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Original Paper

Premedication with controlled release diclofenac sodium reduces post-operative pain after minor gynaecological surgery

Bamber, M. J.; Tweedie, I. E.; Breeze, C.; Williams, N. E.

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European Journal of Anaesthesiology: July 1997 - Volume 14 - Issue 4 - p 421-427

Abstract

Introduction

A significant number of women complain of abdominal pain after evacuation of retained products of conception (ERPC) and vaginal termination of pregnancy (VTOP). Up to 59% of patients complain of mild abdominal pain, 6–10% of severe abdominal pain and 21–40% experience some backache following minor gynaecological surgery [1]. Even after dilatation and curettage, 31% spontaneously complained of pain and 57% if specifically questioned (57% of these had backache and 47% lower abdominal pain) [2].

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely accepted to be of great value in the treatment of mild to moderate acute and chronic pain as well as that associated with arthritis [3]. Their role in the treatment of post-operative pain continues to develop. As their peripheral mode of action is to inhibit prostaglandin formation they may have a specific application in the alleviation of uterine pain associated with cervical stimulation and endometrial curettage. Many studies have demonstrated the beneficial effects of NSAIDs given post-operatively for minor gynaecological surgery, in the treatment of dysmenorrhoea pain, and post-partum uterine pain. However, few of these studies used diclofenac and a search of the literature failed to reveal any studies using the oral controlled release preparation prophylactically for minor surgery. Therefore, it was decided to investigate the efficacy of controlled release diclofenac (Voltarol Retard®—CIBA-Geigy Pharmaceuticals, Horsham, UK) in the prevention of post-operative pain when administered as part of the premedication.

Method

Following approval of the protocol for this randomized, controlled, double-blind trial by the Hospital Ethical Committee, 52 women, aged between 15 and 38 years having either ERPC or VTOP were studied. Each patient gave their written informed consent. Twenty-four patients received active drug and 28 placebo. Exclusion criteria included a history of peptic ulceration, gastrointestinal bleeding, known diclofenac sensitivity, aspirin induced asthma, bleeding diatheses or current use of lithium, digoxin or NSAIDs.

Pain scoring

Pre-operatively all patients were interviewed by a researcher blinded as to whether the patient was to receive diclofenac or placebo, and instructed in the use of and scored for their overall level of pain by the patient marking a 100 mm visual analogue scale (VAS). Pain scores were also obtained for three specific elements of pain commonly experienced following minor gynaecological surgery, i.e. abdominal pain, cramp and backache; by asking the patients to give their subjective assessment of their pain in the above three catagories by choosing from a list of descriptive terms to produce a four point verbal rating score (VRS) [no pain=0, mild pain=1, moderate pain=2, severe pain=3]. All the women were reassured that additional analgesia would be available on request if required in the post-operative period.

Drug administration

The controlled release diclofenac sodium 100 mg and placebo tablets (supplied by CIBA-Geigy Pharmaceuticals and identical in size, shape and colour with the active tablets) were randomized by the hospital pharmacy and placed in consecutively numbered bottles. These were then prescribed by sequential number as each patient was recruited into the study. Following assessment of the pre-operative pain scores, the patient was premedicated with oral diazepam 10 mg together with the trial tablet, both being administered 1 1/2–2 h prior to surgery.

Anaesthesia

Anaesthesia was induced intravenously (i.v.) with a sleep dose of sodium thiopentone and 5 μg kg−1 of alfentanil, and maintained with increments of thiopentone 0.5–1.0 mg kg−1 and alfentanil 2.5–5.0 μg kg−1 (to a maximum of 1000 μg). A mixture of nitrous oxide in oxygen 66% was administered via a Mapleson A breathing system and facemask. Oxytocin (Syntocinon®—Sandoz, Camberley, UK) 10 units was given i.v. only after surgical request. At the end of the procedure the patient was allowed to recover spontaneously in the lateral position.

Paracetamol 1g, orally, 6 hourly and morphine 10 mg, intramuscularly (i.m.), 4 hourly, both to be given as required were prescribed by the anaesthetist as post-operative 'rescue' analgesia. The times of premedication, induction, and recovery were recorded and the patients assessed for pain (VAS and VRS) and any other morbidity at 30 min, 1, 2, 6 and 24 h following recovery from anaesthesia. The timing and indication for use of either of the post-operative rescue analgesics was recorded.

Differences in VAS and VRS were analysed using the Mann-Whitney U-test. The VRS were also compared as the number of zero pain scores vs. the number of those greater than one, using the χ2-test. Differences in demographic data, drug dosages and time intervals were analysed using the two sample Student's t-test.

Results

No patients were excluded from the study on the basis of the exclusion criteria, however, two patients were eliminated because of prolonged delays between administration of the trial drug and the induction of anaesthesia. Therefore, data from 23 patients in the diclofenac group and 27 in the placebo group was used in the calculation of the results. Both groups were comparable in terms of age, weight, parity and gravidity (Table 1). There were no significant differences in anaesthetic drug requirements, operating times or test drug administration to recovery times. (Table 2). Several women received either ergometrine to reduce blood loss or prostaglandin E2 pessaries to induce abortion pre-operatively; the active and placebo groups were comparable in terms of numbers of these patients and there was no significant difference between these women's pain scores and the median scores for their group.

Table 1
Table 1:
Demographic data. Mean±SD (range)
Table 2
Table 2:
Anaesthetic drug doses* and time intervals. Mean±SD (range)

No side effects attributable to diclofenac were observed or reported by any of the patients taking part in the study.

Analgesic requirements

Pre-operatively, the active and placebo groups were comparable. Post-operatively, when analysed in two time periods, namely the first 6 and the 7th to 24 hours, no significant difference was found between the groups in either the number of doses of analgesic administered or in the number of patients requiring analgesia for operatively related pain (Table 3). Comparison by operative procedure (ERPC vs. VTOP) revealed no significant differences in analgesic requirements. None of the patients required morphine.

Table 3
Table 3:
Requirements for post-operative analgesia with paracetamol 1 g number (%)

Analysis of visual analogue scales

When the VAS scores for both operative subgroups were analysed collectively there were no significant differences between the active and placebo groups either pre-operatively or at 24 h post-operatively. However, at 30 min and 60 min post-operatively the diclofenac treated patients' VAS scores were significantly lower (P<0.0005 and P<0.01, respectively). The VAS scores marginally failed to reach significance at 120 min and 6 h (Table 4).

Table 4
Table 4:
VAS pain scores (mm). Median (range)

The diclofenac treated group contained more pain free (VAS=0) patients than the placebo group (Fig. 1) but the median pain scores of those patients who complained of pain showed a less clear superiority in the active group.

Fig. 1.
Fig. 1.:
Percentage of patients with no pain (VAS=0) in each group, showing post recovery changes against time.

Analysis of visual analogue scale pain score changes

Since ERPC patients required more analgesia pre-operatively than VTOP patients; the changes between pre- and post-operative VAS pain scores were also analysed. When the data from both operative subgroups was analysed collectively the pre- to post-operative pain score changes in the diclofenac group were significant at 30 min (P<0.001) and at 60 min (0.01<P<0.05) (Table 5).

Table 5
Table 5:
Total VAS pain scores (mm). Pre-operative to post-operative changes. Negative value=decrease in VAS pain score at the post-operative time stated when compared with pre-operative base-line value. Positive value=increase in VAS pain score at post-operative time stated when compared with pre-operative base-line value

Operative Sub-groups. Patients undergoing a surgical abortion had significant pain score changes in the active drug group at all times (pre-operative 30 min, 60 min, 120 min, 6 h (all P<0.01) and 24 h (P<0.05). ERPC patients had pain score changes that failed to reach significance at any time, although they were greater than in the placebo group (Table 5).

Analysis of verbal rating scores

Post-operatively, after 120 min, less than 10% of the patients in either the active or placebo group gave a positive VRS pain score (A1) and no patient gave a positive VRS pain score A3. When the number of zero scores was compared with those A1, it was found that the diclofenac treated patients had highly significantly lower scores for abdominal pain at 30 min (P<0.001), 60 min (P<0.001), and significantly lower scores at 120 min (P<0.02) and 24 h (P<0.05) (Table 6). No significant differences were found for cramp and backache.

Table 6
Table 6:
VRS pain scores for abdominal pain. No pain (score=0) vs. pain (score≥1)

Discussion

Diclofenac sodium is a phenylacetic acid derivative that acts as a cyclo-oxygenase inhibitor; 100 mg controlled release tablets were used on the premise that they would provide analgesia for up to 24 h [2] and it was administered pre-operatively in order that the plasma levels would be at their peak at about the time that the patients would be recovering from anaesthesia (peak plasma levels are reached 90–120 min after oral administration and mean administration to recovery time interval was 114.6 min). The objective of this study was to assess the effectiveness of controlled release diclofenac sodium in the prevention or reduction of discomfort following minor gynaecological surgery.

Prostaglandins play a major role in the physiology and pathology of the uterus and much work has been carried out on the use of NSAIDs in the treatment of dysmenorrhoea. It is known that the administration of prostaglandin to even the non-gravid uterus causes increased contractility and uterine tone [4]. The pain of dysmenorrhoea may be secondary to increased levels of endometrial prostaglandin resulting in myometrial effects as well as sensitization of nociceptors. There is experimental evidence that another NSAID; Mefenamic acid, reduces the discomfort felt by nearly all women suffering from dysmenorrhoea and in 46% of cases caused a measurable reduction in uterine contractility [5]. Therefore it may be postulated that the release of prostaglandins following the trauma of endometrial currettage during ERPC or surgical abortion plays a significant part in the aetiology of the post-operative pain experienced by women by increasing myometrial tone and contractility and possibly by the consequent expulsion of small blood clots. Thus it follows, that if NSAIDs reduce the endogenous production of prostaglandin, then their administration should result in a reduction in the myometrial and nociceptive effects of prostaglandin with a consequent reduction in patient discomfort. The specific activity of NSAIDs in this context should therefore offer advantages over the use of conventional opioid analgesics. The mechanism of action of NSAID's in reducing production rather than release of prostaglandins makes it more logical to administer them prior to the tissue damage.

Reduction in myometrial contractility together with the anti-platelet action of NSAIDs may lead to concerns about haemorrhage. Diclofenac has been administered post-operatively to provide analgesia following Caesarian section with some success [6,7]; however, at least one case of uterine atony has been noted following diclofenac administration, although in this case the authors believed that the dose of diclofenac was too small to have been the cause of myometrial relaxation [7]. Administration of parenteral diclofenac pre-operatively followed by a 24-h continuous post-operative infusion in gynaecological laparotomy patients failed to show significant differences in prostaglandin E2 values, operation time, intra-operative blood loss, bleeding time and frequency of post-operative haematoma although the rise in plasma Thromboxane B2 values seen in untreated subjects was abolished by the use of diclofenac [8]. Although peri-operative blood loss was not measured during this study there were no incidents of post-operative bleeding, no difference in the need for intra-operative oxytocin and no patient required the use of supplemental doses of oxytocic agents for post-operative haemorrhage.

Most studies of NSAIDs used pre-operatively for pain prophylaxis, refer to first trimester vabra currettage under local anaesthesia. Suprapto [9] used naproxen and found that the pain was reduced up to 30 min post-operatively; however, Siddle et al.[10], also using naproxen, found no difference in pain during the procedure but that pain was decreased significantly at 30 and 60 min post-operatively, a finding that agrees with our results. We were unable to find references to the use of oral diclofenac in minor gynaecological surgery, although it has been extensively investigated in the treatment of post-laparoscopy pain when given i.m., i.v. and rectally in the pre-operative, intra-operative, and post-operative phases with varying degrees of success [7,11–14]; also Carlborg et al.[15] and Hodsman et al.[16] both report satisfactory post-operative pain relief enhanced by the use of diclofenac following hysterectomy and abdominal surgery, respectively.

The gynaecological procedures of ERPC and VTOP may be classed as minor and the individual discomfort associated with them is less than that associated with more major surgery, however, the very large numbers of such cases account for a considerable amount of cumulative morbidity. The oral route of administration is prefered by most patients and we conclude that the use of controlled release diclofenac sodium (Voltarol Retard®) given as a premedicant for minor intrauterine surgery reduces post-operative pain for up to 2 h.

Acknowledgments

We would like to thank the staff of Ward H4 at Whiston Hospital for their co-operation, the consultant gynaecologists for access to their patients, and the Whiston Hospital pharmacy for randomizing and coding the drugs. We are grateful to CIBA-Geigy Pharmaceuticals for financial assistance and for supplying a suitable placebo.

Declaration

Dr M. J. Bamber would like to state that owing to reasons of personal conscience he did not administer anaesthesia to any patient undergoing termination of pregnancy during the course of this study.

References

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Keywords:

Analgesics, anti-inflammatory, diclofenac; Anti-inflammatory agents, non-steroidal, diclofenac; Pain, post-operative, minor gynaecological surgery; Diclofenac

© 1997 European Academy of Anaesthesiology