© 2001 Blackwell Science Inc., 1530-7085/01/$15.00 Pain Practice, Volume 1, Number 3, 2001 243–254 Pharmacology of Peripheral Analgesia Timothy J. Ness MD, PhD Associate Professor, Department of Anesthesiology, University of Alabama at Birmingham  Abstract: Pain may begin in the periphery with activa- tion of nociceptor transducers. The present article reviews the pharmacology of drug action at the level of the primary afferent by discussing the following: [1] agents which block transduction processes (vanilloids, sodium ion channel block- ers, antiserotonergic agents, antipurinergic agents); [2] agents inhibiting the transducer site (opioids, cannabinoids, alpha adrenergic agents); [3] agents blocking transducer-based mod- ulation processes (anti-inflammatories, antikinin agents, anti- tachykinins); and [4] agents which block primary afferent- related modification processes (antineurotrophins). There is a clear role for many of these agents in the treatment of in- flammatory pain and they have potential benefits for neuro- pathic pain with peripheral triggers.  Key Words: transducer, sensitization, nociceptor, topical GENERAL OVERVIEW The first step of nociception is transduction, wherein a chemical, thermal, or mechanical stimulus leads to the depolarization of the nerve ending of a nociceptor. When there is sufficient depolarization, an action poten- tial is generated and propagated along the neuron’s ax- onal projection. This carries encoded sensory informa- tion back toward the cell body in the dorsal root ganglion via an axon reflex to the central dorsal horn. In the uninjured system, the reflexes and other responses to painful stimuli are protective and serve to alert and mo- tivate the organism so that injury is avoided or mini- mized. Following injury, however, a cascade of events occurs, which serve to mobilize metabolic resources and minimize energy expenditure so that healing can be opti- mized. The sensory consequences of these events are in- creased pain and immobility due to the development of hypersensitivity to both painful (hyperalgesia) and non- painful (allodynia) stimuli. While pain due to injury and inflammation normally resolves as the healing process progresses, neurological injury may result in persistent neuropathic pain with similar hallmark features (allo- dynia and hyperalgesia). Whereas inflammation-associ- ated pain requires the continued activation of peripheral nerves for pain generation, neuropathic pain may be- come independent of such a drive, but is generally “trig- gered” by peripheral inputs. For the past few decades, much of the focus of pain-related research has been upon the first synapse in the nociceptive pathway with an emphasis on spinal cord nociceptive processing. Ex- periments related to gate control theory, descending in- hibitory influences from the brainstem, central sensitiza- tion processes and their associated spinal physiology, and pharmacology have dominated basic science re- search related to pain. Only recently have more periph- eral processes gained attention as mechanisms of hyper- sensitivity. PERIPHERAL MECHANISMS OF HYPERSENSITIVITY Woolf and Salter, in an elegant review for the journal Science, 1 recently suggested a conceptual framework for the many biochemical events that are associated with hypersensitivity some of which occur at the level of the primary afferent. They broadly categorized these pro- cesses into three groups: [1] autosensitization, [2] het- erosensitization, and [3] modification processes. The first of these processes, autosensitization, is a form of activation-dependent plasticity wherein the repeated ac- tivation of the transducer site leads to an increased ex- Address correspondence and reprint requests to: T.J. Ness, Depart- ment of Anesthesiology, University of Alabama at Birmingham, 937 ZRB – 619 19th St., S. Birmingham, AL 35233-6810, U.S.A.