Clinical evaluation of intravenous paracetamol versus Parecoxib for postoperative analgesia after general anaesthesia.

BACKGROUND: Postoperative pain has a significant impact on patient's recovery and optimal nonopioid analgesia would reduce postoperative pain and pain-related complications. This study was aimed to evaluate the analgesic efficacy and safety of intravenous paracetamol versus parecoxib for postoperative analgesia after surgery.
MATERIALS AND METHODS: Sixty-eight adult consented patients belonging to ASA I and II, scheduled for surgery, were randomly allocated in two treatment groups receiving either infusion of paracetamol (1 gm) or parecoxib (40 mg). The surgical and anesthetic techniques were standardized. Postoperative pain was assessed using visual analog score (VAS) at rest, during coughing and movement. The primary variables were the differences between the mean values of postoperative pain scores, time of first dose of rescue analgesic (tramadol) required, and patient satisfaction throughout the first 12 postoperatively.
RESULTS: There was no significant difference among groups to first request for tramadol. The VAS score was significantly less in parecoxib group at rest compared to paracetamol group (P<0.05), but the same did not differ for pain score while coughing and movement. Patients in the parecoxib group were more satisfied regarding the postoperative pain management at 12 h postoperatively. The incidence of adverse side effects was infrequent in both the groups.
CONCLUSION: Postoperative nonopioid intravenous analgesia with paracetamol and parecoxib is comparable in the early postoperative period with no adverse effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Despite of various therapeutic approaches to pain management, postsurgical pain is treated ineffectively. The effective postoperative analgesia plays an important role in early mobilization and wellbeing of patients. An ideal analgesic would reduce the intensity of movement evoked pain, surgical stress response and improve postoperative outcome.[1] The concept of using effective pain management, whilst minimizing side effects, has been initiated by Kehlet et al. as part of a process of accelerated recovery after surgery.[2] Recent evidence suggests that that this can be achieved by using both centrally and peripherally acting analgesic drugs. The systemic administration of opioids is effective but their usefulness is limited by adverse effects of nausea, vomiting, bowel immobility, and respiratory depression. Nonopioids such as paracetamol, nonsteroidal anti-inflammatory drugs (NSAID), local anesthetics, and regional analgesia have opioid sparing effects.[3]

The paracetamol is used for short-term management of pain as an alternative to opioids as it does not cause opioids or NSAIDs associated side effects.[4] Parecoxib is a selective COX-2 inhibitor NSAID and indicated for the treatment of acute postoperative pain. It has been shown to have only minor effects on the gastrointestinal mucosa or platelet function with better safety profile in contrast to nonselective NSAIDs.[5-7]

This clinical study was aimed to compare the analgesic efficacy of paracetamol and parecoxib for reduction in early postoperative pain intensity at rest and while coughing and movements, any adverse effects, and time to rescue analgesic after surgery.

MATERIALS AND METHODS

Selection criteria and randomization

After approval from the Institutional Ethical Committee and informed patient consent, 68 adult patients consisting of both genders aged between 41 to 65 year having physical status of ASA I to II, scheduled for elective surgery under general anesthesia were enrolled for this randomized double blind prospective cohort study. Patients with known hypersensitivity to paracetamol or parecoxib, patients on anticoagulants or with history of bleeding disorder, and patients on antipsychotic, anticonvulsants, monoamine oxidase (MAO) inhibitors, or on antihypertensive medication were excluded from the study. Patients with diagnosed malignancy, with chronic pain or any disease that the investigator believed would pose a risk to the patient were also excluded. All the patients were explained about VAS score during the preanesthesia visit.

The randomization was based on a computer-generated code number for two treatment groups of 34 patients each. The study solution was prepared and administered by one of the researcher anesthesiologist whereas postoperative data were recorded by one of the authors blinded to group assignment. The group assignment code was retained until the conclusion of the study.

Study procedure and anesthetic technique

All the patients underwent preanesthetic evaluation before enrolment for the study. In the operation theatre, standard monitors were attached and baseline heart rate, noninvasive arterial blood pressure, continuous electrocardiogram, pulse oximetry for peripheral oxygen saturation (SpO2), and end tidal carbon dioxide (EtCO2) were recorded. An intravenous infusion of ringer lactate was started and patients were premedicated with midazolam (2 mg) and glycopyrrolate (0.2 mg) 15 min before induction. After 3 min of preoxygenation with 100% oxygen, anesthesia was induced with fentanyl (1.5 μg kg1) and propofol (2.25 mg kg1) till loss of verbal command. The direct laryngoscopy was facilitated with rocuronium (0.9 mg kg1) and intubation was performed after 90 s. The anesthesia was maintained with isoflurane and a mixture of nitrous oxide 60% in oxygen with increments of fentanyl and rocuronium. The lungs were mechanically ventilated to maintain the normocapnia between 35 to 40 mm Hg. Thirty minutes after induction of general anesthesia, the analgesic study solution was infused over a period of 15 min. The infusions were made to look identical and investigators were blinded to the identification of the analgesic study solution. After completion of surgery, the residual paralysis was antagonized with neostigmine (0.05 mg kg1) and glycopyrrolate (0.01 mg kg1), and extubation was performed when respiratory effort was adequate. The patients were transferred to the postoperative recovery room where further clinical observations were done by the blinded observer.

Postanesthesia care

In the postanesthesia care unit (PACU), hemodynamic variables were recorded along with any postoperative side effects (nausea, vomiting, shivering, and pruritus). In the PACU, patients were asked to quantify their pain intensity at rest and while coughing and movement on a visual analog scale (VAS) between 0=no pain and 10=the worst imaginable pain. It was assessed in the immediate postoperative period and at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 12 h successively by one of the authors blinded to group assignment. The patients were given rescue analgesia with IV tramadol 50 mg as bolus with ondansetron when VAS score reached > 3 and repeated to keep the VAS in the range of mild pain. The timing of first dose of tramadol was recorded.

Group I received first dose of paracetamol 1 gm 30 min after induction of general anesthesia and second dose after 6 h while Group II were given single dose of parecoxib 40 mg and a placebo infusion of normal saline after 6 h in a double blind manner.

Patients was discharged to the ward when awake and oriented, hemodynamically stable, able to breathe adequately with oxygen saturation >98% on room air.

Efficacy assessment

The primary variables for clinical equivalence were the differences between the mean values for pain scores at rest and while coughing and movements at 30 min, 1 h, 2 h, and then every 2 h until 12 h of first dose of analgesic. The quality of analgesia was determined in terms of VAS along with total dose of tramadol required over 12 h. Pain assessment was done at the sixth hour before study drug reinjection. Clinical tolerability and occurrence of adverse events were registered throughout the 24 postoperative hours.

Study population size and statistical analysis

The sample size was based on initial pilot observations, indicated that approximately 28 to 32 patients should be included in each group in order to ensure power 0.80 for detecting clinically meaningful postoperative analgesia with a 5% Type I error. Assuming a 5% dropout rate, the final sample size was set at 68 patients. The results obtained in the study are presented in tabulated manner and analyzed using Microsoft Excel, and SPSS software for windows. Data were presented as mean ± SD or percent of patients. The continuous variables were analyzed using student t test while the Chi-square test was used to compare demographic profile. The nonparametric ordinal data of VAS was analyzed by Mann-Whitney U test. Differences were judged significant at P<0.05.

RESULTS

The total of 68 adult consented patients were randomly selected to receive either paracetamol (n=34) or parecoxib (n=34). As there was no protocol violation in any of the patients studied, the data for all 68 patients were eligible for statistical analysis. The 21 women and 47 men were enrolled for the study. Their average age was 49.38 ± 10.09 year (range 41 to 65 years). There were no intergroup difference with respect to the demographic parameters of the patients (age, weight, ASA physical status, duration of surgery, and anesthesia) [Table 1].

Table 1

Patients demographic and baseline characteristics

None of the study drugs had any effects on the hemodynamic variables. Emergence from anesthesia was also comparable with no statistically significant difference as regards the stay in PACU, respiratory rate and SpO2.

The quality of pain was assessed on a visual analogue scale of 0–10 at rest and while coughing and movements at the 30 min, 1st, 2nd, 3rd, 4th, 6th, till 12th h. The statistically significant difference was detected between Groups I and II as regard VAS during rest in the early postoperative period (P<0.05) but the difference was not of statistical significance while coughing. There was no statistical difference in groups at 30 min and 1 h after surgery but at 2 h and 4 h there was statistically difference in the VAS score between groups [Figures 1 and 2].

Figure 1

Time course of pain intensity at rest assessed by VAS. Treatment effect was significant (P<0.05)

Figure 2

Time course of pain intensity while coughing assessed by VAS. Difference did not reach the threshold of statistical significance (P>0.05)

Rescue analgesic, tramadol, was given when VAS score reached > 3. There was no significant difference in time to first request for tramadol in the PACU. There was one patient of Group II, receiving parecoxib had one episode of vomiting in the PACU just after arrival. Shivering and pruritus were not observed. After 8 h, no statistically significant difference could be detected between study groups as regards VAS during rest and while coughing and movements. All patients were discharged from the hospital in good condition [Table 2].

Table 2

Postanesthesia care unit evaluation

DISCUSSION

This study has comparatively evaluated the postoperative analgesic efficacy of paracetamol and parecoxib after general anesthesia during the early postoperative period. Due to the longer duration of action of parecoxib (8 to 12h), a second dose of paracetamol was repeated after 6 h to cover the time lag resulting from the shorter duration of paracetamol action (4 to 6 h). The mean time of first dose of rescue analgesic did not differ between groups, which showed that the quality of early postoperative analgesia with intravenous paracetamol or parecoxib was effective and comparable.

Adequacy of postoperative analgesia is one of the most important factors for early hospital discharge and mobilization of patient.[3] The opioids effectively reduce the spontaneous pain but their ability to control dynamic pain is limited and their usefulness is also limited due to nausea and vomiting, sedation, constipation, and respiratory depression.

Several studies have shown that nonopioid analgesics such as paracetamol and NSAIDs do provide effective analgesia in early postoperative period. NSAIDs may be effective as sole analgesic after minor to intermediate surgery but their usefulness is limited by adverse effects on the gastro-intestinal, respiratory, renal and hematological systems.[489] The parecoxib has beneficial effects on inflammation and pain with concomitant preservation of homeostatic function and less side effects, hence is suitable for the perioperative period.[10-12]

The paracetamol is a nonopiate para-aminophenol derivative and exhibits analgesic, antipyretic activity, and lowers the need of other analgesics[13] The recent studies have shown that the analgesic effect of paracetamol involves a “self-synergistic” interaction between spinal and supra-spinal sites, with recruitment of endogenous opioid pathways.[13] The intravenous paracetamol provides pain relief within 5 to 10 min and peak analgesic effect is obtained in 1 h with duration of 4 to 6 h. It is devoid of impaired platelet aggregation, gastrointestinal ulceration, hemorrhage, and cardiorenal adverse effects.[14]

Tramadol has weak central action on opioid receptors and owes much of its analgesic effect to the inhibition of the reuptake of norepinephrine and serotonin at descending inhibitory neurons. Its potency is comparable to pethidine but causes less constipation. The risk of respiratory depression is significantly lower; however, nausea and vomiting are its common side effects.[15]

The equipotent doses of the nonopioids analgesics are unknown, so the maximum permissible doses recommended by the manufacturers for initial IV dose in adults were chosen. These are 1 gm for paracetamol and 40 mg for parecoxib. Early parenteral administration of nonopioid analgesics within the intraoperative period could help to control pain better.

Gorocs et al. have evaluated the efficacy and tolerability of IV paracetamol in patients undergoing elective ambulatory surgery and reported that majority of patients have achieved VAS < 3 with no serious adverse events.[14] Cattabriga et al. have examined the efficacy of IV paracetamol as an adjunctive analgesic to a tramadol based analgesia after cardiac surgery and concluded that patients receiving IV paracetamol, required less cumulative morphine.[15] Zhou et al. evaluated its potency in total hip and knee replacement surgery and revealed that paracetamol and diclofenac were effective with no significant difference in the analgesic activity.[16]

Gehling et al. and Beaussier et al. concluded that single parenteral injection of parecoxib 40 mg compares favorably with two infusions of propacetamol 2 g within the first 12 in adult patients.[1718] The COX-2 selective NSAIDs rofecoxib or celecoxib usually demonstrated analgesic efficacy superior to paracetamol when given orally.[1920]

In this study, a single injection of parecoxib compared favorably to paracetamol given twice during 12 h evaluation period, the longer duration of action of parecoxib can be confirmed and considered as a notable advantage.[21]

Both study drugs were well tolerated in this relatively healthy population and have shown no adverse effects on hemodynamic, probably because they were infused slowly over 15 min rather than injected as bolus. The incidence of postoperative nausea and vomiting was less.

CONCLUSION

Nonopioids intravenous analgesia with parecoxib 40 mg and paracetamol 2 gm is comparable in early postoperative period after general anesthesia. The analgesia with parecoxib and paracetamol is efficacious, safe, and devoid of adverse effects.