such as interleukin (IL)-10, and numerous other neuroactive molecules, the genes of which can be introduced into bioengineered cell lines.
