( 1996) 34,428-431 I I

Q 1996 The British Association of Oral and Maxillofacial Surgeons

The absenceof any pre-emptiveanalgesiceffect for non-steroidal anti-

inflammatory drugs

J. B. Bridgman, T. G. Gillgrass, M. Zacharias

Department of Oral Medicine & Oral Surgery, School of Dentistry and Department of Anaesthesia h
Intensive Care, University of Otago, Dunedin, New Zealand

SUMMARY. Pre-emptive analgesic efficacy of the non-steroidal anti-inflammatory drug, diclofenac sodium, was
tested in 21 young, fit, patients undergoing third molar extractions in a double-blind, randomised, cross-over, trial.
Pain scores and mouth opening were observed for 1 week after the operation and these did not show any differences
following pre- and postoperative oral administration of diclofenac sodium 100 mg (P>O.O5). There were no
differences in the patients preference for the two methods of treatment (P>O.O5). The study suggests that the
non-steroidal anti-inflammatory drug diclofenac sodium does not cause any signillcant pre-emptive analgesic effects
in the dose administered.

INTRODUCTION The study design was such that for operation on

Non-steroidal anti-inflammatory drugs (NSAIDs) are
increasingly used for postoperative pain control in
both medical and dental practice. Its use in dentistry
has been widespread for a number of years.
Preoperative administration of NSAIDs has been
shown to be effective in controlling postoperative
dental pain. 2*3 The concept of pre-emptive analgesia
has been put forward in the last few years,4 suggesting
that the use of analgesics like local anaesthetics and
opiates do prevent central nervous system reactivity
(neural plasticity), and thus pain, in the postoperative
period. 5,6 This study was designed to observe any
pre-emptive analgesic properties of the NSAID diclo-
fenac, by giving the drug before or after surgical
extractions of third molar teeth.
METHODS
Healthy patients (ASA l-2), scheduled to undergo
surgical extractions of bilateral, similarly impacted
third molar teeth were invited to take part in the
trial. Approval was given by the Area Health Board
Ethics Committee. The study was designed as a
double-blind, randomised, cross-over trial. The
extractions were performed one side at a time, separ-
ated by at least 2 weeks. There were two surgeons
taking part in the trial, but each patient received the
same surgeon for their two appointments. At each
appointment the patients were administered oral tem-
azepam (30 mg) 1 h before the surgery. The test
drugs used were diclofenac sodium 100 mg (treatment
A) and placebo (treatment B), which were made in
non-distinguishable gelatinous capsules by the
Pharmacy Department of the Dunedin Crown Health
Enterprises.
428
the first side the patients received either treatment A
60 min before surgery and treatment B at the end of
surgery or vice versa. This order was reversed during
operation on side 2. Hence all patients received a
single dose of diclofenac 100 mg, either 1 h before
surgery or at the end of the operation. Both the drug
schedule and side to be operated upon first were
randomly selected. The operations were done during
the late morning in all cases in order to avoid any
influence of diurnal variation in pain.
All patients received local anaesthesia using 2%
lignocaine with 1: 100 000 adrenaline and surgery
proceeded when the anaesthesia was well established.
At the end of surgery they received the appropriate
drug treatment. As well as this all patients were given
an elixir containing paracetamol 1 g with 30 mg
codeine phosphate to be taken 6 hourly for 48 h after
the surgery and thereafter on a as required basis.
This ensured that all patients received the same dose
of postoperative analgesics for the first 48 h. Patients
were asked to record their pain levels on a linear
visual analogue scale (VAS) of O-100 mm at pre-
determined intervals, starting one hour before surgery
and continued regularly for 48 h and then again on
the 7th postoperative day.
The pain recorded was that of continuous pain as
well as pain on opening the mouth. The patients
mouth opening was measured using a ruler before
the surgery as well as on the 1st and 7th postoperative
days. This was done by measuring the distance
between the incisor teeth on three consecutive
occasions and taking the average value. They were
asked about their satisfaction of the analgesic tech-
nique on the 1st and 7th days; at the end of the trial
their preference for the side of operation was also
noted.
The results were analysed by, analysis of variance
 The absence of any pre-emptive analgesic effect for non-steroidal anti-inflammatory drugs 429

(ANOVA), Students t-test and Chi square test using of the study ( P < 0.005) in comparison to the preoper-
the statistical package Statview 4. ative values.
The mouth opening was measured and the ANOVA
results suggested no difference between the two treat-
RESULTS ments (P>O.O5); but during the course of the study
they were significantly different from the preoperative
The mean age of the patients was 21.1 years (95% values on the 1st (P<O.OOl) and on the 7th
CI 20.2-22.0 years). There were 10 males and 11 ( PcO.005) postoperative days (Table 1). Mouth
females in the study (Table 1). The two types of pain opening was considered by us to be a measure of the
measured, both the continuous pain and pain on functional interference caused by the surgery and
opening the mouth, did not show any difference resultant trauma.
between the two treatments (P>O.O5). Hence the The patients preference for the treatment did not
two were combined for further analysis. Repeated differ in the study ( P > 0.05); 43%, preferred treatment
measures analysis of variance did not show any A (diclofenac administration preoperatively) whereas
difference between the two treatments, i.e. diclofenac 48% preferred treatment B (diclofenac administration
before the surgery or at the end of surgery ( P > 0.05). postoperatively) ( P>0.05). This was not due to the
The interaction bar plot for the effect of the treatment side which was operated upon first because 43% of
is given in Figure 1. The study was not influenced by patients opted for the treatment during the first
the random choice of the treatment since there was operation and 48% preferred the treatment during
no difference between the pain scores following oper- the 2nd operation ( P>O.O5). Most patients (95%)
ation on the 1st or 2nd sides ( P> 0.05). The gender considered both the treatments as either good or
did not have any influence on the study as shown by satisfactory on both occasions.
the ANOVA results (P>O.O5). As expected, the pain
scores were significantly different during the course
DISCUSSION
Table 1 -Table showing mean and 95% Confidence Intervals for
age (years) and mouth opening (mm) following the two treatments Significant advances in research into pain control
(treatment A = diclofenac before operation and treatment B= have been made in the last decade. One of the
diclofenac after operation)
established practices is the concept of pre-emptive
Mean CI (95%) analgesia; drugs like local anaesthetics, opiates and
NSAIDs have all been suggested as contributing to
Age (years) 21.1 20.2-22.0 this effect.4-7 But some disagree with this concept as
Mouth opening (mm)
Pre-surgery 43.6 40.0-47. I
being clinically insignificant.- One of the studies
Treatment A supporting pre-emptive analgesia has proposed that
1st post-op day 29.2* 25.0-33.3 the beneficial effects of pre-emptive analgesia could
7th post-op day 37.0* 33.4-40.5 last well into the postoperative period and as much
Treatment B as the 10th postoperative day. We recorded the pain
I st post-op day 30.5* 25.6-35.3
7th post-op day 39.1* 34.0-44.1 score on the 7th postoperative day in order to test
this theory. In order to rule out the influence of
* Significant difference from preoperative values postoperative analgesics on the pain scores, we have

q Diclofenac
n Placebo

pre end disch pm night am noon 7th

Time
Fig. 1 -The effect of the two treatments on the mean pain scores. No difference seen between the two treatments. Diclofenac=diclofenac
sodium before surgery (treatment A): Placebo = diclofenac sodium after surgery (treatment B). Pre = before surgery; end = end of
operation; disch = discharge from ward; pm = afternoon of day of operation; night = night of day of operation; am = morning of day after
operation: noon = noon of day after operation; 7th = 7th postoperative day.
430 British Journal of Oral and Maxillofacial
ensured that all patients take their prescribed anal-
gesics, combination of codeine and paracetamol, at
regular, 6 hourly intervals. There is increasing aware-
ness that functional improvement is the best index of
good analgesia and hence we have attempted to
measure the mouth opening as an index of functional
impairment consequent on surgery and pain.
The present study did not establish any difference
at all between the time of administration of the drug
(receiving diclofenac before the operation or at the
end of the operation) in a group of young fit patients
undergoing third molar extractions in a cross-over
design; the mean pain scores recordings at regular
intervals for 48 h and then again on 7th day, showing
no differences between the two treatments (P> 0.05)
(Fig. 1). The results were not influenced by the gender
or the order of choice of the treatment, thus suggest-
ing absence of any pre-emptive analgesic effects for
NSAIDs. It has been acknowledged that pain follow-
ing third molar surgery, though maximal in the early
postoperative period, persist into the 7th postopera-
tive day, requiring some form of analgesic. Similar
findings were noted in this study (Fig. 1). But the
mean pain scores were well below 20 mm on a
O-100 mm VAS scale by the 7th postoperative day.
The functional restriction following third molar
surgery can be high and the mouth opening, though
only a non-specific measure, gives some estimate of
this. Even though there are likely to be significant
errors in such measurement techniques such as we
used, it is an approximation of patients well being
(presence or absence of pain and ability or inability
to perform normal functions). The restrictions per-
sisted into the 7th day in both groups, as did the
pain experience. However, there were no differences
between the two groups in the degree of mouth
opening recorded. The lack of differences between
the two groups with regard to their preference to
either treatment was also noted in the study, approxi-
mately half of the patients opting for a preoperative
administration of diclofenac and the other half opting
for a postoperative administration of the drug.
Almost all patients reported both treatments as
acceptable.
All NSAIDs effectively reduce the levels of prosta-
glandins, thus producing their analgesic effects.ij The
results of this study demonstrate no significant differ-
ence between preoperative and postoperative admin-
istration of diclofenac, thus ruling out any pre-
emptive analgesic effects for the drug. This lack of
pre-emptive analgesic effect of the NSAID (diclo-
fenac) in the trial can be explained as follows: Pain
following the surgical extraction of wisdom teeth is
generally well controlled during the first 2 or more
postoperative hours by the local anaesthetic.
Continued release of prostaglandins and other chemi-
cal mediators at the site of injury has been attributed
as a major mechanism of post-surgical pain.r3
Diclofenac has a relatively short half-life in plasma
and the blood levels of single dose may not be
sufficient to cover the period when the prostaglandins
are produced maximally at the injury site. Hence it
appears likely that to be effective, NSAIDs should
Surgery
be administered continually during the peri-operative
period, particularly in the period following surgery.
There are a few design problems inherent in a
study like this. One of the problems is the fact that
the local anaesthetic injection itself could lead to pre-
emptive analgesia and hence could influence the
study. This is an obvious problem which could not
be overcome in a study like this where the patients
are operated upon under local anaesthesia. Another
problem is the influence of postoperative analgesic
regimen on the pain scores; we have tried to overcome
this by using a regular medication regimen. In spite
of these problems this study does not support the
theory of pre-emptive analgesia sometimes attributed
to NSAIDs.
The concept of pre-emptive analgesia, though a
very attractive theory, may not be of practical signifi-
cance in many situations like postoperative dental
pain where continuous chemical changes occur at the
site of injury, causing pain.
Acknowledgments
The authors wish to thank Professor Martin M. Ferguson,
Professor of Oral Surgery and Oral Medicine, School of Dentistry,
University of Otago, for advice, Mrs Doreen Eade, Secretary of
the Department of Oral Surgery, University of Otago, Dunedin
for help in organisation and Sr Sharon Dickle, Charge Nurse,
Department of Oral Medicine & Oral Surgery, School of Dentistry,
University of Otago for the technical help offered.
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 The absence of any pre-emptive analgesic effect for non-steroidal anti-inflammatory drugs 431

13. Monica JJ. The Management of Pain. Vol 1,2nd ed. Mathew Zacharias FFARCS, FANZCA, PhD
Philadelphia: Lea & Febinger, 1990: 95-100, Senior Lecturer
Department of Anaesthesia & Intensive Care
University of Otdgo, Dunedin
The Authors New Zealand

John B. Bridgman BDS

Assistant Lecturer Correspondence and requests for offprints to Dr Mathew
Department of Oral Medicine & Oral Surgery Zacharias, Department of Anaesthesia & Intensive Care, School of
School of Dentistry Medicine, University of Otago. Dunedin, New Zealand
Toby G. Gillgrass BDS
Assistant Lecturer
Department of Oral Medicine & Oral Surgery Paper received 14 February 1995
School of Dentistry Accepted 29 March 1995