JBJS | Pain Management in Patients Who Undergo Outpatient Arthroscopic Surgery of the Knee*

The Journal of Bone & Joint Surgery, Volume 82, Issue 12

Current Concepts Review | December 01, 2000

Pain Management in Patients Who Undergo Outpatient Arthroscopic Surgery of the Knee*

Scott S. Reuben, M.D.†; Joseph Sklar, M.D.‡

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
†Department of Anesthesiology, Baystate Medical Center, 759 Chestnut Street, Springfield, Massachusetts 01199. E-mail address: scott.reuben@bhs.org.
‡New England Orthopedic Surgery, 300 Carew Street, Springfield, Massachusetts 01104. E-mail address: jsklar@concentric.net.

The Journal of Bone & Joint Surgery. 2000; 82:1754-1754

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Introduction

?Arthroscopy of the knee joint produces an initial afferent barrage of pain signals that have the capacity to initiate prolonged changes in the nervous system leading to the amplification and prolongation of postoperative pain.

?Preemptive analgesia involves the administration of analgesics prior to painful stimuli to prevent the amplification of postoperative pain.

?It is currently recommended that multimodal analgesic regimens be utilized in the management of postoperative pain.

?Intra-articular bupivacaine and morphine are effective analgesics for arthroscopic knee surgery.

?Intra-articular ketorolac, corticosteroids, and clonidine may also have a role in reducing pain following arthroscopic knee surgery.

?Nonsteroidal anti-inflammatory drugs play an important role in the management of postoperative orthopaedic pain, and the newer cyclooxygenase-2-specific nonsteroidal anti-inflammatory drugs may have additional advantages with respect to safety.

?Preemptive and multimodal analgesic techniques should be utilized in the management of patients undergoing anterior cruciate reconstruction.

Arthroscopy of the knee joint, including reconstruction of the anterior cruciate ligament, is a common procedure that is routinely performed on an outpatient basis. Traditionally, oral analgesics are prescribed for the management of postoperative pain. The routine prescription of oral opioid analgesics administered on an as-needed basis, however, frequently results in inadequate pain relief¹¹². Unrelieved postoperative pain may delay the patient's eligibility for discharge, resulting in a prolonged hospital stay, inability to participate in rehabilitation programs, delayed recovery, poor outcome, and greater use of health-care resources¹¹². At present, several techniques are available to treat pain following arthroscopic knee surgery; these include the use of opioids (providing either peripherally or centrally mediated analgesia), local anesthetics, nonsteroidal anti-inflammatory drugs, corticosteroids, clonidine, and cryotherapy (Fig. 1). In this paper, we will present a review of the current knowledge of the principles of acute pain physiology as well as current techniques for the control of pain associated with arthroscopic knee surgery.

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Fig. 1:: Drawing depicting sites of action of analgesics along the pain pathway from the periphery to the central nervous system (CNS). NSAIDs = nonsteroidal anti-inflammatory drugs.

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Fig. 2:: Surgical trauma leads to the release of inflammatory mediators at the site of injury, resulting in a reduction in the pain threshold at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia). Peripheral sensitization results from a reduction in the threshold of nociceptor afferent terminals secondary to surgical trauma. Central sensitization is an activity-dependent increase in the excitability of spinal neurons (spinal wind-up) as a result of persistent exposure to afferent input from peripheral neurons. CNS = central nervous system, and NSAIDs = nonsteroidal anti-inflammatory drugs.

Principles of Acute Pain Physiology

Operative procedures produce an initial afferent barrage of pain signals and generate a secondary inflammatory response, both of which contribute substantially to postoperative pain. The signals have the capacity to initiate prolonged changes in both the peripheral and the central nervous system that will lead to the amplification and prolongation of postoperative pain¹²¹. Peripheral sensitization, a reduction in the threshold of nociceptor afferent peripheral terminals, is a result of inflammation at the site of surgical trauma⁸². Central sensitization, an activity-dependent increase in the excitability of spinal neurons, is a result of persistent exposure to nociceptive afferent input from the peripheral neurons¹¹⁹. Taken together, these two processes contribute to the postoperative hypersensitivity state ("spinal wind-up") that is responsible for a decrease in the pain threshold, both at the site of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia)¹²¹ (Fig. 2).

Over the past decade, a greater understanding of pain mechanisms has led to the concept of preemptive analgesia. Preemptive analgesia involves the administration of analgesics prior to painful stimuli to prevent the establishment of central sensitization and thus the amplification of postoperative pain¹¹⁴. The concept of preemptive analgesia is based on animal studies^13,23,120 that revealed that local anesthetics or opioids can prevent the development of prolonged behavioral and physiological sequelae following brief noxious stimuli. In contrast, these agents were found to be less effective when they were administered after the development of central hyperexcitability. However, the results of human clinical studies are more controversial⁵⁷. Although the benefits of preemptive analgesia have been extensively reported in the anesthesia and general surgical literature¹²¹, they have received little attention in the orthopaedic literature.

Total or optimal pain relief allowing normal function is difficult to achieve with a single drug or method⁵⁵. It is currently recommended that combined analgesic regimens (multimodal analgesia) that operate through different mechanisms or sites be utilized. A multimodal analgesic regimen takes advantage of the additive or synergistic effects of various analgesics, permitting the use of smaller doses with a concomitant reduction in side effects⁵⁵. At present, several analgesic techniques are available to block nociceptive transmission following arthroscopic knee surgery. At the peripheral level, one may utilize nonsteroidal anti-inflammatory drugs, corticosteroids, opioids, or cryotherapy. Local anesthetics block neuronal transmission at the site of instillation, and oral opioids work at the level of the central nervous system (Fig. 1).

The primary goal of modern pain management is to reduce pain at both the central and the peripheral level, in combination with preemptive analgesia. This strategy should enhance restoration of function by allowing patients to walk and to participate in rehabilitation programs more easily, thereby improving the overall postoperative outcome.

Arthroscopic Knee Surgery

Arthroscopy of the knee has spared patients large incisions and decreased morbidity compared with those of open procedures, but it has not eliminated pain⁴⁴. Most of the intra-articular structures of the knee, including the synovial tissue, the anterior fat pad, and the joint capsule, have free nerve-endings that are capable of sensing painful stimuli and producing severe pain²⁶. Arthroscopic procedures may cause enough pain and swelling to delay rehabilitation and return to work for up to two weeks after surgery^25,108. Patients who cannot complete a rehabilitation program may be at an increased risk for postoperative complications (delay in strength recovery, prolonged knee stiffness, anterior knee pain)^25,77,98,108. Therefore, aggressive pain management in the early postoperative period is essential and can enhance convalescence after arthroscopy⁸⁴.

Intra-Articular Bupivacaine

Intra-articular local anesthetics are frequently used in perioperative pain management. Bupivacaine, an amide local anesthetic, is often utilized because of its extended duration of action⁷⁸. Serum levels peak within thirty to sixty minutes after the injection and remain well below toxic levels following injection of 150 milligrams or less into the knee joint⁷⁵. Intra-articular bupivacaine in doses of 0.5 percent or less does not appear to be harmful to articular cartilage⁸¹.

The analgesic efficacy of bupivacaine that is injected into the intra-articular space remains somewhat controversial. Several studies^43,76 have failed to demonstrate a substantial analgesic effect, while others^12,36,100 have documented at least some benefit. Unfortunately, these studies had serious problems with respect to design, data collection, and reporting. There was considerable variability in the volume and concentration of the intra-articular bupivacaine that was administered. In addition, there were confounding variables that are known to affect postoperative pain, including the use of perioperative nonsteroidal anti-inflammatory drugs, opioids, tourniquets, and epinephrine and infiltration of portals with lidocaine or bupivacaine.

The dose of bupivacaine may be an important factor. Smith et al.¹⁰⁰ believed that the lack of an observed analgesic effect in previous studies of intra-articular bupivacaine^43,76 might have been the result of use of a concentration of only 0.25 percent. Smith et al. assessed the efficacy of 150 milligrams (thirty milliliters of a 0.5 percent solution) of bupivacaine in ninety-seven patients undergoing arthroscopic knee surgery under general anesthesia. Patients were randomized to receive either intra-articular bupivacaine or saline solution at the conclusion of the operative procedure. The patients who received 0.5 percent bupivacaine were less likely to require postoperative narcotics and used lower doses of these medications than did the placebo group. In addition, use of 0.5 percent bupivacaine resulted in earlier walking and discharge than did use of the placebo.

Another factor that may have led to a negative result in studies of the analgesic efficacy of bupivacaine is the relatively low mean visual analog pain scores (less than 3.3 centimeters) in both the bupivacaine and the control group^43,76. Many of the procedures in these studies were diagnostic arthroscopies, which require minimal postoperative analgesia. In the study by Geutjens and Hambidge³⁶, for example, the control (saline-solution) group required no analgesics after ten hours postoperatively. Furthermore, another variable that has not been well documented in the literature is whether patients had postoperative hemarthrosis, which can increase the level of pain and decrease the concentration of bupivacaine within the knee joint.

On balance, the majority of studies have suggested that intra-articular bupivacaine is an effective analgesic and have supported its use in the management of pain following arthroscopic knee surgery. However, better-designed trials are still needed for a more conclusive determination.

Intra-Articular Morphine

Intra-articular bupivacaine may provide effective postoperative analgesia; however, its effectiveness appears to be short-lived (two to four hours)^12,36. Patients recovering from arthroscopic knee surgery may still require supplemental analgesia prior to discharge and later at home. Narcotic analgesics are a popular choice, but they can cause side effects, including respiratory depression, sedation, pruritus, nausea, and vomiting, that can delay discharge from the ambulatory surgical center, increase the overall morbidity of the procedure, and increase the risk to the patient while he or she is at home. Opioids administered orally may not be absorbed due to postoperative nausea, vomiting, or ileus. The recent discovery that opiate receptors exist in peripheral tissue is of great potential value for preventing or reducing postoperative pain.

The presence of opioid receptors in the central nervous system has long been recognized, but recently they also have been demonstrated in peripheral nerve-endings⁶⁴ and have been documented by immunohistochemical analysis of biopsy specimens from inflamed synovial tissue as well as confirmed by specific binding of naloxone to receptor sites in the knee⁶¹. All three opioid receptors (mu, delta, and kappa) have been isolated on peripheral nerves and shown to be responsible for mediating peripheral antinociception¹⁰³. These receptors are synthesized in the cell bodies of primary sensory neurons located in the dorsal root ganglia and are transported distally by means of axoplasmic flow¹⁰⁶.

The fact that locally administered opioids produce analgesia in the presence of inflammation¹⁰⁵ and not in normal tissue has been explained in several ways. First, it has been proposed that inflammation induces a disruption of the perineurium, allowing easier access of opioids to neuronal receptors. Alternatively, or in combination with this mechanism, previously inactive opioid receptors may be rendered active or may be unmasked under conditions of inflammation¹⁰⁷.

The mechanism of the peripheral antinociceptive effect of opioids in inflamed tissues has not been precisely defined. It has been hypothesized to occur by either an analgesic effect or an anti-inflammatory effect, or both⁶¹. An analgesic effect has been postulated because morphine reduces the excitability of the nociceptive input terminal of C-fiber neurons. This results in a reduction in the central processing of pain. Opioids also have a direct anti-inflammatory action in peripheral tissues, since the binding of peripheral opioid receptors seems to inhibit the release of proinflammatory neuropeptides, such as substance P¹⁰⁵.

To our knowledge, Stein et al.¹⁰⁴ were the first to demonstrate a prolonged analgesic effect from the intra-articular administration of morphine in humans. Since then, numerous clinical investigations have confirmed that the administration of relatively small doses of intra-articular morphine can provide effective and long-lasting analgesia^{4,9,11,19,21,22,40-42,45-47,50,52,56,65,66,68,72,80,86,92}. Plasma profiles for morphine and its metabolites following intra-articular injection have been shown to be too low to produce effective systemic analgesia⁴⁷. In other studies^{8,9,11,86,104}, a dose of morphine identical to that given intra-articularly but administered through the systemic route failed to produce substantial analgesia. Finally, Stein et al. showed that the analgesic effect of intra-articular morphine was blocked by intra-articular naloxone, thus confirming a peripheral analgesic effect.

Many of the studies that have demonstrated a positive analgesic effect from intra-articular morphine have also documented a delayed onset of analgesia. Several authors have reported decreased pain scores as late as eight to twelve hours following intra-articular administration of morphine^19,42,46. As a result, many investigators now administer a combination of intra-articular bupivacaine and morphine in an attempt to improve analgesia in the immediate postoperative period.

Several investigators^{1,8,24,60,83,95} have failed to observe any difference in the analgesic efficacy of intra-articular morphine compared with that of either intra-articular saline solution or intra-articular bupivacaine (controls). Some of these results may have been influenced by the perioperative use of systemic opioids or nonsteroidal anti-inflammatory drugs or regional anesthesia, all of which can diminish the surgical inflammatory response, thus decreasing the binding of intra-articular morphine.

Epidural anesthesia can also alter the effect of intra-articular morphine, for at least two reasons. First, epidural anesthesia has been shown to substantially blunt the neuroendocrine response to surgical trauma and to reduce the release of several inflammatory mediators⁹⁴. Furthermore, epidural anesthesia can produce a preemptive and prolonged postoperative analgesic effect^54,71,121. In fact, one study revealed that epidural anesthesia had an extended analgesic effect that was evident for as long as forty-eight hours postoperatively⁵⁴.

Another confounding variable that may affect the analgesic efficacy of intra-articular morphine is the timing of tourniquet release. It is possible that by increasing the time-interval between intra-articular injection and tourniquet release, the local tissue-binding to opioid receptors can be increased, enhancing the analgesic effect. To our knowledge, this effect of tourniquet release has been examined in only two studies, which demonstrated contradictory findings^58,116. Klinken⁵⁸ found that tourniquet time (zero, eight, or sixteen minutes) had no significant effect on the analgesic duration of intra-articular morphine or the need for supplemental analgesia within twenty-four hours. In contrast, Whitford et al.¹¹⁶ observed that keeping the tourniquet inflated for ten minutes provided superior analgesia and decreased the need for supplementary analgesics compared with releasing the tourniquet immediately after intra-articular injection of morphine.

The optimal timing of intra-articular administration of morphine is yet to be established. Although it is typically injected at the end of an arthroscopic procedure, two studies^22,30 confirmed an analgesic benefit from preoperative administration.

In summary, most studies have demonstrated a prolonged analgesic effect from intra-articular administration of morphine, and the unwanted side effects from systemically administered opioids have not been observed with intra-articular morphine. Inflammation of the intra-articular tissue seems to be a prerequisite for morphine to exert its analgesic effect, although the precise mechanisms of action are not known. Concurrent use of nonsteroidal anti-inflammatory drugs and spinal or epidural anesthesia, all of which diminish inflammation, may mask or attenuate the analgesic effect of intra-articular morphine. Taken together, these results support the use of intra-articular morphine in the management of pain following arthroscopic knee surgery.

Alternative Intra-Articular Opioids

Intra-Articular Fentanyl

On the basis of the knowledge that opioid receptors are present in the knee⁶¹, Uysalel et al.¹¹³ studied the analgesic effects of intra-articular fentanyl in patients undergoing arthroscopic knee surgery. They hypothesized that the high liposolubility of fentanyl should provide prolonged analgesia. The authors compared the analgesic efficacy of 100 micrograms of fentanyl to that of one milligram of morphine in combination with 0.25 percent intra-articular bupivacaine. An immediate, but short, analgesic effect (mean, three hours) was observed with intra-articular fentanyl, whereas intra-articular morphine had a delayed but more prolonged analgesic effect (mean, forty-eight hours). Uysalel et al. concluded that a combination of morphine and bupivacaine is the best choice for postoperative analgesia following arthroscopic surgery.

Intra-Articular Meperidine

Meperidine is an opioid agonist with a chemical structure that is similar to that of local anesthetics¹⁵. It has been used as the sole anesthetic agent for epidural, spinal, and intravenous regional anesthesia^2,3,15,29. Ekblom et al.²⁹ investigated the analgesic efficacy of intra-articular meperidine when it was used as the sole anesthetic for arthroscopic knee surgery. Patients were randomly assigned to receive either 250 milligrams of intra-articular prilocaine or 200 milligrams of intra-articular meperidine. There was no difference in the intraoperative pain scores between the two groups. However, patients who received intra-articular meperidine reported significantly less pain at rest and during movement (p < 0.01) in the first twenty-four hours following surgery than did those who received intra-articular prilocaine. In addition, patients who received intra-articular meperidine used significantly fewer analgesics (p < 0.02). Soderlund et al.¹⁰² compared the effect of three doses of intra-articular meperidine (fifty, 100, and 200 milligrams) with that of 250 milligrams of prilocaine in forty patients undergoing arthroscopic surgery. Six of ten patients receiving fifty milligrams of intra-articular meperidine required general anesthesia for the operative procedure because of intense intraoperative pain. There were no differences in intraoperative pain scores between the groups receiving 100 and 200 milligrams of meperidine and the group receiving prilocaine. Postoperatively, the pain scores and analgesic use associated with all three meperidine doses were lower than those associated with the prilocaine. However, use of such large doses of meperidine may have merely resulted in systemic analgesic effects. In addition, these doses of intra-articular meperidine resulted in a higher prevalence of centrally mediated side effects. Lyons et al.⁶⁸ investigated the postoperative analgesic efficacy of fifty milligrams of intra-articular meperidine, five milligrams of morphine, or saline solution in sixty patients undergoing arthroscopic meniscectomy under general anesthesia. Both treatment groups had significantly lower pain scores (p < 0.01) than did the control group. Patients in the meperidine group had lower pain scores than did those in the morphine group at 0.5, one, and two hours, but they had significantly higher scores at twelve and twenty-four hours (p < 0.01). The authors concluded that the local anesthetic effect of meperidine may be responsible for the early analgesia, but its duration of action is less than that of morphine.

In settings where morphine is medically contraindicated, intra-articular meperidine may be a suitable alternative analgesic. The only advantage of meperidine compared with morphine is its earlier onset of analgesia. However, combining bupivacaine with morphine can result in both an early onset and a prolonged duration of analgesia^21,56,66,104. Furthermore, meperidine¹⁰², unlike intra-articular morphine, has been reported to cause unwanted systemic side effects.

Alternative Intra-Articular Analgesics

Intra-Articular Ketorolac

Several investigators have examined the analgesic effect of administering anti-inflammatory drugs intra-articularly. Ketorolac, a nonsteroidal anti-inflammatory drug, has proven to be a useful analgesic when administered parenterally for the management of pain after arthroscopy¹⁰¹. One of us (S. S. R.) and Connelly⁸⁵ examined the analgesic efficacy of administering sixty milligrams of ketorolac through either a parenteral or an intra-articular route following arthroscopic meniscectomy. There was significantly more analgesia of longer duration after intra-articular administration (p < 0.001).

This study⁸⁵ generated considerable controversy regarding the safety of intra-articular ketorolac^31,117. Although there were no previous studies in humans, previous in vitro studies showed that intra-articular ketorolac had no effect on degradation of bovine cartilage plugs⁵. In fact, ketorolac appears to have a protective effect on articular cartilage by preventing the release of proinflammatory cytokines, including interleukin-1, which has been shown to play a pivotal role in inducing cartilage degradation. Concern was also expressed about the possibility that the alcohol content (10 percent weight per volume) in ketorolac would have a deleterious effect on articular cartilage³¹. However, in this study⁸⁵, ketorolac was diluted in a volume of thirty milliliters of 0.25 percent bupivacaine. The resultant alcohol content (0.7 percent weight per volume) was lower than that of sterile triamcinolone acetonide suspension (0.9 percent weight per volume) (Steris Laboratories, Phoenix, Arizona), which has been cleared by the Food and Drug Administration for intra-articular injection.

One of us (S. S. R.) and Connelly⁸⁶ subsequently designed a study to compare the analgesia produced by ketorolac with that produced by morphine and to determine whether a combination of the two agents would provide analgesia that was superior to that provided by either drug alone. Eighty patients undergoing arthroscopic meniscectomy under local anesthesia were randomized to receive ketorolac (either intra-articularly or parenterally) or morphine (either intra-articularly or parenterally). There was a significant benefit when either morphine alone or ketorolac alone was administered intra-articularly (mean analgesic duration, thirteen hours) (p < 0.001), but the combination of these drugs did not result in any additive effect or increase the analgesic duration. We hypothesize that this last finding may have been due to a reduction in synovial tissue inflammation, and thus to a decrease in the binding of intra-articular morphine, brought about by the intra-articular ketorolac. Alternatively, it is possible that no additive effect occurred because each drug alone (when given with intra-articular bupivacaine) provides optimal analgesia that is difficult to enhance.

Intra-Articular Corticosteroids

Wang et al.¹¹⁵ demonstrated that, compared with injection of intra-articular saline solution alone, injection of intra-articular triamcinolone acetonide in saline solution into knees resulted in lower pain scores and a significant opioid-sparing effect (p < 0.001). However, pain relief began six hours after the intra-articular corticosteroid injection and then persisted throughout the twenty-four-hour study period. Rasmussen et al.⁸⁴ compared the effects of a combination of intra-articular bupivacaine, morphine, and methylprednisolone with the effects of intra-articular bupivacaine and morphine or saline solution on pain and the durations of immobilization and convalescence after meniscectomy. Compared with intra-articular bupivacaine and saline solution, the combination of 150 milligrams of bupivacaine and four milligrams of morphine significantly reduced pain and the durations of immobilization and convalescence (p < 0.05). The addition of forty milligrams of methylprednisolone further reduced pain, use of additional analgesics, joint-swelling, and the duration of convalescence; improved muscle function; and prevented the inflammatory response. Rasmussen et al. recommended this multimodal intra-articular analgesic regimen for patients undergoing arthroscopic meniscectomy.

As in the case of intra-articular ketorolac, the potential for intra-articular corticosteroids to reduce pain and enhance convalescence must be weighed against the risk of complications. The reported risks associated with a single dose of intra-articular steroids have been reported to be minimal³⁸ but may include an increased risk of infection, cartilage damage, impaired wound-healing, and adverse systemic side effects. The reported risk of infection is negligible (less than 1:20,000) following intra-articular administration of a single dose of steroids for rheumatic disorders³⁷. Wang et al.¹¹⁵ observed no cases of delayed wound-healing, infection, or other side effects in the thirty patients who received intra-articular triamcinolone in their study. Additional large-scale randomized studies are needed to assess the safety of routine use of intra-articular corticosteroids in the management of pain following arthroscopic knee surgery.

Intra-Articular Clonidine

Several investigators have studied the analgesic effect of administering intra-articular clonidine following arthroscopic knee surgery^35,51,89. Clonidine, an a-2 agonist, demonstrates several analgesic properties. It has been shown to prolong the duration of action of local anesthetics³⁴ as well as to selectively block the conduction of A d and C fibers¹⁰. In addition to its local anesthetic effects, clonidine may produce analgesia by releasing enkephalin-like substances, resulting in peripheral analgesia⁷⁹. Gentili et al.³⁵ compared the analgesic effect of 150 micrograms of clonidine, administered either intra-articularly or subcutaneously, with that of intra-articular saline solution or one milligram of intra-articular morphine in forty patients undergoing arthroscopic knee surgery. Patients receiving intra-articular clonidine had a significantly longer duration of analgesia (533 ± 488 minutes) than did those receiving either the saline solution alone (70 ± 30 minutes) or subcutaneous clonidine (132 ± 90 minutes) (p < 0.05). The analgesic duration of intra-articular clonidine was found to be similar to that of intra-articular morphine (300 ± 419 minutes). Because subcutaneous administration did not produce analgesia effectively, Gentili et al. concluded that clonidine had a peripherally mediated analgesic effect.

Since clonidine can enhance the peripheral nerve block from local anesthetics, one of us (S. S. R.) and Connelly⁸⁹ studied the analgesic efficacy of intra-articular administration of bupivacaine (seventy-five milligrams) with clonidine (one microgram per kilogram of body weight) following arthroscopic meniscectomy. The group that received the combination of intra-articular bupivacaine and clonidine had a significantly decreased need for postoperative analgesics and increased analgesic duration compared with patients treated with either drug alone (p < 0.0001). Joshi et al.⁵¹ attempted to determine if any additional analgesic benefit could be obtained from the intra-articular use of clonidine with morphine in a study of sixty patients undergoing arthroscopic meniscectomy under local anesthesia. The combination of drugs resulted in a significant increase in analgesic duration (1050 ± 227 minutes, p < 0.0001) compared with the analgesic duration of either intra-articular clonidine (640 ± 113 minutes) or intra-articular morphine (715 ± 106 minutes) alone.

In summary, ketorolac and corticosteroids act as potent analgesics by reducing the inflammatory response following arthroscopic knee surgery. In addition, intra-articular clonidine potentiates the effects of intra-articular morphine and bupivacaine. A reduction in pain and joint-swelling may accelerate the recovery of muscle strength^25,108 and reduce the duration of convalescence⁸⁴ following arthroscopic meniscectomy. Taken together, these studies suggest that intra-articular nonsteroidal anti-inflammatory drugs, corticosteroids, and clonidine may play important roles in the analgesic regimen of patients undergoing arthroscopic knee surgery. Additional large-scale randomized studies are needed to assess the safety and efficacy of these regimens.

Postoperative Analgesia After Outpatient Anterior Cruciate Repair

Improvements in surgical, anesthetic, and pain-management techniques are allowing more patients to return home on the day that they have extensive knee surgery such as anterior cruciate reconstruction. This procedure is associated with a considerable degree of postoperative pain that may require more than just intra-articular local anesthetics or opioids. Ineffective pain management may cause unnecessary suffering, delayed recovery, an inability to participate in rehabilitation programs, prolonged hospitalization, and increased medical expenditures. A recent study of anterior cruciate reconstruction revealed that a cost-saving of up to 58 percent could be achieved when this procedure was performed on an outpatient basis⁵³. Furthermore, patient satisfaction depends in part on the degree of discomfort associated with the procedure. More comprehensive pain-management strategies that involve both preemptive and multimodal analgesic techniques have therefore been employed^{22,33,88,90,110}. Currently, multimodal analgesic regimens described in the literature for anterior cruciate reconstruction include intra-articular opioids, perioperative nonsteroidal anti-inflammatory drugs, intra-articular bupivacaine, femoral nerve block, cryotherapy, and oral opioids.

Intra-Articular Morphine

To our knowledge, Joshi et al.^48,49 were the first investigators to report on the analgesic efficacy of intra-articular administration of morphine following anterior cruciate reconstruction. These authors compared the use of five milligrams of intra-articular morphine with that of intra-articular saline solution following anterior cruciate repair performed on an inpatient basis. In both studies^48,49, the group that was given morphine had lower pain scores and morphine use in the twenty-four-hour period following surgery. Denti et al.²² studied the analgesic effects of three different doses of intra-articular morphine (one, two, and five milligrams) in patients undergoing anterior cruciate reconstruction. The highest dose of morphine (five milligrams) provided better analgesia and resulted in lower supplementary analgesic consumption in the first twenty-four hours after the procedure. Interestingly, in this same study, the authors observed that five milligrams of intra-articular morphine did not produce better analgesia than did two milligrams in patients undergoing other knee arthroscopic procedures. This study supports a dose-response relationship for intra-articular morphine and highlights the importance of using larger doses of intra-articular morphine for anterior cruciate reconstruction, which is a more invasive procedure.

In contrast to these studies^22,48,49, that by one of us (S. S. R.) and colleagues⁸⁸ failed to demonstrate an analgesic effect from the addition of five milligrams of intra-articular morphine following anterior cruciate reconstruction. The previous studies^22,48,49, however, did not involve use of multimodal analgesia, including perioperative nonsteroidal anti-inflammatory drugs, cryotherapy, or intra-articular bupivacaine. Multimodal regimens probably provide sufficient analgesia, so that intra-articular morphine provides little additional benefit. Alternatively, intra-articular morphine might not bind effectively to intra-articular opioid receptors in the presence of perioperative nonsteroidal anti-inflammatory drugs.

Nonsteroidal Anti-Inflammatory Drugs

In addition to intra-articular analgesics, adjunctive nonsteroidal anti-inflammatory drugs have been recommended for the management of acute pain following major orthopaedic operations¹⁷. Although nonsteroidal anti-inflammatory drugs by themselves may not relieve severe postoperative pain, their use in combination with opioids can produce a substantial additive analgesic effect¹⁷. The parenteral use of ketorolac has been shown to reduce morphine consumption by approximately 30 percent following major orthopaedic procedures⁸⁷. McGuire et al.⁶⁹ found a substantial reduction in side effects as well as superior pain control when ketorolac was used as an adjunct in the management of pain after outpatient anterior cruciate reconstruction.

Prostaglandins play an important role in promoting the pain and hyperalgesia associated with the inflammatory response that occurs following an operative procedure. Nonsteroidal anti-inflammatory drugs inhibit prostaglandin biosynthesis through the cyclooxygenase enzyme. Cyclooxygenase is now known to exist as two distinct isoforms: cyclooxygenase-1 and cyclooxygenase-2. Cyclooxygenase-1 is constitutively active throughout the body and is responsible for mediating routine physiological functions, including gastric mucosal function and vascular hemostasis³⁹. In contrast, cyclooxygenase-2 is an inducible enzyme that is expressed from both polymorphonuclear leukocytes and macrophages following inflammatory stimuli¹⁶. Conventional nonsteroidal anti-inflammatory drugs nonspecifically inhibit both the cyclooxygenase-1 and the cyclooxygenase-2 isoform⁷⁴. It is believed that the therapeutic effect of nonsteroidal anti-inflammatory drugs is primarily through the inhibition of cyclooxygenase-2, whereas the toxicity results from inhibition of cyclooxygenase-1³⁹. Preliminary data from animal studies have shown that selective inhibition of cyclooxygenase-2 produces analgesia with substantial safety advantages over the nonselective inhibition of both cyclooxygenase-1 and cyclooxygenase-2 with the use of other nonsteroidal anti-inflammatory drugs⁹⁷. The cyclooxygenase-2-specific inhibitors, celecoxib and rofecoxib at therapeutic concentrations, inhibit the cyclooxygenase-2 isoenzyme without affecting the cyclooxygenase-1 isoform^16,39. Rofecoxib is indicated for the management of osteoarthritis and acute postoperative pain, while celecoxib is indicated for the management of both osteoarthritis and rheumatoid arthritis^16,39. In a recent study⁹¹, the perioperative administration of rofecoxib reduced morphine consumption by approximately 35 percent following spinal fusion surgery. Currently, studies are being performed to assess the analgesic efficacy of cyclooxygenase-2-specific nonsteroidal anti-inflammatory drugs in the management of pain following arthroscopic surgery of the knee.

Femoral Nerve Block

Blockade of the femoral nerve has been shown to be a reliable, safe, and effective method of providing analgesia in the immediate postoperative period following anterior cruciate reconstruction. Winnie et al.¹¹⁸ first described a "3-in-1 block" technique for providing anesthesia to the anterior aspect of the thigh and the knee. The femoral sheath is injected with a local anesthetic agent in sufficient volume (more than twenty milliliters) to block the femoral, lateral femoral cutaneous, and obturator nerves. Ringrose and Cross⁹³ first reported the efficacy of this technique in the management of pain following anterior cruciate surgery. This study revealed an 80 percent reduction in opiate use in the recovery room and a 40 percent reduction in the first twenty-four hours following surgery. Edkin et al.²⁷ reported similar results: twenty-two of twenty-four patients undergoing anterior cruciate reconstruction required no parenteral narcotics postoperatively when a femoral nerve block had been performed at the conclusion of the operation. Although these procedures were all done on an inpatient basis, the mean duration of pain control was twenty-nine hours, and the majority of patients believed that discharge was possible within twenty-three hours after the operation.

The use of an indwelling catheter in the femoral sheath has also been described in the management of pain following anterior cruciate reconstruction^67,73,110. Lynch et al.⁶⁷ administered intermittent doses of bupivacaine through a femoral catheter and concluded that this technique provided safe and reliable analgesia while increasing patient mobility and decreasing use of systemic analgesics. Similar results were reported in later studies^73,110 evaluating the analgesic efficacy of continuous femoral nerve block after anterior cruciate reconstruction. Unfortunately, continuous femoral nerve block is not practical in the management of pain following anterior cruciate reconstruction in an ambulatory setting. In addition, caution should be exercised when a femoral nerve block is used in conjunction with intra-articular bupivacaine. The maximum safe dose of bupivacaine recommended for peripheral nerve block is two milligrams per kilogram of body weight⁷⁸.

Cryotherapy

Cryotherapy is the use of cold to decrease swelling and pain when tissue is damaged secondary to trauma or operative intervention. Although the exact mechanism of cold therapy is not completely understood, it is believed to decrease the inflammation, edema, and hematoma formation after surgical trauma^7,96. In addition, cold therapy decreases nerve-conduction velocity, produces a local anesthetic effect in pain fibers⁷⁰, and can reduce muscle spasm⁶³. Although it has been applied for years, the use of cryotherapy remains controversial following anterior cruciate reconstruction. The earliest report evaluating the analgesic efficacy of continuous cold therapy (Hot/Ice Thermal Blanket; Thermo Temp, Tampa, Florida) following anterior cruciate reconstruction revealed a significant reduction in analgesic use, earlier walking, and greater ease in the performance of range-of-motion exercises (p < 0.01)¹⁴.

A later report also confirmed that, compared with the use of crushed ice, cryotherapy (Cryocuff; Aircast, Summit, New Jersey) led to a reduction in the use of pain medications⁹⁹. In contrast to these two studies, other studies have failed to demonstrate any substantial benefit from cryotherapy^20,28,59. To our knowledge, Barber et al.⁶ were the only investigators to evaluate the effects of portable devices for continuous-flow cold therapy following anterior cruciate reconstruction performed in an outpatient setting. Patients were randomized to receive either no cold therapy or continuous-flow cold therapy with use of a device (Orthopedic Technology, Tracy, California, or Aircast, Summit, New Jersey) that was worn constantly for three days. After the initial three days, the unit was worn by the patient in conjunction with the use of a continuous-passive-motion machine and at other times as the subject desired. There was significant reduction in pain scores (p < 0.05) and analgesic use (p < 0.01) among the patients using the cryotherapy, who also had increased knee flexion.

In summary, continuous-flow cold therapy has the capacity to produce local vasoconstriction, which may reduce bleeding, edema, and the local inflammatory response postoperatively. In addition, cooling can depress neuronal pain-signal transmission, inhibit the stretch reflex, and reduce muscle spasm. In order to obtain these beneficial results, it is important that the skin temperature be lowered to about 20 degrees Celsius to obtain measurable changes in intra-articular temperature¹⁸. However, it is difficult to obtain a persistent decrease in intra-articular temperature for more than twenty-four hours in the postoperative setting. Multiple factors, including room temperature, the thickness of the subcutaneous fat, and the thickness of the postoperative dressings, affect the ability to cool the intra-articular space; this may explain the conflicting results reported in the literature on the efficacy of cryotherapy after anterior cruciate reconstruction.

Long-Acting Opioids

Many patients still require postoperative opioids after the effects of the local anesthetic and the intra-articular opioid have dissipated. Although immediate-release oral opioids are usually effective in relieving moderate-to-severe pain, they must be given every four to six hours. A delay in administration, especially when the opioids are ordered on an as-needed basis, may result in a low plasma concentration of the opioid and, thus, the reemergence of pain. It is currently recommended that all patients requiring opioid analgesics for more than forty-eight hours after an operation receive these drugs on a fixed-dose schedule¹¹². However, interruption of an around-the-clock dosage schedule, especially during the hours of sleep, may lead to a recurrence of pain.

A controlled-release formulation of oxycodone (OxyContin; Purdue Pharma, Norwalk, Connecticut) maintains therapeutic opioid concentrations for a more prolonged period, thus providing sustained pain relief¹⁰⁹. One of us (S. S. R.) and colleagues⁹⁰ examined the efficacy of controlled-release oxycodone compared with that of immediate-release oxycodone when administered on either an as-needed basis or a fixed-dose schedule in the multimodal management of pain after anterior cruciate reconstruction in the ambulatory setting. Many patients in the fixed-dose group failed to take the drug in the manner in which it was prescribed, and many failed to take it during the night while they slept. In contrast, the study revealed that use of controlled-release oxycodone in the immediate seventy-two hours postoperatively provided more effective analgesia with less sedation, sleep disturbance, or vomiting compared with oxycodone prescribed on either a fixed-dose or an as-needed basis. These results may have occurred because of improved compliance with controlled-release, twice-per-day dosing of oxycodone, which provided more effective continuous postoperative analgesia.

Preemptive Analgesia

In addition to utilizing various analgesics in a multimodal regimen, one can administer these drugs preemptively, which may provide even longer-lasting pain relief following anterior cruciate reconstruction^{22,30,33,54,62,71,93,111}. The preemptive administration of nonsteroidal anti-inflammatory drugs can reduce primary and secondary hyperalgesia by inhibiting cyclooxygenase and decreasing tissue prostaglandin synthesis and, thereby, can decrease postoperative pain¹³. Lee et al.⁶² observed a significant reduction in pain scores and opioid use when ketorolac had been administered prior to knee arthroscopy (p < 0.04). However, the prophylactic use of ketorolac is contraindicated before any major operation because of the increased risk of bleeding that is associated with all nonsteroidal anti-inflammatory drugs. In a study in which preemptive ibuprofen was given for thirty-six hours prior to anterior cruciate reconstruction⁸⁸, one of us (S. S. R.) and colleagues observed an increased prevalence of perioperative bleeding (unpublished data) and have since discontinued the routine use of preoperative nonsteroidal anti-inflammatory drugs in their practice.

Recent data have demonstrated that the selective cyclooxygenase-2 inhibitors have no clinical effect on coagulation³⁹. Rofecoxib, a cyclooxygenase-2-specific nonsteroidal anti-inflammatory drug, was recently shown to be an effective analgesic, and it did not substantially increase intraoperative blood loss when it was administered prior to major spine operations⁹¹. Studies are currently being performed to determine whether the preoperative administration of cyclooxygenase-2-specific nonsteroidal anti-inflammatory drugs is safe and effective for producing analgesia after knee arthroscopy.

Local anesthetic nerve blocks can produce substantial preemptive analgesic effects^54,71,121, and the preemptive use of a femoral nerve block with 0.5 percent bupivacaine has been demonstrated to have a substantial analgesic effect in patients undergoing anterior cruciate reconstruction⁹³. In that study⁹³, patients who had had a femoral nerve block before the operation had a 50 percent reduction in their requirement for opioids in the first twenty-four hours after the operation compared with patients who had had a femoral nerve block at the conclusion of the operation.

Just as preoperative intra-articular administration of morphine has been shown to be efficacious in reducing pain following arthroscopy^22,30, it has been shown to be efficacious in reducing pain following anterior cruciate reconstruction^22,33,111. While one might assume that intra-articular morphine administered prior to surgery, even as few as ten minutes prior to surgery, may be washed out during the procedure, effective analgesia was reported, thus confirming the presence of some peripheral opioid receptor-binding²².

In summary, both preemptive and multimodal analgesic techniques should be utilized in the management of patients undergoing anterior cruciate reconstruction. Effective pain management should accelerate rehabilitation, decrease the risk of postoperative complications, and speed return to normal activities⁹⁸. We routinely perform anterior cruciate reconstruction on an ambulatory basis, with use of both preemptive and multimodal analgesic techniques^88,90. All patients receive five doses of acetaminophen (650 milligrams every six hours) starting thirty hours prior to surgery. In addition, all adult patients receive intra-articular bupivacaine (seventy-five milligrams) and ketorolac (fifteen milligrams) prior to incision. Postoperatively, all patients receive an additional dose of intra-articular bupivacaine (seventy-five milligrams) with morphine (five milligrams), acetaminophen (650 milligrams) and ibuprofen (600 milligrams) four times per day, controlled-release oxycodone (twenty milligrams) twice per day, and cryotherapy. We have found that these analgesic techniques allow for timely discharge of our patients from the ambulatory surgical center on the day of the anterior cruciate surgery. In addition, the majority of our patients are able to participate more easily in an accelerated rehabilitation program.

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