In this review, we examine the efficacy of a variety of multimodal analgesic techniques and review the evidence regarding whether these analgesics may be administered preemptively to reduce chronic pain following an operation. Four chronic postoperative pain syndromes that are important clinically to orthopaedic surgeons are complex regional pain syndrome, phantom limb pain, chronic donor-site pain, and persistent pain following total joint arthroplasty.
Opioids are still considered to play a major role in the management of pain following orthopaedic surgery, although they may contribute to increased hospital morbidity and health-care costs11. Adverse events associated with the use of opioids in the postoperative setting include nausea and vomiting, respiratory depression, sedation, pruritus, urinary retention, and sleep disturbances12. In July 2000, the Joint Commission on Accreditation of Healthcare Organizations introduced a new standard for pain management, declaring the pain level to be the “fifth vital sign.”13 The Commission concluded that acute and chronic pain are major causes of patient dissatisfaction in the United States health-care system, leading to slower recovery times, creating a burden for patients and their families, and increasing costs. However, reducing postoperative pain with opioids alone will increase the risk of adverse effects14-16.
The concept of multimodal analgesia was introduced more than a decade ago as a technique to improve analgesia and reduce the prevalence of opioid-related adverse events17. The rationale for this strategy is the achievement of sufficient analgesia due to the additive or synergistic effects of different analgesics. This allows a reduction in the doses of these drugs and thus a lower prevalence of adverse effects. Unfortunately, unimodal pain treatment was used in most of the studies on acute pain management in the literature. Such treatment cannot be expected to provide sufficient pain relief to allow normal function without the risk of adverse effects17,18. Most of the literature about pain fails to address the issue of pain during daily function (such as coughing, walking, and physical therapy). It has been demonstrated that, in addition to lowering the prevalence of adverse effects and improving analgesia, multimodal analgesia techniques may shorten hospitalization times, improve recovery and function, and decrease healthcare costs following orthopaedic surgery19-21. Currently, the Agency for Healthcare Research and Quality22 and the American Society of Anesthesiologists Task Force on Acute Pain Management23 advocate the use of multimodal analgesia. As described in the literature, multimodal analgesic regimens for orthopaedic surgery include local anesthetics, α-2 agonists (e.g., clonidine), nonsteroidal anti-inflammatory drugs, acetaminophen, ketamine, α2-δ ligands (e.g., gabapentin and pregabalin), and opioids (Fig. 2).
Clonidine and Other α-2 Agonists
Experimental research on animals supports the contention that α-2 adrenergic agonists have analgesic actions at the peripheral, spinal, and brainstem sites. This is evidenced by the detection of α-2 adrenoceptors on primary afferent terminals, on neurons in the superficial laminae of the spinal cord, and within several brainstem nuclei24. The precise mechanism by which clonidine exerts its analgesic effect remains unknown. Clonidine enhances peripheral nerve blocks with local anesthetics by selectively blocking conduction of A-δ and C fibers25-27. Clonidine also causes local vasoconstriction, thereby reducing the vascular uptake of local anesthetics28, although this mechanism is controversial29. Recent animal studies in which clonidine was used for peripheral nerve blocks have suggested that the mechanism of action is mediated by the hyperpolarization-activated cation current (Ih) and not by the α-2-adrenoceptors30. Clonidine may also produce an analgesic effect by releasing enkephalin-like substances31. In addition, because sympathetic neural activity might increase both somatic32 and sympathetically maintained pain33, clonidine can reduce nociceptive pathways by inhibiting the release of norepinephrine from prejunctional α-2 adrenoceptors. Only recently has clonidine been available in the United States as a parenteral preparation (Duraclon; Roxane Laboratories, Columbus, Ohio). This has led to a multitude of studies focusing on the analgesic efficacy of administering clonidine as a regional analgesic block in the management of both acute and chronic pain34.
A central neuraxial block with a local anesthetic and clonidine improves the quality of analgesia after total joint arthroplasty35-39. The combination of intrathecal clonidine and morphine provided analgesia that was superior to that provided by intrathecal morphine alone following total knee arthroplasty35. Administration of clonidine with an epidural infusion of a local anesthetic and fentanyl improved analgesia and reduced the need for rescue opioid medication following total knee arthroplasty36. Continuous long-term (thirty to forty-day) epidural infusions of clonidine, bupivacaine, and fentanyl through a tunneled epidural catheter improved the range of motion in patients who underwent total knee arthroplasty and had been identified preoperatively as having risk factors for the development of chronic pain37. Clonidine also improved postoperative analgesia when it was added to epidural infusions of a local anesthetic38 or during combined spinal-epidural anesthesia for total hip arthroplasty39.
Clonidine has also been shown to enhance peripheral nerve blocks when added to a variety of local anesthetics34. The addition of clonidine (1 μg/kg) to 0.5% lidocaine for intravenous regional anesthesia was found to improve postoperative analgesia during the first day after hand surgery, with no apparent adverse effects40. Also, the use of clonidine for intravenous regional anesthesia was shown to allow longer tourniquet-inflation times before the onset of intolerable pain in healthy, unsedated volunteers41. In addition to nociceptive pain, sympathetically mediated pain has also been shown to be treated effectively with intravenous regional anesthesia with clonidine42,43. The analgesic effect of intravenous regional anesthesia with clonidine appears to be peripherally mediated and not due to central redistribution, as the same dose administered parenterally provided no additional analgesia40. Furthermore, the concentration of clonidine in plasma (0.12 ng/mL) measured after tourniquet deflation42 was considerably lower than the concentration required for a central analgesic effect (1.5 to 2 ng/mL) when clonidine is administered through the parenteral route to manage postoperative pain44.
In addition to being beneficial when it is administered with local anesthetics, clonidine possesses an analgesic efficacy when it is administered by itself through the intra-articular route45. Furthermore, the addition of intra-articular clonidine to morphine and bupivacaine enhanced the analgesic efficacy of both drugs46. The peripheral administration of clonidine is a useful nonopioid analgesic technique that currently plays an important role in the management of both acute and chronic pain related to orthopaedic surgery.
Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen
It has become apparent that the products of arachidonic metabolism promote the pain and hyperalgesia associated with tissue trauma and inflammation (Fig. 3). Under normal conditions, tissues possess a cell membrane that is composed of a bipolar lipoprotein configuration with phospholipids sequestered within the membrane. Following tissue injury, the cell membrane is disrupted and the previously inaccessible phospholipids are exposed to the enzyme phospholipase A2 in the periphery, which catalyzes the conversion to arachidonic acid (Fig. 3). Arachidonic acid in turn acts as a substrate for the cyclooxygenase (COX)-2 enzyme, which produces the short-lived prostaglandins (PG) including PGG2 and PGH2. Several synthases then convert PGH2 to other prostaglandins (e.g., PGD2, PGE2, PGF2-alpha, and PGI2) and to thromboxane A2. These prostaglandins do not generally activate nociceptors directly but sensitize them to mechanical stimuli and chemical mediators of nociception, resulting in hyperalgesia and thus facilitating pain transmission47. PGE2 is the predominant prostanoid associated with inflammatory responses and is responsible for reducing the pain threshold at the site of injury (primary hyperalgesia), resulting in central sensitization and a lower pain threshold in the surrounding uninjured tissue (secondary hyperalgesia)48. Nonsteroidal anti-inflammatory drugs are thought to reduce postoperative pain by suppressing COX-2-mediated production of PGE2.
The primary site of action of nonsteroidal anti-inflammatory drugs is believed to be in the periphery, although recent research indicates that central inhibition of COX-2 may also play an important role in modulating nociception49.
Nonsteroidal anti-inflammatory drugs inhibit the synthesis of prostaglandins both in the spinal cord and at the periphery, thus diminishing the hyperalgesic state after surgical trauma49. Nonsteroidal anti-inflammatory drugs are useful as the sole analgesic after minor operative procedures50, and they may have an important opioid-sparing effect after a major operation51. The use of these drugs has become increasingly popular because of the concern about opioid-related side effects. All nonsteroidal anti-inflammatory drugs have a ceiling effect for analgesia, but they do not demonstrate a ceiling effect with regard to side effects52. The recent practice guidelines for acute pain management in the perioperative setting specifically state: “Unless contraindicated, all patients should receive an around-the-clock regimen of NSAIDs, COXIBs, or acetaminophen.”23
Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic properties similar to those of aspirin. The mechanism of action of acetaminophen is still poorly defined. Recent evidence has suggested that it may selectively act as an inhibitor of prostaglandin synthesis in the central nervous system rather than in the periphery53. The theory that acetaminophen acts through the COX-3 receptor54 has recently been challenged55. In addition, there is evidence that serotonergic mechanisms are involved in the antinociceptive activity of acetaminophen56. A meta-analysis of randomized controlled trials of the use of acetaminophen for postoperative pain revealed that this analgesic induced a morphine-sparing effect of 20% over the first twenty-four hours postoperatively but did not reduce the prevalence of morphine-related adverse effects57. The authors of a recent qualitative review of acetaminophen, nonsteroidal anti-inflammatory drugs, and their combination concluded that acetaminophen may provide analgesic efficacy similar to that of other nonsteroidal anti-inflammatory drugs following major orthopaedic surgery58. It was thought that acetaminophen may be a viable alternative to nonsteroidal anti-inflammatory drugs in high-risk patients because of the lower prevalence of adverse effects58. Furthermore, it may be appropriate to administer acetaminophen with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors since these two analgesics may act additively or synergistically to improve analgesia59.
A recent meta-analysis was done to examine whether there is any advantage to adding acetaminophen, nonsteroidal anti-inflammatory drugs, or COX-2 inhibitors to patient-controlled analgesia with morphine60. The results suggested that all of the analgesic agents provided an opioid-sparing effect but this decrease in morphine intake did not consistently result in a decrease in opioid-related adverse effects. The use of nonsteroidal anti-inflammatory drugs was associated with a decrease in the prevalence of postoperative nausea and vomiting and sedation. However, the use of COX-2 inhibitors or acetaminophen did not decrease the prevalence of opioid-related adverse events when compared with those associated with a placebo.
A systematic review comparing COX-2 inhibitors with traditional nonsteroidal anti-inflammatory drugs for management of postoperative pain showed that these two analgesics demonstrate equipotent analgesic efficacy after minor and major operative procedures61. Since COX-2 inhibitors are associated with reduced gastrointestinal side effects and an absence of anti-platelet activity, they can be administered to patients treated with orthopaedic surgery without the added risk of increased perioperative bleeding that has been reported with conventional nonsteroidal anti-inflammatory drugs59. Recent studies have demonstrated improved analgesia, shorter hospitalization times, improved recovery and function, and decreased health-care costs with the use of COX-2 inhibitors in the multimodal management of pain following orthopaedic surgery19-21.
One potential concern regarding the use of COX-2 inhibitors has been their possible role in increasing cardiovascular morbidity62. Theoretical concerns were borne out when a fivefold increase in the prevalence of myocardial infarction was seen in the Vioxx Gastrointestinal Outcome Research (VIGOR) study63. Several clinicians attributed the increase in adverse cardiovascular events to a prothrombotic state caused by selective COX-2 inhibitors64. Valdecoxib and the parenteral prodrug parecoxib have also been associated with an increased risk of myocardial infarctions (1.6% compared with 0.7% in a control group) after administration of a supramaximal dose (40 mg twice daily) for fourteen days following coronary artery bypass grafting65. However, no increase in cardiovascular events was observed after administration of a therapeutic dose of parecoxib followed by a therapeutic dose of valdecoxib for patients treated with general and orthopaedic procedures66.
On the basis of a review of data on users of nonsteroidal anti-inflammatory drugs enrolled in the Kaiser Permanente health-care system in California, it became apparent that cardiovascular toxicity may be related to all nonsteroidal anti-inflammatory drugs and not just COX-2-specific inhibitors67. During 2,302,029 person-years of follow-up, this study showed a significantly increased risk of adverse cardiovascular events among users of diclofenac (relative risk = 1.69; p = 0.06), indomethacin (relative risk = 1.30; p = 0.005), and naproxen (relative risk = 1.14; p = 0.01) compared with that among individuals who did not use nonsteroidal anti-inflammatory drugs. A joint meeting of the United States Food and Drug Administration (FDA) Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee in 2005 reaffirmed that COX-2 inhibitors are important treatment options for pain management and that the cardiovascular risk associated with celecoxib is similar to that associated with commonly used nonspecific nonsteroidal anti-inflammatory drugs68. The FDA announced a series of changes applicable to the entire class of nonsteroidal anti-inflammatory drugs68. These included an FDA “black box” warning about the potentially increased risk of cardiovascular events and gastrointestinal bleeding associated with all prescription nonsteroidal anti-inflammatory drugs, including celecoxib. The FDA noted that all nonsteroidal anti-inflammatory drugs can lead to the onset of new hypertension or worsening of preexisting disease, either of which may contribute to an increased prevalence of cardiovascular events. Therefore, nonsteroidal anti-inflammatory drugs and coxibs that are to be used to manage pain should be prescribed at the lowest effective dose for the shortest duration. They should not be prescribed for high-risk patients (e.g., those with a history of ischemic heart disease, stroke, or congestive heart failure or those who have recently undergone coronary artery bypass grafting).
With the withdrawal of rofecoxib and valdecoxib from the worldwide market, celecoxib is currently the only COX-2 nonsteroidal anti-inflammatory drug approved for the management of pain in the United States. Parecoxib (an injectable prodrug of valdecoxib), etoricoxib, and lumaricoxib are currently available in Latin America and Europe.
Ketamine has been a well-known general anesthetic and analgesic for the past three decades. With the discovery of the N-methyl-D-aspartate (NMDA) receptor69 and its links to nociceptive pain transmission and central sensitization70, there has been renewed interest in utilizing ketamine as a potential antihyperalgesic agent given its actions as a noncompetitive NMDA receptor antagonist70. Although high doses (>2 mg/kg) of ketamine have been implicated in causing psychomimetic effects (excessive sedation, cognitive dysfunction, hallucinations, and nightmares), subanesthetic or low doses (<1 mg/kg) of ketamine have demonstrated substantial analgesic efficacy without these side effects71,72. Furthermore, there is no evidence that low-dose ketamine exerts any adverse pharmacological effect on respiratory, cardiovascular, or gastrointestinal function71. Authors of recent systematic reviews have concluded that intravenous, intramuscular, or subcutaneous administration of low-dose ketamine as the sole analgesic agent reduces pain71,72. In contrast, there is little evidence to support the use of low-dose epidural ketamine by itself for postoperative analgesia71. There is a growing body of evidence that low-dose ketamine may play an important role in improving postoperative pain management when used as an adjunct to opioids or local anesthetics71,72. However, despite the opioid-sparing effect observed with the administration of ketamine, to our knowledge no reduction in opioid-related side effects has been documented71,72. Ketamine may also be useful when added to local anesthetic solutions for wound infiltration, resulting in improved analgesia that is mediated by means of a peripheral mechanism73. Ketamine is being used more frequently in the management of pain following orthopaedic surgery. A single intraoperative injection of ketamine (0.15 mg/kg) improved analgesia and passive knee mobilization twenty-four hours after arthroscopic anterior cruciate ligament surgery74 and improved the postoperative functional outcome after outpatient knee arthroscopy75. Low-dose ketamine can also increase pain relief after total knee arthroplasty when it is used in conjunction with either epidural anesthesia76 or a continuous femoral nerve block77. Patients who had received perioperative ketamine also had an earlier improvement in knee function following total knee arthroplasty77.
Local Anesthetics and Regional Analgesia
The use of regional anesthetic techniques for the perioperative management of pain is not a new concept. Crile believed that, compared with general anesthesia alone, a combination of local regional blocks and general anesthesia improved analgesia and enhanced postoperative convalescence, especially when the blocks had been performed in advance of the painful stimulus78. In 1913, he concluded that “patients given inhalational anesthesia still need to be protected by regional anesthesia otherwise they might incur persistent central nervous system changes and enhanced postoperative pain.”78
Infiltrating local anesthetics into the skin and subcutaneous tissues prior to making an incision may be the simplest approach to preemptive analgesia. It is a safe procedure with few side effects and a low risk of toxicity. Although the benefit of local wound infiltration has been documented, there is controversy regarding the appropriate timing of administration of local anesthesia for surgery. In a meta-analysis of fourteen randomized trials (736 patients) comparing pre-incisional with post-incisional wound infiltration for a variety of surgical procedures (including orthopaedic surgery), Moiniche et al.8 found no difference in analgesic efficacy between the two techniques. In contrast, in a review of fifteen randomized trials (671 patients), Ong et al.9 concluded that preemptive local infiltration reduced analgesic consumption and the time to the patient's first request for analgesia but did not reduce pain intensity when compared with post-incisional infiltration. It remains unclear from these data whether local anesthetic infiltration into the wound prevents chronic incisional pain over the long term. Most of the authors of these studies terminated their assessment of the effect at twenty-four to forty-eight hours, well before the abatement of the acute postoperative pain.
With the recent technologic improvements in nonelectric disposable infusion pumps79, techniques for continuous infusion of local anesthetics are increasing in popularity for orthopaedic operations performed both in the hospital and on an outpatient basis80. Continuous infusions of bupivacaine either intra-articularly81 or into the infrapatellar fat pad82 have demonstrated analgesic efficacy for patients undergoing anterior cruciate ligament reconstruction. The effectiveness of anesthetic continuous-infusion devices was also demonstrated for patients treated with outpatient shoulder surgery in a randomized, double-blind trial83. That trial revealed that a continuous infusion of bupivacaine for forty-eight hours after surgery reduced pain and opioid use both during use of the pump and for several days after its use was discontinued. The infusion of bupivacaine either into the wound or as a local nerve block has also proven to be an effective analgesic technique for the management of pain following hand surgery84 and following harvest of iliac crest bone graft85. However, the continuous infusion of bupivacaine has not demonstrated efficacy for the management of pain following total knee arthroplasty86. It was concluded that drug loss from the knee drainage may exceed 25% of the intra-articular infusion, compromising the analgesic effectiveness of this technique for total knee arthroplasty86.
Other concerns about local anesthetic-infusion techniques include the possibility of infection and chondrotoxicity. In a study of the efficacy of continuous infusions of bupivacaine for patients treated with hand surgery, investigators reported that an infection developed at the cannula insertion site in two of 100 subjects after one week84. Furthermore, a recent animal study showed that infusion of bupivacaine for forty-eight hours led to profound histopathologic and metabolic changes in articular cartilage87. The authors of that study cautioned against the use of continuous infusion devices in smaller joints. Future large-scale studies of humans are needed to address the efficacy and safety (with regard to chondrotoxicity and localized infection) of infusion pumps before this technique becomes widely used to manage pain after orthopaedic surgery.
Peripheral Nerve Blocks
Peripheral nerve blocks are an attractive method of providing postoperative analgesia for many orthopaedic surgical procedures. When compared with general anesthesia, these blocks have been associated with superior same-day recovery and decreases in hospital readmissions80. Although single-injection regional anesthesia is effective for early analgesia, it does not provide a long-term benefit compared with general anesthesia88. A recent meta-analysis revealed that, compared with opioid analgesia alone, use of continuous peripheral nerve blocks following orthopaedic surgery provides superior analgesia and reduces opioid use and opioid-related side effects89. Currently, there is insufficient evidence to determine the effectiveness of continuous peripheral analgesic techniques on long-term functional outcomes90.
In addition to providing subjective comfort, physicians need to inhibit trauma-induced afferent pain transmission and to blunt the autonomic and somatic reflex responses to pain following orthopaedic surgery. The neuroendocrine stress response that follows surgery has the capacity to induce important disturbances in body homeostasis such as hypercatabolism, hypercoagulability, and inflammation, which can contribute to adverse perioperative outcomes91. Parenteral opioids do not reduce this stress response adequately following orthopaedic surgery92, and they provide inferior analgesia when compared with epidural techniques for the management of postoperative pain93. Epidural analgesia is superior to either peripheral nerve blocks or patient-controlled analgesia for blunting the stress response following orthopaedic surgery92. The question facing orthopaedic surgeons is whether blocking the neuroendocrine stress response improves patient outcomes. Meta-analyses of hip fracture repairs94 and total hip arthroplasties95 showed that neuraxial block (spinal or epidural) anesthesia decreased the prevalences of deep venous thrombosis and pulmonary embolism, intraoperative blood loss, and blood transfusion requirements but had no effect on the one-year mortality rate. In two other clinical investigations, early administration of continuous epidural analgesia during the stressful preoperative period was associated with a lower prevalence of adverse cardiac events96,97, compared with that associated with conventional analgesia, in high-risk patients with a hip fracture.
Unfortunately, epidural anesthesia and analgesia are contraindicated for patients receiving anticoagulation therapy. For this reason, many institutions are utilizing alternative regional analgesic techniques for orthopaedic surgery. A prospective randomized study was performed to evaluate the effect of continuous epidural anesthesia, a continuous femoral nerve block, or intravenous patient-controlled analgesia maintained for seventy-two hours following total knee arthroplasty98. The first two techniques were performed with use of multimodal analgesics including lidocaine, clonidine, and morphine. Compared with intravenous patient-controlled analgesia, both regional techniques provided superior analgesia, reduced the duration of the rehabilitation stay, and improved functional outcomes. Because the prevalence of side effects associated with a continuous femoral block was lower than that associated with epidural analgesia and because the block does not cause neuraxial hematoma, the authors concluded that this technique has all of the qualities necessary to become the primary choice for regional analgesia after total knee arthroplasty98.
Opioids (Peripheral and Central Acting)
Opioids possess analgesic properties through action on opioid receptors located in the central nervous system. The preoperative administration of opioids may attenuate the central hyperexcitability response that occurs as a result of surgical trauma99. Several clinical investigations have shown preoperative administration of opioids to be an effective analgesic technique for the management of postoperative pain100-103. McQuay et al.102 demonstrated a prolonged duration of analgesia and a reduction in the use of postoperative analgesics when opiates had been administered to patients before they underwent elective orthopaedic surgery. Preoperative opioids have demonstrated efficacy when utilized as a component of a multimodal analgesic regimen for patients undergoing minimally invasive joint-replacement surgery103.
One concern regarding the perioperative use of opioids is the development of opioid-induced hyperalgesia104,105. During the last decade, there has been accumulating evidence that, in addition to the enhanced pain sensitivity found with the long-term administration of opioids, both hyperalgesia and allodynia can occur after the short-term use of opioids following abdominal and orthopaedic procedures104,105. Furthermore, the larger the intraoperative opioid dose, the greater the postoperative opioid requirement106. Therefore, short-term tolerance to an opioid may not be due to a decrease in its efficacy (pharmacological tolerance) but rather may be due to enhancement of pain sensitivity (opioid-induced hyperalgesia) leading to an apparent decrease in the effectiveness of the morphine104,105. The use of multimodal adjuvant drugs for postoperative pain may reduce opioid-induced hyperalgesia. Experimental and clinical studies have suggested that opioids activate both NMDA107 and COX108 pro-nociceptive systems leading to hyperalgesia. Therefore, the use of the NMDA receptor antagonists (ketamine) and nonsteroidal anti-inflammatory drugs not only decreases postoperative pain but may also reduce opioid-induced tolerance and hyperalgesia107,108.
In addition to the central action of opioids, recent studies have revealed that, under conditions of inflammation, these analgesics can produce substantial antinociception through peripheral mechanisms109. This has led to a growing number of clinical studies of the analgesic efficacy of opioids applied locally through the intra-articular, perineural, or intravenous regional route110,111. The most consistent clinical results concerning the analgesic efficacy of peripherally applied opioids in humans have come from studies involving the intra-articular administration of morphine during arthroscopic knee surgery111,112. Similar to the parenteral route99, the preemptive peripheral administration of morphine can also reduce postoperative pain113. Although the majority of investigators112 have examined the analgesic efficacy of administering intra-articular morphine at the conclusion of an operation, two groups of authors114,115 concluded that preoperative intra-articular administration of morphine is a more effective technique for managing pain following arthroscopic knee surgery. Because only small, systemically inactive doses of opioids are required to provide sustained analgesia with minimal side effects, intraarticular administration is an important technique in the management of pain following orthopaedic surgery.
Gabapentin and Pregabalin (α2-δ Ligands)
Both gabapentin and pregabalin are alkylated χ-aminobutyric acid analogs that were first developed clinically as anticonvulsants. These drugs bind to the α2-δ subunit of voltage-gated calcium channels, thus preventing release of nociceptive neurotransmitters including glutamate, substance P, and noradrenaline116. Putative sites of action include peripheral, primary afferent neuron, spinal neuron, and supraspinal sites117. These anticonvulsants can enhance the analgesic effect of morphine118, nonsteroidal anti-inflammatory drugs119, and COX-2 inhibitors120. Recent evidence suggests that, in addition to being effective analgesics for patients with neuropathic or chronic pain syndromes, these anticonvulsants provide effective postoperative analgesia when they are administered preemptively before an operation121,122. The role of certain neural changes common to both neuropathic and postoperative pain may explain these recent observations48,101. Perioperative administration of gabapentin has been found to be efficacious for managing pain following various orthopaedic surgical procedures, including anterior cruciate ligament and spinal operations121,122. A single preoperative 1200-mg dose of gabapentin was shown to reduce preoperative anxiety as well as postoperative pain scores and opioid use and to improve the range of motion for up to forty-eight hours following anterior cruciate ligament surgery123. Furthermore, since these drugs can interact synergistically with nonsteroidal anti-inflammatory drugs to produce antihyperalgesia121,122, the use of nonsteroidal anti-inflammatory drugs and α2-δ ligands together may provide more effective analgesia. The combination of pregabalin and celecoxib was recently shown to be superior to either single agent alone for management of pain following spinal fusion surgery124. This was evidenced by a significant (p < 0.001) reduction in pain scores and morphine use and fewer side effects during the first twenty-four postoperative hours in patients treated perioperatively with celecoxib and pregabalin.
The most commonly observed adverse events associated with the long-term use of gabapentin and pregabalin are dizziness, somnolence, and peripheral edema125. A meta-analysis indicated that perioperative treatment with gabapentin was associated with only a modest increase in sedation122. Although sedation can be interpreted as a negative outcome of gabapentin use, its occurrence in the perioperative setting may be beneficial in terms of contributing to anxiolysis123. Future studies are necessary to determine the optimal timing, duration, dosages, and impact on chronic persistent pain of administration of α2-δ ligands in association with a variety of orthopaedic surgical procedures.
Overview on Multimodal Analgesia
In summary, although these analgesic adjuvant medications (local anesthetics, α-2 agonists, nonsteroidal anti-inflammatory drugs, ketamine, and α2-δ ligands) may have an opioid-sparing effect when utilized alone, they may not effectively reduce opioid-related side effects57,58,60,71,72,122. Unfortunately, many of the investigators assessing opioid-related adverse effects used methodology that does not accurately reflect conditions in actual clinical practice. Nonsteroidal anti-inflammatory drugs are more likely to be used in multiple doses (which provide analgesia that is superior to that resulting from a placebo)60 than in single doses for the management of postoperative pain. In addition, a more comprehensive multimodal approach, rather than bimodal therapy, is probably needed to reduce opioid-related adverse events and improve functional outcomes.
The importance of utilizing a multimodal rather than a bimodal approach for postoperative pain management was recently demonstrated in a study of spinal fusion surgery124. While the administration of either celecoxib or pregabalin alone reduced morphine use, neither reduced opioid-related side effects. In contrast, the combination of these two analgesics reduced both morphine use and the prevalence and severity of opioid-related side effects126.
The beneficial effects of multimodal analgesia have also been demonstrated for patients treated with total knee arthroplasty19-21. In a randomized, placebo-controlled, double-blind trial, Buvanendran et al.19 evaluated the effect of regional anesthesia and analgesia combined with a preoperative and thirteen-day postoperative course of treatment with a COX-2 inhibitor on opioid consumption and outcomes following total knee arthroplasty. The patients who received the COX-2 inhibitor had reductions in epidural analgesic use, in-hospital opioid consumption, pain scores, postoperative vomiting, and sleep disturbance as well as increased satisfaction as compared with patients treated with a placebo. In addition, an improved range of motion of the knee was observed both at the time of discharge and at one month after the surgery in the group treated with the sustained perioperative COX-2 inhibition.
The use of multimodal analgesia has also been found to be efficacious for patients treated with anterior cruciate ligament surgery20. Patients who were treated with a regimen of perioperative acetaminophen, rofecoxib, intra-articular analgesics (bupivacaine, clonidine, and morphine), a femoral nerve block, and postoperative cryotherapy had reduced prevalences of pain, opioid use, and postoperative nausea and vomiting; a shorter stay in the recovery room; and fewer unplanned readmissions to the hospital. In addition, this multimodal regimen effectively reduced the prevalence of long-term patellofemoral complications, including anterior knee pain, flexion contracture, quadriceps weakness, and chronic regional pain syndrome21.
Prevention of Chronic Postoperative Pain Syndromes
Preemptive multimodal analgesic techniques appear to be promising for the treatment of acute postoperative pain and may reduce the prevalence of chronic pain following orthopaedic surgery21. The following is a summary of analgesic techniques aimed at reducing the prevalence of complex regional pain syndrome, phantom limb pain, chronic donor-site pain, and persistent pain following total joint arthroplasty.
Complex Regional Pain Syndrome
Complex regional pain syndrome is a disorder characterized by the presence, following a noxious event, of regional pain and sensory changes such as temperature alterations, abnormal skin color, abnormal sudomotor activity, and/or edema127. Its onset is associated with a history of trauma (that is often innocuous) or immobilization, and there is typically no correlation between the severity of the initial injury and the ensuing painful syndrome128. The Consensus Conference of the International Association for the Study of Pain has identified two forms of complex regional pain syndrome: type I (formerly known as reflex sympathetic dystrophy) and type II (formerly known as causalgia)129. A recent consensus guideline panel provided diagnostic clinical and research criteria with high sensitivity and specificity130. Patients with type-I or II complex regional pain syndrome can have sympathetically maintained pain or sympathetically independent pain131.
The prevalence of complex regional pain syndromes occurring after an operation is variable and may be underreported33. Approximately 20% of patients who present to chronic pain clinics with complex regional pain syndrome have a history of an operative procedure in the affected area132. Most reported cases of postoperative complex regional pain syndrome have occurred after orthopaedic procedures, especially those on the extremities33,132,133. The estimated prevalences have ranged from 2.3% to 4% following arthroscopic knee surgery, 2.1% to 5% following carpal tunnel surgery, 13.6% following ankle surgery, 0.8% to 13% following total knee arthroplasty, 7% to 37% following wrist fractures, and 4.5% to 40% following fasciectomy for Dupuytren contracture33.
Since type-II complex regional pain syndrome is the result of a definable nerve lesion129, utilizing a surgical technique that minimizes the risk of nerve damage is an important factor in preventing the development of this syndrome following surgery33. Nerve injury may occur intraoperatively as a result of direct surgical trauma or excessive retraction or it may occur postoperatively as a result of nerve compression secondary to edema, hematoma, infection, or the application of tight dressings. Therefore, many cases of complex regional pain syndrome can be prevented by “careful technique, knowledge of anatomy, and proper postoperative management.”134 Furthermore, early recognition of the syndrome in the postoperative period is the key to facilitating successful treatment33.
The use of a regional nerve block that provides a perioperative sympathectomy may be advantageous for patients with a history of complex regional pain syndrome who require orthopaedic surgery. It has been our practice to administer a stellate ganglion block to patients with complex regional pain syndrome who are undergoing upper-extremity surgery with local or general anesthesia. We previously performed a retrospective study of 100 patients with complex regional pain syndrome who underwent surgery on the affected upper extremity135. Half of the patients underwent a stellate ganglion block after completion of the operative procedure, and the other half received no intervention after the procedure. During the twelve-month period following the surgery, the rate of recurrence of the complex regional pain syndrome was significantly lower (p < 0.01) in the patients who had received the perioperative stellate ganglion block (five of fifty; 10%) than in those who had not (thirty-six of fifty; 72%).
In addition to stellate ganglion blocks, the perioperative sympathectomy provided by either a brachial plexus block or intravenous regional anesthesia with clonidine may provide a benefit to patients undergoing an operative procedure on the upper extremity. We previously showed that intravenous regional anesthesia with lidocaine and clonidine (1 μg/kg) is an effective way to manage both acute postoperative pain40 and the symptoms of complex regional pain syndrome42,43. A prospective study of four anesthetic techniques (general anesthesia, intravenous regional anesthesia with lidocaine, intravenous regional anesthesia with lidocaine and clonidine, and an axillary block) in a series of 300 consecutive patients undergoing fasciectomy for the treatment of Dupuytren contracture confirmed a beneficial effect of the latter two techniques136. Postoperative complex regional pain syndrome developed in significantly (p < 0.01) more patients in the group treated with general anesthesia (twenty-five; 24%) and the group treated with intravenous regional anesthesia with lidocaine (twelve; 25%) than in either the group treated with an axillary block (five; 5%) or the group treated with intravenous regional anesthesia with lidocaine and clonidine (three; 6%).
In addition to perioperative regional blocks, pharmacologic agents including calcitonin, mannitol, vitamin C, corticosteroids, carnitine, and ketanserin have been advocated for the prevention of postoperative complex regional pain syndrome33. Interestingly, only vitamin C has been shown to be beneficial in prospective, placebo-controlled studies137,138. Vitamin C is a natural antioxidant that is reported to scavenge both hydroxyl radicals139 and superoxide radicals that produce hydroxyl and other free radicals140 that may be responsible for the pathogenesis of complex regional pain syndrome. Zollinger et al.137 evaluated the efficacy of administering either 500 mg of vitamin C or a placebo daily for fifty days to 123 adults with a total of 127 wrist fractures. There was a significant (p < 0.001) reduction in the prevalence of complex regional pain syndrome in the vitamin-C group (7%) compared with the placebo group (22%) at the time of follow-up, at one year. Cazeneuve et al.138 confirmed the benefits of vitamin C in a prospective, nonrandomized study of 195 patients with a wrist fracture who presented for surgery. Patients who received vitamin C (1 g daily) for forty-five days, starting on the day of the fracture, had a fivefold lower prevalence of complex regional pain syndrome (2.1% compared with 10% in patients who did not receive vitamin C; p < 0.01). This simple, safe, and inexpensive technique may have important implications in the development of protocols for the prevention and management of complex regional pain syndrome.
Finally, preventive multimodal analgesic techniques in conjunction with physical therapy and rehabilitation following an operation appears to be a promising technique for reducing the prevalence of postoperative complex regional pain syndrome. Patients who were treated with a regimen of perioperative acetaminophen, rofecoxib, intra-articular analgesics (bupivacaine, clonidine, and morphine), a femoral nerve block, and postoperative cryotherapy demonstrated a significant (p < 0.001) reduction in the prevalence of complex regional pain syndrome at one year following anterior cruciate ligament surgery21.
Phantom Limb Pain
Patients who experience the loss of a limb, either traumatically or surgically, almost always report some degree of perceived sensation in the lost limb. A distinction should be made between phantom limb pain (painful sensations referred to the absent limb), phantom limb sensation (any sensation in the absent limb, except pain), and stump pain (pain localized in the stump), although each may be felt by an individual patient at different times141. Recent reports have suggested that the prevalence of phantom pain is probably between 50% and 80%142-144. Several risk factors have been identified for the development of phantom limb pain, including the degree of preoperative pain, the magnitude of intraoperative noxious input, the intensity of postoperative pain, and psychological factors1,145.
The mechanisms of phantom pain are not completely clear. As is the case with other types of neuropathic pain, there are likely both peripheral and central factors at play. Increased spontaneous activity of both afferent peripheral nerves and dorsal root ganglion cells has been observed experimentally following the transection of a nerve6. In addition, the sympathetic nervous system may have a role in sensitizing and maintaining the abnormal afferent output from damaged nerve fibers after amputation6. It is now known that the central nervous system undergoes substantial functional reorganization following amputation146.
Several investigations have focused on the use of preventive regional analgesic techniques to reduce perioperative pain and phantom pain following surgical amputation of the lower extremity147. Bach et al.148 compared the effect of epidural morphine or bupivacaine, or both in combination, used for three days before the amputation in eleven patients with that of conventional analgesia in fourteen patients. After six months, all patients in the epidural group were pain-free whereas five patients in the control group had phantom pain (p < 0.05). Jahangiri et al.149 confirmed the beneficial effects of perioperative epidural analgesics for preventing phantom pain following amputation surgery in a study in which an epidural infusion of bupivacaine, diamorphine, and clonidine had been administered to thirteen patients for twenty-four to forty-eight hours preoperatively and maintained for at least three days postoperatively. For comparison, a control group of eleven patients received on-demand opioid analgesia. The authors observed a significant (p < 0.01) reduction in the prevalence of phantom pain at one year following the operation in the patients treated with the epidural infusion. However, what we believe to be the largest prospective study of the effect of epidural analgesia on phantom pain (sixty patients) failed to document any benefit150. This study may be criticized, however, because the investigators chose to provide preemptive epidural analgesia for only eighteen hours prior to the amputation.
Similarly, the results of clinical investigations of the efficacy of continuous postoperative regional analgesia with a nerve sheath block following amputation surgery have been equivocal, with some studies revealing beneficial effects151,152 and others demonstrating no long-term benefit153,154. In one study, a preoperative epidural block with bupivacaine and diamorphine was found to prevent phantom pain as effectively as infusion of bupivacaine from an intraoperatively placed perineural catheter, but the epidural analgesic technique was more effective in relieving stump pain in the immediate postoperative period155.
Unfortunately, many of the studies evaluating the ability of regional analgesics to reduce long-term phantom pain have had multiple design flaws, including not being prospective, not being randomized or blinded, either not including a control group or using historical controls, involving a heterogeneous study group, or lacking sufficient power. The authors of a recent systematic review of the literature concluded that, because of poor quality and contradictory results, the randomized and controlled trials that have been reported do not provide evidence to support any particular treatment of phantom limb pain in the acute perioperative period or later147.
Chronic Donor-Site Pain
Chronic pain is not an uncommon complication following spinal fusion surgery. Autogenous bone grafts are frequently harvested from the ilium for the purposes of bone fusion in patients undergoing spinal stabilization surgery. Often, the pain from the donor site is more severe than that from the operative site in the spine156-159. Although this pain usually resolves over a period of several weeks, it may persist and represent a source of postoperative morbidity156-159. In fact, donor site pain has been reported in up to 39% of patients at three months, 38% at six months, 37% at one year, and 19% at two years after harvesting of bone graft from the iliac crest157-160.
The precise mechanism of donor site pain remains obscure. It has been postulated to be muscular or periosteal in nature, secondary to stripping of the hip abductors from the ilium156. In addition, the pain may be neuropathic in origin, secondary to injury to small sensory nerves at the donor site. Two nerves that are frequently injured during the harvest of bone graft from the anterior aspect of the ilium are the lateral femoral cutaneous and ilioinguinal nerves156. The superior cluneal nerves pierce the lumbodorsal fascia and cross the posterior iliac crest 8 cm lateral to the posterior superior iliac spine161. These nerves may be injured while bone graft is harvested from the posterior aspect of the ilium, and the injury may result in transient or permanent numbness and pain over the buttock area.
Three recent studies have demonstrated a substantial reduction in the prevalence of chronic donor-site pain with the preemptive administration of analgesics160,162,163. Houghton et al.164 showed that the local application of a low dose of morphine effectively blocked the development of hyperalgesia and allodynia in a rat model of bone damage. This analgesic effect was considered to be mediated through μ-opioid receptor action in the bone. Gündes et al.163 infused 20 mL of saline solution alone, a solution containing 50 mg of bupivacaine, or a solution containing 50 mg of bupivacaine and 5 mg of morphine through a 17-gauge catheter placed at the iliac crest donor site in forty-five patients undergoing spinal fusion surgery. These investigators reported the absence of chronic donor-site pain at twelve weeks in the group treated with bupivacaine and morphine, whereas five of fifteen patients who had received the saline solution alone and two of fifteen patients treated with the bupivacaine alone had such pain.
We subsequently evaluated the analgesic effect of low-dose morphine alone administered to the site of bone-graft harvesting in patients undergoing spinal fusion surgery160. Of the sixty patients in the study, twenty were randomized to be treated with infiltration of saline solution into the harvest site; twenty, with 5 mg of intramuscular morphine; and twenty, with infiltration of 5 mg of morphine into the harvest site (twenty patients in each group). Infiltration of morphine into the bone graft harvest site significantly reduced the pain scores and opioid use for the first twenty-four hours following surgery (p < 0.0001). Furthermore, the prevalence of chronic donor-site pain was significantly lower (p < 0.05) in the group that had received local morphine (5%) than in those treated with intramuscular morphine (37%) or infiltration of saline solution (33%).
We also examined the analgesic effects of preemptive COX-2 administration on chronic donor-site pain following spinal fusion surgery162. It has been shown that COX-2 plays an integral role in the processes of peripheral and central sensitization165, and it is possible that early and sustained treatment with COX-2 inhibitors may thwart the progression of acute to chronic pain166. Eighty patients scheduled to undergo posterior spinal fusion with instrumentation were randomized either to receive 400 mg of celecoxib one hour prior to surgery followed by 200 mg every twelve hours postoperatively for the first five days or to receive a matching placebo at similar time intervals162. The prevalence of chronic donor site pain was significantly higher (p < 0.01) in the placebo group (twelve of forty patients; 30%) than in the celecoxib group (four of forty patients; 10%) at one year following surgery.
These three studies160,162,163 highlight the importance of utilizing preemptive analgesics for management of pain following spinal fusion surgery. We currently administer 1000 mg of acetaminophen, 400 mg of celecoxib, and 150 mg of pregabalin one to two hours before spinal fusion surgery. Intraoperatively, 20 mg of ketamine is administered intravenously and the graft harvest site is infiltrated with a mixture of 10 mL of 0.25% bupivacaine, 5 mg of morphine, and 50 μg of clonidine. Patients then receive 200 mg of celecoxib and 75 mg of pregabalin twice daily, 1000 mg of acetaminophen four times daily, and 10 mg of controlled-release oxycodone twice daily for the first week postoperatively. We are currently examining the efficacy of this preemptive multimodal analgesic technique for reducing acute and chronic pain. Additional studies are needed to assess the appropriate dosages, timing, and duration of various preventive analgesic techniques to reduce chronic donor-site pain.
Chronic Pain After Total Joint Arthroplasty
Total joint arthroplasty has proved to be a successful operative treatment of hip and knee joints affected by osteoarthritis. In 2003, more than 400,000 total knee arthroplasties and 220,000 total hip arthroplasties were performed in the United States, with reported success rates ranging from 80% to 90%167. A recent nationwide Danish study revealed that 28.1% of more than 1200 consecutive patients who had undergone total hip arthroplasty reported having chronic ipsilateral hip pain twelve to eighteen months after the operation168. Furthermore, this persistent hip pain limited daily activity to a moderate-to-severe degree in 12.1% of these patients. In a prospective observational study, 18.4% of patients reported moderate-to-severe pain at six months following a total knee arthroplasty and 13.1% reported such pain at one year169. Defining who is at risk for the development of chronic pain following total joint arthroplasty would be extremely useful in preventing this outcome.
Severe preoperative pain is a primary indication for total joint arthroplasty167, but it is also the primary predictor of chronic postoperative pain1. Higher pain ratings before rehabilitation predict treatment failure and are associated with poor outcomes in patients with chronic musculoskeletal disorders170. Patients with greater preoperative pain were found to be at greater risk for heightened postoperative pain after total joint arthroplasty irrespective of confounding issues, such as the severity of the preoperative disease or postoperative complications169,171,172. Greater preoperative pain also leads to worse Knee Society function scores at one year postoperatively and is associated with a longer hospital stay, longer inpatient rehabilitation, a lower range of motion, more postoperative knee manipulations, and more home physical therapy visits169. Furthermore, greater preoperative pain intensity is a significant predicting factor (p < 0.01) for the development of complex regional pain syndrome at three and six months following total knee arthroplasty172.
Preoperative psychological factors may also play a role in the development of persistent pain following operative procedures1, including total knee arthroplasty169,172. Psychosocial variables seem to be an important factor in the pain response and can lead to a poor functional outcome in patients with osteoarthritis of the knee173,174. Two recent prospective studies have confirmed that preoperative depression and anxiety are associated with a higher prevalence of chronic pain and complex regional pain syndrome after total knee arthroplasty169,172. Because there are psychosocial risk factors for severe acute pain1 and because psychosocial and pharmacologic interventions can reduce pain and psychosocial distress, the best preventive intervention may be one that combines pharmacologic and psychosocial treatments. Therefore, strategies aimed at screening, identifying, and treating patients with depression, anxiety, and severe pain before an operation may be important to prevent the development of chronic pain and improve outcomes following total joint arthroplasty.
The development of chronic pain continues to be a major source of morbidity following a variety of orthopaedic surgical procedures. Despite its prevalence, our understanding of chronic postoperative pain and the potential means of risk reduction are somewhat deficient. Preventive multimodal analgesic techniques may play a role in reducing the prevalence of certain chronic postoperative pain syndromes. The appropriate timing of analgesic intervention in the perioperative period is an important factor to understand. In order to effectively prevent the development of central neuroplasticity, it is necessary to administer analgesics during the preoperative, intraoperative, and postoperative periods. Furthermore, regional blockade by itself may not be sufficient to provide complete pain relief and prevent central sensitization. It has been demonstrated that, despite adequate neural blockade during surgery, central prostaglandin synthesis can still be induced, potentially leading to central neuroplasticity and increased postoperative pain175. A multimodal analgesic regimen utilizing regional blockade, nonsteroidal anti-inflammatory drugs, and other peripheral and centrally acting analgesics, including α-2 agonists, ketamine, α2-δ ligands, and opioids, administered throughout the perioperative period may be the most efficacious strategy for reducing both acute and chronic pain following orthopaedic surgery. Future large-scale randomized, controlled trials are necessary to better understand the use of preventive multimodal analgesic techniques in reducing chronic postoperative orthopaedic pain syndromes.
Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
1. , Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000;93: 1123-33.
2. , Davies HTO. Chronic postsurgical pain. In: Crombie IK, Croft PR, Linton SJ, Leresche L, Von Korff, M, editors. Epidemiology of pain: a report on the Task Force on Epidemiology. Seattle: IASP Press; 1999. p 125-42.
3. , Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetc basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14: 135-43.
4. . Post-surgical neuralgia. Pain. 2004;111: 3-7.
5. , Wall PD. Pain mechanisms: a new theory. Science. 1965;150: 971-9.
6. , Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993;52: 259-85.
7. , Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288: 1765-9.
8. , Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology. 2002;96: 725-41.
9. , Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg. 2005;100: 757-73.
10. . Preemptive analgesia: terminology and clinical relevance. Anesth Analg. 1994;79: 809-10.
11. , Reese PR, Burch SP. The economic impact of opioids on postoperative pain management. J Clin Anesth. 2002;14: 354-64.
12. , Oderda GM, Ashburn MA, Lipman AG. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain. 2002;3: 159-80.
13. . JCAHO pain management standards are unveiled. Joint Commission on Accreditation of Healthcare Organizations. JAMA. 2000;284: 428-9.
14. . Postoperative opioid sparing to hasten recovery: what are the issues? Anesthesiology. 2005;102: 1083-5.
15. , Voytovich AE, Kozol RA. Has the pendulum swung too far in postoperative pain control? Am J Surg. 2003;186: 472-5.
16. , Smith RA, Augustyniak MJ, Nagi PA, Soto RG, Ross TW, Cantor AB, Strickland JM, Miguel RV. The efficacy and safety of pain management before and after implementation of hospital-wide pain management standards: is patient safety compromised by treatment based solely on numerical pain ratings? Anesth Analg. 2005;101: 474-80.
17. , Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77: 1048-56.
18. , Rosenberg J, Dirkes WE, Mogensen T, Kehlet H. Prevention of postoperative pain by balanced analgesia. Br J Anaesth. 1990;64: 518-20.
19. , Kroin JS, Tuman KJ, Lubenow TR, Elmofty D, Moric M, Rosenberg AG. Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial. JAMA. 2003;290: 2411-8.
20. , Gutta SB, Maciolek H, Sklar J. Effect of initiating a multimodal analgesic regimen upon patient outcomes after anterior cruciate ligament reconstruction for same-day surgery: a 1200-patient case series. Acute Pain. 2004;6: 87-93.
21. , Gutta SB, Maciolek H, Sklar J, Redford J. Effect of initiating a preventative multimodal analgesic regimen upon long-term patient outcomes after anterior cruciate ligament reconstruction for same-day surgery: a 1200-patient case series. Acute Pain. 2005;7: 65-73.
22. . Acute Pain Management: Operative or Medical Procedures and Trauma. Pub. no. 92-0032. Rockville, Maryland, United States Department of Health and Human Services, Public Health Service Agency for Health Care Policy and Research, 1992.
23. , Caplan RA, Carr DB, Connis RT, Ginsburg B, Green CR, Lema MJ, Nickinovich DG, Rice LJ. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2004;100: 1573-81.
24. , Kopajtic TA, Kuhar MJ. Distribution of alpha 2 agonist binding sites in the rat and human central nervous system: analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents. Brain Res. 1984;319: 69-101.
25. , Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesth Analg. 1992;74: 719-25.
26. , Strichartz GR. The 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg. 1993;76: 295-301.
27. , Brunet PC, Jirounek P. Hyperpolarizing afterpotentials in C fibers and local anesthetic effects of clonidine and lidocaine. Pharmacology. 1994;48: 21-9.
28. , Duval N, Massingham R. Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes. J Cardiovasc Pharmacol. 1985;7 Suppl 8: S1-8.
29. , Forster A, Griessen M, Habre W, Poinsot O, Della Santa D. Comparison between clonidine and epinephrine admixture to lidocaine in brachial plexus block. Anesth Analg. 1992;75: 69-74.
30. , Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats is mediated via the hyperpolarization-activated cation current, not by alpha-adrenoreceptors. Anesthesiology. 2004;101: 488-94.
31. , Ferreira SH. Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. Eur J Pharmacol. 1988;146: 223-8.
32. , Julka I. Stellate ganglion blockade for acute postoperative upper extremity pain. Anesthesiology. 2005;102: 1288-9.
33. . Preventing the development of complex regional pain syndrome after surgery. Anesthesiology. 2004;101: 1215-24.
34. , De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;85: 655-74.
35. , Beach M, Biggs R, Rohan C, Wiley C, Rassias A, Gregory J, Fanciullo G. Intrathecal clonidine added to a bupivacaine-morphine spinal anesthetic improves postoperative analgesia for total knee arthroplasty. Anesth Analg. 2003;96: 1083-8.
36. , Rosenberg PH. Small dose of clonidine mixed with low-dose ropivacaine and fentanyl for epidural analgesia after total knee arthroplasty. Br J Anaesth. 2004;93: 670-7.
37. , Lambropoulos A, Moric M, Kroin JS. Long-term epidural infusion for pain management and rehabilitation following total knee arthroplasty [abstract]. Anesthesiology. 2006;105: A1650.
38. , Convery PN, Weir P, Quinn P, Connolly D. The efficacy and safety of epidural infusions of levobupivacaine with and without clonidine for postoperative pain relief in patients undergoing total hip replacement. Anesth Analg. 2000;91: 393-7.
39. , Axelsson K, Gupta A, Lundin A, Holmstrom B, Granath B. Improved analgesia with clonidine when added to local anesthetic during combined spinal-epidural anesthesia for hip arthroplasty: a double-blind, randomized and placebo-controlled study. Acta Anaesthesiol Scand. 2005;49: 538-45.
40. , Steinberg RB, Klatt JL, Klatt ML. Intravenous regional anesthesia using lidocaine and clonidine. Anesthesiology. 1999;91: 654-8.
41. , Reuben SS, Gibson CS, DeLuca PA, Maciolek HA. Effect of clonidine on upper extremity tourniquet pain in healthy volunteers. Reg Anesth Pain Med. 2000;25: 502-5.
42. , Steinberg RB, Madabhushi L, Rosenthal E. Intravenous regional clonidine in the management of sympathetically mediated pain. Anesthesiology. 1998;89: 527-30.
43. , Sklar J. Intravenous regional anesthesia with clonidine in the management of complex regional pain syndrome of the knee. J Clin Anesth. 2002;14: 87-91.
44. , Hommeril JL, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology. 1991;75: 577-82.
45. , Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine. Anesth Analg. 1999;88: 729-33.
46. , Reuben SS, Kilaru PK, Sklar J, Maciolek H. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine and/or morphine. Anesth Analg. 2000;90: 1102-6.
47. . Acute pain and the injury response: immediate and prolonged effects. Reg Anesth. 1989;14: 162-79.
48. , Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology. 1988;68: 571-90.
49. . Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain. 1994;59: 9-43. Erratum in: Pain. 1995;60:353.
50. , Fredman B, White PF. Controversies in the perioperative use of nonsteroidal antiinflammatory drugs. Anesth Analg. 1994;79: 1178-90.
51. , Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth. 1991;66: 703-12.
52. , Connelly NR, Lurie S, Klatt M, Gibson CS. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg. 1998;87: 98-102.
53. , Tegeder I, Brune K, Geisslinger G. Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology. 1999;91: 231-9.
54. , Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA. 2002;99: 13926-31.
55. , Lally ET, Moore PA. Update on cyclooxygenase inhibitors: has a third COX isoform entered the fray? Curr Med Res Opin. 2005;21: 1217-26.
56. , Loriot MA, Libert F, Eschalier A, Beaune P, Dubray C. Analgesic effect of acetaminophen in humans: first evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006;79: 371-8.
57. , Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth. 2005;94: 505-13.
58. , Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth. 2002;88: 199-214.
59. . Role of COX-2 inhibitors in the evolution of acute pain management. J Pain Symptom Manage. 2002;24(1 Suppl): S18-S27.
60. , Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103: 1296-304.
61. , Moiniche S. A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain. Acta Anaesthesiol Scand. 2004;48: 525-46.
62. , Smith RM. Cardiovascular risks of coxibs: the orthopaedic perspective. J Bone Joint Surg Am. 2005;87: 245-6.
63. , Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343: 1520-8.
64. , Topol EJ. Cox-2: where are we in 2003?—cardiovascular risk and Cox-2 inhibitors. Arthritis Res Ther. 2003;5: 8-11.
65. , Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT; Multicenter Study of Perioperative Ischemia (McSPI) Research Group; Ischemia Research and Education Foundation (IREF) Investigators. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2003;125: 1481-92.
66. , Whelton AA, Brown MT, Joshi GP, Langford RM, Singla NK, Boye ME, Verburg KM. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology. 2006:104: 518-26.
67. , Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med. 2005;142: 481-9.
68. . FDA labors over NSAID decisions: panel suggests COX-2 inhibitors stay available. Am J Health Syst Pharm. 2005;62: 668-72.
69. , Fagg GE. Neurobiology. Taking apart NMDA receptors. Nature. 1987;329: 395-6.
70. , Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44: 293-9.
71. , Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82: 111-25.
72. , Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99: 482-95.
73. , Oren M, Vaskovich M, Dashkovsky I, Kissin I. Ketamine enhances local anesthetic and analgesic effects of bupivacaine by peripheral mechanism: a study in postoperative patients. Neurosci Lett. 1996;215: 5-8.
74. , Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg. 2000;90: 129-35.
75. , Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg. 2001;93: 606-12.
76. , Ziegler-Pithamitsis D, Argiriadou H, Martin J, Jelen-Esselborn S, Kochs E. Small-dose S(+)-ketamine reduces postoperative pain when applied with ropivacaine in epidural anesthesia for total knee arthroplasty. Anesth Analg. 2001;92: 1290-5.
77. , Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D. Small-dose ketamine infusion improves postoperative analgesia and rehabilitation after total knee arthroplasty. Anesth Analg. 2005;100: 475-80.
78. . The kinetic theory of shock and its prevention through anoci association (shockless operation). Lancet. 1913;185: 7-16.
79. , Dunn TS. Disposable infusion pumps. Am J Health Syst Pharm. 2006;63: 1260-8.
80. , Ben-David B, Williams BA, Kentor ML. Anesthesia and postoperative analgesia: outcomes following orthopedic surgery. Orthopedics. 2003;26(8 Suppl): 865-71.
81. , Pulido PA, Morris BA, Fronek J. The efficacy of continuous bupivacaine infiltration following anterior cruciate ligament reconstruction. Arthroscopy. 2002;18: 854-8.
82. , Evans NA, Stanish WD. Patient-controlled bupivacaine infusion into the infrapatellar fat pad after anterior cruciate ligament reconstruction. Arthroscopy. 2003;19: 500-5.
83. , Herbert MA. The effectiveness of an anesthetic continuous-infusion device on postoperative pain control. Arthroscopy. 2002;18: 76-81.
84. , Elliot D. Local anaesthetic infusion for postoperative pain. J Hand Surg [Br]. 2003;28: 300-6.
85. , Samartzis D, Strom J, Manning D, Campbell-Hupp M, Wetzel FT, Gupta P, Phillips FM. A prospective, randomized, double-blind study evaluating the efficacy of postoperative continuous local anesthetic infusion at the iliac crest bone graft site after spinal arthrodesis. Spine. 2005;30: 2477-83. Erratum in: Spine. 2006;31:43.
86. , Rogers V, Cortina G, Cooney T. Continuous intra-articular infusion of bupivacaine for postoperative pain following total knee arthroplasty. J Knee Surg. 2005;18: 197-202.
87. , Kang RW, Williams JM, Bach BR, Cole BJ. Chondrolysis after continuous intra-articular bupivacaine infusion: an experimental model investigating chondrotoxicity in the rabbit shoulder. Arthroscopy. 2006;22: 813-9.
88. , Brull R, Chan VW, Katz J, Abbas S, Graham B, Nova H, Rawson R, Anastakis DJ, Von Schroeder H. Early but no long-term benefit of regional compared with general anesthesia for ambulatory hand surgery. Anesthesiology. 2004;101: 461-7. Erratum in: Anesthesiology. 2004;101:1057.
89. , Liu SS, Courpas G, Wong R, Rowlingson AJ, McGready J, Cohen SR, Wu CL. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. Anesth Analg. 2006;102: 248-57.
90. , Wu CL, Sinatra RS, Ballantyne JC, Ginsberg B, Gordon DB, Liu SS, Perkins FM, Reuben SS, Rosenquist RW, Viscusi ER. Acute post-surgical pain management: a critical appraisal of current practice, December 2-4, 2005. Reg Anesth Pain Med. 2006;31(4 Suppl 1): 1-42.
91. . The stress response to trauma and surgery. Br J Anaesth. 2000;85: 109-17.
92. , Saatweber P, Schmitz CS, Hecker H. Postoperative pain management in orthopaedic patients: no differences in pain score, but improved stress control by epidural anaesthesia. Eur J Anaesthesiol. 2002;19: 658-65.
93. , Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA. 2003;290: 2455-63.
94. , Handoll HH, Griffiths R. Anaesthesia for hip fracture surgery in adults. Cochrane Database Syst Rev. 2001;4: CD000521.
95. , Shilling AM, Zuo Z. A comparison of neuraxial block versus general anesthesia for elective total hip replacement: a meta-analysis. Anesth Analg. 2006;103: 1018-25.
96. , Virtanen T, Kentala E, Uotila P, Laitio T, Hartiala J, Heikkila H, Sariola-Heinonen K, Pullisaar O, Yli-Mayry S, Jalonen J. Epidural infusion of bupivacaine and fentanyl reduces perioperative myocardial ischemia in elderly patients with hip fracture—a randomized controlled trial. Acta Anaesthesiol Scand. 2000;44: 1061-70.
97. , Oppenheim-Eden A, Ratrot R, Baranova J, Davidson E, Eylon S, Peyser A, Liebergall M. Preoperative cardiac events in elderly patients with hip fracture randomized to epidural or conventional analgesia. Anesthesiology. 2003;98: 156-63.
98. , Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d'Athis F. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology. 1999;91: 8-15.
99. , Wall PD. Morphine-sensitive and morphine-insensitive actions of C-fibre input on the rat spinal cord. Neurosci Lett. 1986;64: 221-5.
100. , Steinberg RB, Maciolek H, Joshi W. Preoperative administration of controlled-release oxycodone for the management of pain after ambulatory laparoscopic tubal ligation surgery. J Clin Anesth. 2002;14: 223-7.
101. , Chong MS. Preemptive analgesia—treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg. 1993;77: 362-79.
102. , Carroll D, Moore RA. Postoperative orthopaedic pain—the effect of opiate premedication and local anaesthetic blocks. Pain. 1988;33: 291-5.
103. , Tuman KJ, McCoy DD, Matusic B, Chelly JE. Anesthetic techniques for minimally invasive total knee arthroplasty. J Knee Surg. 2006;19: 133-6.
104. . Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002;100: 213-7.
105. , Ferrera P, Villari P, Arcuri E. Hyperalgesia: an emerging iatrogenic syndrome. J Pain Symptom Manage. 2003;26: 769-75.
106. , Liu K, Wang JJ, Kuo MC, Ho ST. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth. 1999;46: 872-7.
107. , Laulin JP, Celerier E, Le Moal M, Simonnet G. Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilatory systems. Neuroscience. 1998;84: 583-9.
108. , Hosokawa A, Bell A, Sutak M, Milne B, Quirion R, Jhamandas K. Comparative effects of cyclo-oxygenase and nitrous oxide synthase inhibition on the development and reversal of spinal opioid tolerance. Br J Pharmacol. 1999;127: 631-44.
109. . Peripheral mechanisms of opioid analgesia. Anesth Analg. 1993;76: 182-91.
110. , Tramer MR, McQuay HJ, Moore RA. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain. 1997;72: 309-18.
111. , Smith L, McQuay HJ, Andrew Moore R. No pain, no gain: clinical excellence and scientific rigour—lessons learned from IA morphine. Pain. 2002;98: 269-75.
112. , Sklar J. Pain management in patients who undergo outpatient arthroscopic surgery of the knee. J Bone Joint Surg Am. 2000;82: 1754-66.
113. , Daughters RS, Rivard R, Simone DA. Peripheral and preemptive opioid antinociception in a mouse visceral pain model. Pain. 2001;89: 221-7.
114. , Randelli P, Bigoni M, Vitale G, Marino MR, Fraschini N. Pre- and postoperative intra-articular analgesia for arthroscopic surgery of the knee and arthroscopic-assisted anterior cruciate ligament reconstruction. A double-blind randomized, prospective study. Knee Surg Sports Traumatol Arthrosc. 1997;5: 206-12.
115. , Sklar J, El-Mansouri M. The preemptive analgesic effect of intraarticular bupivacaine and morphine after ambulatory arthroscopic knee surgery. Anesth Analg. 2001;92: 923-6.
116. , Yagel S, Momplaisir ML, Codd EE, D'Andrea MR. Molecular cloning and characterization of the human voltage-gated calcium channel alpha(2)delta-4 subunit. Mol Pharmacol. 2002;62: 485-96.
117. . Is gabapentin a “broad-spectrum” analgesic? Anesthesiology. 2002;97: 537-9.
118. , Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg. 2000;91: 185-91.
119. , Chatterjea D, Rose Feng M, Taylor CP, Hammond DL. Gabapentin and pregabalin can interact synergistically with naproxen to produce antihyperalgesia. Anesthesiology. 2002;97: 1263-73.
120. , Orr E, Tu D, O'Neill JP, Zamora JE, Bell AC. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Pain. 2005;113: 191-200.
121. , Mathiesen O, Moiniche S. `Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anesthesiol Scand. 2004;48: 1130-6.
122. , Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med. 2006;31: 237-47.
123. , Adam F, Guignard B, Sessler DI, Chauvin M. Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery. Anesth Analg. 2005;100: 1394-9.
124. , Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg. 2006;103: 1271-7.
125. . Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurol. 2004;3: 618-21.
126. , Raghunathan K, Cheung R. Dose-response relationship between opioid use and adverse events after spinal fusion surgery [abstract]. Anesthesiology. 2006;105: A1646.
127. , Janig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain. 1995;63: 127-33.
128. , Grabow TS. Complex regional pain syndrome I (reflex sympathetic dystrophy). Anesthesiology. 2002;96: 1254-60.
129. , Bogduk N. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle: IASP Press; 1994.
130. . Complex regional pain syndromes: symptoms, signs, and differential diagnosis. In: Stanton-Hicks M, Jänig W, editors. Reflex sympathetic dystrophy: a reappraisal. Seattle: IASP Press; 1996. p 79-92.
131. . Sympathetic nerve blocks: in search of a role. Reg Anesth Pain Med. 1998;23: 292-305.
132. , Martin GM, Magness JL, Kavanaugh GJ. Reflex sympathetic dystrophy. Review of 140 cases. Minn Med. 1970;53: 507-12.
133. , Galer BS, Schwartz L. Epidemiology of complex regional pain syndrome: a retrospective chart review of 134 patients. Pain. 1999;80: 539-44.
134. , Florio RL, Mack GR. Carpal tunnel release under local anesthesia: evaluation of the outpatient procedure. J Hand Surg [Am]. 1979;4: 544-6.
135. , Rosenthal EA, Steinberg RB. Surgery on the affected upper extremity of patients with a history of complex regional pain syndrome: a retrospective study of 100 patients. J Hand Surg [Am]. 2000;25: 1147-51.
136. , Pristas R, Dixon D, Faruqi S, Madabhushi L, Wenner S. The incidence of complex regional pain syndrome after fasciectomy for Dupuytren's contracture: a prospective observational study of four anesthetic techniques. Anesth Analg. 2006;102: 499-503.
137. , Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999;354: 2025-8.
138. , Leborgne JM, Kermad K, Hassan Y. [Vitamin C and prevention of reflex sympathetic dystrophy following surgical management of distal radius fractures]. Acta Orthop Belg. 2002;68: 481-4. French.
139. , Richter HW, Chan PC. Some properties of ascorbate free radical. Ann NY Acad Sci. 1975;258: 231-7.
140. . Oxidation of ascorbic acid with superoxide anion generated by the xanthine-xanthine oxidase system. Biochem Biophys Res Commun. 1975;63: 463-8.
141. , Jensen TS. Phantom limb pain. Br J Anaesth. 2001;87: 107-16.
142. , Hamann W, Wedley JR, McColl I. Phantom pain and sensation among British veteran amputees. Br J Anaesth. 1997;78: 652-9.
143. , Nicholls G, Houghton AL, Saadah E, McColl L. Phantom pain: natural history and association with rehabilitation. Ann R Coll Surg Engl. 1994;76: 22-5.
144. , Dijkstra PU, Geertzen JH, Elzinga A, van der Schans CP. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain. 2000;87: 33-41.
145. . Factors determining the persistence of phantom pain in the amputee. J Psychosom Res. 1973;17: 97-108.
146. , Birbaumer N, Lutzenberger W, Cohen LG, Flor H. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci. 2001;21: 3609-18.
147. , Crotty M, Cameron ID. Evidence for the optimal management of acute and chronic phantom pain: a systematic review. Clin J Pain. 2002;18: 84-92.
148. , Noreng MF, Tjellden NU. Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain. 1988;33: 297-301.
149. , Jayatunga AP, Bradley JW, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl. 1994;76: 324-6.
150. , Ilkjaer S, Christensen JH, Kroner K, Jensen TS. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet. 1997;350: 1353-7.
151. , Meller Y. Continuous postoperative regional analgesia by nerve sheath block for amputation surgery—a pilot study. Anesth Analg. 1991;72: 300-3.
152. , Buch R, Khurana JS, Garvey T, Rice L. Postoperative infusional continuous regional analgesia. A technique for relief of postoperative pain following major extremity surgery. Clin Orthop Relat Res. 1991;266: 227-37.
153. , Smith DG, Sharar SR, Edwards WT, Hansen ST Jr. Continuous regional analgesia by intraneural block: effect on postoperative opioid requirements and phantom limb pain following amputation. J Rehabil Res Devel. 1994;31: 179-87.
154. , Garla PG, Pluth T, Vrbos L. Continuous postoperative infusion of a regional anesthetic after an amputation of the lower extremity. A randomized clinical trial. J Bone Joint Surg Am. 1996;78: 1501-5.
155. , Dashfield AK, Cosgrove C, Wilkins DC, Walker AJ, Ashley S. Randomized prospective study comparing preoperative epidural and intraoperative perineural analgesia for the prevention of postoperative stump and phantom limb pain following major amputation. Reg Anesth Pain Med. 2001;26: 316-21.
156. , Eisenstein SM. Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br. 1989;71: 677-80.
157. , Garfin SR, Booth RE Jr. Harvesting autogenous iliac bone grafts. A review of complications and techniques. Spine. 1989;14: 1324-31.
158. , Schimandle JJ, Weigel MC, Edwards CC, Levine AM. Chronic donor site pain complicating bone graft harvesting from the posterior iliac crest for spinal fusion. Spine. 1992;17: 1474-80.
159. , Senunas LE, DeSilva GL, Greenfield ML. Autogenous iliac crest bone graft. Complications and functional assessment. Clin Orthop Relat Res. 1997;339: 76-81.
160. , Vieira P, Faruqi S, Verghis A, Kilaru PA, Maciolek H. Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology. 2001;95: 390-4.
161. . Lumbar spine. In: Goldstein LA, Dickerson R, editors. Atlas of orthopaedic surgery. St. Louis: Mosby; 1974. p 450-3.
162. , Ekman EF, Raghunathan K, Steinberg RB, Blinder JL, Adesioye J. The effect of cyclooxygenase-2 inhibition on acute and chronic donor-site pain after spinal-fusion surgery. Reg Anesth Pain Med. 2006;31: 6-13.
163. , Kilickan L, Gürkan Y, Sarlak A, Toker K. Short- and long-term effects of regional application of morphine and bupivacaine on the iliac crest donor site. Acta Orthop Belg. 2000;66: 341-4.
164. , Valdez JG, Westlund KN. Peripheral morphine administration blocks the development of hyperalgesia and allodynia after bone damage in the rat. Anesthesiology. 1998;89: 190-201.
165. , Sapirstein A, Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002;8: 390-6.
166. , Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63: 1979-84.
167. : Number of total hip replacements and total knee replacements done 1991-2003. http://http://www.aaos.org
168. , Brandsborg B, Lucht U, Jensen TS, Kehlet H. Chronic pain following total hip arthroplasty: a nationwide questionnaire study. Acta Anaesthesiol Scand. 2006;50: 495-500.
169. , Stulberg SD, Adams AD, Harden RN, Bruehl S, Stanos SP, Houle T. Predicting total knee replacement pain: a prospective, observational study. Clin Orthop Relat Res. 2003;416: 27-36.
170. , Mayer TG, Gatchel RJ. High pain ratings predict treatment failure in chronic occupational musculoskeletal disorders. J Bone Joint Surg Am. 2006;88: 317-25.
171. , Weber EW, Bugter ML, Dirksen R. The intensity of preoperative pain is directly correlated with the amount of morphine needed for postoperative analgesia. Anesth Analg. 1999;88: 146-8.
172. , Bruehl S, Stanos S, Brander V, Chung OY, Saltz S, Adams A, Stulberg SD. Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain. 2003;106: 393-400.
173. , Hochberg MC. The relationship between psychosocial variables and pain reporting in osteoarthritis of the knee. Arthritis Care Res. 1998;11: 60-5.
174. , Cahue S, Song J, Hayes K, Pai YC, Dunlop D. Physical functioning over three years in knee osteoarthritis: role of psychosocial, local mechanical, and neuromuscular factors. Arthritis Rheum. 2003;48: 3359-70.
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175. , Buvanendran A, Kroin JS, Steinberg RB. Postoperative modulation of central nervous system prostaglandin E2 by cyclooxygenase inhibitors after vascular surgery. Anesthesiology. 2006;104: 411-6.