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ANESTHETIC PHARMACOLOGY

Intravenous Administration of Propacetamol Reduces Morphine Consumption After Spinal Fusion Surgery

Joaquín Hernández-Palazón, MD, PhD^*, José A. Tortosa, MD, PhD^*, Juan F. Martínez-Lage, MD, and Domingo Pérez-Flores, MD, PhD

Departments of *Anesthesiology and Neurosurgery, Hospital Universitario ‘Virgen de la Arrixaca,‘ Murcia, Spain; and Department of Biostatistics, School of Medicine, University of Murcia, Murcia, Spain

Address correspondence and reprint requests to José A. Tortosa, MD, PhD, C/Ricardo Gil 26, 2° B, 30 002 Murcia, Spain. Address e-mail to isv01mu{at}nacom.es

	Abstract

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We sought to determine the analgesic efficacy, opioid-sparing effects, and tolerability of propacetamol, an injectable prodrug of acetaminophen, in combination with morphine administered by patient-controlled analgesia (PCA) after spinal fusion surgery. Forty-two patients undergoing spinal stabilization surgery were randomized into two groups, which were given either an IV placebo or an IV injection of 2 g propacetamol every 6 h for 3 days after surgery. The postoperative opioid analgesic requirement was assessed with a PCA device used to self-administer morphine. Pain relief was evaluated by a visual analog pain scale and by verbal rating scores of pain relief at 8-h intervals for up to 72 h after surgery. The cumulative dose of morphine at 72 h was smaller in the Propacetamol group than in the Placebo group (60.3 ± 20.5 vs 112.2 ± 39.1 mg; P < 0.001). The pain scores were significantly lower in the Propacetamol group measured at two intervals of the study, although visual analog scale pain intensity scores were smaller than 3 in both groups. Most patients in the Placebo group obtained a greater degree of sedation on postoperative Day 3 (P < 0.05). This study demonstrates the usefulness of propacetamol as an adjunct to PCA morphine in the treatment of postoperative pain after spinal fusion.

Implications: We evaluated the utility of propacetamol as an adjunct to the administration of patient-controlled analgesia morphine in the treatment of postoperative pain after spine stabilization surgery. This combination was associated with an appropriate analgesic effect and with a smaller morphine consumption.

	Introduction

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Combining nonsteroidal antiinflammatory medications (NSAIDs) or acetaminophen with opioid analgesics in the immediate postoperative period may improve analgesia and also opioid sparing, which results in improved respiratory function, a reduction in nausea and vomiting, and decreased sedation (1–3). This fact explains the growing number of studies on the combined use of a nonopioid with an opioid (4–10), which have shown that NSAIDs enhance patient-controlled analgesia (PCA) with morphine. However, the use of adjunctive NSAIDs after abdominal or gynecologic surgery is controversial, because not all studies report significant benefits (7,10). Propacetamol (Pro-Efferalgan^®; Laboratories UPSA, Agen Lot et Garonne, France) is a prodrug of acetaminophen that can be administered parenterally. As the hydrolysis of the ester function is complete because of nonspecific plasma esterases, the IV administration of 1 g of propacetamol hydrochloride yields 0.5 g of acetaminophen. Propacetamol is a non-NSAID, nonopioid analgesic that may act at both peripheral and central sites (11–13). Propacetamol is not contraindicated in patients with disorders of the gastric mucosa, hemostasis, or respiratory function (14,15). Propacetamol is effective in treating postoperative pain (16–22). Ang et al. (16) also demonstrated that 2 g of propacetamol has a maximum effect and a similar duration effect to 30 mg pentazocine after orthopedic surgery. Propacetamol is also as potent as dipyrone or morphine in alleviating pain after aortic vascular surgery (17,18). Several authors (19,20) have shown that propacetamol administration reduces morphine consumption significantly after orthopedic surgery. In the same way, propacetamol and ketorolac combined with PCA morphine showed similar analgesic efficacy after gynecologic surgery (21).

This placebo-controlled study was conducted to evaluate the analgesic efficacy and the incidence of side effects when propacetamol, in addition to IV PCA with morphine, was given to patients after spinal fusion surgery.

	Methods

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We preformed a prospective, randomized, double-blinded study with the approval of the Ethics Committee of the hospital. Written informed consent to participate was obtained from all patients. The study group included 42 ASA physical status I and II patients of each sex between 23 and 59 yr old who were scheduled to undergo elective decompressive lumbar laminectomy with spinal fusion under general anesthesia. Patients were given detailed instructions regarding the use of the PCA device during the preoperative visit. Patients with psychiatric illnesses, allergic reactions to opioids or paracetamol, severe renal or hepatic disease, or obesity were excluded from the survey. Anesthesia was induced with thiopental (4–5 mg/kg), fentanyl (3–5 µg/kg), and vecuronium (0.1 mg/kg) and was maintained with isoflurane in 70% N₂O in oxygen, fentanyl infusion, and vecuronium.

The patients were randomly assigned by a closed-envelope technique to receive an IV infusion every 6 h (100 mL saline in 15 min) with either 2 g of propacetamol (Propacetamol group; n = 21) or a placebo (Placebo group; n = 21) during a period of 72 h. The patients received their first infusion 30 min before the end of the surgical procedure. In the postanesthesia care unit, the patients were given 1–2 mg IV morphine administered in bolus doses at 10-min intervals until they appeared to be comfortable and were capable of using an Abbott PCA device. The PCA solution contained morphine 1 mg/mL. The PCA setting was the following: bolus dose, 0.01 mg/kg; lockout period, 10 min; and maximum dose per 4 h, 0.15 mg/kg. The 4-h limit was increased to 0.20 mg/kg if analgesia was inadequate after 1 h. If analgesia remained inadequate in the following hour, the dose was further increased to 0.25 mg/kg.

Assessment of the postoperative PCA morphine usage and analgesia was performed at 8-h intervals. Patients were asked to quantify their pain on a verbal analog pain scale (VAS) from 0 to 10, with 0 representing no pain and 10 representing the worst imaginable pain. Pain relief was rated by patients on a 4-point verbal rating score (VRS): 0 = no pain relief; 1 = partial pain relief; 2 = good pain relief; and 3 = excellent relief and complete analgesia. Sedation was rated on a numeric scale: 1 = completely awake; 2 = awake but drowsy; 3 = asleep but responding to verbal commands; 4 = asleep but responding to tactile stimuli; and 5 = asleep and not responding to any stimuli. At the end of each 24-h period, the patient was asked to rate the overall pain relief received during that day as either satisfactory or unsatisfactory. The VRS recorded during each 24-h period was summed to yield the Total Pain Relief (TOTPAR) score for that period. TOTPAR scores are used widely in analgesia clinical trials, where higher scores signify better analgesia. Postoperative nausea, vomiting, pruritus, respiratory rate, and urinary retention were recorded throughout the study period. The patients, nurses, and physician evaluators were all unaware of group assignments of the patients. Respiratory depression and sedation were assessed by the ward nurses more frequently, and the results were recorded.

Statistical assessment included analysis of variance and unpaired Student’s t-tests for continuous data and VAS pain data. Ordinal data, including TOTPAR, were analyzed with nonparametric tests. Nominal data were analyzed with ² and Fisher’s exact tests. A sample size of 21 patients by group was calculated to detect a significant difference of 20% or more in morphine consumption with a power of 80% and a significance level of 5%. Data were reported as mean ± SD in the table and mean ± SEM in figures. A P value of <0.05 was considered statistically significant.

	Results

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Both groups were similar in regard to age, sex, height, weight, duration of surgery, morphine titration in the postanesthesia care unit, and amount of intraoperative fentanyl used (Table 1). Of the 44 patients enrolled, 42 completed the study. One patient in the Control group was withdrawn because he received another analgesic ordered by the surgeon, and another patient treated with propacetamol was excluded for technical reasons.

View larger version (24K): [in this window] [in a new window]   Figure 1. Time course of the cumulative doses of morphine in the two groups. Values are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 from the Placebo group.

Scores of 2 (good relief) or 3 (complete relief) on the VRS were reported more often by patients in the Propacetamol than in the Placebo group; this resulted in higher TOTPAR scores, mainly at Days 1 and 2, although the difference was not statistically significant.

The degree of sedation of all patients was generally mild. During the first 48 h, the two groups exhibited a similar sedation score. No patient reached the point of sedation level 4 or 5. However, the degree of sedation was significantly less at the third day after surgery for patients receiving propacetamol (P < 0.05) as compared with those in the Control group (Fig. 2). The incidences of nausea or vomiting, pruritus, and urinary retention were similar in both groups (43% vs 52%, 14% vs 24%, and 9% vs 24% in the Propacetamol and Placebo groups, respectively). No patient had a respiratory rate <10 breaths/min during the study period.

View larger version (17K): [in this window] [in a new window]   Figure 2. Proportion of patients with sedation level 2 (awake but drowsy) or 3 (asleep but responding to verbal commands). *P < 0.05.

	Discussion

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The most significant finding of our study was that the use of propacetamol as an adjunct to postoperative opioid administration after spinal fusion surgery produced a significant opioid-sparing effect. The reduction in the cumulative opioid consumption over 72 hours because of the concurrent use of propacetamol was 46% less than in the Placebo group. Taking into account the usage of morphine for each period, the difference was statistically lower in the Propacetamol group, except during the first hours, because of the analgesic effect for the titration. A similar benefit has been previously demonstrated by combining NSAIDs or propacetamol with opioids, where the addition of these analgesics reduced the consumption of opioids (3–10,16,17,21–25). However, the reduction in the morphine consumption observed in our study demonstrated the power of propacetamol. Propacetamol behaves favorably according to the reduction observed in similar studies with different ketorolac doses, which were reported to produce a 31%–37% decrease in the morphine requirement during the first 24 hours after surgery (8,9). Despite its opioid dose-sparing effects, propacetamol did not significantly alter the overall incidence of other common opioid side effects. Somnolence was significantly smaller only on postoperative Day 3 in the Propacetamol group. In the same way, fewer patients presented urinary retention among those receiving propacetamol, although this difference was not significant. As in many studies that evaluate analgesic drug combinations, our results did not show a reduction of side effects, as might be expected because of the decrease in total morphine dose (3–10,16,17,25,26). This may be because of the limited number of patients included in this and other studies. Larger studies should demonstrate the reduction of dose-dependent side effects of morphine, such as sedation, respiratory depression, urinary retention, or nausea.

No differences between groups in the adequacy of analgesia were observed, as assessed by VAS scores, although those values were only significantly lower at two intervals in the Propacetamol group. In a protocol in which analgesia was available on a patient-controlled basis, it was anticipated that there would be no differences in pain scores between groups. The median pain scores of the Placebo and Propacetamol groups were within the "zone of analgesic success" of VAS < 3.0 suggested by Manthra et al. (27). Although postoperative pain after spinal fusion surgery can be very severe and difficult to control, it was possible to accomplish good and similar pain relief (TOTPAR scores) in both groups.

Our study demonstrates a possible additive effect of combining propacetamol with systemic morphine on postoperative analgesia, resulting in a decreased opioid amount and in slightly improved or similar pain relief. These drugs have different sites of action in the nervous system, which may result in a better pain relief. Propacetamol is a prodrug hydrolyzed by plasma esterases to acetaminophen. Its site of action is mainly central, although there are different hypotheses concerning the precise mechanism involved: inhibition of prostaglandins (28) and activation of descending serotoninergic inhibitory pathways (29). A few studies (30,31) have suggested a peripheral antiinflammatory action of acetaminophen. However, opioids produce analgesia as a result of their agonist effect on opioid receptors in the central nervous system. Therefore, these two drugs have complementary analgesic actions—peripheral and central nervous system levels—making this combination an important component of multimodal pain therapy.

In conclusion, our study demonstrates the usefulness of propacetamol as an adjunct to PCA morphine for treatment of postoperative pain after spine stabilization surgery. Propacetamol use was associated with a satisfactory analgesia, smaller morphine consumption, and less sedation. The combination of IV propacetamol and PCA morphine may be beneficial in the management of acute pain after major surgery in patients prone to opioid-related complications.

	References

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