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AMBULATORY ANESTHESIA

Postoperative Analgesia with Controlled-Release Oxycodone for Outpatient Anterior Cruciate Ligament Surgery

Scott S. Reuben, MD^*, Neil Roy Connelly, MD, and Holly Maciolek, RN^*

*Acute Pain Service and Department of Anesthesiology, Baystate Medical Center and Tufts University School of Medicine, Springfield, Massachusetts

Address correspondence and reprint requests to Scott S. Reuben, MD, Department of Anesthesiology, Baystate Medical Center, 759 Chestnut St., Springfield, MA 01199. Address e-mail to Scott .reuben{at}bhs.org

	Abstract

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Reconstruction of the anterior cruciate ligament (ACL) of the knee is associated with a considerable degree of postoperative pain. Although immediate-release oral opioids are usually effective in relieving moderate to severe pain, they must be given every 4–6 h. A controlled-release (CR) formulation of oxycodone maintains therapeutic opioid concentrations for a more prolonged period, thus providing sustained pain relief. We designed this study to determine whether CR oxycodone is more effective and clinically acceptable than immediate-release oxycodone for managing pain after ambulatory ACL repair surgery. All patients received a standard general anesthetic and postoperative analgesic regimen with one of three oxycodone dosing regimens: oxycodone 10 mg every 4 h as needed, oxycodone 10 mg every 4 h, and CR oxycodone 20 mg every 12 h. Rescue analgesic consisted of oxycodone 5 mg every 6 h as needed. At 24, 36, 48, 60, and 72 h, there was a difference in pain scores among the groups (P < 0.0001); there was less pain in the CR oxycodone group. At most times, the fixed-dose group had lower pain scores than the as-needed group. The sedation scores were significantly different at 12 h (P < 0.02) and at 24, 36, 48, 60, and 72 h (P < 0.0001); the patients were more alert in the CR oxycodone group. The 72-h consumption of oxycodone was less in the CR oxycodone group (P < 0.0001). The patients had less sleep disturbance (P < 0.0001), were more satisfied (P < 0.0001), and experienced less vomiting (P < 0.02) in the CR oxycodone group compared with the other two groups. In conclusion, using CR oxycodone in the immediate 72 h after ambulatory ACL surgery provides more effective analgesia with less sedation, sleep disturbance, and postoperative vomiting compared with oxycodone prescribed on either a fixed dose or as-needed schedule.

Implications: A controlled-release formulation of oxycodone in patients undergoing anterior cruciate ligament repair on an ambulatory basis provides significant analgesic benefit and a lowering of side effects compared with either fixed-dose or as-needed oxycodone regimens.

	Introduction

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Improvements in anesthetic and surgical techniques are allowing more patients to return home on the day of surgery. To contain rising medical costs, many procedures previously performed on an inpatient basis are now being performed in the ambulatory setting. A major barrier to performing ambulatory surgical procedures is ineffective postoperative pain management. Severe postoperative pain is common reason for delayed discharge, unanticipated hospital admission, and frequent contact with the physician (1–3).

Reconstruction of the anterior cruciate ligament (ACL) of the knee is associated with a considerable degree of postoperative pain. Effective postoperative analgesia has been achieved by using epidural and patient-controlled analgesia with opioids (4). These techniques require expensive equipment and monitoring and are associated with side effects that limit their use in the outpatient setting. The use of a femoral nerve block after ACL surgery also provides improved patient comfort and reduced parenteral narcotic administration (5). However, we believe that the bupivacaine dose administered (2–3 mg/kg) would preclude the use of pre- and postincisional intraarticular (IA) bupivacaine. We currently use a multimodal analgesic regimen for ACL repair consisting of perioperative nonsteroidal antiinflammatory drugs (NSAIDs), pre- and postincisional IA bupivacaine, IA morphine, postoperative cryotherapy using an external cooling system, and systemic short-acting opioids when necessary (6).

Although immediate-release oral opioids are usually effective in relieving moderate to severe pain, they must be given every 4–6 h. A delay in administration, especially when ordered on a PRN basis, may result in lower plasma opioid concentrations and, thus, the reemergence of pain. It is currently recommended that all patients requiring opioid analgesics >48 h after surgery be administered these drugs on a fixed-dose schedule (7). However, as in dosing with other drugs that require a steady blood level to remain effective, interruption of an around-the-clock dosage schedule, especially during the hours of sleep, may cause pain. A controlled-release (CR) formulation of oxycodone (OxyContin^TM; Purdue Pharma, Norwalk, CT) maintains therapeutic opioid concentrations for a more prolonged period, thus providing sustained pain relief (8). We hypothesized that this opioid preparation may provide greater convenience, improved patient compliance, and uninterrupted nighttime sleep for patients in pain after surgery. We designed this study to determine the clinical acceptability and analgesic efficacy of CR oxycodone compared with immediate-release oxycodone when administered either on a PRN or fixed-dose schedule in the management of pain after ambulatory ACL repair surgery.

	Methods

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After institutional review board approval, informed written consent was obtained from 60 patients scheduled to undergo elective ACL surgery by a single surgeon. Patients were eligible for participation if they spoke English, were >18 yr of age, or were ASA physical status I or II. Patients were excluded if they were medicated with narcotics preoperatively or if they had a contraindication to the use of NSAIDs or oxycodone.

Starting 30 h before surgery, all patients received five doses of oral acetaminophen 650 mg every 6 h. All patients received a standard general anesthetic after placement of ASA standard monitors. Anesthesia was induced with propofol (2 mg/kg), and fentanyl (2 µg/kg) and was maintained with isoflurane in 70% N₂O in O₂. Tracheal intubation was facilitated with cisatracurium (0.2 mg/kg). All patients received 30 mL of IA bupivacaine 0.25% and IV ketorolac 30 mg before surgical incision. Neuromuscular blockade was antagonized with neostigmine (50 µg/kg) and glycopyrrolate (100 µg/kg). Before awakening, all patients received 30 mL of IA bupivacaine 0.25% and 5 mg of IA morphine. At the completion of surgery, an external cooling system was placed on the operative knee and was used continually throughout the first 72 h postoperatively. Patients were instructed to take acetaminophen 650 mg every 4 h and ibuprofen 600 mg every 6 h throughout the 72-h study period. Patients were randomized into the following three postoperative pain regimens: Group 1 (PRN group) was instructed to take oxycodone 10 mg every 4 h as needed; Group 2 (fixed-dose group) received oxycodone 10 mg every 4 h beginning in the ambulatory surgical unit 1 h before discharge; Group 3 (CR oxycodone group) received CR oxycodone (OxyContin^TM) 20 mg every 12 h beginning in the ambulatory surgical unit 1 h before discharge. Rescue analgesic in Groups 1 and 2 consisted of oxycodone 5 mg every 6 h as needed.

The patients were instructed to record (every 12 h) on a numerical scale their pain at rest and with movement (walking) (0 = no pain to 10 = the worst imaginable pain), and their degree of sedation (0 = very awake to 10 = very sleepy). Side effects such as nausea, vomiting, and pruritus were documented by the patients. At the completion of the study (72 h postoperatively), the patients recorded their degree of satisfaction with their analgesic medications (0 = not satisfied to 10 = complete satisfaction). Patients rated their sleep disturbance at each interval (0 = no sleep disturbance to 10 = greatest sleep disturbance). Total oxycodone dosing (including the use of CR oxycodone) was also recorded. All data were recorded by patients in a pain diary, which was returned to the surgeon during the patients' follow-up visits. After the study, it became evident that several patients did not take their pain medications as prescribed. These patients were later questioned by telephone regarding their reasons for noncompliance.

Demographic data were analyzed by using analysis of variance. Pain scores, sedation scores, satisfaction scores, and amount of postoperative analgesics were analyzed by using Kruskal-Wallis analysis. If a significant result was obtained, the Mann-Whitney U-test was performed to determine between which groups there was significance; a Bonferroni adjustment was made for multiple comparisons. The presence of side effects was evaluated by using Fisher's exact test. Significance was determined at the P < 0.05 level.

	Results

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There were no significant differences among the three treatment groups with respect to age, height, or weight (Table 1). All patients returned their pain diary for data analysis. Significantly fewer patients experienced vomiting in the CR oxycodone group (P < 0.02) (Table 1); there was no significant difference in the incidences of nausea or pruritus (Table 1).

View larger version (19K): [in this window] [in a new window]   Figure 1. The movement-associated pain scores in the three groups at 24, 48, and 72 h postoperatively were significantly different among the groups (P < 0.0001). There were lower pain scores in the controlled-release (CR) oxycodone group than in either of the other groups. At 24 and 72 h, the fixed-dose group had lower pain scores than the PRN group. The box represents the 25th–75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th–90th percentiles. = values outside this range.

View larger version (19K): [in this window] [in a new window]   Figure 2. The sedation scores in the three groups at 24, 48, and 72 h were significantly different among the groups (P < 0.0001). The patients were more alert in the controlled-release (CR) oxycodone group than in the other two groups at these intervals. The box represents the 25th–75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th–90th percentiles. = values outside this range.

There was a difference in the patients' rating of their sleep disturbance (P < 0.0001) (Table 1). The patients had less sleep disturbance in the CR oxycodone group than in the other two groups; there was no significant difference between the two other groups.

There was a difference with total satisfaction (P < 0.0001) (Table 1). The patients were more satisfied in the CR oxycodone group than in the other two groups; there was no significant difference between the other two groups.

No patient in any of the groups required readmission to the hospital for uncontrollable pain. Four patients required contact with the surgeon due to inadequate pain control; all four of these patients were in the PRN group.

The patients in the CR oxycodone group reported that they took all the CR oxycodone pills prescribed. Many of the patients in the fixed-dose group failed to take some of the prescribed oxycodone at the scheduled time. Of the 20 patients in the fixed-dose group, 14 had at least one interval >6 h between two of the scheduled doses. Four of the patients in the fixed-dose group failed to take one of the scheduled doses.

	Discussion

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Cost-containment issues have had a major impact on the volume of ambulatory surgical procedures. As surgical and pain management techniques continue to improve, more complex surgeries will be performed on an outpatient basis. ACL reconstruction, which has previously been associated with hospital stays of up to 1 wk, is now routinely performed in an outpatient setting for most patients (4,9). Kao et al. (9) were the first to report the effectiveness of outpatient ACL reconstruction; they revealed cost-savings of up to 58%. Effective pain management, however, may become the limiting factor in determining discharge eligibility in patients undergoing ambulatory ACL repair surgery.

We perform ACL reconstructive surgery as an ambulatory procedure using both preemptive and multimodal analgesic techniques. All patients are administered oral acetaminophen in the 30 h before surgery, as well as IV ketorolac before surgical incision. Although the literature is inconclusive regarding the efficacy of preemptive analgesia, most clinical studies evaluating the preoperative administration of NSAIDs during ambulatory surgery show a decrease in pain and opioid use in the early postoperative period (10). In addition to using preemptive NSAIDs, all patients in the present study received IA bupivacaine before incision. The preemptive analgesic effect of IA bupivacaine has been shown to be effective in reducing postoperative pain after ACL surgery (11).

In addition to preemptive NSAIDs and bupivacaine, we used a multimodal regimen consisting of postoperative NSAIDs, postincisional IA bupivacaine, IA morphine, and postoperative cryotherapy using an external cooling system. This strategy takes advantage of additive or synergistic effects among various analgesics, permitting the use of smaller doses with a concomitant reduction in side effects (12). The adjunctive use of NSAIDs has been recommended for managing pain after major orthopedic surgery (13). In fact, McGuire et al. (14) revealed a significant reduction in side effects and superior pain control when ketorolac was used in the management of pain after ambulatory ACL procedures. We also included IA morphine, which has been shown to be effective in the management of pain after ACL surgery (15), in our multimodal analgesic regimen. Finally, we used a Cryocuff (Aircast, Summit, NJ), which was placed on the operative knee immediately after surgery to provide continual cold therapy during the postoperative study period. Although the exact mechanism of cold therapy is not completely understood, it is believed to be beneficial in reducing the inflammatory reaction and in decreasing edema and hematoma formation after surgical trauma (16). Cohn et al. (17) revealed a significant opioid-sparing effect when cold therapy was used in the management of pain after ACL surgery.

Despite using these multimodal analgesic techniques, we previously observed that when the IA analgesic effect dissipates while patients are at home, patients can experience considerable pain (6). In our current study, we demonstrated significantly improved postoperative analgesia with the use of CR oxycodone compared with fixed or as-needed dosing with oxycodone. This improvement in analgesia was achieved despite using a smaller total dose of oxycodone. OxyContin^TM, a new opioid preparation in tablet form, is designed to provide the controlled delivery of oxycodone over 12 h. Onset of pain relief occurs within 1 h of dosing (8). Although frequently used in the management of chronic pain, OxyContin^TM has been shown to be effective in the management of acute postoperative pain after abdominal or gynecologic surgery (8).

One might argue that administering oxycodone on a 4-h dosing schedule should be as effective in preventing postoperative pain as CR oxycodone. However, the patients in the fixed-dose group often failed to take the drug in the manner in which it was prescribed. Some of the patients in our study cited fear of addiction or side effects as reasons for their noncompliance. Furthermore, some of the patients failed to take the oxycodone during the night while they slept. They stated that they woke up in pain and attributed this to the reason they had sleep disturbance. These barriers to effective pain management are similar to those previously reported in the medical literature (18). In contrast, we noted greater compliance in the patients in the CR oxycodone group.

In addition to having improved analgesia, patients in the CR oxycodone group were less sedated and reported a lower incidence of postoperative vomiting. This probably reflects the lower consumption of oxycodone during the 72-h study period. Although there were no unanticipated admissions among the patients, four patients in the PRN dose group contacted the surgeon due to inadequate pain control. No patients in either the fixed-dose group or the CR oxycodone group contacted the surgeon due to inadequate pain control.

No discussion in the present times would be complete without mentioning costs. At our institution, patients are charged $2.67 per 20-mg tablet of OxyContin^TM compared with $0.43 (generic) or $0.70 (brand) per 5-mg tablet of oxycodone. This equates to $5.34/d for OxyContin^TM compared with $5.16/d (generic) or $8.40/d for oxycodone, assuming that patients received 10 mg every 4 h. This does not take into account the adverse effect that severe pain might have on medical costs. Many of our patients receiving oxycodone on an as-needed basis were unable to tolerate our accelerated rehabilitation program. Although we did not study the long-term implications of inadequate pain relief, a previous study revealed a higher incidence of postoperative complications (prolonged knee stiffness, delay in strength recovery, and anterior knee pain) in patients unable to complete an accelerated rehabilitation program after ACL reconstruction (19).

This study design may be criticized because it was not a double-blinded study and did not include placebo tablets in each of the groups. Although our patients were unaware of the drug and dosage, the dosing regimen may have biased patients. However, the aim of this study was not to document the pharmacokinetic properties of CR oxycodone, but rather to examine the clinical acceptance of this drug in the ambulatory postoperative setting. We believe that patients experienced greater compliance, less sleep disturbance, and greater satisfaction with CR oxycodone because of its more convenient dosing schedule. These results may not have been evident if the study design had mandated the administration of tablets every 4 h.

In conclusion, using CR oxycodone in the 72 h immediately after ambulatory ACL surgery provides more effective analgesia with less sedation, sleep disturbance, and postoperative vomiting compared with oxycodone prescribed on either a fixed-dose or as-needed basis. This may be a reflection of improved compliance with CR oxycodone, thereby providing more effective continuous postoperative analgesia. CR oxycodone has previously been described in the management of acute pain (8), but this is the first clinical investigation to document its efficacy in the management of pain after ambulatory surgery.

	Footnotes

 
Presented in part at the 1998 annual meeting of the American Society of Regional Anesthesia, Seattle, WA.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999