Cyclooxygenase-2-Selective Inhibitors in the Management of Acute and Perioperative Pain

Understanding pain is central to the goals of medicine as pain may be both a cardinal manifestation of disease and a cause of suffering. Strategies of pain management have evolved to include an appreciation that pain is composed of physiologic as well as psychologic dimensions. Current concepts in pain management recognize the sensory perception of pain (nociception) as the progenitor of the psychic experience of pain, which can lead to suffering.(1) In chronic pain, there may be no discernible pathologic basis for pain, making syndromes like low-back pain and fibromyalgia difficult to understand and treat.(2,3) The importance of pain management to the care of patients is underscored by the fact that pain is now likened to a "fifth vital sign."

The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standard for management of pain stresses the adverse physiologic and psychologic burden of unrelieved pain.(4) The main tenets of the JCAHO standard are: continuous pain assessment-specially tailored assessments for special populations (ie, the elderly, people with AIDS or cancer, children); education about pain and pain management for patients and providers; and thorough ongoing documentation of reported pain as well as pharmacologic and nonpharmacologic interventions.(4)

Clinicians frequently cite several barriers to providing ample pain treatment. Among these are the safety and efficacy of analgesics. For opioid analgesics, several concerns exist, some more supported by clinical evidence than others, including serious side effects, the development of tolerance, and regulatory considerations. Such concerns may lead to the curtailed use of opioids in chronic pain.(5) However, concern for dependence may be exaggerated.(6) Increased education is needed in order that clinicians avail themselves of advances in diagnosis and pharmacologic management of pain.(5)

Unmet Need in Pain Management

The clinical significance of pain may be said to lie fundamentally in its undertreatment.(5,7-9) As much as 10% to 20% of the adult population of the United States suffers from chronic pain, which is often inadequately treated and debilitating.(3) In the large Outpatient Pain Needs Assessment Survey (1990-1991), 42% of respondents reported they experienced cancer pain that was undertreated with inadequate analgesia.(7) Elderly persons are more likely to suffer from pain-especially chronic pain- and are more likely to be undertreated.(10) An extensive study of nursing home residents' nonmalignant pain, and impact of pain on their functional status and psychologic well-being, found, briefly, that of the 26.3% who experienced daily pain, 25% received no form of analgesia.(11)

It is estimated that over 31 million people in the United States each year undergo painful surgical and nonsurgical operative procedures, half of which may be inadequately treated for pain.(9,12) Undertreatment of pain has broad clinical implications and has been correlated with poor surgical outcomes such as delayed return to respiratory, bowel, and gastric function after surgery, immune suppression, and development of chronic pain.

A study of acute pain management in the postoperative setting showed that 77% of adults experienced inadequately treated pain after surgery: 71% still experienced pain even after being administered medication, and most of these (80%) described the pain as moderate to extreme.(13)

The Agency for Healthcare Policy and Research (AHCPR) and, more recently, the American Society of Anesthesiologists, published guidelines for the management of acute pain in the perioperative setting.(14,15) The major goals of these guidelines are to facilitate the efficacious and safe use of perioperative analgesia while reducing the severity of postoperative pain. The guidelines stress the importance of being proactive in planning analgesia and having patients and families involved in pain management. Education of patients and healthcare providers is needed to encourage optimal and safe use of analgesics. While authoritative guidelines are available, considerable effort is needed in their implementation. A study in 1995 found that only 46% of the hospitals surveyed had acute pain management programs or written guidelines, though an additional 22% planned to implement a pain management program in the near future.(13)

Pathophysiology of Pain

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.(5) Nociceptive pain is transiently invoked when pain-sensitive neurons (nociceptors) are activated by noxious stimuli (eg, physical, chemical, thermal). This pain is a protective response to adverse stimuli and subsides with removal of the stimulus. Nociceptive pain may initiate a phase of persistent acute pain triggered by tissue damage; the cellular and neuronal release of inflammatory mediators, such as prostaglandins, is involved.(16) Uncontrolled pain here increases patients' sensitivity.(8) Prolonged tissue damage and inflammation sensitizes nociceptors, resulting in a decreased pain threshold and protracted response (frequency of neuronal firing), or, hyperalgesia. Like nociceptive pain, hyperalgesia is linked to an adverse stimulus and diminishes with healing and decreased inflammation. Prolonged acute pain and hyperalgesia, however, can evolve into chronic pain.(16)

In contrast to acute pain, chronic pain is not a protective response and is no longer linked to a stimulus.(3) Progressive and prolonged stimulation of pain causes increased excitation of neurons in the dorsal horn of the spinal cord.(5) This phenomenon is sometimes referred to as "wind-up pain." Once established, this abnormal condition continues independently of the initial cause (stimulus) and, for that reason, is considered pathologic pain.(17) Acute pain and hyperalgesia, which take place in the peripheral nervous system can, therefore, be distinguished from chronic pain, which takes place in the central nervous system. Mechanisms maintaining chronic pain are poorly understood.

The role of COX-2 in pain

Management of resolvable pain (eg, postsurgical pain) has benefited from advancements in understanding of the biochemical and molecular basis of pain. In injured tissue, acute pain is evoked locally, being mediated by released cellular components of the inflammatory process. Prominent among these are products of the cyclooxygenase (COX)-2 enzyme, in particular prostaglandin E2 (PGE2) and prostacyclin.(3) PGE2 signals pain input by binding to receptors that regulate the calcium and sodium channels of nociceptive neurons.(18) PGE2 can activate neurons or increase their sensitivity to pain. Following tissue injury, nociceptive fibers themselves are neuroeffective, as stimulated fibers release polypeptide mediators such as substance P, which enhances prostaglandin production.(6)

Inflammation in the periphery also generates pain hypersensitivity in adjacent tissues (secondary hyperalgesia) caused by spinal sensitization and a syndrome of muscle and joint pain, fever, lethargy, and anorexia.(19,20) Therefore, the effects of acute pain are inexorably linked to secondary events resulting from the widespread induction of COX-2 expression and subsequent production of prostaglandins in the spinal cord and brain. Inhibiting central COX-2 activity greatly reduces inflammatory pain hypersensitivity. The role of COX-2 in peripheral and central pain is the rationale for the use of COX-2-selective inhibitors to treat pain and its accompanying syndromes.(21)

Katz WA. Cyclooxygenase-2-selective inhibitors in the management of acute and perioperative pain. Cleve Clin J Med 2002;69:SI65-75.