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Improving the Analgesic Efficacy of Intrathecal Morphine with Parecoxib After Total Abdominal Hysterectomy

Niruthisard, Supranee MD*; Werawataganon, Thewarug MD, MSc*; Bunburaphong, Pavena MD*; Ussawanophakiat, Montson MD; Wongsakornchaikul, Chuthayuth MD; Toleb, Kusonsi BNS

doi: 10.1213/01.ane.0000277489.87015.1d
Analgesia: Pain Medicine: Brief Report
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BACKGROUND: The addition of parecoxib to intrathecal morphine and bupivacaine may improve analgesia and reduce morphine’s opioid-related side effects.

METHODS: In this prospective, double-blind, randomized, placebo-controlled trial, total abdominal hysterectomy patients received either IV normal saline or parecoxib 40 mg before receiving intrathecal bupivacaine and morphine 0.2 mg. Twelve hours later, this administration was repeated. Patients were observed for 48 h.

RESULTS: The addition of parecoxib to intrathecal morphine and bupivacaine significantly reduced cumulative morphine consumption, Visual Analog Pain scores, and increased patient satisfaction for 24 h postoperatively without an obvious decrease of adverse side effects.

CONCLUSION: Perioperative parecoxib enhanced the postoperative analgesia of intrathecal morphine and bupivacaine and improved patient satisfaction.

IMPLICATIONS: Perioperative parecoxib enhanced the postoperative analgesia of intrathecal morphine/bupivacaine and improved satisfaction in patients undergoing total abdominal hysterectomy.

From the *Department of Anesthesiology, Faculty of Medicine, Chulalongkorn University, and †Department of Anesthesia, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

Accepted for publication May 17, 2007.

Supported by Ratchadapiseksompotch Fund 2005, Faculty of Medicine, Chulalongkorn University.

Address correspondence and reprint requests to Supranee Niruthisard, MD, Department of Anesthesiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. Address e-mail to drsupranee@hotmail.com.

The recommended dose for intrathecal morphine after total abdominal hysterectomy (TAH) is 0.2 mg (1), but this dose may not provide sufficient postoperative analgesia. The addition of cyclooxygenase-2 (COX-2) inhibitors may be useful in this setting. IV parecoxib, approved for acute postoperative pain, has not been investigated with intrathecal morphine in gynecologic surgery.

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METHODS

This study was approved by the hospital ethics committee. Written, informed consent was obtained from each patient. ASA physical status I or II patients, aged 30–60 yr, capable of using a patient-controlled analgesia (PCA) pump and scheduled to have spinal anesthesia for TAH were recruited for this study. Exclusion criteria were: cancer, chronic pain, history of drug abuse, contraindications for spinal anesthesia, serum creatinine >1.5 mg/dL, or a history of cardiovascular disease, gastrointestinal disease, bleeding disorders, asthma, use of analgesics 1 wk before surgery, or allergy to the studied medications.

All procedures were standardized. Patients randomly received either 2 mL of parecoxib 40 mg or normal saline IV 30 min before spinal anesthesia. This procedure was repeated 12 h later. Spinal anesthesia was induced via a 27G spinal needle at L2,3 or L3,4 interspace by using 0.5% hyperbaric bupivacaine 3.6–3.8 mL plus morphine 0.2 mg (0.2 mL). General anesthesia without opioids was administered when required. For 48 h, postoperative pain control was accomplished using the PCA morphine pump with a demand dose of 1 mg and 6 min lockout.

We recorded the cumulative morphine dose at 24 h, time to first analgesic demand, Visual Analog Pain Scale 0–10 score (0 = no pain, 10 = worst pain imaginable), patient satisfaction 0–10 score (0 = dissatisfaction, 10 = most satisfaction), and the severity of side effects (nausea/vomiting, pruritus, shivering, and sedation). Side effects were treated at patient request or when the pain scale score was assessed as more than moderate. Nausea or vomiting was treated with 10 mg IV metoclopramide or ondansetron 4 mg and IV nalbuphine 3 mg for pruritus every 4 h when needed.

The sample size estimation for 50% 24-h opioid reduction with [alpha] = 0.05, power = 80% was 71 in each group (2). Analyses were done on an intent-to-treat basis. Analysis of variance and unpaired Student’s t-test were used for intergroup comparison of parametric data. The time to first analgesic demand was analyzed by survival analysis. Nonparametric data were analyzed using Pearson χ2 test, Fisher’s exact, test or Mann–Whitney U-test where appropriate. Results are expressed as mean ± sd or median (range). Statistical significance was inferred at P < 0.05 (with Bonferroni Correction for multiple comparison).

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RESULTS

The patients’ preoperative and intraoperative data were similar (Table 1). Five patients did not require additional morphine (control/parecoxib = 1/4) and three patients in the parecoxib group stopped PCA morphine before 48 h. Only 70 patients in the parecoxib group were included in the statistical analysis for morphine use because of the missing PCA data. Postoperatively, there was a significant decrease in morphine use at 12, 24, 36, and 48 h, but not at 6 h (P = 0.12) in the parecoxib group compared with that in the control group: (P < 0.01) with 24- and 48-h cumulative morphine consumption of 4.9 ± 7.0 vs 13.1 ± 12.7 and 11.7 ± 13.7 vs 28.0 ± 24.2 mg, respectively, (Fig. 1). The median time (range) to first analgesic demand between the two groups was not statistically different, P = 0.19 (Table 1).

Table 1

Table 1

Figure 1

Figure 1

The Visual Analog Pain Scale scores in the parecoxib group were significantly lower than those in the control group, P < 0.05 (Table 2). Side effects were similar in both groups with less pruritus at 48 h in the parecoxib group (P < 0.05). The satisfaction score in the parecoxib group was significantly higher than that in the control group at 24 h (9.1 ± 1.1 vs 8.5 ± 2.0, P < 0.05), but not at 48 h postoperatively (9.4 ± 1.0 vs 9.1 ± 1.5, P = 0.207). The reasons for a satisfaction score below 8 in 16 patients (control/parecoxib = 12/4) were nausea, vomiting, pruritus, and dizziness.

Table 2

Table 2

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DISCUSSION

This study showed that parecoxib and intrathecal morphine improved analgesia, with an opioid-sparing effect, and increased patient satisfaction when compared with intrathecal morphine alone.

Previous studies showed enhanced analgesic efficacy of intrathecal morphine with perioperative use of diclofenac (3,4), and studies of parecoxib after TAH under general anesthesia reported excellent analgesia and opioid-sparing effects (5–10) with more effective prevention of acute pain when administered preoperatively (10). Because of the lack of IV active comparators in Thailand (i.e., ketorolac or paracetamol) we compared parecoxib with placebo. Thus, it remains possible that these and other multimodal analgesics may have similar efficacy to parecoxib within our study context. Nevertheless, we observed that preoperative administration of parecoxib enhanced analgesic efficacy of intrathecal morphine with an opioid-sparing effect of 63% at 24-h. This may be explained by central nervous system COX-2 inhibition of parecoxib, which can penetrate the central nervous system rapidly (11) and reduce the cerebrospinal fluid prostaglandin E2 concentration and postoperative pain, even when administered postoperatively (12). In contrast to our results, recent studies of postoperative administration of valdecoxib and celecoxib failed to demonstrate better analgesia of intrathecal morphine after cesarean delivery (13,14). It could be that the COX-2 inhibitors are less effective in relieving pain of a cramping nature as in postcesarean pain models.

Prophylactic use of parecoxib in this study demonstrated better patient satisfaction at 24 h without an obvious decrease of adverse side effects. This result is similar to that of a previous review comparing placebo, morphine, and ketorolac (15). There was a lower incidence of pruritus at 48 h, probably due to less morphine consumption in the parecoxib group, but this did not result in a prolongation of patient satisfaction beyond 24 h.

We observed that perioperative administration of two doses of parecoxib 40 mg IV every 12 h improved analgesia of single-dose intrathecal morphine 0.2 mg after TAH by decreasing additional morphine requirements and increasing patient satisfaction for 24 h.

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ACKNOWLEDGMENT

We acknowledge help from the Division of Research Affairs of the Faculty of Medicine, Chulalongkorn University.

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