Anesth Analg 2007;105:233-237
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000266451.77524.0d
ANALGESIA
Postoperative Intravenous Morphine Consumption, Pain Scores, and Side Effects with Perioperative Oral Controlled-Release Oxycodone After Lumbar Discectomy
Stephan Blumenthal, MD*,
Kan Min, MD ,
Michael Marquardt, MD*, and
Alain Borgeat, MD*
From the Departments of *Anesthesiology; and Orthopedic Surgery, Orthopedic University Clinic Zurich/Balgrist, Switzerland.
Address correspondence to Alain Borgeat, MD, Department of Anesthesiology, Orthopedic University Clinic Zurich/Balgrist, Forchstrasse 340, CH-8008 Zurich, Switzerland. Address e-mail to alain.borgeat{at}balgrist.ch.
Abstract
BACKGROUND: Oral opioid formulations contribute to postoperative analgesia. In this study, we evaluated the perioperative application of oral controlled-release oxycodone to reduce postoperative IV morphine consumption and opioid side effects after lumbar discectomy.
METHODS: Forty patients scheduled for elective lumbar discectomy over 1 or 2 levels were included in this prospective, randomized, double-blind, placebo-controlled study. Every 12 h patients received either 20 mg oral controlled-release oxycodone or placebo, from the evening before surgery until the second postoperative morning. All patients received IV morphine via a morphine patient-controlled analgesia device for postoperative analgesia. Acetaminophen 1 g was administered to all patients every 6 h. Postoperative IV morphine consumption was assessed separately for T0–T24 and T24–T48. Postoperative assessments were conducted every 6 h for the first 48 h after surgery. Postoperative analgesia assessments included pain at rest, during coughing, and with motion, using a visual analog scale. Nausea, vomiting, pruritus, sedation, and bowel function were also assessed every 6 h. Patients rated their satisfaction with postoperative analgesia 72 h postoperatively.
RESULTS: Postoperative IV morphine consumption was significantly reduced during T0–T24 (26 ± 10 mg vs 52 ± 29 mg) and T24–T48 (13 ± 8 mg vs 33 ± 18 mg) in the controlled-release oxycodone group compared with that in the placebo group. Pain scores at rest, during coughing, and with motion were significantly lower during the first 48 postoperative hours in the controlled-release oxycodone group. Postoperative nausea and vomiting were significantly reduced during the first 24 h in the controlled-release oxycodone group. Lastly, the controlled-release oxycodone group also experienced significantly earlier recovery of bowel function and had higher patient satisfaction with pain therapy.
CONCLUSIONS: Perioperative oral controlled-release oxycodone reduces postoperative IV morphine consumption after lumbar discectomy while providing good analgesia with fewer side effects compared with placebo.
Opioids are cornerstones of postoperative analgesia after orthopedic surgery. However, pain treatment is sometimes inadequate, despite the availability of effective opioids (1). Oral controlled-release opioids with 8–12 h duration of action have the advantage, compared to immediate-release opioids, of reducing the number of administrations, which may avoid peak-and-trough plasma levels and provide more uniform analgesia (2,3). Compared to controlled-release morphine, a predominant µ agonist, controlled-release oxycodone (CRO), a µ- and  -agonist (4), is almost twice as potent and has a three times higher oral bioavailability (5). Additionally, CRO is associated with a lower incidence of side effects in cancer patients compared to controlled-release morphine (6).
Oxycodone has been in clinical use since 1917, and in northern Europe parenteral oxycodone is used for acute pain. In the United States, Canada, and Australia, oral oxycodone was used mainly in combination with acetaminophen for moderate pain. Today the CRO formulation is marketed primarily for chronic pain. The influence of CRO on postoperative pain and analgesic consumption has been evaluated after various surgical interventions (7–10), but not in the context of spine surgery. The aim of this study was to investigate the effects of perioperative coadministration of CRO and IV morphine compared to IV morphine with placebo after lumbar discectomy.
METHODS
After approval of the local ethics committee (Gesundheitsdirektion des Kantons Zürich, Kantonale Ethik-Kommission, Zürich, Switzerland) and written informed consent were obtained, 40 adult patients scheduled for elective primary open lumbar discectomy over one or two levels were prospectively included. According to a computer-generated randomization list, patients were allocated to either the CRO group or the placebo group. The study medication consisted of either 20 mg CRO or a placebo tablet of equal size, color, and shape. The study design was double-blind: neither the patient nor the medical staff (nurse, anesthesiologist, and surgeon) was aware of study group assignment. The only person with access to the key for unblinding was the hospital pharmacist. Exclusion criteria were ASA physical status >III, known allergy or intolerance to any of the drugs used in the trial, pregnancy, history of drug abuse, preoperative opioid medication, preoperative pain other than from the lumbar spine, history of postoperative nausea and vomiting (PONV), history of ileus, liver dysfunction defined as elevation of serum alanine aminotransferase and serum aspartate aminotransferase three times above the upper normal range, inability to use a patient-controlled analgesia (PCA) device, and inability to use and understand a visual analog scale (VAS). During the study, patients were excluded if a surgical complication occurred.
The evening before surgery, patients were instructed on how to use the PCA device postoperatively and familiarized with the VAS pain score for postoperative pain assessment. Beginning on the preoperative evening, patients received the oral study medication every 12 h until the second postoperative morning. Every patient received six doses over the course of the study. On the day of surgery, patients were scheduled as the first operation (incision at 8 o’clock in the morning), and 1 h before surgery, they were premedicated with the study medication (either 20 mg CRO or placebo). In the induction room, standard monitoring (electrocardiography, pulse oximetry, noninvasive arterial blood pressure) was applied and an IV catheter was placed. Anesthesia was induced and maintained with propofol using a target-controlled infusion system (Deltec Graseby 3500, Laubscher Basel, Switzerland, and Diprifusor subsystem, AstraZeneca, Macclesfield, Cheshire, United Kingdom). The initial target concentration was set at 4–6 µg/mL. When loss of consciousness (defined as absence of eyelid reflex) was observed, the individual effect-site concentration was doubled. This value was determined as the new target concentration. Fentanyl 5 µg/kg (or 4 µg/kg if older than 60 yr) was administered IV. Rocuronium 0.8 mg/kg was given IV to facilitate tracheal intubation and repeated intraoperatively if necessary. Within the first 30 min after induction, fentanyl administration was repeated, yielding a final dose of 10 µg/kg (or 8 µg/kg if older than 60 yr). After induction, IV acetaminophen 1 g was given to all patients. This dose was repeated postoperatively every 6 h until the end of the study. IV cefuroxim 1.5 g was given once for preoperative antibiotic prophylaxis. All operations were performed by the same surgeon using a standardized technique.
After tracheal extubation, patients were transferred to the recovery room, where analgesia was given by nurse-controlled administration of 2 mg IV morphine with a delay of 6 min before the next bolus. Pain was assessed with a VAS ranging from 0 (= no pain) to 100 (= worst pain imaginable). IV morphine could be repeated until VAS at rest was lower than 30. Two hours after arrival in the recovery room, all patients received a PCA device for IV morphine administration with the following settings: no basal infusion, 2 mg bolus, 8 min lockout time. Patients were discharged to the ward according to the criteria of the modified Aldrete score (11), when the VAS score for pain at rest was lower than 30, and after confirmation that the patient managed the PCA device properly.
Arrival in the recovery room was defined as T0. At this time, data collection started. All data were collected by a study nurse unaware of the study group assignment. The primary end-point was total IV morphine consumption after the first 24 h (T0–T24) and after the second 24 h (T24–T48) postoperatively. Total consumption after the first 24 h was defined as the sum of morphine administered by the nurse in the recovery room and morphine administered through the PCA device. Total consumption after the second 24 h was defined as the morphine administered through the PCA device. Secondary end-points were postoperative pain at rest, during coughing, during mobilization for the first 48 h postoperatively, analgesia-related side effects, and patient satisfaction with postoperative pain therapy. Patients were asked to rate their pain at rest and while coughing at T0 and then every 6 h until T48. Pain with motion was assessed during mobilization at T24, T36, and T48. Mobilization was defined as standing beside the bed at T24, walking around the bed at T36 and walking to the toilet at T48. These activities were performed with a physiotherapist. PONV was assessed whenever it occurred. Any episode of PONV was treated with tropisetron 2 mg IV. Pruritus was assessed whenever it occurred, and was treated with clemastine 2 mg if the patient requested treatment. Sedation was assessed every 6 h until T48 and graded with a 4-point scale: 0 = not sedated, awake, 1 = mildly sedated, patient easily arousable, 2 = severely sedated, patient difficult to arouse, 3 = patient unarousable. The time point of the first postoperative bowel movement was noted. No supportive digestive therapies were given during the first 48 h postoperatively. When patients were asleep during the night, they were not awakened for data assessment. Patients were asked to rate their satisfaction with postoperative pain management on a scale ranging from 0 (not satisfied at all) to 10 (very satisfied) 72 h postoperatively.
For this type of surgery, a 25% difference in daily interindividual morphine consumption was observed in an unpublished pilot study. A reduction of IV morphine consumption of 30% in the CRO group was considered clinically significant. Based on these data, a power analysis indicated that a sample size of 15 patients per group was sufficient to have an 80% power at the 95% significance level. To increase the power and to compensate for possible dropouts (patients that have to be excluded during the study), we decided to include 20 patients per group. Demographic data, morphine consumption, and patient satisfaction were compared with the Mann–Whitney test. Pain intensity was analyzed with the Mann– Whitney test with Bonferroni correction for repeated measurements. Side effects were analyzed with the Fisher’s exact test. For all statistical analysis, a P < 0.05 was considered significant. For statistical analysis, the software SPSS for windows, Version 11.5 (SPSS, Chicago, IL) was used. Demographic data are expressed as mean ± sd. Morphine consumption and pain intensity are graphically reported as median with 25th–75th and 10th–90th percentile whiskers.
RESULTS
Over a 12-mo period, from June 2004 to June 2005, 40 patients were studied, 20 in the CRO group and 20 in the placebo group. No patient had to be excluded after allocation. There were no surgical complications. Patient and surgical characteristics, as well as intraoperative consumption of fentanyl, did not differ between the two groups (Table 1).
The total postoperative IV morphine consumption was significantly reduced in the CRO group compared with that in the placebo for T0–T24 (26 ± 10 mg vs 52 ± 29 mg) and for T24–T48 (13 ± 8 mg vs 33 ± 18 mg) (Fig. 1, P < 0.001).
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Figure 1. Postoperative IV morphine consumption. The postoperative IV morphine consumption in milligrams was calculated at T24 for the time period T0–T24 from the sum of the morphine given by the nurse in the recovery room and that received through the PCA device. At T48 the morphine consumption for the time period T24–T48 was calculated from the morphine received through the PCA device. The open box indicates the controlled-release oxycodone (CRO) group and the filled box indicates the placebo group. The black horizontal lines indicate the median. The box represents the 25th–75th percentiles. The extended bars represent the 10th–90th percentiles. *P < 0.001.
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Pain scores at rest, during coughing, and with motion were significantly lower during the first 48 h postoperatively in the CRO group compared with that in the placebo group (Figs. 2–4, P < 0.005).
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Figure 2. Pain at rest. Postoperative pain at rest was assessed every 6 h until 48 h postoperatively. The y-axis indicates pain intensity. The x-axis indicates postoperative time. The open box indicates the CRO group and the filled box indicates the placebo group. The black horizontal lines indicate the median. The box represents the 25th–75th percentiles. The extended bars represent the 10th–90th percentiles. *P < 0.005.
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Figure 3. Pain during coughing. Postoperative pain during coughing was assessed every 6 h until 48 h postoperatively. The y-axis indicates pain intensity. The x-axis indicates postoperative time. The open box indicates the CRO group and the filled box indicates the placebo group. The black horizontal lines indicate the median. The box represents the 25th–75th percentiles. The extended bars represent the 10th–90th percentiles. *P < 0.005.
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Figure 4. Pain with motion. Pain with motion was assessed at 24, 36, and 48 h postoperatively. The y-axis indicates the pain intensity. The x-axis indicates postoperative time. The open box indicates the CRO group and the filled box indicates the placebo group. The black horizontal lines indicate the median. The box represents the 25th–75th percentiles. The extended bars represent the 10th–90th percentiles. *P < 0.005.
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The incidence of adverse events is shown in Table 2. In the first 24 h postoperatively, PONV occurred significantly less frequently in CRO group patients compared with that in placebo group patients (P < 0.05). There was no difference in PONV on the second postoperative day. Ten percent of the patients in the CRO had pruritus at some point in time, versus 25% of patients in the placebo group, a difference that did not reach statistical significance. Severe sedation (grade 2 + 3) was not observed in either group. The occurrence of mild sedation (grade 1) was similar between the groups.
More patients in the CRO group than in the placebo group had a first bowel movement within the first 48 h postoperatively (75% vs 20%, P < 0.005).
Patient satisfaction with pain therapy 72 h postoperatively was significantly higher in the CRO group compared with that in the placebo group (9.1 vs 7.5, P < 0.05).
DISCUSSION
Lumbar discectomy is one of the most frequent orthopedic and neurosurgical procedures (12). The present study shows that perioperative administration of 20 mg CRO significantly reduces total IV morphine consumption after surgery while also providing better analgesia and reducing opioid side effects.
The dose of the CRO treatment was based on former studies. Bourke et al. (13) concluded that 30 mg oral sustained-release morphine every 12 h might be an appropriate dose for postoperative analgesia after hip arthroplasty. Considering the almost double potency of CRO compared with that of oral sustained-release morphine (5), and the good results reported by Reuben et al. (8), using 20 mg CRO every 12 h for cruciate ligament surgery, we chose to administer 20 mg CRO every 12 h.
The finding of reduced postoperative morphine consumption confirmed our hypothesis, and is in accordance with that of previous studies (7–9). Reuben et al. (7) compared the effects of a preoperative single dose of 10 mg CRO and placebo before ambulatory laparoscopic tubal ligation. The authors observed reduced fentanyl consumption for the CRO group in the postanesthesia care unit and reduced consumption of acetaminophen/oxycodone tablets in the first 24 h postoperatively. The same group evaluated the use of CRO after ambulatory anterior cruciate ligament surgery (8). CRO was given 1 h preoperatively and then every 12 h for 72 h. CRO significantly decreased postoperative opioid consumption. Kampe et al. (9) assessed the clinical efficacy of 20 mg CRO given preoperatively, followed by a second dose 12 h later after breast surgery. In this study, the postoperative opioid consumption 24 h postoperatively was reduced by 47% compared to the placebo group.
Controlled-release opioid preparations produce relatively constant serum opioid levels (6). This is advantageous compared with the repeated administration of short half-life opioids. The latter results in fluctuating plasma opioid concentrations responsible for a clinical response ranging from ineffective analgesia to toxicity and side effects, with relatively brief periods of adequate analgesia (2). Bourke et al. (13) compared sustained-release oral morphine with IM morphine for postoperative analgesia after total hip replacement. They found a higher incidence of PONV in the IM morphine group, which they interpreted as reflecting the peak effect of IM drug administration. Indeed less PONV was also demonstrated in patients receiving CRO after different surgical interventions (7,8,10). These results are in accordance with the decreased incidence of PONV during the first 24 h postoperatively in our CRO group. This is in contrast to a study by Thienthong et al. (14), who evaluated the analgesic efficacy of two doses of sustained release tramadol on postoperative pain and morphine consumption after radical mastectomy. They found no positive effect from their treatment. However, more patients had PONV in the tramadol group than in the placebo group.
There are different possible explanations for the lower pain scores in the CRO group: First, preoperative analgesic treatment might result in diminished central sensitization (15), and produce a "preemptive analgesic" effect by attenuating the constant afferent barrage of nociceptive transmission during surgery. Earlier studies have revealed that the dose of systemically administered morphine needed to prevent the establishment of central hyperexcitability before trauma was one-tenth the dose required to abolish the prolonged activity once it had developed (16). Second, it has been shown in rats that systemic coadministration of subanalgesic doses of the µ- and -agonist oxycodone and the predominant µ agonist morphine may provide excellent pain relief with a reduction in opioid-related central nervous system side effects (4). This synergistic antinociceptive effect was interpreted from the simultaneous activation of both opioid receptors. An explanation for this synergism might be the functional interactions among opioid receptors as described by Khotib et al (17). In an experimental animal study, they found that repeated stimulation of -opioid receptors leads to an up-regulation of µ- and  -receptor functions in the mouse thalamus region, which may be associated with µ- and -receptor-mediated antinociception. Third, our placebo group patients might have preferred higher pain scores rather than to suffer from morphine-induced side effects. Further studies are needed to clarify the responsible mechanism(s).
In the past, the perioperative use of oral morphine has been cautioned against because of concerns about delayed drug absorption in the presence of decreased gastric emptying secondary to pharmacological, physiological, or pathological reasons (18). The results of the present trial, with earlier return of bowel function in the CRO group, could help to reduce the fear of these potential gastrointestinal interactions, at least with oxycodone.
We conclude that perioperative treatment with 20 mg CRO every 12 h for lumbar discectomy reduces postoperative IV morphine consumption. The combined regimen with CRO and IV morphine provides effective pain relief at rest, while coughing, and with motion, and reduces the incidence of opioid side effects.
Footnotes
Accepted for publication March 12, 2007.
Reprints will not be available from the author.
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