Does midazolam sedation in oral surgery affect the potency or duration of diflunisal analgesia? M . R. C. Rodrigo, MH BS, FFARCS, FFAKCSI* J. B. Rosenquist, DDS, P h D t
Key words: Analgesia, postoperative pain control, sedation. Abstract A randomized cross-over study was carried out to determine whether midazolam in doses used for conscious sedation had any effect on the potency or duration of diflunisal, a non-narcotic analgesic used for postoperative pain in oral surgery. Thirtytwo Hong Kong Chinese patients of either sex, aged between 16 and 28 years, were given either midazolam to supplement local anaesthesia or local anaesthesia alone at one visit and the alternative at the other visit, for surgical removal of bilateral symmetrically impacted third molars. Surgery was carried out on one side only at each visit. Diflunisal was given for postoperative pain relief. Midazolam had no effect on the potency or duration of action of diflunisal. Independent of the method, more patients had better pain relief following the second procedure than following the first, probably due to a degree of adaptation to the pain, at the second visit.
(Received for publication July 1988. Accepted April 1989.)
Midazolam is a benzodiazepine closely related to diazepam. Due to its water solubility’ it can be easily diluted. It can be injected into a vein on the dorsum of the hand without inducing pain and thrombophlebitis.z Midazolam produces profound
*Senior Lecturer in Anaesthetics, Department of Oral Surgery and Oral Medicine, University of Hong Kong. ?Professor and Head, Department of Oral Surgery and Oral Medicine, University of Hong Kong. Australian Dental Journal 1990;35(4):333-7
amnesia in addition to anxiolysis’ and has a shorter action than diazepam due to the short half life,’ absence of long acting metabolites3 and absence of enterohepatic recirculation.’ Patients appear to prefer midazolam to diazepam sedation.’ Due to these advantages over diazepam, midazolani is becoming very popular in dentistry. Midazolam injected into the periaqueductal grey matter has been shown to antagonize the analgesic effect of morphine.’ In complete contrast, in a study done by De Castro et al. (1980)” ir was found that midazolam, in doses used for induction of anaesthesia potentiated the action of a centrally acting analgesic, alfentanyl. The two results appear conflicting. In conscious sedation the doses of midazolam used are much smaller than those used for induc. tion and the analgesics given for postoperative pain in dentistry are usually non-narcotic analgesics. There are no reports of studies carried out to find out whether midazolam in doses used for conscious sedation had any effect on non-narcotic analgesics. Thus it was decided in a randomized cross-over study to determine whether midazolam in doses used for conscious sedation had any effect on the potency or duration of non-narcotic analgesics used for postoperative pain in patients undergoing third molar surgery. T h e non-narcotic analgesic chosen was diflunisa1,S as it is commonly used in this Department. Diflunisal is related to aspirin. It has analgesic, antipyretic and anti-inflammatory properties like aspirin but is more potent, acts longer due to its long half-life (10-11 hours), and causes less
iDolobid. M u c k . Shdrp & I h h m c Ltd, Hoddmton, Hcrt\. I’h
333
gastro-intestinal irritation, occult blood loss, and interference with platelet function.' However, it is best given pre-operatively because of the time taken to reach peak plasma levels.'' Materials and methods Hong Kong Chinese patients of either sex between 16 and 30 years of age requiring surgical removal of bilateral symmetrically impacted lower third molars were selected for the study. Patients were excluded if they had a history of hypersensitivity to the drugs or acetylsalicylic acid, or medical conditions like asthma, gastro-intestinal bleeding or gastro-enteritis and any disease that would affect the absorption, metabolism or excretion of the drugs to be studied. Patients were also excluded if they were pregnant or lactating or were taking analgesics, tranquillizers or sedatives. Thirty-two patients were included in the study following informed consent. In the surgery, just prior to sedation or surgery, patients ingested two 250 mg diflunisal tablets. Randomly, qatients either received sedation with intravenous midazolam until drooping of the eye lids (Verril's sign) to supplement local anaesthesia (2 per cent lidocaine with 1:80,000 epinephrine), or received local anaesthesia alone. T h e doses of midazolam, and local anaesthesia given were noted. Selected randomly, surgical removal of the lower third molar on one side was carried out by a standardized technique. Any unerupted upper third molar on the same side was also extracted at the same time. Duration of surgery was recorded. Post-operatively each patient was provided with a timer, a recording sheet containing 100 mm visual analogue scales" where the end points 0 and 100 were marked as 'no pain' and 'very severe pain', and a packet containing two 250 mg tablets of diflunisal. They were instructed to mark the intensity of the pain on the visual analogue scale every hour for ten hours from the time of ingestion of the tablets in the surgery. They were also instructed to take both tablets from the packet if they needed further analgesic tablets and to note the time they ingested them. At the second visit they received the same dose of diflunisal with the alternative procedure. Surgery was carried out on the opposite side by the same surgeon. T h e overall mean pain score was defined as the total pain scores for the observation period (10 h) number of observations (10). T h e data were statistically analysed using Chisquare test and Student's r-test. 334
Table 1. Overall mean pain score Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
LA supplemented with sedation 20.1 13.6 8.1 27.4* 21.8* 10.7* 22.8 46.1 61.1 14.5 30.5* 16.9* 17.0* 22.8 9.4 52.7 15.3 15.7 6.6
33.0 17.1 28.3* 46.3* 21.3* 17.7* 14.0* 14.3* 17.7* 19.8* 14.6* 16.2 5.4
LA alone 32.7* 17.3* 10.6* 4.1 21.7 8.0 24.8* 16.8* 50.1* 14.7* 7.5 17.6 17.5 22.5* 10.3* 9.8* 13.5* 43.3* 13.2* 80.7* 10.2* 30.8 33.8 13.3 33.8 30.1 13.8 12.9 15.3 28.9 18.7* 8.4*
*First procedure was under this method.
Results An equal number of males and females, with a mean age of 21 years (range 16 to 28 years) ( S D f 3 . 3 ) and a mean body mass of 55.5 kg (SD f 9.9) participated in the study. T h e mean dose of midazolam used was 4.7 mg (SD f 1) with a range of 3-6 mg. T h e mean dose of local anaesthesia used for a lower and an upper third molar when local anaesthesia was supplemented with sedation was 3 m L (SD f .25) and 1.2 m L (SD f .13), respectively. When local anaesthesia was used alone it was 3 m L (SD f .29) and 1.3 m L (SD f .34), respectively. Thus the doses used were comparable. Mean duration of surgery when local anaesthesia was supplemented with sedation was 17.6 minutes (SD f 6.6). When local anaesthesia was used alone it was 15.7 minutes (SD f 5.6). T h e difference was not statistically significant and the groups were comparable. T h e overall mean percentage pain score (Table 1) at the operation when patients had local anaesAustralian Dental Journal 1990;35:4.
100
90
80
7c
: 0 0 6C v)
.-C
g
5c
c a a)
4c
I
3c
2c
1c
C 2
3
4
5
6
7
8
9
10
Hours following ingestion of diflunisal Fig. 1. -Mean pain scores following procedure when LA was supplemented with rnidazolam (--) and when LA was used alone (--).
thesia supplemented with sedation was less in 17 patients compared with the time they did not have sedation and the alternative was true in 15 patients, thus showing no significant statistical difference in the overall mean pain score at the two visits. Although in each patient the overall mean pain score at one visit was less than in the other visit, in the majority the difference was not statistically significant. T h e graph (Fig. 1) showing the mean pain score at each hour does not show any significant difference in pain scores following the two methods. T h e first procedure was carried out under local anaesthesia alone in 17 patients and under local anaesthesia supplemented with midazolam in 15 patients. Of the 17 patients who had the first procedure done under local anaesthesia alone, lower pain scores were reported by 6 patients following the first procedure and 11 following the second procedure. Of the 15 patients who had the first procedure done under local anaesthesia supplemented with midazolam sedation, lower pain scores were reported by 6 following the first procedure and by 9 following the second procedure. Australian Dental Journal 1990;35:4
Thirteen patients needed a second dose of diflunisal following the procedure when local anaesthesia was supplemented with sedation and 12 patients needed a second dose of diflunisal following the procedure when local anaesthesia was used alone. Of these, 10 patients needed the second dose following both procedures, thus showing no significant statistical difference in the two groups. In those who needed a second dose of diflunisal the mean duration from first dose to second dose was 11 hours and 27 minutes when local anaesthesia was supplemented with sedation, and 12 hours and 33 minutes when local anaesthesia was used alone, thus, once again, showing no significant statistical difference among the two groups. Discussion Surgical removal of bilaterally symmetrical third molars permits the removal of two teeth on the same side at one session and the other two teeth a t a second session. This procedure is unique in that two essentially identical out-patient operations carried out on healthy subjects offer the opportunity to study the intra-individual effect of drugs before, during and after surgery. Because patients act as 335
their own controls in this model, variation resulting from individual differences is eliminated. Moreover, fewer patients are needed to demonstrate a difference between different treatments than in a parallel groups design. Thus this model was used in this study. Here a placebo was not used with the analgesic as 500 mg of diflunisal has been shown to provide adequate analgesia following third molar surgery1” and as both groups were receiving, at the same time, the same dose of the same drug (diflunisal) for pain relief’. T h e design was not double blind as both the patients and the investigators would have easily identified the procedure where patients had the placebo for sedation because patients would not have been sedated. Intravenous diazepam is said to possess analgesic properties. Brown and Dundee (1968)” demonstrated analgesic action following intravenous diazepam. Yang et al. (1979)13 revealed that diazepam decreased discrimination among thermal stimuli and increased subject response bias producing fewer pain reports. Due to these, they suggested that diazepam had an analgesic action. Kaufman et al. ( 1984)14using response to elective tooth pulp stimulation and sensitivity to a fixed painful stimulus showed a decrease in these parameters with doses of diazepam used for conscious sedation thus suggesting the possibility of an analgesic action of diazepam. Midazolam is closely related to diazepam. Though there are no such studies for midazolam, due to its greater potency it may be expected to have even more analgesic action than diazepam. In doses used for induction, midazolam has been shown to potentiate the effect of alfentanyl.8 This may have been due to the additive effect of its sedative action which probably involves a dampening of neuronal excitability on all levels of the neuraxis. l S As the doses of midazolam used for conscious sedation are much lower, this dampening effect may have been lesser in this study. Further, alfentanyl is a short acting analgesicIb and the action is prolonged when it is given immediately prior to or after an induction dose of midazolam. In contrast, in this study the analgesic action of the local anaesthetic 2 per cent lignocaine with 1:80,000 adrenaline would have produced a pain-free period of up to about 2 hours. This would have masked any potentiating effect of midazolam on the analgesic effect of diflunisal during this period. With a single dose of midazolam the major sedation effect lasts only for about 1.5-2 h o ~ r s from ~ ~ ” ~ the time of optimum sedation. Following this period 336
patients recover so as to be able to go home with an escort. Thus due to the decreased sedative action following 1.5 to 2 hours from the time of optimum sedation, the potentiating effect of midazolam may be low. Therefore, when the effect of the local anaesthetic subsided and the peak effect9 of diflunisal was reached 2-3 hours from the time of ingestion of the drug prior to sedation, the potentiating action of midazolam may have subsided to such an extent that it may have not had any effect on the action of the analgesic. It is stated that midazolam may have an interaction on opioid antinociceptor activity via gamma-amino butyric acid receptors. However, in this study the analgesics used were non-narcotic analgesics which act peripherally by prostaglandin inhibition.’ Thus benzodiazepines probably may not have any action on prostaglandins. It is seen from this study that more patients had lower pain scores following the second procedure than the first procedure. It probably shows a degree of adaptation to the pain following third molar surgery at the second visit which should be remembered in pain relief studies. Thus, in conclusion, in this study midazolam in doses used for conscious sedation had no effect on the potency or duration of action of a non-narcotic analgesic, namely, diflunisal. Acknowledgements The authors wish to thank Nurse Lora Yuen for co-ordinating the study, M r S . L. Lee for help in statistics and Mrs Sybil Kwan for secretarial assistance. References 1. Kanto JH. Midazolam: the first water-soluble benzodiaze-
pine. Pharmacology, pharmacokinetics and eflicacy in insomnia and anesthesia. Pharmacotherapy 1985;5: 138-55. 2. Rodrigo MRC, Clark RNW. A study of intravenous sedation with diazepam and midazolam for dentistry in Hong Kong Chinese. Anaesth Intens Care 1986;14:404-11. 3. Smith M T , Eadie MJ, O’Rourke Brophy T. The pharmacokinetics of midazolam in man. Eur J Clin Pharmol 1981;19:271-8. 4. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981;30:653-61. 5 . Dundee JW, Samuel 10, Wilson DB, Toner W, Howard PJ. Midazolam maleate: a water soluble benzodiazepine: preliminary results. Br J Clin Pharm 1980;9:305-6. 6. Clark RN, Rodrigo MRC. A comparative study of diazepam and midazolam for IV sedation. J Oral Maxillofac Surg 1986;44:860-3. 7. Mantegazza P, Parenti M, Tammiso R, Vita P, Zambotti F, Zonta N . Modification of the antinociceptive effect of ~ ~ morphine by centrally administered diazepam and midazolam. Br J Pharmacol 1982;75:569-72. Australian Dental Journal 1990;35:4
8. De Casrro PJ, Andrieu S, Dubois A, Van Heuneghem. T h e use of midazolam for the induction, correction and potenti-
9. 10.
11.
12. 13.
ation of analgesic anaesthesia based on alfentanil. Arzneim-ForschlDrug Research I Y8 1 ; 3 I:225 1-2. Davies RO. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy IY83;3:YS-228. Rodrigo M R C , Chau M , Rosenquisr JB. A comparison of paracetamol and diflunisal for pain control following third molar surgery. Int J Oral Maxillofac Surg 1989;18: 130-2. Quiding H, Oksala E, Happonew KO, Lehtimaki K, Ojala T. T h e visual analog scale in multiple-dose evaluations of analysis. J Clin Pharmacol 1981;21:424-9. Hrown SS, Dundee JW. Clinical studies ofinduction agents, XXV: Diazepam. Brit J Anaesth 1968;40:108-12. Yang JC, Clark WC, Ngai SH, Rerkowitz BA, Spector S . Analgesic action and pharmacokinetics of morphine and diazepam in man: An evaluation from sensory decision theory. Anesthesiology 1979;5 1:495-502.
Australian Dental Journal 1990;35.4
14. Kaufman E, Dworkin
15. 16.
17. 18.
SF,Leresche I., Chen ACN, Schubert M M , Benedetti C. Analgesic action of intravenous diazepam. Anesthesia Progress 1984;3 1:70-3 . Haefely WE. Mechanism of dction o f t h e benzodiazepines. London: Roche Products Ltd, 1Y83:44. Research report. Hull CJ. T h e pharmacokinetics ot' alfentanil in man. Br J Anaesth 1983;55: 157S-164S. Wood N, Sheikh A. Midazolam and diazepam for minor oral surgery. Br Dent J 1986;160:9-12. Aun C, Flynn PJ, Richards J. A comparison of midazolam and diazepam for intravenous sedation in dentistry. Anaesthesia 1984;39:589-Q 3 .
Address f o r correspondence: M. R. C. Rodrigo, Block 1, Flat A8, 23 Sha Wan Drive, Pokfulam, Hong Kong.
337
Key words: Analgesia, postoperative pain control, sedation. Abstract A randomized cross-over study was carried out to determine whether midazolam in doses used for conscious sedation had any effect on the potency or duration of diflunisal, a non-narcotic analgesic used for postoperative pain in oral surgery. Thirtytwo Hong Kong Chinese patients of either sex, aged between 16 and 28 years, were given either midazolam to supplement local anaesthesia or local anaesthesia alone at one visit and the alternative at the other visit, for surgical removal of bilateral symmetrically impacted third molars. Surgery was carried out on one side only at each visit. Diflunisal was given for postoperative pain relief. Midazolam had no effect on the potency or duration of action of diflunisal. Independent of the method, more patients had better pain relief following the second procedure than following the first, probably due to a degree of adaptation to the pain, at the second visit.
(Received for publication July 1988. Accepted April 1989.)
Midazolam is a benzodiazepine closely related to diazepam. Due to its water solubility’ it can be easily diluted. It can be injected into a vein on the dorsum of the hand without inducing pain and thrombophlebitis.z Midazolam produces profound
*Senior Lecturer in Anaesthetics, Department of Oral Surgery and Oral Medicine, University of Hong Kong. ?Professor and Head, Department of Oral Surgery and Oral Medicine, University of Hong Kong. Australian Dental Journal 1990;35(4):333-7
amnesia in addition to anxiolysis’ and has a shorter action than diazepam due to the short half life,’ absence of long acting metabolites3 and absence of enterohepatic recirculation.’ Patients appear to prefer midazolam to diazepam sedation.’ Due to these advantages over diazepam, midazolani is becoming very popular in dentistry. Midazolam injected into the periaqueductal grey matter has been shown to antagonize the analgesic effect of morphine.’ In complete contrast, in a study done by De Castro et al. (1980)” ir was found that midazolam, in doses used for induction of anaesthesia potentiated the action of a centrally acting analgesic, alfentanyl. The two results appear conflicting. In conscious sedation the doses of midazolam used are much smaller than those used for induc. tion and the analgesics given for postoperative pain in dentistry are usually non-narcotic analgesics. There are no reports of studies carried out to find out whether midazolam in doses used for conscious sedation had any effect on non-narcotic analgesics. Thus it was decided in a randomized cross-over study to determine whether midazolam in doses used for conscious sedation had any effect on the potency or duration of non-narcotic analgesics used for postoperative pain in patients undergoing third molar surgery. T h e non-narcotic analgesic chosen was diflunisa1,S as it is commonly used in this Department. Diflunisal is related to aspirin. It has analgesic, antipyretic and anti-inflammatory properties like aspirin but is more potent, acts longer due to its long half-life (10-11 hours), and causes less
iDolobid. M u c k . Shdrp & I h h m c Ltd, Hoddmton, Hcrt\. I’h
333
gastro-intestinal irritation, occult blood loss, and interference with platelet function.' However, it is best given pre-operatively because of the time taken to reach peak plasma levels.'' Materials and methods Hong Kong Chinese patients of either sex between 16 and 30 years of age requiring surgical removal of bilateral symmetrically impacted lower third molars were selected for the study. Patients were excluded if they had a history of hypersensitivity to the drugs or acetylsalicylic acid, or medical conditions like asthma, gastro-intestinal bleeding or gastro-enteritis and any disease that would affect the absorption, metabolism or excretion of the drugs to be studied. Patients were also excluded if they were pregnant or lactating or were taking analgesics, tranquillizers or sedatives. Thirty-two patients were included in the study following informed consent. In the surgery, just prior to sedation or surgery, patients ingested two 250 mg diflunisal tablets. Randomly, qatients either received sedation with intravenous midazolam until drooping of the eye lids (Verril's sign) to supplement local anaesthesia (2 per cent lidocaine with 1:80,000 epinephrine), or received local anaesthesia alone. T h e doses of midazolam, and local anaesthesia given were noted. Selected randomly, surgical removal of the lower third molar on one side was carried out by a standardized technique. Any unerupted upper third molar on the same side was also extracted at the same time. Duration of surgery was recorded. Post-operatively each patient was provided with a timer, a recording sheet containing 100 mm visual analogue scales" where the end points 0 and 100 were marked as 'no pain' and 'very severe pain', and a packet containing two 250 mg tablets of diflunisal. They were instructed to mark the intensity of the pain on the visual analogue scale every hour for ten hours from the time of ingestion of the tablets in the surgery. They were also instructed to take both tablets from the packet if they needed further analgesic tablets and to note the time they ingested them. At the second visit they received the same dose of diflunisal with the alternative procedure. Surgery was carried out on the opposite side by the same surgeon. T h e overall mean pain score was defined as the total pain scores for the observation period (10 h) number of observations (10). T h e data were statistically analysed using Chisquare test and Student's r-test. 334
Table 1. Overall mean pain score Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
LA supplemented with sedation 20.1 13.6 8.1 27.4* 21.8* 10.7* 22.8 46.1 61.1 14.5 30.5* 16.9* 17.0* 22.8 9.4 52.7 15.3 15.7 6.6
33.0 17.1 28.3* 46.3* 21.3* 17.7* 14.0* 14.3* 17.7* 19.8* 14.6* 16.2 5.4
LA alone 32.7* 17.3* 10.6* 4.1 21.7 8.0 24.8* 16.8* 50.1* 14.7* 7.5 17.6 17.5 22.5* 10.3* 9.8* 13.5* 43.3* 13.2* 80.7* 10.2* 30.8 33.8 13.3 33.8 30.1 13.8 12.9 15.3 28.9 18.7* 8.4*
*First procedure was under this method.
Results An equal number of males and females, with a mean age of 21 years (range 16 to 28 years) ( S D f 3 . 3 ) and a mean body mass of 55.5 kg (SD f 9.9) participated in the study. T h e mean dose of midazolam used was 4.7 mg (SD f 1) with a range of 3-6 mg. T h e mean dose of local anaesthesia used for a lower and an upper third molar when local anaesthesia was supplemented with sedation was 3 m L (SD f .25) and 1.2 m L (SD f .13), respectively. When local anaesthesia was used alone it was 3 m L (SD f .29) and 1.3 m L (SD f .34), respectively. Thus the doses used were comparable. Mean duration of surgery when local anaesthesia was supplemented with sedation was 17.6 minutes (SD f 6.6). When local anaesthesia was used alone it was 15.7 minutes (SD f 5.6). T h e difference was not statistically significant and the groups were comparable. T h e overall mean percentage pain score (Table 1) at the operation when patients had local anaesAustralian Dental Journal 1990;35:4.
100
90
80
7c
: 0 0 6C v)
.-C
g
5c
c a a)
4c
I
3c
2c
1c
C 2
3
4
5
6
7
8
9
10
Hours following ingestion of diflunisal Fig. 1. -Mean pain scores following procedure when LA was supplemented with rnidazolam (--) and when LA was used alone (--).
thesia supplemented with sedation was less in 17 patients compared with the time they did not have sedation and the alternative was true in 15 patients, thus showing no significant statistical difference in the overall mean pain score at the two visits. Although in each patient the overall mean pain score at one visit was less than in the other visit, in the majority the difference was not statistically significant. T h e graph (Fig. 1) showing the mean pain score at each hour does not show any significant difference in pain scores following the two methods. T h e first procedure was carried out under local anaesthesia alone in 17 patients and under local anaesthesia supplemented with midazolam in 15 patients. Of the 17 patients who had the first procedure done under local anaesthesia alone, lower pain scores were reported by 6 patients following the first procedure and 11 following the second procedure. Of the 15 patients who had the first procedure done under local anaesthesia supplemented with midazolam sedation, lower pain scores were reported by 6 following the first procedure and by 9 following the second procedure. Australian Dental Journal 1990;35:4
Thirteen patients needed a second dose of diflunisal following the procedure when local anaesthesia was supplemented with sedation and 12 patients needed a second dose of diflunisal following the procedure when local anaesthesia was used alone. Of these, 10 patients needed the second dose following both procedures, thus showing no significant statistical difference in the two groups. In those who needed a second dose of diflunisal the mean duration from first dose to second dose was 11 hours and 27 minutes when local anaesthesia was supplemented with sedation, and 12 hours and 33 minutes when local anaesthesia was used alone, thus, once again, showing no significant statistical difference among the two groups. Discussion Surgical removal of bilaterally symmetrical third molars permits the removal of two teeth on the same side at one session and the other two teeth a t a second session. This procedure is unique in that two essentially identical out-patient operations carried out on healthy subjects offer the opportunity to study the intra-individual effect of drugs before, during and after surgery. Because patients act as 335
their own controls in this model, variation resulting from individual differences is eliminated. Moreover, fewer patients are needed to demonstrate a difference between different treatments than in a parallel groups design. Thus this model was used in this study. Here a placebo was not used with the analgesic as 500 mg of diflunisal has been shown to provide adequate analgesia following third molar surgery1” and as both groups were receiving, at the same time, the same dose of the same drug (diflunisal) for pain relief’. T h e design was not double blind as both the patients and the investigators would have easily identified the procedure where patients had the placebo for sedation because patients would not have been sedated. Intravenous diazepam is said to possess analgesic properties. Brown and Dundee (1968)” demonstrated analgesic action following intravenous diazepam. Yang et al. (1979)13 revealed that diazepam decreased discrimination among thermal stimuli and increased subject response bias producing fewer pain reports. Due to these, they suggested that diazepam had an analgesic action. Kaufman et al. ( 1984)14using response to elective tooth pulp stimulation and sensitivity to a fixed painful stimulus showed a decrease in these parameters with doses of diazepam used for conscious sedation thus suggesting the possibility of an analgesic action of diazepam. Midazolam is closely related to diazepam. Though there are no such studies for midazolam, due to its greater potency it may be expected to have even more analgesic action than diazepam. In doses used for induction, midazolam has been shown to potentiate the effect of alfentanyl.8 This may have been due to the additive effect of its sedative action which probably involves a dampening of neuronal excitability on all levels of the neuraxis. l S As the doses of midazolam used for conscious sedation are much lower, this dampening effect may have been lesser in this study. Further, alfentanyl is a short acting analgesicIb and the action is prolonged when it is given immediately prior to or after an induction dose of midazolam. In contrast, in this study the analgesic action of the local anaesthetic 2 per cent lignocaine with 1:80,000 adrenaline would have produced a pain-free period of up to about 2 hours. This would have masked any potentiating effect of midazolam on the analgesic effect of diflunisal during this period. With a single dose of midazolam the major sedation effect lasts only for about 1.5-2 h o ~ r s from ~ ~ ” ~ the time of optimum sedation. Following this period 336
patients recover so as to be able to go home with an escort. Thus due to the decreased sedative action following 1.5 to 2 hours from the time of optimum sedation, the potentiating effect of midazolam may be low. Therefore, when the effect of the local anaesthetic subsided and the peak effect9 of diflunisal was reached 2-3 hours from the time of ingestion of the drug prior to sedation, the potentiating action of midazolam may have subsided to such an extent that it may have not had any effect on the action of the analgesic. It is stated that midazolam may have an interaction on opioid antinociceptor activity via gamma-amino butyric acid receptors. However, in this study the analgesics used were non-narcotic analgesics which act peripherally by prostaglandin inhibition.’ Thus benzodiazepines probably may not have any action on prostaglandins. It is seen from this study that more patients had lower pain scores following the second procedure than the first procedure. It probably shows a degree of adaptation to the pain following third molar surgery at the second visit which should be remembered in pain relief studies. Thus, in conclusion, in this study midazolam in doses used for conscious sedation had no effect on the potency or duration of action of a non-narcotic analgesic, namely, diflunisal. Acknowledgements The authors wish to thank Nurse Lora Yuen for co-ordinating the study, M r S . L. Lee for help in statistics and Mrs Sybil Kwan for secretarial assistance. References 1. Kanto JH. Midazolam: the first water-soluble benzodiaze-
pine. Pharmacology, pharmacokinetics and eflicacy in insomnia and anesthesia. Pharmacotherapy 1985;5: 138-55. 2. Rodrigo MRC, Clark RNW. A study of intravenous sedation with diazepam and midazolam for dentistry in Hong Kong Chinese. Anaesth Intens Care 1986;14:404-11. 3. Smith M T , Eadie MJ, O’Rourke Brophy T. The pharmacokinetics of midazolam in man. Eur J Clin Pharmol 1981;19:271-8. 4. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin Pharmacol Ther 1981;30:653-61. 5 . Dundee JW, Samuel 10, Wilson DB, Toner W, Howard PJ. Midazolam maleate: a water soluble benzodiazepine: preliminary results. Br J Clin Pharm 1980;9:305-6. 6. Clark RN, Rodrigo MRC. A comparative study of diazepam and midazolam for IV sedation. J Oral Maxillofac Surg 1986;44:860-3. 7. Mantegazza P, Parenti M, Tammiso R, Vita P, Zambotti F, Zonta N . Modification of the antinociceptive effect of ~ ~ morphine by centrally administered diazepam and midazolam. Br J Pharmacol 1982;75:569-72. Australian Dental Journal 1990;35:4
8. De Casrro PJ, Andrieu S, Dubois A, Van Heuneghem. T h e use of midazolam for the induction, correction and potenti-
9. 10.
11.
12. 13.
ation of analgesic anaesthesia based on alfentanil. Arzneim-ForschlDrug Research I Y8 1 ; 3 I:225 1-2. Davies RO. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy IY83;3:YS-228. Rodrigo M R C , Chau M , Rosenquisr JB. A comparison of paracetamol and diflunisal for pain control following third molar surgery. Int J Oral Maxillofac Surg 1989;18: 130-2. Quiding H, Oksala E, Happonew KO, Lehtimaki K, Ojala T. T h e visual analog scale in multiple-dose evaluations of analysis. J Clin Pharmacol 1981;21:424-9. Hrown SS, Dundee JW. Clinical studies ofinduction agents, XXV: Diazepam. Brit J Anaesth 1968;40:108-12. Yang JC, Clark WC, Ngai SH, Rerkowitz BA, Spector S . Analgesic action and pharmacokinetics of morphine and diazepam in man: An evaluation from sensory decision theory. Anesthesiology 1979;5 1:495-502.
Australian Dental Journal 1990;35.4
14. Kaufman E, Dworkin
15. 16.
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Address f o r correspondence: M. R. C. Rodrigo, Block 1, Flat A8, 23 Sha Wan Drive, Pokfulam, Hong Kong.
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