British Joumal
of Oral
and Maxillofacial Surgery (1990) 28,2&228
iQ 1990 The British Awxiation
A preliminary anaesthetic
of Oral and Maxillofacial Surgeons
report using oxethazainea
potential new dental local
P. A. Brennan, J. D. Langdon Department of Oral and Maxillofacial Surgery, King’s College Hospital, London
SUMMARY. Oxethazaine is the most potent local anaesthetic in use. It is claimed to be 2000 times more potent than lignocaine and 500 times more potent than cocaine as assessed in rabbits eyes. Currently, oxethazaine is used in an antacid preparation for the topical relief of pain in conditions such as hiatus hernia, where the local pH is very low. Since oxethazaine is active in an acidic environment, it was decided to use oxethazaine, in a pilot study of 20 patients requiring minor oral surgery procedures, at a concentration of 0.1% at pH 3, to assess its value in achieving dental local anaesthesia. It was found that the local anaesthesia achieved was sufficient in all patients to allow the operative procedure to proceed. In two of the patients, who presented with acute periapical pathology, satisfactory local anaesthesia was achieved with 0.1% oxethazaine following a failure with lignocaine 2% and 1:SO 000 adrenaline. The duration of anaesthesia was found to be similar to the average achieved with lignocaine 2% and 1:SO 000 adrenaline.
INTRODUCTION
Local anaesthetic drugs may be classified into several groups (Roberts & Sowray, 1979). The two most common are the amide type of local anaesthetic, such as lignocaine and prilocaine, and the ester type such as cocaine and amethocaine. Oxethazaine is a member of another group of local anaesthetic agents noted for their potency. It is an N-substituted bis-acetamide local anaesthetic agent, claimed to be 2000 times more potent than lignocaine and 500 times more potent than cocaine as assessed by Seifter et al. (1962) in rabbits eyes. The chemical structure is illustrated in Figure 1. Oxethazaine possesses mephertamine and ethanolamine (adrenergic and anticholinergic) portions, but Seifter et al. (1962) were unsure as to their significance. Oxethazaine is capable of acting over a wide pH range (pH 1 to 7), and Seifter et al. (1962) claim it to be effective in producing topical local anaesthesia of the stomach lining, an area of the body where the local pH is around 1. It is therefore used in an antacid preparation for the relief of pain in such conditions as hiatus hernia and gastric ulceration (British National Formulary , 1989). It is claimed by Covino and Vassallo (1976) that one of the many causes of failure of local anaesthesia in areas of acute inflammation is due to changes in the local pH-where the area becomes more acidic. This results in protonisation of the local anaesthetic molecule, reducing the ratio of the uncharged, so called, active form of the local anaesthetic molecule, to the charged form of the molecule. In an attempt to prove this hypothesis, an earlier trial involving 40 volunteers was carried out by Brennan et al. (1987). It was found that when using 2% lignocaine local
:
ADRENERGIC PROPERTIES
Fig - The chemical structure of oxethazaine, showing adrenergic site of the molecule.
anaesthetic solution buffered at different pH values, an acidic solution of 2% lignocaine at pH 3, produced the fastest onset and greatest duration of soft tissue anaesthesia as compared with either the commercially available solution of 2% lignocaine (pH 6.8), or an alkaline preparation (pH 7.3). In the light of these results, it was decided to investigate the possibilities of using alternative local anaesthetic agents at lower pH values. Although first reports on the use of the drug were documented in 1962, no further clinical uses of oxethazaine have been published. However, extensive animal experimentation has demonstrated that, although oxethazaine is far more potent than drugs. such as lignocaine, its toxicity is not as high as might be expected. The LD50 value for oxethazaine is O..54mg/kg as compared to a value of 34mg/kg for lignocaine. A starting concentration of 0.1% oxethazaine was initially chosen to provide a solution with effective local anaesthetic properties and minimal toxicity. 26
Preliminary report using oxethazaine
MATERIALS
AND METHOD
The local Ethical Committee was approached and approval was granted for the trial. The solution of 0.1% oxethazaine was prepared by the hospital pharmacy under aseptic conditions, by dissolving lmg/ml of the oxethazaine powder in a hydrochloric acid buffer at pH 3. The prepared solution was presented in 10ml vials. It was decided to perform an initial pilot study involving 20 patients requiring local anaesthesia for minor oral surgical procedures. These procedures included routine exodontia, wisdom teeth removal and apicectomies. The patients were questioned as to their past medical history and their willingness to take part in the study. Those with cardiovascular problems were excluded although we have no reason to suspect that oxethazaine is hazardous to such patients. Pregnant patients were also excluded. No more than 4ml of the 0.1% oxethazaine solution was used on each patient this being administered in the conventional way. All injections were given by the same operator (PAB). A stopwatch was started as the solution was being injected and the area being anaesthetised was checked with a sharp probe every 20 s to determine the onset of local anaesthesia. When both the patient and operator were content that adequate local anaesthesia was obtained, the oral surgical procedure was commenced. During the trial, four patients presented with acute periapical pathology. In two of these, another operator in the Dental School had administered lignocaine 2% with 1:SOO000 adrenaline, but had been unable to achieve satisfactory anaesthesia. These patients were then anaesthetised with the oxethazaine solution. The other two had not had any other local anaesthetic agent prior to the administration of the oxethazaine. The patients were questioned following the procedure about the effectiveness of the local anaesthesia and were asked to return 1 week post-operatively for review. The patients were asked to time when the local anaesthesia wore off with complete return of sensation, although it must be stressed that this is a subjective assessment of duration.
RESULTS
Twenty patients took part in the trial, 14 male and 6 female with a mean age of 34 years. Nine patients required extraction of one or more wisdom teeth, five patients required routine extractions, two patients required apicectomies of upper incisor teeth and the remaining four patients presented with acute periapical pathology requiring extraction of teeth. In all 20 patients, complete local anaesthesia was achieved to enable the proposed procedure to be carried out. The mean onset of anaesthesia, as assessed by applying a sharp probe to the area that was being anaesthetised was found to be 2 minutes 13 s with a standard deviation of 38 s. Fifteen of the 20 patients
27
thought that the injections were more painful than injections that they had previously received, and 5 thought that there was no difference. The mean duration of local anaesthesia was found to be 2 h 16 minutes with a standard deviation of 15 minutes. In all 20 patients, complete local anaesthesia was achieved to enable the proposed procedure to be carried out. The patients were reviewed 1 week after the procedure, at which time the wound was checked and the patients reported on the duration of local anaesthesia and any other problems. All 20 patients reported that the local anaesthesia wore off without any complications.
DISCUSSION
The results obtained are interesting and show that oxethazaine in a concentration of 0.1% induces local anaesthesia of dental tissues sufficient to enable routine and more complicated extractions and apicectomies to be carried out. The duration of local anaesthesia with the 0.1% oxethazaine solution is similar to that obtained with lignocaine 2% solution containing 1: 80 000 adrenaline. Since oxethazaine appears to have vasoconstrictor properties, it was unnecessary to add a vasoconstrictor. This may be of value, since high doses of, for example adrenaline, can cause cardiovascular complications as suggested by Cawson et al. (1983). The success of oxethazaine in inducing local anaesthesia in areas of acute inflammation is very interesting. Since the drug has not been used before in an injectable form, the mechanism by which local anaesthesia is produced cannot be explained. The present theories about local anaesthetic drug action, such as blocking of sodium channels, or inhibition of the ATP-ase system within the nerve itself, as put forward by Covino and Vassallo (1976) may be responsible for the induction of anaesthesia. However, it may be that because oxethazaine is so potent, it overcomes the problems of nerve hyperexcitability: this having been illustrated by Rood and Pateromichelakis in 1981. Laboratory work is currently being undertaken to clarify this matter. The problem with pain on injection may be explained by inadequate buffering, or by hypo or hyper tonicity of the solution. Again, further work is needed to develop a suitable buffer. Acknowledgements We would like to thank Wyeth Laboratories for supplying the oxethazaine powder and the Rings College Hospital Pharmacy for the preparation of the solutions.
References Brennan, P. A., Morley, M. R. & Langdon, J. D. (1987). A study of the effectiveness of 2% lignocaine local anaesthetic solution at different pH values. British Dental Journal, 163, 158. British1 National Formulary. (1988). Chapter 1 page 49. Cawsasn, R. A., Curson, I. & Whittington, D. R. (1983).
28
British Journal of Oral and Maxillofacial Suraerv The hazards of dental local anaesthetics. British Dental Journal, 154,253.
Covino, B. G. & Vassallo, G. H. (1976). Local Anaesthesia Mechanisms of action and clinical use. New York: Grune and Stratton. Roberts, D. H. & Sowray, J. H. (1979). Local Analgesia in Dentistry. Bristol: Wright, Rood, J. P. & Pateromichelakis, S. (1981). Inflammation and peripheral nerve sensitization. British Journal of Oral Surgery, 19,67.
Seifter,‘J., Glassman, J. M. & Hudyama, G. M. (1962). Oxethazaine and related congenors: a series of highly potent local anaesthetics. Proceedings of the Society of
The Authors Mr P. A. Brennan BDS Honorary Research Assistant Mr J. D. Langdon FDSRCS, FRCS Senior Lecturer and Honorary Consultant Department of Oral and Maxillofacial Surgery Ring’s College Hospital Denmark Hill London SE5 8RX Correspondence
and requests for offprints to Mr J. D. Langdon
Experimental Biology in Medicine, 109,664.
Paper received 4 August 1989 Accepted 24 September 1989
of Oral
and Maxillofacial Surgery (1990) 28,2&228
iQ 1990 The British Awxiation
A preliminary anaesthetic
of Oral and Maxillofacial Surgeons
report using oxethazainea
potential new dental local
P. A. Brennan, J. D. Langdon Department of Oral and Maxillofacial Surgery, King’s College Hospital, London
SUMMARY. Oxethazaine is the most potent local anaesthetic in use. It is claimed to be 2000 times more potent than lignocaine and 500 times more potent than cocaine as assessed in rabbits eyes. Currently, oxethazaine is used in an antacid preparation for the topical relief of pain in conditions such as hiatus hernia, where the local pH is very low. Since oxethazaine is active in an acidic environment, it was decided to use oxethazaine, in a pilot study of 20 patients requiring minor oral surgery procedures, at a concentration of 0.1% at pH 3, to assess its value in achieving dental local anaesthesia. It was found that the local anaesthesia achieved was sufficient in all patients to allow the operative procedure to proceed. In two of the patients, who presented with acute periapical pathology, satisfactory local anaesthesia was achieved with 0.1% oxethazaine following a failure with lignocaine 2% and 1:SO 000 adrenaline. The duration of anaesthesia was found to be similar to the average achieved with lignocaine 2% and 1:SO 000 adrenaline.
INTRODUCTION
Local anaesthetic drugs may be classified into several groups (Roberts & Sowray, 1979). The two most common are the amide type of local anaesthetic, such as lignocaine and prilocaine, and the ester type such as cocaine and amethocaine. Oxethazaine is a member of another group of local anaesthetic agents noted for their potency. It is an N-substituted bis-acetamide local anaesthetic agent, claimed to be 2000 times more potent than lignocaine and 500 times more potent than cocaine as assessed by Seifter et al. (1962) in rabbits eyes. The chemical structure is illustrated in Figure 1. Oxethazaine possesses mephertamine and ethanolamine (adrenergic and anticholinergic) portions, but Seifter et al. (1962) were unsure as to their significance. Oxethazaine is capable of acting over a wide pH range (pH 1 to 7), and Seifter et al. (1962) claim it to be effective in producing topical local anaesthesia of the stomach lining, an area of the body where the local pH is around 1. It is therefore used in an antacid preparation for the relief of pain in such conditions as hiatus hernia and gastric ulceration (British National Formulary , 1989). It is claimed by Covino and Vassallo (1976) that one of the many causes of failure of local anaesthesia in areas of acute inflammation is due to changes in the local pH-where the area becomes more acidic. This results in protonisation of the local anaesthetic molecule, reducing the ratio of the uncharged, so called, active form of the local anaesthetic molecule, to the charged form of the molecule. In an attempt to prove this hypothesis, an earlier trial involving 40 volunteers was carried out by Brennan et al. (1987). It was found that when using 2% lignocaine local
:
ADRENERGIC PROPERTIES
Fig - The chemical structure of oxethazaine, showing adrenergic site of the molecule.
anaesthetic solution buffered at different pH values, an acidic solution of 2% lignocaine at pH 3, produced the fastest onset and greatest duration of soft tissue anaesthesia as compared with either the commercially available solution of 2% lignocaine (pH 6.8), or an alkaline preparation (pH 7.3). In the light of these results, it was decided to investigate the possibilities of using alternative local anaesthetic agents at lower pH values. Although first reports on the use of the drug were documented in 1962, no further clinical uses of oxethazaine have been published. However, extensive animal experimentation has demonstrated that, although oxethazaine is far more potent than drugs. such as lignocaine, its toxicity is not as high as might be expected. The LD50 value for oxethazaine is O..54mg/kg as compared to a value of 34mg/kg for lignocaine. A starting concentration of 0.1% oxethazaine was initially chosen to provide a solution with effective local anaesthetic properties and minimal toxicity. 26
Preliminary report using oxethazaine
MATERIALS
AND METHOD
The local Ethical Committee was approached and approval was granted for the trial. The solution of 0.1% oxethazaine was prepared by the hospital pharmacy under aseptic conditions, by dissolving lmg/ml of the oxethazaine powder in a hydrochloric acid buffer at pH 3. The prepared solution was presented in 10ml vials. It was decided to perform an initial pilot study involving 20 patients requiring local anaesthesia for minor oral surgical procedures. These procedures included routine exodontia, wisdom teeth removal and apicectomies. The patients were questioned as to their past medical history and their willingness to take part in the study. Those with cardiovascular problems were excluded although we have no reason to suspect that oxethazaine is hazardous to such patients. Pregnant patients were also excluded. No more than 4ml of the 0.1% oxethazaine solution was used on each patient this being administered in the conventional way. All injections were given by the same operator (PAB). A stopwatch was started as the solution was being injected and the area being anaesthetised was checked with a sharp probe every 20 s to determine the onset of local anaesthesia. When both the patient and operator were content that adequate local anaesthesia was obtained, the oral surgical procedure was commenced. During the trial, four patients presented with acute periapical pathology. In two of these, another operator in the Dental School had administered lignocaine 2% with 1:SOO000 adrenaline, but had been unable to achieve satisfactory anaesthesia. These patients were then anaesthetised with the oxethazaine solution. The other two had not had any other local anaesthetic agent prior to the administration of the oxethazaine. The patients were questioned following the procedure about the effectiveness of the local anaesthesia and were asked to return 1 week post-operatively for review. The patients were asked to time when the local anaesthesia wore off with complete return of sensation, although it must be stressed that this is a subjective assessment of duration.
RESULTS
Twenty patients took part in the trial, 14 male and 6 female with a mean age of 34 years. Nine patients required extraction of one or more wisdom teeth, five patients required routine extractions, two patients required apicectomies of upper incisor teeth and the remaining four patients presented with acute periapical pathology requiring extraction of teeth. In all 20 patients, complete local anaesthesia was achieved to enable the proposed procedure to be carried out. The mean onset of anaesthesia, as assessed by applying a sharp probe to the area that was being anaesthetised was found to be 2 minutes 13 s with a standard deviation of 38 s. Fifteen of the 20 patients
27
thought that the injections were more painful than injections that they had previously received, and 5 thought that there was no difference. The mean duration of local anaesthesia was found to be 2 h 16 minutes with a standard deviation of 15 minutes. In all 20 patients, complete local anaesthesia was achieved to enable the proposed procedure to be carried out. The patients were reviewed 1 week after the procedure, at which time the wound was checked and the patients reported on the duration of local anaesthesia and any other problems. All 20 patients reported that the local anaesthesia wore off without any complications.
DISCUSSION
The results obtained are interesting and show that oxethazaine in a concentration of 0.1% induces local anaesthesia of dental tissues sufficient to enable routine and more complicated extractions and apicectomies to be carried out. The duration of local anaesthesia with the 0.1% oxethazaine solution is similar to that obtained with lignocaine 2% solution containing 1: 80 000 adrenaline. Since oxethazaine appears to have vasoconstrictor properties, it was unnecessary to add a vasoconstrictor. This may be of value, since high doses of, for example adrenaline, can cause cardiovascular complications as suggested by Cawson et al. (1983). The success of oxethazaine in inducing local anaesthesia in areas of acute inflammation is very interesting. Since the drug has not been used before in an injectable form, the mechanism by which local anaesthesia is produced cannot be explained. The present theories about local anaesthetic drug action, such as blocking of sodium channels, or inhibition of the ATP-ase system within the nerve itself, as put forward by Covino and Vassallo (1976) may be responsible for the induction of anaesthesia. However, it may be that because oxethazaine is so potent, it overcomes the problems of nerve hyperexcitability: this having been illustrated by Rood and Pateromichelakis in 1981. Laboratory work is currently being undertaken to clarify this matter. The problem with pain on injection may be explained by inadequate buffering, or by hypo or hyper tonicity of the solution. Again, further work is needed to develop a suitable buffer. Acknowledgements We would like to thank Wyeth Laboratories for supplying the oxethazaine powder and the Rings College Hospital Pharmacy for the preparation of the solutions.
References Brennan, P. A., Morley, M. R. & Langdon, J. D. (1987). A study of the effectiveness of 2% lignocaine local anaesthetic solution at different pH values. British Dental Journal, 163, 158. British1 National Formulary. (1988). Chapter 1 page 49. Cawsasn, R. A., Curson, I. & Whittington, D. R. (1983).
28
British Journal of Oral and Maxillofacial Suraerv The hazards of dental local anaesthetics. British Dental Journal, 154,253.
Covino, B. G. & Vassallo, G. H. (1976). Local Anaesthesia Mechanisms of action and clinical use. New York: Grune and Stratton. Roberts, D. H. & Sowray, J. H. (1979). Local Analgesia in Dentistry. Bristol: Wright, Rood, J. P. & Pateromichelakis, S. (1981). Inflammation and peripheral nerve sensitization. British Journal of Oral Surgery, 19,67.
Seifter,‘J., Glassman, J. M. & Hudyama, G. M. (1962). Oxethazaine and related congenors: a series of highly potent local anaesthetics. Proceedings of the Society of
The Authors Mr P. A. Brennan BDS Honorary Research Assistant Mr J. D. Langdon FDSRCS, FRCS Senior Lecturer and Honorary Consultant Department of Oral and Maxillofacial Surgery Ring’s College Hospital Denmark Hill London SE5 8RX Correspondence
and requests for offprints to Mr J. D. Langdon
Experimental Biology in Medicine, 109,664.
Paper received 4 August 1989 Accepted 24 September 1989
