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OBSTETRIC ANESTHESIA

A Randomized Controlled Trial Examining the Effect of Naproxen on Analgesia During the Second Day After Cesarean Delivery

Pamela J. Angle, MD FRCPC^*, Stephen H. Halpern, MD FRCPC^*, Barbara L. Leighton, MD, J. P. Szalai, PhD, K. Gnanendran, MD FRCPC^*, and Jean E. Kronberg, MD PhD^*

*Department of Anesthesia, Women’s College Hospital Campus, Sunnybrook and Women’s College Health Sciences Center, University of Toronto; Visiting Professor of Obstetric Anesthesia, University of Toronto; and Director, Research Design and Biostatistics, Sunnybrook and Women’s College Health Sciences Center, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Pamela J. Angle, MD, Department of Anesthesiology, Women’s College Campus, Sunnybrook and Women’s College Health Sciences Centre, 76 Grenville St., Toronto, Ontario, M5S 1B2. Address e-mail to pamela.angle{at}swchsc.on.ca

	Abstract

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Whereas nonsteroidal antiinflammatory drugs augment spinal morphine on Day l, the analgesia gained by simply combining these drugs with conventional "on request" oral regimens on Day 2 is less clear. In this trial, we randomized 80 women undergoing elective cesarean delivery with spinal morphine (0.2 mg) to receive naproxen (500 mg) or placebo every 12 h after surgery. Both groups received conventional therapy with acetaminophen with codeine (on request) and rescue IM opioids. Incision pain on sitting (IPS), incision pain at rest, uterine cramping, and gas pain were evaluated with visual analog scales (0–100). Worst interval pain (0–10), analgesic use, and side effects were measured over 72 h. At 36 h (primary outcome), naproxen use was associated with reductions in IPS (38.2 ± 26.0 versus 51.4 ± 25.7; P = 0.05), incision pain at rest, uterine cramping, and worst interval pain scores. Clinically modest, statistically significant reductions in IPS (P = 0.0001) and opioid use were found over time (P < 0.0l). Reductions in the incidence of inadequate analgesia and improvements in overall pain relief (P = 0.0006) on Day l did not persist on Day 2 (overall pain relief, P = 0.057; inadequate analgesia, 24% naproxen versus 27% controls; P = 1.00). The addition of regular doses of naproxen to conventional oral pain therapy after cesarean delivery leads to reductions in IPS at 36 h and pain over Day 2 but does not reduce the incidence of inadequate analgesia.

IMPLICATIONS: This randomized trial suggests that adding regular doses of naproxen to conventional "on request" acetaminophen and codeine therapy provides small reductions in pain on the second day after cesarean delivery. The greatest effects occur at 36 h, when pain peaks.

	Introduction

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Pain is generally worst for the first 2 days after cesarean delivery. Although neuraxial morphine provides profound analgesia for many women on Day l, previous work suggests that use of this drug shifts peak pain levels from the first to the second day (1,2).

Analgesic therapy for many women on Day 2 consists of the waning effects of neuraxial morphine, relatively weak oral analgesics (variably dosed and administered), and a nonsteroidal antiinflammatory drug (NSAID). Many studies of analgesia in these patients have focused on pain relief up to the first 24 h rather than over the normal course of hospitalization (3–8).

Previous work suggests that adding NSAIDs in the immediate perioperative period augments the analgesic effects of spinal morphine on Day l (2,9,10). The magnitude of reductions in pain actually achieved by adding these drugs to existing oral regimens on Day 2, however, is less clear (2,9). Our impression was that conventional analgesia (acetaminophen and codeine on request and rescue IM opioids) provided relatively poor analgesia for some women during this time. Although adding naproxen appeared to improve pain relief in many women, the number of women with poor pain relief did not appear to differ. We conducted a prospective, randomized, controlled trial to examine analgesia on Day 2 with conventional oral analgesia alone versus the same therapy combined with regular doses of naproxen.

	Methods

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After hospital research ethics board approval and written informed consent, 80 ASA physical status I–II term parturients (37–42 wk gestational age) scheduled for elective cesarean delivery under spinal anesthesia were recruited to participate. A computer-generated randomization table (block randomized in random groups of four to eight) was made before the study onset. Pharmacy staff maintained the randomization key until study completion. Randomization codes were concealed in sequentially ordered sealed opaque envelopes. Staff, patients, and interviewers were blinded to treatment groups. Pharmacy staff supplied identical drug forms for administration. Exclusion criteria included contraindication to spinal anesthesia, known hypersensitivity or intolerance to study drugs, diabetes, severe preeclampsia, and active peptic ulcer disease within the past year. Asthmatic women with known tolerance to aspirin or NSAIDs were allowed to participate.

After routine preloading with 1000–1500 crystalloid, spinal anesthesia was administered at L2-3, L3-4, or L4-5 in the sitting or left lateral decubitus position by using a 25-gauge Whitacre needle. The spinal anesthetic consisted of 0.75% bupivacaine in 8.25% dextrose (1.2–1.8 mL), fentanyl 10–20 µg, and preservative-free intrathecal morphine 0.2 mg. All patients had low transverse abdominal (Pfannenstiel) incisions. At the end of surgery, the placebo group received an Anusol^® suppository (zinc sulfate monohydrate; Warner-Lambert Consumer Healthcare, Toronto) per rectum followed by oral lactose capsules every 12 h for six doses. The experimental group received naproxen as a 500-mg suppository (Naprosyn^®; Hoffman-LaRoche Ltd., Mississauga, Ontario), followed by oral naproxen sodium 550 mg (Anaprox^®; Hoffman-La Roche Ltd.) every 12 h for six doses. Rescue suppositories were available as a substitute for oral preparations in women with vomiting in both study arms. Pain therapy thereafter consisted of Tylenol No. 3^® (acetaminophen 300 mg, caffeine 15 mg, and codeine 30 mg; Janssen-Ortho Inc., Toronto, Ontario), one or two tablets every 3–4 h as needed, with backup IM morphine or meperidine on patient request. Receipt of parenteral opioids within the first 24 h after intrathecal morphine was given by the order of a staff anesthesiologist only. For the purposes of analysis, opioids used after surgery were converted to milligram equivalents of oral codeine by using the following formula: morphine 10 mg IM = meperidine 75 mg IM = oral codeine 200 mg (11).

Women in the study were encouraged to mobilize early (within 12 h) in keeping with practice in our institution. Questionnaire-based interviews were performed at regular intervals to determine pain type (incision, uterine cramping, or gas) and severity. Pain measurements were taken at rest and with sitting (30° from a reclining position) by using a nongraduated 10-cm visual analog scale (VAS) with 0 marked at one end (equal to no pain) and 100 at the other end (the worst pain ever experienced). Worst pain type and worst pain scores (0 to 10) were recorded for each 12- and 24-h interval during the study period. The interval worst pain score was defined as the highest level of pain experienced over a designated time interval (with either rest or movement) up to the time of the interview. The interval worst pain type was identified as the type of pain (uterine cramping, incision pain, or gas pain) associated with the interval worst pain score over each designated time period. Analgesic requirements and time to first analgesic request were recorded. Overall pain relief was measured at 24-h intervals by using a six-point Likert-type scale (0 = no pain relief and 5 = excellent pain relief). Overall pain relief was also collapsed into adequate pain relief (good, very good, or excellent) and inadequate pain relief (none, poor, or fair) categories.

Maternal and neonatal side effects were measured in a standardized fashion over the entire study period and included pruritus (nongraduated 10-cm VAS), nausea or vomiting (four-point ordinal scale), sedation scores, respiratory rate, use of additional uterotonic drugs, and neonatal bruising, bleeding, or jaundice. Maternal vaginal blood loss was measured with standardized maternity pads and a standardized method of scoring over predetermined intervals of time. The scoring method of vaginal blood loss used by nursing staff was adapted from our institutional protocol and was visually graded as follows: scant, <2.5 cm blood loss; small, <10 cm; moderate, >10 cm; heavy, fully saturated; and excessive bleeding, menstrual pad saturated. All patients were observed until the time of discharge or up to 72 h after surgery.

An a priori sample size calculation revealed that 73 patients were required to achieve a study power of 0.8 to detect a 30% reduction in incision VAS scores on sitting at 36 h at a conventional level of statistical significance of 5%. Analysis of the primary outcome was by intent to treat, with a P value of <0.05 considered statistically significant. Secondary analyses were considered exploratory, and for this purpose a P value of <0.05 was also considered significant. At 36 h, normally distributed data were analyzed with independent Student’s t-tests; nonnormally distributed data were analyzed with the Mann-Whitney U-test. Repeated-measures analysis of variance was used to examine between-group differences (drug versus placebo) over time (six levels of time) as they related to the following dependent variables: incision pain with sitting and opioid use. Dichotomous data were analyzed with Fisher’s exact test. Overall pain relief scores were analyzed with the Mann-Whitney U-test and were later collapsed into inadequate (none, poor, or fair) and adequate (good, very good, or excellent) categories of pain relief and examined by using Fisher’s exact test.

	Results

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Eighty women were recruited. Two breaches of protocol occurred, both involving patients randomized to the naproxen group. One patient received an epidural instead of a spinal for surgery, and one patient was given ibuprofen instead of the study drug at 24 h. The data from both patients were included as part of the data for the naproxen group as part of an intent-to-treat analysis. Demographic data and performance of additional procedures (tubal ligation and myomectomy) at the time of cesarean delivery did not differ significantly between groups (Table 1). Breast-feeding and the severity of dysmenorrhea before pregnancy did not differ significantly between groups.

View larger version (22K): [in this window] [in a new window]   Figure 1. Incision pain on sitting (expressed as mean) and 95% confidence intervals. VAS = visual analog scale; RMANOVA = repeated-measures analysis of variance; RR = recovery room. Admission = time zero.

View larger version (25K): [in this window] [in a new window]   Figure 2. Incision pain at rest (expressed as median and range). VAS = visual analog scale; RR = recovery room. Admission = time zero.

View larger version (21K): [in this window] [in a new window]   Figure 3. Uterine cramping pain at rest (expressed as median and range). VAS = visual analog scale; RR = recovery room. Admission = time zero.

View larger version (20K): [in this window] [in a new window]   Figure 4. Oral codeine use in milligram equivalents (expressed as mean) over time by group. VAS = visual analog scale.

No differences were found in pruritus, nausea or vomiting, maternal sedation or respiratory rates, vaginal blood loss, or use of additional uterotonic drugs. Wound hematomas were not present in either group. Bruising or bleeding was not found in breast-feeding neonates in either group. Three neonates developed jaundice requiring phototherapy in the naproxen group, compared with none in the placebo group (P = 0.2).

	Discussion

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Ideally, high-quality postoperative analgesia should be tailored to match the changing severity of pain over time, providing seamless transitions in pain relief as dependency shifts from more potent (e.g., spinal morphine or patient-controlled analgesia) to less potent (e.g., oral) analgesic regimens. Although NSAIDs are a recognized part of multimodal pain therapy (12), the degree of additional pain relief afforded by simply combining these drugs with existing oral regimens on the second day, when pain levels are increasing, is less clear. By using multiple overlapping instruments to measure pain over the time, this study provides a more complete picture of analgesia achieved by adding regular doses of naproxen to conventional "on request" therapy over Day 2.

Our work suggests that naproxen, like other NSAIDs (2,9), augments the analgesia provided by spinal morphine on the first day after cesarean delivery. Naproxen is also associated with a delay in the time to first request for analgesia and an overall reduction in the use of analgesics. In addition, our study indicates that use of naproxen leads to improved overall pain relief ratings and a marked reduction in the incidence of poor to fair pain relief on the first day.

On Day 2, the simple addition of regular doses of naproxen to conventional "on request" therapy produces a more variable picture of pain relief. Our study demonstrates that pain levels increase and peak at 36 hours after cesarean delivery in women receiving placebo, with blunting of this peak in women receiving naproxen. The small reductions found in VAS pain scores on Day l and Day 2 in the naproxen group were found to increase in magnitude at 36 hours and were considered to reach statistical significance at this time (P = 0.05), given the consistency of reductions found for pain of all types.

Although the benefits of using naproxen on Day 2 are apparent, we do not wish to exaggerate the degree of the benefit derived from its use. Previous work has shown that NSAIDs are associated with a decrease in additional analgesic use over time (2,9). Because the goal of multimodal therapy is to reduce pain rather than simply to avoid opioids, the adequacy of therapy should be judged accordingly.

Work performed by McQuay and Moore (13) helps in the interpretation of VAS scores for pain. Their work suggests that patients with moderate pain (scored on a scale of none, slight, moderate, or severe) would score moderate pain on the VAS as >30 mm (mean, 49 mm) and would score severe pain starting at approximately 54 mm (mean, 75 mm). Thus, although naproxen reduced incision pain with sitting at 36 hours, the magnitude of the reduction might be interpreted as a move from moderately severe to moderate levels of pain. Likewise, the reductions achieved in worst interval pain scores from 25 to 36 hours, where the gap in analgesia is most apparent, are still small and indicate severe pain in both groups. In addition, the incidence of women with inadequate pain relief did not differ on Day 2 despite the use of naproxen, suggesting inadequacy of the other components of conventional therapy. The greatest benefits of naproxen on Day 2 appear to be at 36 hours for incision pain at rest and uterine cramping pain, where VAS scores were reduced from moderate to mild levels.

In summary, this study shows that adding regular doses of naproxen to spinal morphine and conventional "on request" oral analgesia leads to improved analgesia on Day l and has added benefits of a lesser degree on Day 2. These benefits are most evident as reductions in VAS pain scores at 36 hours, when pain levels peak in women receiving placebo. Although the use of naproxen was associated with a statistically significant improvement in overall pain relief and a reduction in the number of women with inadequate analgesia on Day l, these differences did not persist for the naproxen group as a whole on Day 2. The overall mixed effect of naproxen on Day 2 suggests that the use of naproxen is beneficial but that further efforts are needed to optimize the other components of conventional analgesia used in this study.

	Acknowledgments

 
Supported by departmental research funds from the Department of Anesthesiology, Women’s College Campus, Sunnybrook and Women’s College Health Sciences Center, Toronto, Ontario, Canada.

The authors would like to acknowledge the efforts of Michael Ritchie, PhD, Women’s College Campus pharmacy, for his help in drug preparation and maintenance of the randomization key and Michael Wong, Medical Visual Arts, for his help with graphs. They would also like to thank Holly Owen, RN, Leigh Andrews, RN, and Donna Wilson, RN, anesthesia research nurses, for their help with patient interviews and data entry; the nurses in the labor and delivery suite and postpartum floors; the medical library staff; and the patient participants for their help in completing the study.

	Footnotes

 
Presented in part at the International Anesthesia Research Society 2000 meeting, Honolulu, HI, March 11, 2000.

	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