The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 86, Issue 6

Selected Instructional Course Lecture | June 01, 2004

Acute Pain Following Musculoskeletal Injuries and Orthopaedic Surgery: Mechanisms and Management

Evan F. Ekman, MD¹; L. Andrew Koman, MD²

¹ Southern Orthopaedic Sports Medicine, 1718 St. Julian Place, Columbia, SC 29204. E-mail address: evanekman@msn.com
² Department of Orthopaedic Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157

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The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. E.F. Ekman received payments or other benefits or a commitment or agreement to provide such benefits (none directly related to this manuscript) from commercial entities (Pfizer, Merck, Ortho-McNeil, and DeRoyal). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Printed with permission of the American Academy of Orthopaedic Surgeons. This article, as well as other lectures presented at the Academy's Annual Meeting, will be available in February 2005 in Instructional Course Lectures, Volume 54. The complete volume can be ordered online at , or by calling 800-626-6726 (8 a.m.-5 p.m., Central time).

An Instructional Course Lecture, American Academy of Orthopaedic Surgeons

The Journal of Bone and Joint Surgery, Incorporated

J Bone Joint Surg Am, 2004 Jun 01;86(6):1316-1327

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With the advent of new pain assessment standards and guidelines and advances in the development of analgesic agents, it is timely to discuss current and future approaches to the management of acute pain in orthopaedic practice. With the percentage of elderly patients increasing in the general population, orthopaedic specialists will see an unprecedented number of patients who not only are burdened by pain from acute musculoskeletal conditions but who also expect to stay active longer than did previous generations.

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It is increasingly acknowledged that acute postoperative pain from ambulatory surgery is undertreated and that the consequences of this add to the already huge burden of pain management on patients and society^1-3. Recent advances in the elucidation of the biologic mechanisms underlying the development of both acute and chronic pain suggest that inadequately treated acute pain can result in the sensitization of the peripheral and central nervous system, which may ultimately lead to the development of chronic pain^4-6.

Look for this and other related articles inInstructional Course Lectures, Volume 54, which will be published by the American Academy of Orthopaedic Surgeons in February 2005:• "Complex Regional Pain Syndrome," by L. Andrew Koman, MD, Beth Paterson Smith, PhD, Evan Ekman, MD, and Thomas L. Smith, PhD

Look for this and other related articles inInstructional Course Lectures, Volume 54, which will be published by the American Academy of Orthopaedic Surgeons in February 2005:

• "Complex Regional Pain Syndrome," by L. Andrew Koman, MD, Beth Paterson Smith, PhD, Evan Ekman, MD, and Thomas L. Smith, PhD

The most common musculoskeletal injuries are those involving the back or spine, followed by sprains, dislocations, and fractures—the sum of which account for almost one-half of all musculoskeletal injuries⁷. Ankle injuries are the most common sports and recreational injuries, accounting for 38% to 45% of those injuries^8,9. In 2001, 2.6 million people in North America were seen for foot and ankle injuries¹⁰. More than 40% of ankle sprains can progress to chronic problems¹¹. Knee injuries also burden a considerable portion of the general population.

Arthroscopy of the knee is the second most common type of ambulatory surgical procedure in individuals between the ages of fifteen and fortyfour years, with 357,000 such procedures performed in the United States in 1995¹². Approximately 95,000 new cases of acute rupture of the anterior cruciate ligament occur annually in the United States, and approximately 50,000 of those are reconstructed each year¹³.

Orthopaedic procedures may induce more intense pain than do other surgical procedures because bone injury is more painful than soft-tissue injury. This is due to the periosteum having the lowest pain threshold of the deep somatic structures¹⁴. In two separate studies involving more than 10,000 patients in Canada and Sweden, patients who had undergone orthopaedic surgery had the most intense pain of all patients who had undergone ambulatory surgery^1,15.

On the basis of these trends and statistics, orthopaedists should be adept at addressing acute pain associated with a variety of musculoskeletal conditions, including ankle sprains, back pain, and outpatient procedures. However, studies have suggested that the pain associated with these problems is often undertreated, particularly after ambulatory surgery. One study implied that orthopaedic surgeons undertreat pain, especially after shoulder surgery, operations for hardware removal, and elbow arthroscopy¹.

In addition, health care professionals may lack formal education in pain management or may have mistaken beliefs regarding potential opioid addiction and drug tolerance. Additional factors may be inadequate pain assessment, misinterpretation of orders, and the traditional emphasis on p.r.n. dosing^16,17.

Clinicians have primarily considered undertreatment of pain to be a humanitarian concern. However, consequences can include adverse clinical outcomes and additional economic costs to the patient and provider^18-20. Acute pain results in various physiologic changes that have important effects on the patient's clinical course. Unrelieved pain is likely to cause adverse effects on more than one body system, particularly in high-risk surgical patients, and the development of chronic pain^21-23. For example, severe postoperative pain and increased levels of sympathetic activity may cause reductions in arterial inflow and venous emptying. In a patient who is relatively immobilized because of pain, a hypercoagulable state can lead to venous thrombosis and pulmonary embolism^17,24. It is also generally believed that joint splinting and relative immobilization lead to joint stiffness (e.g., arthrofibrosis in the knee and adhesive capsulitis in the shoulder). Reduced mobility of high-risk patients may also lead to pneumonia²⁵.

Moreover, severe postoperative pain is a common reason for delays in hospital discharge and unanticipated hospital admissions²⁶. Effective pain relief after surgery or acute injury can increase mobility and expedite a patient's return to normal function²². Furthermore, effective pain relief can lead to an earlier return to work and to psychologic benefits.

Over the past thirty years, great strides have been made in understanding the anatomic, physiologic, and molecular basis of pain mechanisms as well as in developing new therapeutic agents to manage pain. There have been major initiatives to refine and standardize guidelines for the assessment and treatment of acute pain. This review will discuss these developments and their relevance to current and future orthopaedic practice.

Anatomic, Physiologic, Cellular, and Molecular Considerations in Acute and Postoperative Pain Management

Pain Transmission in the Peripheral and Central Nervous Systems

To determine the most effective methods of treatment of acute pain and to avoid the subsequent development of chronic pain, it is important to understand the biologic mechanisms by which perception of acute pain develops and how acute pain can progress to chronic pain. Acute pain results from mechanically, chemically, or thermally induced damage to tissue integrity. Nociceptors, which are specialized peripheral sensory neurons, are activated in response to noxious stimuli and lead to neurotransmitter release in dorsal horn neurons in the spinal cord. Neurotransmitters, in turn, relay sensory information to the cerebral cortex by means of the thalamus and elicit acute pain as well as the withdrawal reflex and a variety of heightened physiologic and emotional responses⁵.

A variety of chemicals released by damaged cells in response to tissue injury and local inflammation, including histamine, bradykinin, prostaglandins, serotonin, substance P, acetylcholine, and leukotrienes, further sensitize nociceptors to other noxious stimuli^4,27,28. Sensitization lowers the nociceptive threshold to painful stimuli and can result in repeated afferent input into the nervous system that leads to activation-dependent neuronal plasticity, or the ability of neurons to profoundly alter their structure, function, or biochemical profile. Plasticity has been described as proceeding in three dynamically overlapping stages: activation, modulation, and modification (Fig. 1)⁵.

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Fig. 1:: Activation of nociceptive pathways begins at peripheral terminals of primary sensory neurons. Neuronal plasticity (activation, modulation, and modification) contributes to alteration of the nociceptor terminal threshold. (Reprinted, with permission, from: Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765-9. Copyright [2000] AAAS.)

If inflammation from an injury is treated appropriately, the hypersensitivity that normally develops in damaged tissue resolves without causing major biochemical or cellular changes in the neurons. If inflammation persists, modulation of the pain perception system by inflammatory mediators induces biochemical alterations in receptors and ion channels on the cell surface of peripheral nociceptors. This results in increased sensitization of peripheral sensory neurons (peripheral sensitization)^5,29-31.

Increased and persistent afferent input to the dorsal horn leads to increased neurotransmitter release, activating signaling cascades in postsynaptic neurons. This increased signaling causes posttranslational changes (modulation) in secondary sensory neurons, such as phosphorylation of neuropeptide receptors (e.g., N-methyl-d-aspartate [NMDA] and alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid [AMPA] ion channels), which result in increased sensitivity to neurotransmitter activity, an influx of calcium and potassium ions, and depolarization of the neuronal membrane. These changes in neuronal sensitivity enhance activity in pain transmission neurons (central sensitization). These processes lead to amplified responses to all sensory input and result in allodynia, or pain evoked by a normally innocuous stimulus, and hyperalgesia, an exaggerated, prolonged pain response. Disinhibition of spinal inhibitory mechanisms also occurs. Modification occurs in both peripheral and central neurons and involves induced expression of normally dormant genes that encode ion channels, receptors, and neurotransmitters^31-36.

Cyclooxygenase-2 (COX-2) is also induced in dorsal horn neurons, with a concomitant increase in production of inflammatory prostaglandins such as prostaglandin E₂ (PGE₂). Additionally, there is widespread induction of COX-2 throughout the central nervous system, including the thalamus, ventral midbrain, and pons. Administration of nerve blocks in animal models of inflammation has resulted in partial, but not complete, inhibition of central COX-2 expression, suggesting that factors other than afferent input from the periphery are responsible for COX-2 induction in the central nervous system⁶. The inflammatory cytokine interleukin-1 (IL-1) also induces COX-2 expression and subsequent PGE₂ production in the central nervous system⁶. Administration of a COX-2-specific inhibitor or IL-1 receptor antagonist in these animal models reduced mechanical hyperalgesia, suggesting a role for COX-2 in the development of central sensitization⁶.

Sensitization of the peripheral and central nervous systems, if improperly treated, can result in neuronal plasticity such that hypersensitive pain responses persist even after the initial injury has resolved. It is believed that such modification of the central nervous system may ultimately lead to the development of chronic pain in some patients. Additionally, there is evidence of a neuropathic component in some chronic conditions arising from acute pain syndromes when nerve damage may have been sustained during the initial trauma⁵.

The complexity of the pain pathways involved in the perception and transmission of pain and in the development of peripheral and central sensitization suggests that no single analgesic agent will manage pain adequately. Multimodal therapy—i.e., the use of two or more analgesic agents with different modes of action—is becoming increasingly common and will be discussed in more detail.

Cognitive and Metabolic Modifiers of the Physiologic Pain Process

Pain is recognized not only as a sensory experience but also as a phenomenon with affective and cognitive components^28,37. Factors such as age, gender, culture, communication skills, and previous pain experiences may play a role in determining an individual's perception of pain^38,39. Physiologic and behavioral studies have shown that perception of pain is altered by previously conditioned cues in the environment or by the expectation of pain and suffering. In addition to pain, tissue injury produces stress, which leads to the release of chemical mediators from the injury site, the adrenal cortex, and the immune system, all of which, in turn, interact with mediators of pain⁴⁰.

The general stress response to surgical and other trauma results in endocrine and metabolic changes that affect respiratory, cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems. These changes can cause nausea, intestinal stasis, alterations in blood flow, coagulation, and fibrinolysis; increase demands on the cardiovascular and respiratory systems; and affect water and electrolyte flux^23,41. The general stress response may be caused by nociceptive impulses and by factors including anxiety, hemorrhage, and infection as well as local tissue factors^22,42.

Unrelieved pain can produce physiologic and psychologic effects, including delayed wound repair, muscle spasm, sensitization, limited mobility, and impaired immunocompetence. Anxiety and fear resulting from unrelieved severe acute pain can exacerbate the perception of pain and lead to behavioral changes, including depression. Pain also can cause sleeplessness, which can compound a vicious cycle of acute pain, anxiety, and additional sleep deprivation^22,43. Acute pain has been associated with decreased peripheral blood flow, which can have deleterious effects on wound repair. Reflex responses, such as vasoconstriction, may be partly reversed by effective pain relief^16,17.

Segmental and suprasegmental motor activity in response to pain results in muscle spasm, which can compound the pain. This cycle also may activate sharp increases in sympathetic activity and further increase the sensitivity of peripheral nociceptors²². Persistent postoperative pain and limited mobility may be associated with impaired muscle metabolism, muscular atrophy, and marked delays in the return to normal muscular function. In addition, changes in immunocompetence and acute-phase proteins after surgical trauma have been documented²².

The profound effects of pain transmission on the nervous system as well as the cognitive, metabolic, and physiologic responses to pain greatly emphasize the need for further development of effective therapeutic agents. After decades without fundamental advances in pain management options, discoveries in the past thirty years have led to the development of a variety of new modalities and the refinement of old ones^44,45. Inflammatory mediators that sensitize nociceptors—e.g., prostaglandins and neurotransmitters—are major targets of both old and new drugs.

Pain Assessment Guidelines and Standards

Over the last twenty years, new pain management guidelines and standards have been proposed. In 1986, the World Health Organization proposed guidelines for the selection of appropriate drug regimens for pain⁴⁶. Guidelines specifically for postoperative pain management were introduced in Australia in 1988⁴⁷ and in the United Kingdom in 1990⁴⁸. The first Clinical Practice Guidelines for pain treatment were published in 1992 by the Agency for Health Care Policy and Research⁴⁹ (now called the Agency for Healthcare Research and Quality). The American Society of Anesthesiologists published Clinical Practice Guidelines for managing both acute⁵⁰ and chronic pain⁵¹.

The National Pharmaceutical Council in collaboration with the Joint Commission on Accreditation of Healthcare Organizations recently published a comprehensive review of pain assessment and treatment guidelines⁵². These and other organizations have also developed Clinical Practice Guidelines in specific disciplines and for management of pain due to specific conditions. The most current initiatives in postoperative pain management focus on providing comprehensive evidence-based research related to specific anatomic sites of surgery^53,54. One such initiative is the online Procedure Specific Postoperative Pain Management (PROSPECT) initiative, which can be found online (). The American Academy of Orthopaedic Surgeons has produced clinical guidelines, which are also available online (), for managing hip, knee, low-back, wrist, and shoulder pain; ankle and knee injury; and knee osteoarthritis.

In 1995, the American Pain Society coined the phrase "Pain: The 5th Vital Sign," with the intention that pain assessment should be considered to be as important as measurement of other vital signs⁵⁵. The standards recommend that patients be assessed for pain every time pulse, blood pressure, core temperature, and respiration are measured. The Joint Commission on Accreditation of Healthcare Organizations adopted this idea and proposed that pain become a fifth vital sign for their 2000-2001 pain standards. An important concept in these standards is that patients have a right to have appropriate assessment and management of their pain. Organizations accredited by the Joint Commission on Accreditation of Healthcare Organizations are required not only to recognize each patient's right to pain assessment and treatment, but also to monitor responses to pain interventions and to provide pain management education to staff and patients⁵⁶.

The development of a pain management plan should be a collaborative effort among the physician, nursing staff, anesthesiology team, patient, and patient's family⁵⁷. A member of the anesthesiology department should obtain a pain history during the preoperative visit⁵⁷.

According to the guidelines of the American Society of Anesthesiologists, pain assessment and reassessment should take place during the preoperative, intraoperative, and postoperative management of pain. The patient and family should be prepared preoperatively to understand their responsibilities in pain management, and pain management tools should be reviewed. The guidelines of the American Society of Anesthesiologists also recommend that the patient be involved in the determination of the pain score criteria that will result in a dose increment or another intervention and that the assessment of pain after surgery be frequent and simple⁵⁸. Once the patient has recovered from anesthesia, the mainstay of pain assessment should be the patient's self-report, which should be used to assess pain perceptions and cognitive response, and the patient should be assessed for pain during routine activity such as movement⁵⁷. It should be recognized that a patient's behavior and selfreport of pain may show discrepancies as a result of excellent coping skills. Therefore, members of the health care team should emphasize the importance of a factual report from the patient⁵⁷.

Pain Assessment Instruments

Pain measurement instruments are employed to evaluate and document pain and are useful for studying pain mechanisms and for assessing methods for controlling pain. Clinicians also use pain end points as sensitive surrogates to demonstrate how a method of pain relief mediates postoperative responses, such as clinical course or recovery time. However, proving a correlation between a pain relief modality and postoperative responses requires very large sample populations because major outcomes, such as death or morbidity, are uncommon events among patients undergoing elective surgery. Other outcome variables, such as hypoxemia, return of bowel function, and pulmonary function, can be defined clearly and timed, but relationships between such variables and outcomes such as major morbidity are indirect.

Common pain assessment measures include pain intensity, pain relief, and function. When an appropriate measurement tool is being selected, the patient's age; developmental status; physical, emotional, or cognitive condition; and preference should be considered. Most pain instruments rely on verbal assessments of pain because the correlation between physical abnormalities and patients' reports of pain has been found to be poor and ambiguous. Intensity is considered to be the most salient dimension of pain, and many procedures for quantifying this dimension have been validated. However, because pain is a complex, multidimensional, subjective experience, the use of a single dimension, such as intensity, does not capture the other qualities and dimensions of the pain experience.

The visual analog scale⁵⁹ is commonly employed to measure pain intensity and pain relief. It consists of a 10-cm horizontal line with the descriptors "no pain" and "pain as bad as it could possibly be" at the two ends. The patient places a mark at the point between the two ends that best represents the intensity of his or her pain. This scale has the advantage of being easy to administer and minimally obtrusive, but it does not take into account the subjective and multidimensional characteristics of pain, including affective qualities. It is, however, widely accepted and validated, and it is easily added to any existing medical record.

Another common tool for measuring pain intensity or pain relief is the Patient's Global Evaluation. Typically, the assessment uses a query such as, "How would you rate the maximum pain relief after treatment?" or "How would you rate the study medication you received for pain?" Patients respond with a discrete number on a scale or select from among possible ratings such as excellent, very good, good, fair, or poor. The format of the Patient's Global Evaluation can also be used to measure a specific component, such as nausea.

In addition to the visual analog scale, the McGill Pain Questionnaire is the most frequently used self-rating instrument. It was designed to assess the multidimensional nature of the pain experience with use of sensory, affective, and evaluative words, and it has been demonstrated to be a reliable, valid, and consistent measurement tool. The McGill Pain Questionnaire evolved into components of the American Pain Society Patient Outcome Questionnaire⁶⁰. It uses small groups of descriptive words to assess the sensory, subjective, and affective qualities of pain. The questionnaire is often used to assess chronic pain. Its purpose is to examine the level of disability and interference caused by pain.

Other ways to measure pain include assessing physical function, the behavioral manifestations of pain, and the psychologic contributions to the pain experience. Physical function can be evaluated with objective measures as well as with individuals' self-reports of their abilities to engage in a range of functional activities. Self-report devices measure components such as function, interference, and other affective qualities. Studies have shown high correlations among self-reports, disease characteristics, physicians' ratings of functional abilities, and objective functional performance. Although pain behaviors have not been found to be uniquely or invariably associated with the experience of pain, psychologic factors have been found to modulate pain responses. Therefore, instruments to assess psychologic factors associated with pain also have been developed and validated. Psychologic status, particularly anxiety, seems to influence pain and patient-controlled analgesia. Education of the patient about what to expect before, during, and after surgery can decrease anxiety and decrease postoperative pain. Anxiety can be measured by using a combination of qualitative components from the McGill Pain Questionnaire and the State-Trait Anxiety Inventory. Comprehensive approaches that address psychologic contributions to pain and suffering have been proposed for the measurement of pain.

Approaches to the Treatment of Acute Pain

Some of the oldest known analgesics are still used for the treatment of acute injury as well as pain after orthopaedic surgery. Use of opium as an analgesic dates back to before the first century BC. In the mid-nineteenth century, morphine and codeine were purified as alkaloids from opium. The bark of the willow tree, long known for its medicinal properties, was the predecessor to aspirin, which was first synthesized in 1860 for use as an antipyretic. Acetaminophen was first used medically in 1893⁶¹. In the late 1970s, ibuprofen was the first propionic acid derivative to be used in the United States. Naproxen, ketoprofen, and others followed in the 1980s.

In 1971, Vane proposed inhibition of prostaglandin synthesis as the primary mechanism of action of nonsteroidal anti-inflammatory drugs⁶². The enzyme responsible for the initial steps of prostaglandin synthesis from arachidonic acid, COX, was first isolated and purified in enzymatically active form in 1976⁶³. The discovery in the early 1990s of two isoforms of COX (COX-1 and COX-2)^64,65 was followed by the development of a novel group of anti-inflammatory agents, the COX-2-specific inhibitors. A third COX enzyme, COX-3, was recently identified⁶⁶ and will be discussed in greater detail.

In 1999, neuropeptides, including substance P, were discovered to have a role as the primary transmitters of nociceptive information; subsequently, a substance-P agonist was discovered⁶⁷.

Although many targets for pain and analgesia have been discovered, no individual therapy targets them all, and it is unlikely that therapies under development will do so. Therefore, multimodal approaches to pain relief⁴¹ and the potential for preemptive pain relief^68,69 have been studied.

Mechanisms and Actions of Therapies

The goals of pain management in orthopaedics are to meet the humanitarian need for pain relief and to facilitate rehabilitation and return to normal function. These goals are accomplished by reducing pain and inflammation at both the central and the peripheral level. The various approaches to achieving these goals—both current and investigational—are discussed in this section.

Opioids

Opioids include all endogenous and exogenous compounds that possess morphine-like analgesic properties. They are classified as agonists, agonist-antagonists, and antagonists and are characterized by their effects on individual or multiple opioid receptors. Categories of agonists commonly used for analgesia include the phenanthrene alkaloids (such as morphine and codeine), the semisynthetic opioids (such as hydrocodone and oxycodone), and the synthetic opioids (such as meperidine, fentanyl, and sufentanil). Commonly used agonist-antagonists are the semisynthetic opioids (such as buprenorphine and nalbuphine).

In orthopaedic practice, opioids are commonly used to treat moderate-to-severe pain, usually acute in nature, such as that associated with fractures and soft-tissue injury. Opioids produce their analgesic effect by mimicking the actions of endogenous opioid peptides at specific receptors within the central nervous system. The three major classes of opioid receptors are mu (µ) (to which morphine binds), kappa (?), and delta (d); in addition, there are subtype receptors within each class. For example, µ₁ produces supraspinal analgesia, and µ ₂ affects respiratory, cardiovascular, and gastrointestinal function. The kappa and delta receptors also produce spinal analgesia, and sedation results from the activation of the ? receptors⁷⁰.

Although µ agonists produce alterations in mood and sleep, unconsciousness cannot be guaranteed at anesthetic doses. The effects of µ agonists on bowel motility are the result of concomitant reduction in the propulsive peristaltic contractions of both the small and the large intestine and enhanced sphincteric tone. Also, by stimulating the vagal nucleus in the medulla, agonists produce dose-dependent bradycardia^70,71.

Nonspecific Nonsteroidal Anti-Inflammatory Drugs

The primary mechanism of action of nonsteroidal anti-inflammatory drugs is inhibition of prostaglandin production by the COX enzyme⁶². Analgesia and the anti-inflammatory activity of nonsteroidal anti-inflammatory drugs are produced by inhibition of the COX-2 isoenzyme.

Arachidonic acid metabolism produces prostanoids that regulate normal cell activity, notably in the gastric mucosa, kidney, and vascular endothelial cells. COX-1 is expressed constitutively in these and most other tissues, whereas COX-2 is inducibly expressed only in the central nervous system, kidney, tracheal epithelium, and testicles⁷². PGE₂ is produced in the gastrointestinal tract; it acts as a vasodilator and plays a key role in defense and repair mechanisms designed to maintain gastrointestinal mucosal integrity. In the kidney, PGE₂ induces diuresis and natriuresis⁷³. It also exerts an inhibitory action on lymphocytes and on other cells that participate in inflammatory and allergic responses⁷⁴. In platelets, thromboxane A₂ is the primary metabolite of arachidonic acid⁷³. Prostacyclin (PGI₂) potently inhibits platelet aggregation and has vasodilatory effects⁷³. Conventional nonsteroidal anti-inflammatory drugs such as ibuprofen, meloxicam, naproxen, and diclofenac have a relatively linear structure, which allows them to fit readily into the active site of both COX-1 and COX-2 and thus to nonspecifically inhibit both isoforms^75,76. The anti-inflammatory and analgesic effects of nonspecific nonsteroidal anti-inflammatory drugs result from the inhibition of COX-2, whereas the inhibition of COX-1 adversely affects the production of prostanoids involved in normal homeostatic mechanisms such as protection of gastric mucosa.

COX-2-Specific Inhibitors

In contrast to nonspecific nonsteroidal anti-inflammatory drugs, COX-2-specific agents, including celecoxib, rofecoxib, and valdecoxib, were developed with a bulky side chain that binds to the catalytic binding site of COX-2 with substantially greater affinity than it binds to the binding site of COX-1, allowing selective inhibition.

A parenteral water-soluble prodrug of valdecoxib, parecoxib sodium (parecoxib), is available in the European Union for treatment of short-term postoperative pain⁷⁷ and is currently an investigational drug in the United States. Other COX-2-specific inhibitors, such as etoricoxib^78,79 and lumiracoxib⁸⁰, are also being investigated.

COX-2-specific inhibitors are at least as effective as nonspecific nonsteroidal anti-inflammatory drugs for managing pain associated with chronic conditions such as osteoarthritis^81-86 and rheumatoid arthritis^87-89 as well as pain resulting from acute soft-tissue injury. In a study of acute ankle sprains, the time to return to normal activity was reduced by one day for patients treated with celecoxib compared with those treated with a nonspecific nonsteroidal anti-inflammatory drug⁹⁰. COX-2-specific inhibitors have also been shown to be as effective as hydrocodone or acetaminophen in relieving postoperative pain following various ambulatory orthopaedic procedures, including anterior cruciate ligament repair, laminectomy, open reduction and internal fixation of long-bone fractures, and osteotomy⁹¹. They have also demonstrated efficacy in relieving postoperative pain from oral surgery⁹², hip arthroplasty⁹³, and bunionectomy⁹⁴.

COX-2-specific inhibitors not only have similar efficacy but also have greater gastrointestinal safety and tolerability compared with nonspecific nonsteroidal anti-inflammatory drugs. The results of multiple clinical trials have shown that treatment with COX-2-specific inhibitors is associated with significantly fewer ulcer-related complications than is treatment with nonspecific nonsteroidal anti-inflammatory drugs (p < 0.05)⁹⁵. One example is the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial⁹⁶, which compared the safety and efficacy of rofecoxib (50 mg daily) and naproxen (500 mg daily) in 8076 patients with rheumatoid arthritis who were treated over nine months. The results of this trial indicated that rofecoxib caused significantly fewer upper gastrointestinal events than did naproxen (p < 0.05). Another example is the Celecoxib Long-Term Arthritis Safety Study (CLASS)⁹⁷, which was conducted over six months and involved 8059 patients with osteoarthritis and rheumatoid arthritis. The results of this study showed that, even at supratherapeutic doses (400 mg twice daily), celecoxib was associated with a lower prevalence of gastrointestinal ulcers and ulcer-related complications than were therapeutic doses of ibuprofen (800 mg three times daily) or diclofenac (75 mg twice daily). Analysis of long-term (thirteen to fifteen-month) follow-up data from the CLASS study revealed that the combined prevalence of complicated and symptomatic gastrointestinal ulcers associated with nonspecific nonsteroidal anti-inflammatory drugs was greater than that associated with celecoxib⁹⁸.

Other studies have shown that even short-term use of COX-2-specific inhibitors is significantly less toxic to the upper gastrointestinal mucosa than is short-term use of nonspecific nonsteroidal anti-inflammatory drugs (p < 0.05). A preliminary endoscopic study of the upper gastrointestinal tract demonstrated gastric ulcers in 19% of patients who had taken naproxen for one week but in none who had taken celecoxib for the same duration⁹⁹. Another study comparing the effects of valdecoxib (40 mg twice daily) and naproxen (500 mg twice daily) in healthy elderly subjects showed that, even after only one week of treatment, naproxen was associated with a significantly higher prevalence of gastroduodenal ulcers than was valdecoxib (p < 0.05)¹⁰⁰.

There is some evidence that use of rofecoxib is associated with an increased prevalence of adverse cardiovascular events. In the VIGOR trial, the rate of myocardial infarction with rofecoxib was threefold to fourfold higher than the rate with naproxen⁹⁶. However, in the CLASS trial, there were no significant differences among celecoxib, diclofenac, and ibuprofen with regard to the prevalence of adverse cardiovascular events, even in patients who were not taking aspirin⁹⁷. In a recent matched case-control study of 54,475 patients with osteoarthritis taking either celecoxib or rofecoxib, use of rofecoxib was associated with an increased adjusted relative risk of acute myocardial infarction¹⁰¹. This risk was highest in patients taking >25 mg of rofecoxib.

Platelet aggregation and hemostasis depend on the ability of platelets to generate thromboxane A₂, which is synthesized from arachidonic acid by COX. Platelets lack COX-2 and depend on COX-1 to indirectly produce thromboxane. Because nonspecific nonsteroidal anti-inflammatory drugs prevent the formation of prostaglandins through the inhibition of COX-1, the tendency toward bleeding is increased¹⁰². Aspirin exerts these effects irreversibly for the life of the circulating platelet, whereas other nonspecific nonsteroidal anti-inflammatory drugs have a reversible, dose-dependent effect. Normal platelet function is reflected by a normal bleeding time. For the orthopaedist, normal platelet function is clinically important in surgically treated patients, in whom appropriate hemostasis decreases perioperative bleeding and the comorbidities associated with it (including hemarthrosis, wound problems, infection, poor visualization during arthroscopy, and an increased need for transfusion). In acute injuries such as ankle sprain, bleeding causes volumetric changes in addition to pain and inflammation; thus, normal platelet aggregation is again important. Bleeding also has a bearing on rehabilitation because hemarthroses have a deleterious effect on motion and strength. In this area, COX-2-specific inhibitors are an attractive alternative to nonspecific nonsteroidal anti-inflammatory drugs because of their lack of clinically important effects on platelet aggregation and bleeding time. All COX-2-specific inhibitors, including celecoxib, valdecoxib, parecoxib, and rofecoxib—even at supratherapeutic doses—have been shown to not interfere with platelet function, even in elderly patients^103-107.

The decision whether to use a nonspecific nonsteroidal anti-inflammatory drug or a COX-2-specific inhibitor depends on the individual situation. Although COX-2-specific inhibitors and nonspecific nonsteroidal anti-inflammatory drugs have similar efficacy, care must be taken to assess the risks, limitations, and benefits prior to selecting the appropriate treatment. When the risk of gastrointestinal complications and compromised platelet function is not a consideration, nonspecific nonsteroidal anti-inflammatory drugs may be the treatment of choice. On the other hand, if there is an elevated risk of gastrointestinal bleeding, ulceration, or ulcer-related complications, it would be preferable to use a COX-2-specific inhibitor—even if only short-term treatment is warranted. In situations in which normal platelet function is useful, as in any surgical procedure, or in cases of acute injury in which bleeding, hemarthrosis, and ecchymosis may be part of the pathology, a COX-2-specific inhibitor should be considered. However, in patients with cardiovascular disease, rofecoxib should be used only with caution.

Centrally Acting Nonopioids

The antipyretic and analgesic effects of acetaminophen (paracetamol) are centrally mediated. Acetaminophen is believed to exert its analgesic effects by increasing the pain threshold, possibly by means of central inhibition of prostaglandin production. Its antipyretic properties have been attributed to its action on the hypothalamic heat center¹⁰⁸. Acetaminophen has been shown to selectively inhibit COX-3, a COX-1 variant recently cloned from the canine cerebral cortex⁶⁶. There is some biochemical evidence of the existence of a third human COX isoform, the human COX-3 isoform, which may play a role in the central analgesic and antipyretic effects of acetaminophen^66,109-111.

Acetaminophen or aspirin, when compounded with narcotics, effectively relieves moderate-to-severe acute postoperative pain¹⁷. Oral preparations of opioids such as morphine and meperidine are not well absorbed alone. However, oxycodone is particularly effective as a result of its relatively high absorption rate, and it is often used in combination with acetaminophen¹⁷.

Tramadol, a synthetic analog of codeine¹¹², has a dual mode of action, both as a centrally acting analgesic agent with a weak affinity for the µ, omega (?), and opioid receptors and as an inhibitor of norepinephrine and serotonin uptake. Orally administered tramadol and nonsteroidal anti-inflammatory drugs are useful as supplements to treatment with regional neural blockade in patients with mild-to-moderate pain.

The combination of tramadol and acetaminophen has been used successfully to treat moderate to moderately severe acute and chronic pain. This combination has several advantages, including rapid onset of analgesia, due to the acetaminophen, and a longer duration of analgesia, due to the tramadol. Adverse events associated with this combination are similar to those observed with tramadol monotherapy, such as dizziness or vertigo and seizure^113,114. In studies of postoperative dental pain, the combination of tramadol and acetaminophen has been shown to be more effective than either agent alone and to provide efficacy similar to that of a hydrocodoneparacetamol combination¹¹⁵.

Local and Regional Anesthesia

Local anesthetics are used primarily for surgery, as opposed to acute injury or nonsurgical pain. Local anesthesia and regional blocks are often used by themselves for anesthesia and as part of a multimodal approach to perioperative pain management.

Local anesthetics may block peripheral nerve function through several mechanisms, with their primary mode being through sodium channel and axonal conductive blockade. These agents may reduce sodium conductance by interacting with the surrounding lipid membrane or by altering membrane fluidity¹¹⁶. Local anesthetics have extensive effects on presynaptic calcium channels that function to stimulate the release of neurotransmitters. Interference with calcium channel conductance can potentiate spinal anesthesia¹¹⁷.

When administered as an epidural infusion, local anesthetics such as ropivacaine or bupivacaine are effective analgesics, particularly in patients who are highly susceptible to the adverse effects associated with opioids. Placement of the epidural tip at the dermatomal level relevant to the surgery, with continuous infusions of dilute anesthetic (approximately 0.1% at 5 to 12 mL/hr) can minimize adverse events such as hypotension and impaired micturition and can maximize the analgesic effect¹⁷.

It is important to note that the analgesic effects of neuraxial blocks only partially inhibit pain responses and do not affect any humoral component such as the activity of inflammatory cytokines like IL-1⁶. Additionally, the analgesic effects are quickly reversed when the block is removed¹⁶. Therefore, these agents should be used in conjunction with other forms of pain control.

Neuraxial analgesia can be associated with adverse effects such as respiratory depression, nausea, and pruritus; patients should be monitored constantly to minimize these problems. Prophylactic naloxone infusions can relieve respiratory depression as well as other opioid-related side effects in elderly patients¹¹⁸. Prophylaxis against deep venous thrombosis with low-molecular-weight heparin in patients treated with spinal or epidural neuraxial analgesia is associated with a risk of epidural hematoma. Guidelines for preventing this problem were recently proposed by the American Society of Regional Anesthesia and Pain Medicine¹¹⁹.

Novel Approaches to Treatment of Acute PainMultimodal Analgesia

There is a trend toward increasing utilization of multimodal analgesia in orthopaedic surgery and for the management of musculoskeletal injury. A combination of approaches, both pharmacologic and nonpharmacologic (such as the use of ice or "cooling units"), can address multiple mechanisms of pain, with the added benefit of reducing side effects through the use of lower doses of individual modalities¹²⁰. There is increasing evidence that multimodal therapy can shorten the hospital stay, lessen the adverse effects of opioids by decreasing dosage, and improve patient outcomes⁴¹.

A number of randomized trials have demonstrated the effectiveness and opioid-sparing properties of nonspecific nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac¹²¹, and piroxicam¹²² in the relief of acute postoperative pain.

Recently, several studies have shown that, following hip or knee arthroplasty, administration of the COX-2-specific inhibitors valdecoxib^93,123 (off-label use) and parecoxib^124,125 (investigational in the United States) significantly reduces the dose of opioid required for effective acute postoperative analgesia and provides better pain relief than does opioid analgesia alone (p < 0.05). A study of the efficacy of intravenous doses of parecoxib (20 and 40 mg), ketorolac (30 mg), and morphine (4 mg) in relieving postoperative pain following total knee replacement showed that parecoxib and ketorolac have a similar onset of action, duration of analgesia, and level of analgesia¹²⁶. Morphine was similar to parecoxib and ketorolac with regard to onset of action but provided a significantly shorter duration and lower level of analgesia (p < 0.01).

Several studies have shown that parecoxib administered intravenously prior to laparoscopic cholecystectomy followed by postoperative treatment with oral valdecoxib (off-label use) reduces opioid use, with concomitant improvement in health outcomes and a reduction in opioid-related adverse effects^127-129.

A recent study provides evidence that preoperative administration of COX-2-specific inhibitors increases the time until postoperative opioid use and is opioid sparing¹³⁰. Patients who received rofecoxib (50 mg) one hour before undergoing ambulatory arthroscopic knee surgery required postoperative opioid treatment later and received lower doses of opioids than did those who received a placebo. Rofecoxib, 50 mg administered both before and after total knee arthroplasty, significantly reduced epidural and in-hospital opioid consumption (p < 0.05)¹³¹.

Preemptive Analgesia

The overall value of preemptive analgesia has been examined in several reviews and still remains controversial^68,132. Until recently, the central question regarding preemptive analgesia was whether an intervention carried out before pain starts has a greater analgesic effect than does the same intervention (with the same route and dose) performed after the onset of pain¹³³. Using this strict definition of preemptive analgesia, McQuay et al. concluded that there was no evidence that nonsteroidal anti-inflammatory drugs or acetaminophen had a preemptive effect¹³³. Their studies of opioid or local anesthetic infiltration showed mixed results, and they did not find spinal and nerve blocks to have any effect.

Few studies have provided unequivocal support for the concept of preemptive analgesia according to this conventional definition. However, Kissin reviewed the studies on preemptive analgesia and recommended that the definition be extended to include the reduction of central sensitization⁶⁹. Using this definition, he concluded that the evidence from positive clinical studies in combination with basic science sufficiently validates the phenomenon of preemptive analgesia.

Preemptive analgesia may have less of an effect in patients with preoperative pain who undergo orthopaedic procedures, as was demonstrated in a study showing a definitive preemptive effect on postoperative pain following hardware removal and mass excision but less of an effect after fracture and arthritis-related surgery^134,135. While preemptive analgesia had been considered the turf of anesthesiologists, orthopaedic surgeons are now taking a more active role in developing preemptive analgesia protocols.

It has also been suggested that the timing of preemptive analgesia, coordinated so that the analgesic reaches peak levels in the peripheral and central nervous system as a surgical procedure begins, may influence the effectiveness of postoperative pain relief. It has been proposed that additional studies on the timing of aggressive "protective" perioperative multimodal therapy, rather than conventional perioperative doses, be performed to determine whether this is the case¹³⁶.

The terms "preoperative analgesia" and "preemptive analgesia" have often been used interchangeably; however, they are not necessarily equivalent. Preemptive analgesia is preventive and does not simply imply administration prior to surgery. Therefore, not all preoperative analgesia is preemptive^69,136.

Nonpharmacologic Management

Nonpharmacologic interventions include behavioral interventions and physical agents. Cognitive behavioral therapies can change patients' perceptions of pain, alter pain behavior, and provide patients with a greater sense of control over pain. Physical agents provide comfort, correct physical dysfunction, alter physiologic responses, and reduce fears associated with pain-related immobility or restriction of activity. Examples of physical modalities include application of superficial heat or cold, massage, exercise, immobility, and electroanalgesia, such as transcutaneous electrical nerve stimulation (TENS). Nonpharmacologic interventions are not intended to substitute for pharmacologic or other invasive techniques of pain management. However, they are sometimes used in the multimodal approach to analgesia by contributing to the effects of pharmacologic analgesia⁵⁷.

Overview

In recent years, we have become increasingly aware of the problems caused by undertreated acute pain following musculoskeletal injuries and orthopaedic surgery. As outlined above, many steps have been taken to improve awareness as well as treatment of acute pain. In addition, there are new approaches to anesthesia and analgesia, including preemptive analgesia and multimodal therapy. Potential future therapeutic targets include IL-1, which has been shown to induce expression of COX-2 in the central nervous system⁶. Inhibition of IL-1 possibly prevents not only production of COX-2 but also other mediators of inflammation such as PGE synthase⁴⁵. The future of pain management requires further development of standards, guidelines, and pain assessment tools rooted in evidence-based practice. Advances in the understanding of the molecular mechanisms underlying neuronal plasticity should provide the basis for the next generation of therapies for effective management of acute pain in orthopaedic practice.

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Topics

analgesics ; anti-inflammatory agents, non-steroidal ; pain ; pain measurement ; pain, postoperative ; pain management ; analgesia (pain absence) ; acute pain ; musculoskeletal injuries ; preemptive analgesia

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Evan F. Ekman, L. Andrew Koman; Acute Pain Following Musculoskeletal Injuries and Orthopaedic SurgeryMechanisms and Management. The Journal of Bone & Joint Surgery. 2004 Jun;86(6):1316-1327.

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