Professor of Anaesthesiology
Department of Anesthesiology
Flemish Free University of Brussels Medical Center
Recent research has increased our understanding of the role of the cyclooxygenase (cox) enzymes, and particularly of the cox-2 enzyme, in peripheral and central pain sensitisation mechanisms. Sensitisation results in heightened sensitivity of neurons to subsequent noxious input (hyperalgesia) in the injured tissue. Efforts have focused on understanding the neurochemistry of peripheral sensitisation and the plastic changes in the spinal cord (central sensitisation), with the hope of developing new strategies for a more rational, mechanistic approach to the treatment of pain.
The role of cox-2 in nociception and pain
Cyclooxygenase plays a key role in the nociceptive process, converting arachidonic acid to a variety of prostaglandins that can cause inflammation and pain. It exists as two isoenzymes, cox-1 and cox-2. Cox-1 is a constitutive enzyme with housekeeping functions that is present in all cells. In contrast to most other tissues, both cox enzymes are constitutively expressed in the spinal cord and the brain.
Nociceptive neurons display plasticity and have the capacity to change function, chemical profile and structure in response to continuous painful stimulation. In nociceptive pain (ie, pain elicited by noxious stimulations), the cox-2 enzyme is expressed following immediate early gene upregulation at the site of injury in response to tissue damage and inflammatory stimuli. This cox-2 activity generates large amounts of prostaglandins (PGE2, PGI2) that activate signalling pathways in peripheral sensory neurons, increasing the sensitivity of these neurons to other painful stimuli such as heat, pressure and protons.(1) The enzyme thereby contributes to a prolonged and more intense pain experience beyond the period and the area of tissue damage (the phenomenon of primary hyperalgesia).
PGE2 and other inflammatory mediators (eg, cytokines) increase the afferent sensory nerve traffic to the dorsal horn of the spinal cord. This results in enhanced activation of N-methyl-D-aspartate receptors and second messengers. Here, too, cox-2 behaves as an immediate early gene that is rapidly upregulated in dorsal horn neurons in response to peripheral noxious stimulation. It was recently discovered that cox-2 plays a significant role in the central processing of the nociceptive or pain signals at the dorsal horn of the spinal cord and certain areas of the brain. Here, the enzyme contributes to the phenomenon of central sensitisation to pain.(2) Central sensitisation involves changes in patterns of gene expression that cause functional alterations of the second-order neurons and glial cells. In response to tissue damage and inflammatory cytokines, there is a dramatic increase in expression of cox-2 in the central nervous system (CNS), not only in localised areas of the spinal cord that correspond to the sensory inflow from the damaged tissue, but throughout the spinal cord and the brain. The increased levels of PGE2 produced through this cox-2 induction affect central sensory neurons in the pain pathways in several ways. They enhance neurotransmitter release from afferent C-fibers, hyperpolarise postsynaptic neurons and decrease the effect of inhibitory interneurons on the pain signals.
Circulating proinflammatory cytokines also enhance cox-2 transcription and explain the widespread distribution of the cox-2 induction in the CNS. Subsequent studies suggested a role for cytokines IL-6 and IL-1b (see Figure 1).(3)
As a consequence, exaggerated pain responses appear in an area far larger than the area of the initial tissue damage (secondary hyperalgesia), and the patient develops painful sensitivity to normally innocuous stimuli (allodynia). The development of peripheral and central sensitisation results in pain that is more intractable to treatment and that can potentially develop into chronic pain.
The peripheral and central roles of cox-2 in pain sensitisation suggest that, to be effective, cox-2-selective inhibitors should act at the periphery, but also directly on the CNS. It is thus essential that the chemical structure of these agents allows their penetration through the blood–brain barrier (BBB) to inhibit the cox-2 enzyme expressed in the spinal cord and brain.
The induction of cox-2, both peripherally and centrally, in response to painful stimuli is rapid, and maximal levels of cox-2 protein are observed within 6–12 hours of initial tissue damage.(3) This enzyme induction is maintained as long as inflammation exists. Early dosing of cox-2-selective inhibitors will not affect nociceptive responses or immediate pain perception, but it is important to administer these agents early enough so that tissue drug levels are optimal before any massive induction of cox-2.
Rationale for inhibiting the cox-2 enzyme
Nonsteroidal anti-inflammatory agents (NSAIDs) and cox-2-selective inhibitors are able to block nociceptive input by attenuating production of inflammatory cytokines and prostaglandins. NSAIDs are widely used clinically to decrease peripheral inflammation, and it is generally accepted that this occurs mainly through inhibition of the cox-2 enzyme expressed in response to tissue injury. Therefore, a desirable anti-inflammatory agent is one that inhibits cox-2 at low concentrations and inhibits cox-1 only at high, supratherapeutic concentrations.(4) Furthermore, drugs with cox-2 selectivity must not inhibit cox-1 activity in clinically relevant targets (ie, gastrointestinal mucosa or platelets) at therapeutic plasma concentrations.
Several cox-2-selective inhibitors have been approved for clinical use in a variety of painful conditions. They include celecoxib, rofecoxib, valdecoxib, parecoxib sodium (an injectable prodrug of valdecoxib) and etoricoxib. Differences in analgesic and anti-inflammatory efficacy among these agents relate to their molecular structure, the binding to the cox-2 enzyme,(5) their rate of penetration into the cerebrospinal fluid and their pharmacokinetics. For some agents, the duration of pharmacological activity is longer than would be expected based on elimination half-life. Both rofecoxib and valdecoxib have been shown to cross the BBB and prevent inflammation and PGE2 production in the periphery and cerebrospinal fluid.(6)
The central actions of cox-2-selective inhibitors may be clinically very important, because the marked attenuation of central sensitisation may be the principal mechanism involved in relieving severe pain associated with surgery, trauma or acute inflammation. Furthermore, cox-2-selective inhibitors, administered as part of multimodal analgesic treatments, provide effective opioid-sparing analgesia, which can lead to improved patient comfort and mobilisation, faster recovery and shortened hospital stays.(7–9) Therefore, cox-2 inhibition should be considered as an important analgesic therapy in addition to which other analgesic adjuncts, such as opioids and paracetamol, should be added.
- Smith CJ, Zhang Y, Koboldt CM, et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA 1998;15:13313-8.
- Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-8.
- Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471-5.
- FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.
- Kurumbail RG, Stevens AM, Gierse JK, et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 1996;384:644-8.
- Zhang JY, Yuan JJ, Wang YF, et al. Pharmacokinetics and metabolism of a COX-2 inhibitor, valdecoxib, in mice. Drug Metab Dispos 2003;31:491-501.
- Gan TJ, Joshi GP, Viscusi ER, et al. Preoperative arenteral parecoxib and follow-up oral valdecoxib reduce length of stay and improve quality of patient recovery after laparoscopic cholecystectomy surgery. Anesth Analg 2004;98:1665-73.
- Joshi GP, Viscusi ER, Gan TJ, et al. Effective treatment of laparoscopic cholecystectomy pain with intravenous followed by oral cox-2 specific inhibitor. Anesth Analg 2004;98:336-42.
- Camu F, Beecher T, Recker DP, et al. Valdecoxib, a cox-2 specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty. Am J Ther 2002;9:43-51.
American Pain Society
International Anesthesia Research Society
International Association for the Study of Pain