Long‐term spinal analgesic delivery: A review of the preclinical and clinical literature

The demonstration by James Leonard Corning in 18851 that cocaine delivered into the perispinal space would produce a state of hind-limb paralysis in dogs and a degree of anesthesia in humans set the stage for a rapid turn-of-the-century growth, in which local drug delivery was used therapeutically for altering the pain state. The subsequent report by Bier in 18992 reflecting the potent anesthetic effect in himself, his assistant, and in several patients was followed by numerous reports in which local anesthetics were delivered by a number of routes, including caudal and lumbar epidural as well as cervical and thoracic intrathecal.3-5 Although continuous intrathecal access using a catheter was achieved as early as 1935 by Love,6 a neurosurgeon at Mayo Clinic who used this approach for cerebrospinal fluid (CSF) shunting, spinal catheters for anesthetic delivery were first described by Manalan7 and Hingson and Southworth.8 Touhey9 then described the use of a catheter placed using a needle with a side-opening tip developed by Huber. Such implanted catheters with percutaneous injection ports or subcutaneous pumps permitted the longterm delivery of pharmacological agents. As reviewed in detail by Mackey,10 the early history related to the development of spinal drug delivery evolved amazingly fast. Mackey notes that by January 1901, there had been nearly 1,000 reports on this ‘‘new’’ anesthetic technique of spinal anesthesia. By the first decade of this century, issues related to side effects (headache, total spinal) and characteristics (anesthetic level v concentrations, volume, baricity, and the use of vasoconstrictors) were well appreciated. While much of the early work used anesthetics such as cocaine and concurrently synthesized analogues (such as stovaine, tropacocaine, or novocaine), the occasional effort to deliver other agents such as strychnine or morphine were reported11-13 and presaged the changes in practice that arose from the rapid growth in spinal pharmacology that constitutes the focus of much of this review. Early work emphasized the likely importance of amino acids, such as glutamate, in sensory function.14 However, the identification of the peptide substance P in small dorsal root ganglion cells15 and the observation that opiates with a spinal action would produce a selective analgesia,16 as well as the observation that substance P release evoked from C fibers was blocked by morphine,17 marked the beginning of the current trend toward focusing on the selective regulation of spinal afferent processing (Table 1). Of particular importance in the evolution of spinal agents was the developing appreciation that nociceptive processes could be considered broadly divided into mechanisms that involved the following: (1) the acute activation of nociceptors; (2) the posttissue injury state in which nociceptive afferents displayed a persistent ongoing barrage; and (3) the change in processing that reflected changes in function after nerve injury (Table 2). Thus, in the middle 1960s the importance of spinal facilitatory processes to behavior was first noted by Mendell and Wall (‘‘wind-up’’). 17a In the late 1980s, changes in spinal function secondary to peripheral nerve injury were beginning to be elucidated and preclinical models were developed that permitted assessment of the spinal pharmacology of various neuropathic conditions. In each case, preclinical behavioral models have been developed which permit assessment of the role of different transmitter-receptor systems in the several pain states. Such models confirmed the behavioral relevance in models of hyperalgesia and allodynia of excitatory amino acid receptors, of various channels From the Department of Anesthesiology, University of California, San Diego, California. Accepted for publication September 7, 1999. Reprint requests: Mark Wallace, M.D., UCSD, Department of Anesthesiology, 9500 Gilman Dr #0924, La Jolla, CA 920930924. 2000 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/00/2502-0004$5.00/0