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Pain after surgery: Can protective analgesia reduce pain? A randomised clinical trial
International Journal of Surgery 8 (2010) 283e289
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Pain after surgery: Can protective analgesia reduce pain? A randomised clinical trial Sin Leong Yong*, Paul Coulthard School of Dentistry, The University of Manchester, Higher Cambridge Street, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2009 Received in revised form 15 February 2010 Accepted 3 March 2010 Available online 17 March 2010
Aim: To improve the patients postoperative pain experience using protective analgesia for patients undergoing third molar surgery under day case general anaesthesia. Material and methods: Patients were randomly allocated to a protective analgesia (1.6 g modified release ibuprofen) or conventional analgesia (400 mg conventional ibuprofen) orally 2 h preoperatively. Surgical model was third molar surgery. Postoperative outcomes of interest were pain intensity at 30 min, 1, 6, 24 and 48 h. The time to rescue analgesia, overall assessment of pain control, safety and tolerability profiles were also recorded. Results: 122 patients entered the study providing 98 evaluable patients for analysis. Patients in the protective analgesia group reported more pain than those in the conventional group at 30 min, 1, 6 and 48 h following surgery, although this difference was only statistically significant at the 30 min time point. 62.2% of patients required rescue analgesia within 6 h after surgery. The median time for patients who had to take rescue analgesia was 3.1 h. Patients in the protective analgesia group reported a longer time to rescue analgesia compared with those in conventional analgesia group. Overall, 91.7% of patients were at least satisfied with their pain control. Conclusion: There was no difference in the protective analgesia group compared with conventional analgesia group in improving postoperative pain experience. A different protective analgesia regime may be necessary, which employs a more aggressive and multimodal strategy for postoperative pain management. Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Postoperative pain Third molar Protective analgesia
1. Introduction The concept of preemptive analgesia began with Crile in 1913 when he described a technique to eliminate preoperative fear and tension. Crile advocated the use of generous premedication with morphine and atropine, regional (procaine) block, and anaesthesia by inhalation of nitrous oxide and oxygen in his theory to prevent shock during surgery.1 The idea of preemptive analgesia was later revived and described by Woolf, who demonstrated evidence for the central component of post injury pain hypersensitivity in a series of animal studies.2 Pain may be produced peripherally as a result of tissue damage and inflammation (inflammatory pain); damage within the central nervous system (neuropathic pain); or due to alterations in the normal functions of the nervous system (functional pain).3 Pain hypersensitivity can be a common postoperative complication. Pain sensation at the surgical site may be increased and persist long after
noxious stimuli are removed (hyperalgesia). Pain hypersensitivity may also result in pain sensation being felt in other areas close to the surgical site (allodynia). There are two mechanisms involved in pain hypersensitivity: central and peripheral sensitisation. 1.1. Peripheral sensitisation Peripheral sensitisation is the reduction in the threshold and increased responsiveness of nociceptive afferent peripheral terminals.4 Peripheral nociceptors become more responsive with repeated application of noxious stimuli. Sensitivity of the peripheral nociceptors can be further enhanced by several tissue factors and inflammatory mediators released in the course of tissue injury.5 During inflammation and tissue injury, prostaglandins and leukotrienes are released directly activating the ends of peripheral nociceptors leading to sensitisation and increasing responsiveness to other stimuli.4 1.2. Central sensitisation
* Corresponding author. Fax: þ44 0161 275 6631. E-mail addresses: [email protected] (S.L. Yong), paul.coulthard@ manchester.ac.uk (P. Coulthard).
Following peripheral tissue injury, chemical changes can occur within the central nervous system. A variety of neurotransmitters
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are released, of which one of the most important is substance P. Substance P in turn induces the release of excitatory amino acids such as glutamate and aspartate, which are involved in the increased excitability of N-methyl-D-aspartate (NMDA) receptor sites within the spinal cord. It has been proposed that activation of NMDA receptor sites by the excitatory amino acids enhance depolarisation, making the neurons more responsive and thereby leads to amplification and increased duration of pain.6 Central sensitisation or ‘wind-up’ is used to describe the enhanced excitability and sensitisation of dorsal horn cells induced by the above mechanisms.7 Preemptive analgesia aims to minimise or prevent onset of peripheral and central sensitisation by employing various interventions at different stages of the pain pathway. Although the evidence for preemptive analgesia is promising in animal studies, there is still controversial evidence of success in reducing postoperative pain in human trials. This may be due to variations in the definition of preemptive analgesia. Kissin et al. found that the definition for preemptive analgesia was far from uniform. He identified three different definitions for preemptive analgesia used in current clinical trials. Preemptive analgesia has been defined as treatment that: 1. starts before surgery; 2. prevents the establishment of central sensitisation caused by incisional injury (covers only the period of surgery); 3. prevents the establishment of central sensitisation caused by incisional and inflammatory injuries (covers the period of surgery and the initial postoperative period). In order to demonstrate the maximum benefits of preemptive analgesia in clinical trials, two conditions should be met. Firstly, the intervention should be effective in suppressing afferent input and of sufficient duration of action, covering the initial postoperative period. Secondly, combined treatment modalities should be employed to maintain preemptive effects and reverse central sensitisation.8 This is a concept called protective analgesia. Several other terms have also been used e ‘balanced multimodal analgesia’ and ‘preventive analgesia’ but all employ a similar concept.9,10 The treatment approach aims to control the development of central sensitisation in the postoperative period. This advocates the use of multimodal techniques with several drugs to attenuate peripheral and central hypersensitivity and with a sufficient duration of treatment.11 Although nociceptive pain is often regarded as the key feature of acute postoperative pain, the focus should be redirected from the timing of perioperative analgesia to protective analgesia. Aggressive and multimodal strategy for postoperative pain management should therefore be adopted.12 The aim of this study was to investigate the efficacy of protective analgesia in improving the postoperative pain experience. We compared the combined effects of sustained release ibuprofen and bupivacaine nerve block with the combined effects of conventional ibuprofen and bupivacaine nerve block. Whilst the effect of the local anaesthesia would make it more difficult to demonstrate difference between types of ibuprofen, this design was chosen to limit the variables under investigation. Third molar surgery was the chosen surgical model as this is validated model for pain clinical trials. Our hypothesis was that the combined effects of sustained released ibuprofen and bupivacaine nerve block would reduce the proportion of patients with moderate to severe pain compared to the combined effects of conventional ibuprofen and bupivacaine nerve block. The safety and tolerability profile were also documented.
2. Materials and methods 2.1. Study design and patient selection The setting for this double blind, active control, randomised clinical trial was the Oral Surgery Day Case Unit at Central Manchester University Hospitals NHS Foundation Trust. The study was approved by the Regional Ethics Committee and the Medicines and Healthcare products Regulatory Agency (MHRA). Patients were considered eligible for study inclusion if they were male or female, aged 18 and over, ASA I or II, able to understand and cooperate with the requirements of the protocol and able and willing to exercise an appropriate written informed consent. Patients were excluded from participating in the study if they had a known hypersensitivity to NSAIDs, paracetamol or bupivacaine, or if they were pregnant. Patients were also excluded if they had used analgesics within 48 h prior to the day of surgery, alcohol within 24 h prior to the day of surgery or had a suspected or known history of alcohol or drug abuse. 2.2. Sample size We calculated that 48 patients in each group would be required to detect the difference between Group 1 proportion of 0.55 and a Group 2 proportion of 0.25 (odds ratio of 0.273). The statistical power of the study was 80%. The sample size was based on our primary outcome measure of proportion of patients requiring rescue medication within 6 h of surgery. Seymour et al.13 previously reported this outcome at 55% in their 400 mg ibuprofen group and Morse et al.14 reported rofecoxib, with similar efficacy but longer duration than ibuprofen, at 25%. We recruited 122 patients to produce 96 evaluable patients. 2.3. Allocation concealment and blinding Patients were allocated to the protective analgesia group or conventional analgesia group according to computer generated randomisation code that were concealed in sealed envelopes and opened 2 h before surgery. Each patient was given a unique identification number based on the randomisation information and this code was held by the hospital pharmacist. The protective analgesia group received 1.6 g modified release ibuprofen (2 800 mg) orally 2 h prior to surgery and the conventional analgesia group received conventional release 400 mg ibuprofen (2 200 mg) orally 2 h prior to surgery. The study medication was administered by a qualified nurse or other study staff member blinded to study assessments. All participants and investigators were blinded to the treatment allocation throughout the study period. Only the statistician who generated the random numbers and hospital pharmacist had access to the randomisation code but none were involved in the recruitment, allocation or assessment of the study participants. 2.4. Surgery Third molar surgical technique and general anaesthetic techniques were standardised as far as possible and prophylactic antibiotics, 200 mg metronidazole, 8 hourly for 5 days, were prescribed for all patients. Surgery was undertaken by five experienced surgeons using standard third molar mucoperiosteal flap with bone removal with a surgical bur cooled with normal saline. An anaesthetic protocol was formulated to eliminate possible confounding drugs which may give a preemptive effect by delivery of analgesics during induction and maintenance of general anaesthesia (Table 1). Patients in both groups received 5 ml bupivacaine 0.5% with
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requiring rescue analgesia as well as the time it was taken was recorded.
Table 1 Anaesthetic protocol. Induction Maintenance Airway
Sleep dose of propofol Air/Oxygen/Sevoflurane LMA/COERTT/CNETT as indicated (NB. A nasal tube makes the placement of the inferior dental nerve block much easier) Muscle relaxant Mivacurium 0.2 mg/kg if using IPPV Other drugs
1. Anti-emetics as required (but not Dexamethasone) 2. Neostigmine/Glycopyrrolate as required
Drugs to be avoided
1. All opiods (a small bolus of remifentinil or alfentanil to facilitate intubation should be ok if really necessary) 2. Non-opiod analgesics (tramadol, paracetamol, NSAID’s) 3. Dexamethasone 4. Nitrous Oxide
2.5.3. Overall assessment of pain control At the end of the 48-h period, patients were asked to provide an overall assessment of treatment efficacy with regard to pain experience using a numerical rating scale. The scale ranged from 0 ¼ Extremely poor to 10 ¼ Excellent. The initial assessments were carried out by the study investigator who was not involved in the administration of the study medications. Subsequent assessments were carried out by patients self reported pain intensity using a pain diary. 2.6. Statistical methods
1:200,000 adrenaline for inferior alveolar nerve block and infiltration of long buccal nerve per side immediately prior to surgical incision. 2.5. Pain measures
The t-test, z-test and Chi-square test were applied for differences in mean and proportion between groups. The analysis of time to rescue medication was analysed by log-rank test. The median time estimations and 95% confidence intervals on the median time for the time variables was provided by using Kaplan Meier. We used SPSS (version 15) for statistical analysis.
The outcomes of interest were as follows: 3. Results 2.5.1. Pain intensity Postoperative pain intensity was measured using a 10 cm Visual Analogue Scale labelled ‘no pain’ to ‘worst pain imaginable’ at 30 min and 1, 6, 24 and 48 h following surgery. Surgery end point was defined as the time when intravenous drugs or anaesthetic gases for the maintenance of anaesthesia were stopped. Following at least 1-h observation period after surgery, patients were discharged from the day case unit based on their recovery as assessed by nursing staff. A pain diary with a stamped return address envelope was provided and a 3 day supply of codeine/paracetamol (30/500) to be used as rescue analgesia as required. 2.5.2. Time to rescue analgesia Rescue analgesia (codeine/paracetamol) was administered at the request of the patients after surgery. The number of patients
We invited and screened a total of 122 patients in order to achieve number needed for each group based on the power calculation. Of these, 12 patients were excluded for not meeting the study criteria and 9 did not return the pain diary (Fig. 1). The reasons for exclusion are shown in Table 2. Successful inferior alveolar nerve block was demonstrated by patient’s reported signs of altered lip and gingival sensation. Seven patients were excluded as not demonstrating signs of successful inferior alveolar nerve block. Four patients withdrew consent as they were unable to tolerate taking the study medication. Three patients were cancelled for failing to comply with starvation times prior to general anaesthesia and one patient suffered bronchospasm during induction of anaesthesia and surgery was abandoned.
Assessed for eligibility (n = 122)
Excluded (n = 3) Enrollment
Reason: Not starved for GA
Randomized (n = 119) Allocated to intervention (n = 59) Received allocated intervention (n = 58) Did not receive allocated intervention (n = 1) Reason: Can’t tolerate study medication
Lost to follow-up (n = 4)
Allocated to intervention (n = 60) Allocation
Follow-Up
Discontinued intervention (n = 4) Reason: Failed ID block
Lost to follow-up (n = 5) Discontinued intervention (n = 3) Reason: Failed ID block
Analyzed (n = 48)
Analyzed (n = 50) Excluded from analysis (n = 8) Reasons: Lost to follow-up (n = 4) Failed ID block (n = 4)
Received allocated intervention (n = 56) Did not receive allocated intervention (n = 3) Reasons: Can’t tolerate study medication (n = 3) Asthma attack (n = 1)
Analysis
Fig. 1. CONSORT flow diagram.
Excluded from analysis (n = 8) Reasons: Lost to follow-up (n = 5) Failed ID block (n = 3)
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The median time for patients who had to take rescue analgesia for the duration of the study was 3.1 h. Patients in the protective analgesia group reported a longer time to rescue analgesia (median 3.2 h) compared with those who received conventional ibuprofen (median 2.7 h). The difference, however, was not statistically significant (log-rank test, p ¼ 0.386). The proportion of patients taking rescue analgesia over the 48 h period is shown in the survival curves in Fig. 4. The results indicate that the estimated cumulative probability of rescue analgesia requirement was more for patients in the conventional analgesia group until about 8 h. Thereafter, the estimated cumulative probability of rescue analgesia requirement was more for patients in the protective analgesia group. There were 61 (62.2%) patients requiring rescue analgesia within 6 h following surgery. There were 29 (58%) patients in the protective analgesia group who required rescue analgesia compared to 32 (66.7%) patients in the conventional analgesia group but the difference was not significant (Chi-square test, p ¼ 0.701). In both groups, there were a high number of patients with no or mild pain reported to require rescue medication. There was no significant difference in the median time to rescue medication between the two groups (Table 7).
Table 2 Reasons for exclusion from study. Number (%) of patients
Protective analgesia
Conventional analgesia
Unable to tolerate medication Unsuccessful nerve blockade Did not return pain dairy Bronchospasm event
1 4 4 0
3 3 5 1
Total
9 (15.2%)
12 (20%)
Table 3 Demographic details of patients where age is expressed as mean SD. Characteristic
Protective analgesia
Conventional analgesia
Number of patients Male Female Age (years)
50 13 37 28.82 6.26
48 16 32 28.71 5.8
Data from 98 patients were analysed. There were 29 males (29.6%) and 69 females (70.4%) ranging from 20 to 55 years, with a mean age of 28.77 6.01 years. The patients’ demographic detail for each group is shown in Table 3.
3.3. Overall assessment of pain control
3.1. Pain intensity
Patients rated their overall satisfaction about pain control on a numerical rating scale. The mean reported score about satisfaction with pain control for protective analgesia group was 7.6, whereas for conventional analgesia group it was 7.38 (t-test, p ¼ 0.606). Patient self report assessment of pain control was categorised as follows:
Patients in the protective analgesia group reported more pain than those in the conventional analgesia group at 30 min, 1, 6 and 48 h following surgery, although this difference was only statistically significant at the 30 min time point. The mean pain intensity scores throughout the 48 h period are shown in Table 4 and Fig. 2. Patients self report pain intensity scores were categorised as follows. This validated data transformation enables a more sensitive analysis:15
0 ¼ totally dissatisfied 1e4 ¼ dissatisfied 5e7 ¼ satisfied 8e10 ¼ excellent
0 ¼ No pain 1e4 ¼ Mild pain 5e6 ¼ Moderate pain 7e10 ¼ Severe pain
A higher proportion of patients were at least satisfied with their pain control in the protective analgesia group (48, 96%) compared to 42 (87.5%) in the conventional analgesia group but the difference was not significant (Fig. 5). This is similarly reflected by the number of patients who were not satisfied with their pain control, with a much lower proportion 2 (4%) in the sustained released ibuprofen group compared to 6 (12.5%) in the conventional ibuprofen group.
There were more patients with moderate to severe pain in the protective analgesia group at 30 min, 1 h and at 48 h. The difference was not statistically significant for any of the time intervals (Table 5 and Fig. 3).
3.4. Safety profile and tolerability 3.2. Time to rescue analgesia Overall, the safety profile of both sustained release ibuprofen and conventional ibuprofen was good and well tolerated. One patient with asthma but no known history of intolerance to ibuprofen suffered bronchoconstriction during the induction of general anaesthesia. The patients reported side effects is shown in Table 8.
Over the 48 h period, 11 patients (11.2%) did not require rescue analgesia. There were more patients in the conventional analgesia group who did not require rescue analgesia but the difference was not significant (Chi-square test, p ¼ 0.366). Table 6 shows the rescue analgesia requirement over 48 h between the two groups. Table 4 Pain intensity scores over 48 h period. VAS Protective analgesia n ¼ 50 Conventional analgesia n ¼ 48 Difference (95% CI) mm P value (t-test)
30 min
1h
6h
24 h
48 h
Mean SD (mm)
26.08 29.54
23.59 25.13
26.55 24.02
25.04 23.77
25.14 22.81
Mean SD (mm)
15.77 20.37
17.43 22.63
25.14 23.68
26.36 22.79
23.65 23.57
10.31 (0.30, 20.32) 0.048
6.16 (3.30, 15.62) 0.207
1.41 (8.03, 10.85) 0.771
1.32 (10.54, 7.90) 0.779
1.49 (7.70, 10.68) 0.752
P values of the original pain intensity scores with level of statistical significance set at 0.05.
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Mean pain intensity over 48 hours
30
30
25
25 20 Protective analgesia
15
Conventional analgesia
10 5
Proportion (%)
Mean pain intensity (mm)
287
20 Protective analgesia
15
Conventional analgesia
10 5
0 0.5
1
6
24
0
48
0.5
Tim e (hours)
1
6
24
48
Tim e (hours)
Fig. 2. Graph of mean pain intensity scores over 48 h period. Fig. 3. Graph showing proportion of patients with moderate to severe pain over 48 h.
3.5. Lost to follow-up Patients were given a choice of telephone or clinic follow-up assessment at 1 week after surgery. All patients preferred and opted for telephone follow-up. This was carried out by the study investigator. Patients who had not returned the pain diary at this point were reminded to do so during the telephone follow-up. A total of 9 (9.2%) patients failed return the pain diary despite further attempts to contact patients by telephone. We also wrote to the patients who were unable to be contacted by telephone with a further pain diary and a letter to emphasise the importance of the study. 4. Discussion The objective of this randomised clinical trial was to investigate the efficacy of protective analgesia using the combined effects of sustained release ibuprofen and bupivacaine nerve block in attenuation of postoperative pain using third molar surgery under day case general anaesthesia as the surgical model. The efficacy was compared with a similar group receiving conventional ibuprofen. No difference was found in the attenuation of postoperative pain between sustained release ibuprofen and conventional ibuprofen groups. Third molar surgery is a recognised clinical model for evaluating oral analgesics as postoperative pain is predictable and easily reproducible.16 Surgery may be standardised since the variation in duration and severity of surgery do not affect the degree of postoperative pain experienced. Five surgeons of similar experience performed the surgeries using a standardised technique. Randomisation was by patient and not stratified by surgeon. This is a potential limitation to our study. The analgesic efficacy of selective COX-2 inhibitors has been demonstrated in single dose dental pain studies resulting in less pain, longer time to needing rescue analgesia as well as less analgesic consumption. The benefits over conventional NSAIDs include selective inhibition of COX-2 enzyme as well as analgesic effect for up to 24 h with a single dose, reducing the risk of over dosage and
toxicity. Pain following third molar surgery is usually most severe between 6 and 8 h following surgery.17 This longer duration of action also allows analgesic effects of selective COX-2 inhibitors to be extended into the postoperative period, an ideal property for protective analgesia. However, selective COX-2 inhibitors are not approved for routine use of postoperative dental pain due to increased risk of cardiovascular events. As a result, several COX-2 preparations have been withdrawn from the market. Sustained release ibuprofen has a similar mode of action to ibuprofen. Preemptive use of conventional ibuprofen has been shown to be effective in reducing postoperative pain.18e20 Sustained release ibuprofen, on the other hand, has a longer duration of action of up to 24 h compared to 6 h for conventional ibuprofen.21 The effectiveness of sustained release ibuprofen over conventional ibuprofen was demonstrated in a study conducted by O’Connor and colleagues.22 However, no studies investigated and compared the preemptive use of sustained release ibuprofen with conventional ibuprofen. Several studies also showed the effectiveness of bupivacaine block on reducing postoperative pain following third molar surgery. Our hypothesis was that the group receiving sustained release ibuprofen combined with the effects of bupivacaine nerve block would show reduced postoperative pain following surgery. In this study, we found 62.2% of patients needing rescue analgesia within 6 h following surgery. Although there were fewer patients in the protective analgesia group needing rescue analgesia, the difference was not significant. The findings were similar to that of Morse et al. who compared the preemptive analgesic effects of rofecoxib to ibuprofen and placebo in a randomised double blind clinical trial in patients undergoing lower third molar surgery.14 They found no significant difference between rofecoxib and ibuprofen in reducing postoperative pain and in the number of patients needing rescue analgesia. Patients in the protective analgesia group reported a longer median time to rescue analgesia over the 48 h investigation period. Despite the longer duration of action of sustained release ibuprofen, the time to rescue analgesia was not significantly different compared to the conventional analgesia group. Overall, our intervention delayed the requirement for rescue analgesia to a median time of
Table 5 Number of patients with moderate to severe pain over 48 h.
Protective analgesia (n ¼ 50)
Moderate to severe pain
Conventional analgesia (n ¼ 48)
Moderate to severe pain
Odds ratio (95% CI) Z value (significant)
30 min
1h
6h
24 h
48 h
14 (28%) 7 (14.6%) 2.28 (0.83, 6.26) 1.44 (no)
12 (24%) 5 (10.4%) 2.71 (0.87, 8.41) 1.65 (no)
11 (22%) 11 (22.9%) 0.95 (0.37, 2.45) 0.13 (no)
10 (20%) 12 (25%) 0.75 (0.29, 1.94) 0.35 (no)
11 (22%) 8 (16.7%) 1.41 (0.51, 3.88) 0.41 (no)
Z value of difference in proportions between groups with confidence level at 95%.
288
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Table 6 Time to rescue analgesia requirement over 48 h.
Table 7 Time to rescue analgesia requirement within 6 h.
Time to rescue medication (mins)
Protective analgesia
Conventional analgesia
Time to rescue medication (mins)
Protective analgesia group
Conventional analgesia group
Number of patients who used rescue analgesia Minimum Median Number of patient who did not require rescue analgesia Odds ratio (95% CI) P value (chi-square)
46 (92%)
41 (85.4%)
29 (58%)
32 (66.7%)
20 192 (3.2 h) 4
17 162 (2.7 h) 7
Number of patients who used rescue medication Minimum Median Number of patients with no or mild pain Number of patient who did not require rescue medication Odds ratio (95% CI) P value (chi-square)
20 100 (1.7 h) 18 (62%)
17 117.5 (1.9 h) 23 (71.8%)
21
16
1.96 (0.53, 7.19) 0.366
3.1 h and up to 48 h in 2 patients. By contrast, a study showed that pretreatment with rofecoxib 50 mg had a much extended mean time to rescue analgesia of 11 h.23 However, the sample size of this study was small and common among other studies; patients were only allowed rescue analgesia when postoperative pain reached a certain threshold, typically a VAS score of 30 or more. Patients in our study were not restricted by this threshold and were allowed to take rescue analgesia at any time depending on individual’s pain tolerance and perception. This may explain the shorter time to needing rescue analgesia in our study. It is common for anaesthetists to utilise opioids and other nonopioid analgesics perioperatively for the maintenance of anaesthesia, which may mask the effects on the intervention assessed. This may be one of the reasons for previous clinical trials for failing to show any preemptive effects of NSAIDs.24 We used a specific anaesthetic protocol which had no analgesia component for the induction and maintenance of general anaesthesia. This gave a more accurate assessment and true account of the efficacy of our intervention. As with the proportion of patients needing rescue analgesia and time to rescue analgesia, pain intensity did not differ significantly between the protective analgesia and conventional analgesia groups. In chronic pain studies, sustained release ibuprofen has been shown to provide better efficacy with added convenience of single dosing but this was not the case in this acute pain setting. The peak plasma concentration following initial dosing of sustained release ibuprofen and conventional ibuprofen are very similar.25 No clinically significant differences can be observed most likely as a result of similarities in the pharmacokinetics of both drugs. The
0.69 (0.30, 1.57) 0.701
preemptive effects of sustained release ibuprofen do not seem to be comparable to that of the selective COX-2 inhibitor, rofecoxib. A systematic review was conducted on individual patient metaanalysis of single dose rofecoxib in postoperative pain. It was found that single dose of 50 mg rofecoxib had comparable analgesic efficacy to ibuprofen 400 mg over 6 h. The NNT for rofecoxib was fairly constant over a 24 h period whereas with ibuprofen, the NNT increased sharply after 6 h.26 This may explain why sustained release ibuprofen was no more effective than conventional ibuprofen in our clinical trial and that it did not achieve the same preemptive effects as with rofecoxib. A much higher loading dose may be required to achieve a significant preemptive effect for sustained release ibuprofen. Increasing the loading dose would however inevitably increase the risk of adverse effects. It was surprising to find such high postoperative pain scores in both groups despite administrating a local anaesthetic nerve block. This suggests that there is merit to using preoperative ibuprofen even when using intraoperative local anaesthesia, consistent with the theory of protective analgesia. The duration of action of bupivacaine has been reported to be up to 8 h.27e29 It has been shown to reduce postoperative pain in patients undergoing lower third molar surgery by decreasing the development of central hyperexcitability.30,31 However, it is often difficult to ensure that a true inferior alveolar block has been achieved whilst patients is under general anaesthetic. This is a limitation to our study where a subjective assessment was carried out with our patients based on reported alteration in lip and gingival sensation. An altered lip and gingival sensation however, may not necessarily indicate a sufficient inferior alveolar nerve block and attenuation of central hyperexcitability. A more accurate assessment using plasma betaendorphin levels, giving a better indication of the nociceptive pathway and efficacy of the inferior alveolar nerve block, may have been helpful. Seven patients in our study failed to demonstrate a successful inferior alveolar nerve block and were excluded from the study and analysis. An intention to treat analysis could not be performed as
30
27
25
25
21 20
17
Num ber of 15 patients (n)
Protective analgesia
10
Conventional analgesia
5
5 0
0
1
Totally dissatisfied
Fig. 4. Survival curves for sustained release ibuprofen and conventional ibuprofen, representing the proportion of patients in each group who did not require rescue analgesia.
2 Dissatisfied
Satisfied
Excellent
Satisfaction levels
Fig. 5. Overall rating of pain control.
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References
Table 8 Number of reported side effects. Events
Protective analgesia
Conventional analgesia
Headache Dizziness Nausea and vomiting Swelling Alveolar osteitis Numb tongue Bronchospasm event
1 1 1 6 0 2 0
1 2 5 4 1 5 1
Total
11 (22%)
19 (39%)
the postoperative pain assessment for these patients were not recorded. We acknowledge that this is a limitation to our study. However, these 7 patients were almost equally distributed between the 2 groups and in order to evaluate the true effects of protective analgesia; patients are required to have a successful inferior alveolar nerve block. Therefore, the exclusion of these patients as per protocol would not have a significant effect on the analysis. Prolonged alteration of lip and gingival sensation may be unpleasant experience but none of the patients in our trial reported significant morbidity associated with this. There were no prolonged or unexpected adverse events reported in either treatment groups. All reported side effects resolved spontaneously without additional intervention. One patient developed bronchospasm during induction of anaesthesia. The symptoms spontaneously resolved following administration of oxygen and bronchodilator. This patient had no history of asthma and did not report any sensitivity to NSAIDs. The patient had previously used ibuprofen on more than one occasion without any side effects. The bronchospasm was believed to be related to the patient’s history of smoking. The proportion of patients lost to follow-up in our study was 9.2%. Despite efforts to contact these patients, we were unable to retrieve information required. A lost to follow-up of more than 20% is generally considered of concern to validity.32 However, further strategies could possibly have been employed to minimise the number lost to follow-up such as financial incentives for the patients. 5. Conclusion We were unable to demonstrate a statistically significant improvement in the pain experience using sustained release ibuprofen and bupivacaine nerve block as protective analgesia when compared to a conventional analgesic drug regime for patients undergoing third molar surgery. Conflict of interest None declared. Funding Oral and Maxillofacial Surgery, School of Dentistry, The University of Manchester. Ethical approval REC reference: 07/Q1403/29. EudraCT number: 2006-000193-77. Acknowledgments We wish to thank everyone at the Oral surgery day case unit, Manchester Royal Infirmary for making this study possible. The clinical study is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre. The authors have no conflict of interest to report.
1. Crile G. The kinetic theory of shock and its prevention through anoci-association (shockless operation). Lancet 1913;2:7e16. 2. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983 Dec 15e21;306(5944):686e8. 3. Woolf CJ. Pain hypersensitivity. The Wellcome Trust; Wellcome Trust Publication [updated Wellcome Trust Publication; cited Last accessed 6 September]; Available from: http://www.wellcome.ac.uk/en/pain/microsite/science4.html. 4. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia II: recent advances and current trends. Can J Anaesth 2001 Dec;48(11):1091e101. 5. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician 2001 May 15;63(10):1979e84. 6. Woolf CJ. An overview of the mechanisms of hyperalgesia. Pulm Pharmacol 1995 AugeOct;8(4e5):161e7. 7. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth [Review] 2001 Nov;48(10):1000e10. 8. Kissin I. Preemptive analgesia. Anesthesiology 2000 Oct;93(4):1138e43. 9. Pogatzki-Zahn EM, Zahn PK. [Systemic analgesia: an update]. Anasthesiol Intensivmed Notfallmed Schmerzther 2007 Jan;42(1):22e31. 10. Bromley L. Pre-emptive analgesia and protective premedication. What is the difference? Biomed Pharmacother 2006 Aug;60(7):336e40. 11. Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006 Oct;19(5):551e5. 12. Dahl JB, Moiniche S. Pre-emptive analgesia. Br Med Bull 2004;71:13e27. 13. Seymour RA, Frame J, Negus TW, Hawkesford JE, Marsden J, Matthew IR. The comparative efficacy of aceclofenac and ibuprofen in postoperative pain after third molar surgery. Br J Oral Maxillofac Surg 1998 Oct;36(5):375e9. 14. Morse Z, Tump A, Kevelham E. Ibuprofen as a pre-emptive analgesic is as effective as rofecoxib for mandibular third molar surgery. Odontol 2006 Sep;94(1):59e63. 15. Li KK, Harris K, Hadi S, Chow E. What should be the optimal cut points for mild, moderate, and severe pain? J Palliat Med 2007 Dec;10(6):1338e46. 16. Urquhart E. Analgesic agents and strategies in the dental pain model. J Dent 1994 Dec;22(6):336e41. 17. Seymour RA, Meechan JG, Blair GS. An investigation into post-operative pain after third molar surgery under local analgesia. Br J Oral Maxillofac Surg 1985 Dec;23(6):410e8. 18. Dionne RA, Cooper SA. Evaluation of preoperative ibuprofen for postoperative pain after removal of third molars. Oral Surg Oral Med Oral Pathol 1978 Jun;45 (6):851e6. 19. Joshi A, Parara E, Macfarlane TV. A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars. Br J Oral Maxillofac Surg 2004 Aug;42(4):299e306. 20. Savage MG, Henry MA. Preoperative nonsteroidal anti-inflammatory agents: review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004 Aug;98(2):146e52. 21. Fernandes L, Jenkins R. Investigation into the duration of action of sustainedrelease ibuprofen in osteoarthritis and rheumatoid arthritis. Curr Med Res Opin 1994;13(4):242e50. 22. O’Connor TP, Anderson AM, Lennox B, Muldoon C. A novel sustained-release formulation of ibuprofen provides effective once-daily therapy in the treatment of rheumatoid arthritis and osteoarthritis. [[Clinical trial comparative study multicenter study randomized controlled trial]]. Br J Clin Pract 1993 JaneFeb;47(1):10e3. 23. Ong KS, Seymour RA, Yeo JF, Ho KH, Lirk P. The efficacy of preoperative versus postoperative rofecoxib for preventing acute postoperative dental pain: a prospective randomized crossover study using bilateral symmetrical oral surgery. Clin J Pain 2005 NoveDec;21(6):536e42. 24. Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002 Mar;96(3):725e41. 25. Kendall MJ, Jubb R, Bird HA, le Gallez P, Hill J, Taggart AJ, et al. A pharmacokinetic comparison of ibuprofen sustained-release tablets given to young and elderly patients. J Clin Pharm Ther 1990 Feb;15(1):35e40. 26. Edwards JE, Moore RA, McQuay HJ. Individual patient meta-analysis of singledose rofecoxib in postoperative pain. BMC Anesthesiol 2004 Feb 11;4(1):3. 27. Moore PA, Dunsky JL. Bupivacaine anesthesiaea clinical trial for endodontic therapy. Oral Surg Oral Med Oral Pathol 1983 Feb;55(2):176e9. 28. Dyhre H, Lang M, Wallin R, Renck H. The duration of action of bupivacaine, levobupivacaine, ropivacaine and pethidine in peripheral nerve block in the rat. Acta Anaesthesiol Scand 1997 Nov;41(10):1346e52. 29. Fawcett JP, Kennedy JM, Kumar A, Ledger R, Kumara GM, Patel MJ, et al. Comparative efficacy and pharmacokinetics of racemic bupivacaine and S-bupivacaine in third molar surgery. J Pharm Pharm Sci 2002 MayeAug;5(2):199e204. 30. Gordon SM, Dionne RA, Brahim J, Jabir F, Dubner R. Blockade of peripheral neuronal barrage reduces postoperative pain. Pain 1997 Apr;70(2e3):209e15. 31. Gordon SM, Brahim JS, Dubner R, McCullagh LM, Sang C, Dionne RA. Attenuation of pain in a randomized trial by suppression of peripheral nociceptive activity in the immediate postoperative period. Anesth Analg 2002 Nov;95 (5):1351e7. table of contents. 32. Phillips B, Ball C, Sackett D, Badenoch D, Straus S, Haynes B, et al. Oxford centre for evidence-based medicine e levels of evidence [updated 2009; cited July 2009]; Available from: http://www.cebm.net/levels_of_evidence.asp; 2009.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.theijs.com
Pain after surgery: Can protective analgesia reduce pain? A randomised clinical trial Sin Leong Yong*, Paul Coulthard School of Dentistry, The University of Manchester, Higher Cambridge Street, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 May 2009 Received in revised form 15 February 2010 Accepted 3 March 2010 Available online 17 March 2010
Aim: To improve the patients postoperative pain experience using protective analgesia for patients undergoing third molar surgery under day case general anaesthesia. Material and methods: Patients were randomly allocated to a protective analgesia (1.6 g modified release ibuprofen) or conventional analgesia (400 mg conventional ibuprofen) orally 2 h preoperatively. Surgical model was third molar surgery. Postoperative outcomes of interest were pain intensity at 30 min, 1, 6, 24 and 48 h. The time to rescue analgesia, overall assessment of pain control, safety and tolerability profiles were also recorded. Results: 122 patients entered the study providing 98 evaluable patients for analysis. Patients in the protective analgesia group reported more pain than those in the conventional group at 30 min, 1, 6 and 48 h following surgery, although this difference was only statistically significant at the 30 min time point. 62.2% of patients required rescue analgesia within 6 h after surgery. The median time for patients who had to take rescue analgesia was 3.1 h. Patients in the protective analgesia group reported a longer time to rescue analgesia compared with those in conventional analgesia group. Overall, 91.7% of patients were at least satisfied with their pain control. Conclusion: There was no difference in the protective analgesia group compared with conventional analgesia group in improving postoperative pain experience. A different protective analgesia regime may be necessary, which employs a more aggressive and multimodal strategy for postoperative pain management. Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Postoperative pain Third molar Protective analgesia
1. Introduction The concept of preemptive analgesia began with Crile in 1913 when he described a technique to eliminate preoperative fear and tension. Crile advocated the use of generous premedication with morphine and atropine, regional (procaine) block, and anaesthesia by inhalation of nitrous oxide and oxygen in his theory to prevent shock during surgery.1 The idea of preemptive analgesia was later revived and described by Woolf, who demonstrated evidence for the central component of post injury pain hypersensitivity in a series of animal studies.2 Pain may be produced peripherally as a result of tissue damage and inflammation (inflammatory pain); damage within the central nervous system (neuropathic pain); or due to alterations in the normal functions of the nervous system (functional pain).3 Pain hypersensitivity can be a common postoperative complication. Pain sensation at the surgical site may be increased and persist long after
noxious stimuli are removed (hyperalgesia). Pain hypersensitivity may also result in pain sensation being felt in other areas close to the surgical site (allodynia). There are two mechanisms involved in pain hypersensitivity: central and peripheral sensitisation. 1.1. Peripheral sensitisation Peripheral sensitisation is the reduction in the threshold and increased responsiveness of nociceptive afferent peripheral terminals.4 Peripheral nociceptors become more responsive with repeated application of noxious stimuli. Sensitivity of the peripheral nociceptors can be further enhanced by several tissue factors and inflammatory mediators released in the course of tissue injury.5 During inflammation and tissue injury, prostaglandins and leukotrienes are released directly activating the ends of peripheral nociceptors leading to sensitisation and increasing responsiveness to other stimuli.4 1.2. Central sensitisation
* Corresponding author. Fax: þ44 0161 275 6631. E-mail addresses: [email protected] (S.L. Yong), paul.coulthard@ manchester.ac.uk (P. Coulthard).
Following peripheral tissue injury, chemical changes can occur within the central nervous system. A variety of neurotransmitters
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are released, of which one of the most important is substance P. Substance P in turn induces the release of excitatory amino acids such as glutamate and aspartate, which are involved in the increased excitability of N-methyl-D-aspartate (NMDA) receptor sites within the spinal cord. It has been proposed that activation of NMDA receptor sites by the excitatory amino acids enhance depolarisation, making the neurons more responsive and thereby leads to amplification and increased duration of pain.6 Central sensitisation or ‘wind-up’ is used to describe the enhanced excitability and sensitisation of dorsal horn cells induced by the above mechanisms.7 Preemptive analgesia aims to minimise or prevent onset of peripheral and central sensitisation by employing various interventions at different stages of the pain pathway. Although the evidence for preemptive analgesia is promising in animal studies, there is still controversial evidence of success in reducing postoperative pain in human trials. This may be due to variations in the definition of preemptive analgesia. Kissin et al. found that the definition for preemptive analgesia was far from uniform. He identified three different definitions for preemptive analgesia used in current clinical trials. Preemptive analgesia has been defined as treatment that: 1. starts before surgery; 2. prevents the establishment of central sensitisation caused by incisional injury (covers only the period of surgery); 3. prevents the establishment of central sensitisation caused by incisional and inflammatory injuries (covers the period of surgery and the initial postoperative period). In order to demonstrate the maximum benefits of preemptive analgesia in clinical trials, two conditions should be met. Firstly, the intervention should be effective in suppressing afferent input and of sufficient duration of action, covering the initial postoperative period. Secondly, combined treatment modalities should be employed to maintain preemptive effects and reverse central sensitisation.8 This is a concept called protective analgesia. Several other terms have also been used e ‘balanced multimodal analgesia’ and ‘preventive analgesia’ but all employ a similar concept.9,10 The treatment approach aims to control the development of central sensitisation in the postoperative period. This advocates the use of multimodal techniques with several drugs to attenuate peripheral and central hypersensitivity and with a sufficient duration of treatment.11 Although nociceptive pain is often regarded as the key feature of acute postoperative pain, the focus should be redirected from the timing of perioperative analgesia to protective analgesia. Aggressive and multimodal strategy for postoperative pain management should therefore be adopted.12 The aim of this study was to investigate the efficacy of protective analgesia in improving the postoperative pain experience. We compared the combined effects of sustained release ibuprofen and bupivacaine nerve block with the combined effects of conventional ibuprofen and bupivacaine nerve block. Whilst the effect of the local anaesthesia would make it more difficult to demonstrate difference between types of ibuprofen, this design was chosen to limit the variables under investigation. Third molar surgery was the chosen surgical model as this is validated model for pain clinical trials. Our hypothesis was that the combined effects of sustained released ibuprofen and bupivacaine nerve block would reduce the proportion of patients with moderate to severe pain compared to the combined effects of conventional ibuprofen and bupivacaine nerve block. The safety and tolerability profile were also documented.
2. Materials and methods 2.1. Study design and patient selection The setting for this double blind, active control, randomised clinical trial was the Oral Surgery Day Case Unit at Central Manchester University Hospitals NHS Foundation Trust. The study was approved by the Regional Ethics Committee and the Medicines and Healthcare products Regulatory Agency (MHRA). Patients were considered eligible for study inclusion if they were male or female, aged 18 and over, ASA I or II, able to understand and cooperate with the requirements of the protocol and able and willing to exercise an appropriate written informed consent. Patients were excluded from participating in the study if they had a known hypersensitivity to NSAIDs, paracetamol or bupivacaine, or if they were pregnant. Patients were also excluded if they had used analgesics within 48 h prior to the day of surgery, alcohol within 24 h prior to the day of surgery or had a suspected or known history of alcohol or drug abuse. 2.2. Sample size We calculated that 48 patients in each group would be required to detect the difference between Group 1 proportion of 0.55 and a Group 2 proportion of 0.25 (odds ratio of 0.273). The statistical power of the study was 80%. The sample size was based on our primary outcome measure of proportion of patients requiring rescue medication within 6 h of surgery. Seymour et al.13 previously reported this outcome at 55% in their 400 mg ibuprofen group and Morse et al.14 reported rofecoxib, with similar efficacy but longer duration than ibuprofen, at 25%. We recruited 122 patients to produce 96 evaluable patients. 2.3. Allocation concealment and blinding Patients were allocated to the protective analgesia group or conventional analgesia group according to computer generated randomisation code that were concealed in sealed envelopes and opened 2 h before surgery. Each patient was given a unique identification number based on the randomisation information and this code was held by the hospital pharmacist. The protective analgesia group received 1.6 g modified release ibuprofen (2 800 mg) orally 2 h prior to surgery and the conventional analgesia group received conventional release 400 mg ibuprofen (2 200 mg) orally 2 h prior to surgery. The study medication was administered by a qualified nurse or other study staff member blinded to study assessments. All participants and investigators were blinded to the treatment allocation throughout the study period. Only the statistician who generated the random numbers and hospital pharmacist had access to the randomisation code but none were involved in the recruitment, allocation or assessment of the study participants. 2.4. Surgery Third molar surgical technique and general anaesthetic techniques were standardised as far as possible and prophylactic antibiotics, 200 mg metronidazole, 8 hourly for 5 days, were prescribed for all patients. Surgery was undertaken by five experienced surgeons using standard third molar mucoperiosteal flap with bone removal with a surgical bur cooled with normal saline. An anaesthetic protocol was formulated to eliminate possible confounding drugs which may give a preemptive effect by delivery of analgesics during induction and maintenance of general anaesthesia (Table 1). Patients in both groups received 5 ml bupivacaine 0.5% with
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285
requiring rescue analgesia as well as the time it was taken was recorded.
Table 1 Anaesthetic protocol. Induction Maintenance Airway
Sleep dose of propofol Air/Oxygen/Sevoflurane LMA/COERTT/CNETT as indicated (NB. A nasal tube makes the placement of the inferior dental nerve block much easier) Muscle relaxant Mivacurium 0.2 mg/kg if using IPPV Other drugs
1. Anti-emetics as required (but not Dexamethasone) 2. Neostigmine/Glycopyrrolate as required
Drugs to be avoided
1. All opiods (a small bolus of remifentinil or alfentanil to facilitate intubation should be ok if really necessary) 2. Non-opiod analgesics (tramadol, paracetamol, NSAID’s) 3. Dexamethasone 4. Nitrous Oxide
2.5.3. Overall assessment of pain control At the end of the 48-h period, patients were asked to provide an overall assessment of treatment efficacy with regard to pain experience using a numerical rating scale. The scale ranged from 0 ¼ Extremely poor to 10 ¼ Excellent. The initial assessments were carried out by the study investigator who was not involved in the administration of the study medications. Subsequent assessments were carried out by patients self reported pain intensity using a pain diary. 2.6. Statistical methods
1:200,000 adrenaline for inferior alveolar nerve block and infiltration of long buccal nerve per side immediately prior to surgical incision. 2.5. Pain measures
The t-test, z-test and Chi-square test were applied for differences in mean and proportion between groups. The analysis of time to rescue medication was analysed by log-rank test. The median time estimations and 95% confidence intervals on the median time for the time variables was provided by using Kaplan Meier. We used SPSS (version 15) for statistical analysis.
The outcomes of interest were as follows: 3. Results 2.5.1. Pain intensity Postoperative pain intensity was measured using a 10 cm Visual Analogue Scale labelled ‘no pain’ to ‘worst pain imaginable’ at 30 min and 1, 6, 24 and 48 h following surgery. Surgery end point was defined as the time when intravenous drugs or anaesthetic gases for the maintenance of anaesthesia were stopped. Following at least 1-h observation period after surgery, patients were discharged from the day case unit based on their recovery as assessed by nursing staff. A pain diary with a stamped return address envelope was provided and a 3 day supply of codeine/paracetamol (30/500) to be used as rescue analgesia as required. 2.5.2. Time to rescue analgesia Rescue analgesia (codeine/paracetamol) was administered at the request of the patients after surgery. The number of patients
We invited and screened a total of 122 patients in order to achieve number needed for each group based on the power calculation. Of these, 12 patients were excluded for not meeting the study criteria and 9 did not return the pain diary (Fig. 1). The reasons for exclusion are shown in Table 2. Successful inferior alveolar nerve block was demonstrated by patient’s reported signs of altered lip and gingival sensation. Seven patients were excluded as not demonstrating signs of successful inferior alveolar nerve block. Four patients withdrew consent as they were unable to tolerate taking the study medication. Three patients were cancelled for failing to comply with starvation times prior to general anaesthesia and one patient suffered bronchospasm during induction of anaesthesia and surgery was abandoned.
Assessed for eligibility (n = 122)
Excluded (n = 3) Enrollment
Reason: Not starved for GA
Randomized (n = 119) Allocated to intervention (n = 59) Received allocated intervention (n = 58) Did not receive allocated intervention (n = 1) Reason: Can’t tolerate study medication
Lost to follow-up (n = 4)
Allocated to intervention (n = 60) Allocation
Follow-Up
Discontinued intervention (n = 4) Reason: Failed ID block
Lost to follow-up (n = 5) Discontinued intervention (n = 3) Reason: Failed ID block
Analyzed (n = 48)
Analyzed (n = 50) Excluded from analysis (n = 8) Reasons: Lost to follow-up (n = 4) Failed ID block (n = 4)
Received allocated intervention (n = 56) Did not receive allocated intervention (n = 3) Reasons: Can’t tolerate study medication (n = 3) Asthma attack (n = 1)
Analysis
Fig. 1. CONSORT flow diagram.
Excluded from analysis (n = 8) Reasons: Lost to follow-up (n = 5) Failed ID block (n = 3)
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The median time for patients who had to take rescue analgesia for the duration of the study was 3.1 h. Patients in the protective analgesia group reported a longer time to rescue analgesia (median 3.2 h) compared with those who received conventional ibuprofen (median 2.7 h). The difference, however, was not statistically significant (log-rank test, p ¼ 0.386). The proportion of patients taking rescue analgesia over the 48 h period is shown in the survival curves in Fig. 4. The results indicate that the estimated cumulative probability of rescue analgesia requirement was more for patients in the conventional analgesia group until about 8 h. Thereafter, the estimated cumulative probability of rescue analgesia requirement was more for patients in the protective analgesia group. There were 61 (62.2%) patients requiring rescue analgesia within 6 h following surgery. There were 29 (58%) patients in the protective analgesia group who required rescue analgesia compared to 32 (66.7%) patients in the conventional analgesia group but the difference was not significant (Chi-square test, p ¼ 0.701). In both groups, there were a high number of patients with no or mild pain reported to require rescue medication. There was no significant difference in the median time to rescue medication between the two groups (Table 7).
Table 2 Reasons for exclusion from study. Number (%) of patients
Protective analgesia
Conventional analgesia
Unable to tolerate medication Unsuccessful nerve blockade Did not return pain dairy Bronchospasm event
1 4 4 0
3 3 5 1
Total
9 (15.2%)
12 (20%)
Table 3 Demographic details of patients where age is expressed as mean SD. Characteristic
Protective analgesia
Conventional analgesia
Number of patients Male Female Age (years)
50 13 37 28.82 6.26
48 16 32 28.71 5.8
Data from 98 patients were analysed. There were 29 males (29.6%) and 69 females (70.4%) ranging from 20 to 55 years, with a mean age of 28.77 6.01 years. The patients’ demographic detail for each group is shown in Table 3.
3.3. Overall assessment of pain control
3.1. Pain intensity
Patients rated their overall satisfaction about pain control on a numerical rating scale. The mean reported score about satisfaction with pain control for protective analgesia group was 7.6, whereas for conventional analgesia group it was 7.38 (t-test, p ¼ 0.606). Patient self report assessment of pain control was categorised as follows:
Patients in the protective analgesia group reported more pain than those in the conventional analgesia group at 30 min, 1, 6 and 48 h following surgery, although this difference was only statistically significant at the 30 min time point. The mean pain intensity scores throughout the 48 h period are shown in Table 4 and Fig. 2. Patients self report pain intensity scores were categorised as follows. This validated data transformation enables a more sensitive analysis:15
0 ¼ totally dissatisfied 1e4 ¼ dissatisfied 5e7 ¼ satisfied 8e10 ¼ excellent
0 ¼ No pain 1e4 ¼ Mild pain 5e6 ¼ Moderate pain 7e10 ¼ Severe pain
A higher proportion of patients were at least satisfied with their pain control in the protective analgesia group (48, 96%) compared to 42 (87.5%) in the conventional analgesia group but the difference was not significant (Fig. 5). This is similarly reflected by the number of patients who were not satisfied with their pain control, with a much lower proportion 2 (4%) in the sustained released ibuprofen group compared to 6 (12.5%) in the conventional ibuprofen group.
There were more patients with moderate to severe pain in the protective analgesia group at 30 min, 1 h and at 48 h. The difference was not statistically significant for any of the time intervals (Table 5 and Fig. 3).
3.4. Safety profile and tolerability 3.2. Time to rescue analgesia Overall, the safety profile of both sustained release ibuprofen and conventional ibuprofen was good and well tolerated. One patient with asthma but no known history of intolerance to ibuprofen suffered bronchoconstriction during the induction of general anaesthesia. The patients reported side effects is shown in Table 8.
Over the 48 h period, 11 patients (11.2%) did not require rescue analgesia. There were more patients in the conventional analgesia group who did not require rescue analgesia but the difference was not significant (Chi-square test, p ¼ 0.366). Table 6 shows the rescue analgesia requirement over 48 h between the two groups. Table 4 Pain intensity scores over 48 h period. VAS Protective analgesia n ¼ 50 Conventional analgesia n ¼ 48 Difference (95% CI) mm P value (t-test)
30 min
1h
6h
24 h
48 h
Mean SD (mm)
26.08 29.54
23.59 25.13
26.55 24.02
25.04 23.77
25.14 22.81
Mean SD (mm)
15.77 20.37
17.43 22.63
25.14 23.68
26.36 22.79
23.65 23.57
10.31 (0.30, 20.32) 0.048
6.16 (3.30, 15.62) 0.207
1.41 (8.03, 10.85) 0.771
1.32 (10.54, 7.90) 0.779
1.49 (7.70, 10.68) 0.752
P values of the original pain intensity scores with level of statistical significance set at 0.05.
S.L. Yong, P. Coulthard / International Journal of Surgery 8 (2010) 283e289
Mean pain intensity over 48 hours
30
30
25
25 20 Protective analgesia
15
Conventional analgesia
10 5
Proportion (%)
Mean pain intensity (mm)
287
20 Protective analgesia
15
Conventional analgesia
10 5
0 0.5
1
6
24
0
48
0.5
Tim e (hours)
1
6
24
48
Tim e (hours)
Fig. 2. Graph of mean pain intensity scores over 48 h period. Fig. 3. Graph showing proportion of patients with moderate to severe pain over 48 h.
3.5. Lost to follow-up Patients were given a choice of telephone or clinic follow-up assessment at 1 week after surgery. All patients preferred and opted for telephone follow-up. This was carried out by the study investigator. Patients who had not returned the pain diary at this point were reminded to do so during the telephone follow-up. A total of 9 (9.2%) patients failed return the pain diary despite further attempts to contact patients by telephone. We also wrote to the patients who were unable to be contacted by telephone with a further pain diary and a letter to emphasise the importance of the study. 4. Discussion The objective of this randomised clinical trial was to investigate the efficacy of protective analgesia using the combined effects of sustained release ibuprofen and bupivacaine nerve block in attenuation of postoperative pain using third molar surgery under day case general anaesthesia as the surgical model. The efficacy was compared with a similar group receiving conventional ibuprofen. No difference was found in the attenuation of postoperative pain between sustained release ibuprofen and conventional ibuprofen groups. Third molar surgery is a recognised clinical model for evaluating oral analgesics as postoperative pain is predictable and easily reproducible.16 Surgery may be standardised since the variation in duration and severity of surgery do not affect the degree of postoperative pain experienced. Five surgeons of similar experience performed the surgeries using a standardised technique. Randomisation was by patient and not stratified by surgeon. This is a potential limitation to our study. The analgesic efficacy of selective COX-2 inhibitors has been demonstrated in single dose dental pain studies resulting in less pain, longer time to needing rescue analgesia as well as less analgesic consumption. The benefits over conventional NSAIDs include selective inhibition of COX-2 enzyme as well as analgesic effect for up to 24 h with a single dose, reducing the risk of over dosage and
toxicity. Pain following third molar surgery is usually most severe between 6 and 8 h following surgery.17 This longer duration of action also allows analgesic effects of selective COX-2 inhibitors to be extended into the postoperative period, an ideal property for protective analgesia. However, selective COX-2 inhibitors are not approved for routine use of postoperative dental pain due to increased risk of cardiovascular events. As a result, several COX-2 preparations have been withdrawn from the market. Sustained release ibuprofen has a similar mode of action to ibuprofen. Preemptive use of conventional ibuprofen has been shown to be effective in reducing postoperative pain.18e20 Sustained release ibuprofen, on the other hand, has a longer duration of action of up to 24 h compared to 6 h for conventional ibuprofen.21 The effectiveness of sustained release ibuprofen over conventional ibuprofen was demonstrated in a study conducted by O’Connor and colleagues.22 However, no studies investigated and compared the preemptive use of sustained release ibuprofen with conventional ibuprofen. Several studies also showed the effectiveness of bupivacaine block on reducing postoperative pain following third molar surgery. Our hypothesis was that the group receiving sustained release ibuprofen combined with the effects of bupivacaine nerve block would show reduced postoperative pain following surgery. In this study, we found 62.2% of patients needing rescue analgesia within 6 h following surgery. Although there were fewer patients in the protective analgesia group needing rescue analgesia, the difference was not significant. The findings were similar to that of Morse et al. who compared the preemptive analgesic effects of rofecoxib to ibuprofen and placebo in a randomised double blind clinical trial in patients undergoing lower third molar surgery.14 They found no significant difference between rofecoxib and ibuprofen in reducing postoperative pain and in the number of patients needing rescue analgesia. Patients in the protective analgesia group reported a longer median time to rescue analgesia over the 48 h investigation period. Despite the longer duration of action of sustained release ibuprofen, the time to rescue analgesia was not significantly different compared to the conventional analgesia group. Overall, our intervention delayed the requirement for rescue analgesia to a median time of
Table 5 Number of patients with moderate to severe pain over 48 h.
Protective analgesia (n ¼ 50)
Moderate to severe pain
Conventional analgesia (n ¼ 48)
Moderate to severe pain
Odds ratio (95% CI) Z value (significant)
30 min
1h
6h
24 h
48 h
14 (28%) 7 (14.6%) 2.28 (0.83, 6.26) 1.44 (no)
12 (24%) 5 (10.4%) 2.71 (0.87, 8.41) 1.65 (no)
11 (22%) 11 (22.9%) 0.95 (0.37, 2.45) 0.13 (no)
10 (20%) 12 (25%) 0.75 (0.29, 1.94) 0.35 (no)
11 (22%) 8 (16.7%) 1.41 (0.51, 3.88) 0.41 (no)
Z value of difference in proportions between groups with confidence level at 95%.
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Table 6 Time to rescue analgesia requirement over 48 h.
Table 7 Time to rescue analgesia requirement within 6 h.
Time to rescue medication (mins)
Protective analgesia
Conventional analgesia
Time to rescue medication (mins)
Protective analgesia group
Conventional analgesia group
Number of patients who used rescue analgesia Minimum Median Number of patient who did not require rescue analgesia Odds ratio (95% CI) P value (chi-square)
46 (92%)
41 (85.4%)
29 (58%)
32 (66.7%)
20 192 (3.2 h) 4
17 162 (2.7 h) 7
Number of patients who used rescue medication Minimum Median Number of patients with no or mild pain Number of patient who did not require rescue medication Odds ratio (95% CI) P value (chi-square)
20 100 (1.7 h) 18 (62%)
17 117.5 (1.9 h) 23 (71.8%)
21
16
1.96 (0.53, 7.19) 0.366
3.1 h and up to 48 h in 2 patients. By contrast, a study showed that pretreatment with rofecoxib 50 mg had a much extended mean time to rescue analgesia of 11 h.23 However, the sample size of this study was small and common among other studies; patients were only allowed rescue analgesia when postoperative pain reached a certain threshold, typically a VAS score of 30 or more. Patients in our study were not restricted by this threshold and were allowed to take rescue analgesia at any time depending on individual’s pain tolerance and perception. This may explain the shorter time to needing rescue analgesia in our study. It is common for anaesthetists to utilise opioids and other nonopioid analgesics perioperatively for the maintenance of anaesthesia, which may mask the effects on the intervention assessed. This may be one of the reasons for previous clinical trials for failing to show any preemptive effects of NSAIDs.24 We used a specific anaesthetic protocol which had no analgesia component for the induction and maintenance of general anaesthesia. This gave a more accurate assessment and true account of the efficacy of our intervention. As with the proportion of patients needing rescue analgesia and time to rescue analgesia, pain intensity did not differ significantly between the protective analgesia and conventional analgesia groups. In chronic pain studies, sustained release ibuprofen has been shown to provide better efficacy with added convenience of single dosing but this was not the case in this acute pain setting. The peak plasma concentration following initial dosing of sustained release ibuprofen and conventional ibuprofen are very similar.25 No clinically significant differences can be observed most likely as a result of similarities in the pharmacokinetics of both drugs. The
0.69 (0.30, 1.57) 0.701
preemptive effects of sustained release ibuprofen do not seem to be comparable to that of the selective COX-2 inhibitor, rofecoxib. A systematic review was conducted on individual patient metaanalysis of single dose rofecoxib in postoperative pain. It was found that single dose of 50 mg rofecoxib had comparable analgesic efficacy to ibuprofen 400 mg over 6 h. The NNT for rofecoxib was fairly constant over a 24 h period whereas with ibuprofen, the NNT increased sharply after 6 h.26 This may explain why sustained release ibuprofen was no more effective than conventional ibuprofen in our clinical trial and that it did not achieve the same preemptive effects as with rofecoxib. A much higher loading dose may be required to achieve a significant preemptive effect for sustained release ibuprofen. Increasing the loading dose would however inevitably increase the risk of adverse effects. It was surprising to find such high postoperative pain scores in both groups despite administrating a local anaesthetic nerve block. This suggests that there is merit to using preoperative ibuprofen even when using intraoperative local anaesthesia, consistent with the theory of protective analgesia. The duration of action of bupivacaine has been reported to be up to 8 h.27e29 It has been shown to reduce postoperative pain in patients undergoing lower third molar surgery by decreasing the development of central hyperexcitability.30,31 However, it is often difficult to ensure that a true inferior alveolar block has been achieved whilst patients is under general anaesthetic. This is a limitation to our study where a subjective assessment was carried out with our patients based on reported alteration in lip and gingival sensation. An altered lip and gingival sensation however, may not necessarily indicate a sufficient inferior alveolar nerve block and attenuation of central hyperexcitability. A more accurate assessment using plasma betaendorphin levels, giving a better indication of the nociceptive pathway and efficacy of the inferior alveolar nerve block, may have been helpful. Seven patients in our study failed to demonstrate a successful inferior alveolar nerve block and were excluded from the study and analysis. An intention to treat analysis could not be performed as
30
27
25
25
21 20
17
Num ber of 15 patients (n)
Protective analgesia
10
Conventional analgesia
5
5 0
0
1
Totally dissatisfied
Fig. 4. Survival curves for sustained release ibuprofen and conventional ibuprofen, representing the proportion of patients in each group who did not require rescue analgesia.
2 Dissatisfied
Satisfied
Excellent
Satisfaction levels
Fig. 5. Overall rating of pain control.
S.L. Yong, P. Coulthard / International Journal of Surgery 8 (2010) 283e289
289
References
Table 8 Number of reported side effects. Events
Protective analgesia
Conventional analgesia
Headache Dizziness Nausea and vomiting Swelling Alveolar osteitis Numb tongue Bronchospasm event
1 1 1 6 0 2 0
1 2 5 4 1 5 1
Total
11 (22%)
19 (39%)
the postoperative pain assessment for these patients were not recorded. We acknowledge that this is a limitation to our study. However, these 7 patients were almost equally distributed between the 2 groups and in order to evaluate the true effects of protective analgesia; patients are required to have a successful inferior alveolar nerve block. Therefore, the exclusion of these patients as per protocol would not have a significant effect on the analysis. Prolonged alteration of lip and gingival sensation may be unpleasant experience but none of the patients in our trial reported significant morbidity associated with this. There were no prolonged or unexpected adverse events reported in either treatment groups. All reported side effects resolved spontaneously without additional intervention. One patient developed bronchospasm during induction of anaesthesia. The symptoms spontaneously resolved following administration of oxygen and bronchodilator. This patient had no history of asthma and did not report any sensitivity to NSAIDs. The patient had previously used ibuprofen on more than one occasion without any side effects. The bronchospasm was believed to be related to the patient’s history of smoking. The proportion of patients lost to follow-up in our study was 9.2%. Despite efforts to contact these patients, we were unable to retrieve information required. A lost to follow-up of more than 20% is generally considered of concern to validity.32 However, further strategies could possibly have been employed to minimise the number lost to follow-up such as financial incentives for the patients. 5. Conclusion We were unable to demonstrate a statistically significant improvement in the pain experience using sustained release ibuprofen and bupivacaine nerve block as protective analgesia when compared to a conventional analgesic drug regime for patients undergoing third molar surgery. Conflict of interest None declared. Funding Oral and Maxillofacial Surgery, School of Dentistry, The University of Manchester. Ethical approval REC reference: 07/Q1403/29. EudraCT number: 2006-000193-77. Acknowledgments We wish to thank everyone at the Oral surgery day case unit, Manchester Royal Infirmary for making this study possible. The clinical study is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre. The authors have no conflict of interest to report.
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