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A lignocaine patch for dental analgesia safety and early pharmacology
journal
of
183
Controlled Release, 10 (1989) 183-188
Eisevier Science Publishers
B.V., Amsterdam
-
Printed
in The Netherlands
A LIGNOCAINE PATCN FOR DENTAL ANALGESIA SAFETY AND EARLY PHARMACOLOGY I.M. Brook’“, G.T. Tucker2, E.C. Tuckley’ and R.N. Boyes3 ’ Department of Oral and Maxillofaciai Surgery and ‘Department of Pharmacology and Therapeutics, University of Sheffield, Sheffield S 10 2SZ (Great Britain) 3/nnovata Biomed Ltd., St Albans AL 34 ES (Great Britain)
(ReceivedJanuary 4, 1989; accepted in revised form March 22, 1989) Key words: lignocaine;dental analgesia; topical toxicology
The safety and early clinical dental~harma~o~~gy if a patch device containing 50 mg ofEignocaine was eva~~ted on a placebo controlled double blind basis in nine volunteers. Ap~l~~ati~~of the patch to the oral mucosa prodded soft tissue anaesthe~~u of ~~milurdepth and extent to that uchieued by infi~trution anaesthet~~s and raised the electrical threats stirn~~ of the adjacent teeth. The risk of systemic toxicity was ~~l~~ible since maximum plasma Iignocaine concentrations were very low (7-94 n&ml).
INTRODUCTION Controlled release drug technology which enables drugs to be delivered to a specific site and then maintained at the site in order for the drug’s therapeutic potential to be realised [ 1,2 ] may enable patients to experience “needle free” dentistry. The aim of this study was to establish the safety of a topical drug delivery [ l] patch for dental analgesia and provide pharmacological and pharmacokinetic data upon which to base future trials and development. The patches were designed to adhere to the oral mucosa, releasing lignocaine from their occlusive surface thereby creating a concentration gradient which would allow lignocaine to diffuse into the tissues. MATERIALS AND METHODS Following local Ethics Committee approval, nine volunteers (five female, four male, mean *Towhomcorrespondence shouldbe addressed.
0168-3659/89/$03.50
0 1989 Elsevier Science Publishers
age 23.8 y, S.D. 2.9 y) from the staff of the Charles Clifford Dental Hospital gave informed consent to participate in a double blind randomised placebo controlled trial of the patch. Each subject had a lignocaine patch placed on the buccal mucosa between the sulcus reflection and the junction of the uuattached/attaehed gingivae centred around the first premolar tooth of either the upper (five cases) or lower (four cases 1 jaw (Fig. 1). The experimental patches were produced using a film-casting procedure resulting in a laminated patch 2 cm x 1 cm and 0.5 mm thick containing lignocaine approximately 50 mg per patch (52.4 + 1.6 SD. mg 1 in a proprietary mucoadhesive support system. The patches incorporated an impermeable polyurethane backing which ensured that diffusional release of lignocaine from the patch was uni~rectional 131. The release profile was first order while the concentration of lignocaine in patch is high, changing to an exponential rate of decay as the patch is depleted. Identical placebo patches (Innovata Biomed
B.V.
184
Fig. 1. Patch in place centred on the upper left premolar.
Ltd., St Albans, Great Britain) were placed on the subjects’ contra-lateral side, the investigators and subjects being unaware on which side the active patch was placed. Only sound, vital unrestored teeth with no concomitant periodontal disease were used. Patches were left in place for 30 min, after which they were removed. Blood lignocaine concentration was determined at 15,30,45,60, and 90 min after application of the patch. Venous blood was taken from the left antecubital fossa, allowed to clot, and whole blood lignocaine concentration measured by gas chromatography [ 41. The coefficient of variation of the method was 5% at 5 ng/ ml and the minimum assayable concentration was 1 ng/ml. To determine if there was any effect on the teeth, the minimum amount of electrical current required to elicit pain (minimum threshold stimulus) [ 51 of the first premolar tooth was determined prior to placement of the patch and at 5, 10, 15, 20, 30 min following patch placement and at lo,30 and 60 min after removal of the patch. This was done by taking the mean of three readings obtained with a Scoone MK II pulp tester (H.C.D. Research Ltd., Burgess Hill Sussex, Great Britain) (readings being taken alternatively from each side to allow a resting
phase between stimuli ) . Prior to stimulus testing the teeth a water-soluble jelly (K.-Y. Johnson and Johnson Ltd., Slough, Great Britain) was placed on the stimulating electrode to ensure good electrical contact. Care was taken to ensure that the electrode was positioned at the same site on the tooth for all readings [5,6]. The results obtained from electrical stimulation were expressed as the percentage change in threshold values from the pre-patch placement value, and differences between the placebo and active patches were compared using a chi-square test. The timing of sensory changes in the lip/attached gingiva were recorded by the subjects’ response to sharp stimuli with a dental probe and two-point discrimination using dividers. The tests were done by the same investigator prior to patch placement and at 1 min intervals for the first ten minutes and then at 5 min intervals until return of normal sensation. The total area of sensory loss on the skin and mucosa was mapped by the subject on a standard form following patch removal at thirty minutes. The mucosa over which the patches were placed was examined following their removal and 24 h after the test. Subjects were also asked to note and report any subsequent reactions and
185
invited to comment on the taste and feel of the patches.
RESULTS
Once adhesion of the patches had occurred (after approximately 30 s) they were self-retaining (Fig. 1) and well tolerated. No change in soft tissue sensation occurred with the placebo patches. The li~ocaine patches abolished perception to touch/pai~ stimuli (induced by a sharp probe) of the mucosalattached gingivae covered and surrounding the patch in a mean time of 7.4 +-3.4 (S.D. J min and reduced sensitivity to pain of the external skin and vermilion by a mean of 112 3.7 min (Fig. 4 ) . On removal of the patch sensitivity of the occluded mucosa returned to normal at a mean of 26.4 2 8.9 min. and the lip was normal at 22.6 -t 5.2 min. Maximum whole blood li~ocaine concentrations occurred at between 45 and 60 min following patch placement (15-30 min after removal of patch 1, the highest individual value recorded being 95 ng/ml (Fig. 2). No systemic reactions to the patches occurred during the test or subsequently. Local reactions occurred in two patients: at 24 h the superficial layer of mucosa which had been occluded by the lignocaine-containing patch became white (Fig. 31, Obse~ation of the sit.es in both cases at 48 h revealed normal mucosa in~stin~ishable from the surrounding mucosa. Five subjects reported the active patch to have a mild bitter taste, one subject thought it had a nutty taste and three subjects reported no taste from either patch. All the teeth in the study remained sensitive to electrical stimulation. There was, however, a significant elevation in minimum threshold stimuli of the premolar teeth with the lignoCaine patches compared to initial baseline values and compared to the placebo (Fig. 5 ).
DISCUSSION
A topically applied patch for dental anaesthesia has several potential advantages over conventional delivery techniques. These include improved patient compliance, the capability of being used by para-dental workers (hygienists >, reduction of cross-infection risks and elimination of bleeding problems associated with injections in haematologically compromised patients. The total dose given to the patient can be reduced as on completion of the dental procedure the patch containing its remaining drug can be removed, allowing rapid recovery of sensation. The dose of lignocaine contained in the patches was similar to that used for a single dental block or infiltration (2 ml of 2% lignoCaine - 50 mg). However the maximum blood drug concentrations achieved with the patches (Fig. 2) (when kept in the mouth for 30 min) were 5 to 50 times less than maximum concentrations that have been reported following perioral injections (0.5-4.7 pg/ml) [ 7,8], indicating that very little of the dose in the patch was absorbed systemically. The concentrations were also well below those associated with antiarrhythmic activity (2-3 pg/ml) and systemic effects (5 fig/ml) [ 93. The two local reactions observed were attributed to mild lignocaine “chemical burns” (Fig. 3 > due to the high lignocaine concentration in contact with the epithelium. In both cases the subjects reported no discomfort and felt they would not have noticed the change in the epithelium had they not been told to check the area. Intra-oral soft tissue anaesthesia of similar distribution to that expected from a dental infiltration was achieved, except for reduced sensitivity of the tip of the tongue due to licking the edge of the patch (Fig. 4). Mucosal anaesthesia was achieved in a clinically acceptable time and recovery following removal of the patches was rapid (under 30 min ) compared to dental infiltration anaesthesia (60-120 min),
186
(m,ns)
TIllIt?
Fig. 2. Whole blood lignocaine concentration n=9. (mean (A) andrange (- - -)).
following application
of patches,
removal at 30 min (dashed
vertical line),
Fig. 3. Local reaction to patch occurred in two subjects at 24 h.
The patches altered the response of the teeth to electrical stimulation. The method of measurement used was by its nature imprecise [ 431; the conclusion can be drawn, however, that there was an analgesic effect on the pulps of teeth IlO] (Fig. 5). We feel this is sufficient to suggest that clinical trials to test the efficacy of the patches for pulpal analgesia are warranted.
All the subjects reported loss of proprioceptive feeling on biting the premolar teeth together suggesting analgesia of the periodontal membrane was achieved. This together with the profound anaesthesia of the gingival tissues indicates that the patches could be used in place of in~~tration anaesthesia for periodontal curettage and root planing procedures. This may
187
Anaesthesia
Fig. 4. Schematic
complication
of the mapped changes in soft tissue sensation
0
10
20
Fig. 5. Percentage change in the minimum threshold (A ) placebo: ( + 1 chi square= 19.6, d.f.8, P=O.Oll,
30
40
60
(no changes noted for placebo patches).
1 90
stimuli from baseline values (Mean and S.D. ): ( 0 ) lignocaine patch, d.f.8, P=O.O02.
( -I- + ) chi square=24.1,
188
be of particular importance in countries such as the United Kingdom where ancillary dental workers that carry out these periodontal procedures are not permitted to perform infiltration anaesthetic injections.
REFERENCES
1
2
CONCLUSIONS
3
The patches were easy to apply and well tolerated. The maximum plasma lignocaine levels achieved were well below those associated with systemic effects. Further clinical trials to establish the efficacy of the patch and study local toxicity are needed.
4
5
6
7
ACKNOWLEDGEMENT 8
We thank the staff of tbe Charles Clifford Dental Hospital who volunteered to participate in this study.
9
10
I.M. Brook and R. van Noort, Controlled delivery of drugs. A review of polymer based devices, Br. Dent. J., 157 (1984) 11. I.M. Brook and R. van Noort, Controlling drug release from acrylic polymers: In uitro studies with potential oral inserts, Biomaterials, 7 (1986) 292. R.N. Boyes, Information on file, Innovata Biomed. Ltd., 21A George St., St Albans, Her& AL8 4ES, Great Britain. G.T. Tucker and M.S. Lennard, Analysis of local anaesthetics, in: Analytical Methods in Human Toxicology, Part I, Macmillan Press, London, 1984, p. 170. J.M. Mumford and H. Bjorn, Problems in electric pulp testinganddental algesimetry, Int. Dent. J., 12 (1962) 161. B.N. Seale, D. Adams and R. Linden, Thresholds of vital and non-vital teeth to stimulation with electric pulp testers, Br. Dent. J., 137 (1974) 352. H. Cannell, H. Walters, AH. Bekett and A. Saunders, Circulating levels of lignocaine after peri-oral injections, Br. Dent. J., 138 (1975) 87. J.P. Rood and H. Cannell, Plasma levels of lignocaine after peri-oral injections of two different concentrations, Pharm. Ther. Dent., 3 (1978) 45. G.T. Tucker and L.E. Mather, Clinical pharmacokinetics of local anaesthetics, Clin. Pharmacokin., 4 (1979) 241. J. Gabka and R.K.J. Price, Tooth pulp stimulation: A method of de~rmining the analgesic efficacy of meptazinol in man, Br. J. Chn. Pharmacol., 14 (1982) 104.
of
183
Controlled Release, 10 (1989) 183-188
Eisevier Science Publishers
B.V., Amsterdam
-
Printed
in The Netherlands
A LIGNOCAINE PATCN FOR DENTAL ANALGESIA SAFETY AND EARLY PHARMACOLOGY I.M. Brook’“, G.T. Tucker2, E.C. Tuckley’ and R.N. Boyes3 ’ Department of Oral and Maxillofaciai Surgery and ‘Department of Pharmacology and Therapeutics, University of Sheffield, Sheffield S 10 2SZ (Great Britain) 3/nnovata Biomed Ltd., St Albans AL 34 ES (Great Britain)
(ReceivedJanuary 4, 1989; accepted in revised form March 22, 1989) Key words: lignocaine;dental analgesia; topical toxicology
The safety and early clinical dental~harma~o~~gy if a patch device containing 50 mg ofEignocaine was eva~~ted on a placebo controlled double blind basis in nine volunteers. Ap~l~~ati~~of the patch to the oral mucosa prodded soft tissue anaesthe~~u of ~~milurdepth and extent to that uchieued by infi~trution anaesthet~~s and raised the electrical threats stirn~~ of the adjacent teeth. The risk of systemic toxicity was ~~l~~ible since maximum plasma Iignocaine concentrations were very low (7-94 n&ml).
INTRODUCTION Controlled release drug technology which enables drugs to be delivered to a specific site and then maintained at the site in order for the drug’s therapeutic potential to be realised [ 1,2 ] may enable patients to experience “needle free” dentistry. The aim of this study was to establish the safety of a topical drug delivery [ l] patch for dental analgesia and provide pharmacological and pharmacokinetic data upon which to base future trials and development. The patches were designed to adhere to the oral mucosa, releasing lignocaine from their occlusive surface thereby creating a concentration gradient which would allow lignocaine to diffuse into the tissues. MATERIALS AND METHODS Following local Ethics Committee approval, nine volunteers (five female, four male, mean *Towhomcorrespondence shouldbe addressed.
0168-3659/89/$03.50
0 1989 Elsevier Science Publishers
age 23.8 y, S.D. 2.9 y) from the staff of the Charles Clifford Dental Hospital gave informed consent to participate in a double blind randomised placebo controlled trial of the patch. Each subject had a lignocaine patch placed on the buccal mucosa between the sulcus reflection and the junction of the uuattached/attaehed gingivae centred around the first premolar tooth of either the upper (five cases) or lower (four cases 1 jaw (Fig. 1). The experimental patches were produced using a film-casting procedure resulting in a laminated patch 2 cm x 1 cm and 0.5 mm thick containing lignocaine approximately 50 mg per patch (52.4 + 1.6 SD. mg 1 in a proprietary mucoadhesive support system. The patches incorporated an impermeable polyurethane backing which ensured that diffusional release of lignocaine from the patch was uni~rectional 131. The release profile was first order while the concentration of lignocaine in patch is high, changing to an exponential rate of decay as the patch is depleted. Identical placebo patches (Innovata Biomed
B.V.
184
Fig. 1. Patch in place centred on the upper left premolar.
Ltd., St Albans, Great Britain) were placed on the subjects’ contra-lateral side, the investigators and subjects being unaware on which side the active patch was placed. Only sound, vital unrestored teeth with no concomitant periodontal disease were used. Patches were left in place for 30 min, after which they were removed. Blood lignocaine concentration was determined at 15,30,45,60, and 90 min after application of the patch. Venous blood was taken from the left antecubital fossa, allowed to clot, and whole blood lignocaine concentration measured by gas chromatography [ 41. The coefficient of variation of the method was 5% at 5 ng/ ml and the minimum assayable concentration was 1 ng/ml. To determine if there was any effect on the teeth, the minimum amount of electrical current required to elicit pain (minimum threshold stimulus) [ 51 of the first premolar tooth was determined prior to placement of the patch and at 5, 10, 15, 20, 30 min following patch placement and at lo,30 and 60 min after removal of the patch. This was done by taking the mean of three readings obtained with a Scoone MK II pulp tester (H.C.D. Research Ltd., Burgess Hill Sussex, Great Britain) (readings being taken alternatively from each side to allow a resting
phase between stimuli ) . Prior to stimulus testing the teeth a water-soluble jelly (K.-Y. Johnson and Johnson Ltd., Slough, Great Britain) was placed on the stimulating electrode to ensure good electrical contact. Care was taken to ensure that the electrode was positioned at the same site on the tooth for all readings [5,6]. The results obtained from electrical stimulation were expressed as the percentage change in threshold values from the pre-patch placement value, and differences between the placebo and active patches were compared using a chi-square test. The timing of sensory changes in the lip/attached gingiva were recorded by the subjects’ response to sharp stimuli with a dental probe and two-point discrimination using dividers. The tests were done by the same investigator prior to patch placement and at 1 min intervals for the first ten minutes and then at 5 min intervals until return of normal sensation. The total area of sensory loss on the skin and mucosa was mapped by the subject on a standard form following patch removal at thirty minutes. The mucosa over which the patches were placed was examined following their removal and 24 h after the test. Subjects were also asked to note and report any subsequent reactions and
185
invited to comment on the taste and feel of the patches.
RESULTS
Once adhesion of the patches had occurred (after approximately 30 s) they were self-retaining (Fig. 1) and well tolerated. No change in soft tissue sensation occurred with the placebo patches. The li~ocaine patches abolished perception to touch/pai~ stimuli (induced by a sharp probe) of the mucosalattached gingivae covered and surrounding the patch in a mean time of 7.4 +-3.4 (S.D. J min and reduced sensitivity to pain of the external skin and vermilion by a mean of 112 3.7 min (Fig. 4 ) . On removal of the patch sensitivity of the occluded mucosa returned to normal at a mean of 26.4 2 8.9 min. and the lip was normal at 22.6 -t 5.2 min. Maximum whole blood li~ocaine concentrations occurred at between 45 and 60 min following patch placement (15-30 min after removal of patch 1, the highest individual value recorded being 95 ng/ml (Fig. 2). No systemic reactions to the patches occurred during the test or subsequently. Local reactions occurred in two patients: at 24 h the superficial layer of mucosa which had been occluded by the lignocaine-containing patch became white (Fig. 31, Obse~ation of the sit.es in both cases at 48 h revealed normal mucosa in~stin~ishable from the surrounding mucosa. Five subjects reported the active patch to have a mild bitter taste, one subject thought it had a nutty taste and three subjects reported no taste from either patch. All the teeth in the study remained sensitive to electrical stimulation. There was, however, a significant elevation in minimum threshold stimuli of the premolar teeth with the lignoCaine patches compared to initial baseline values and compared to the placebo (Fig. 5 ).
DISCUSSION
A topically applied patch for dental anaesthesia has several potential advantages over conventional delivery techniques. These include improved patient compliance, the capability of being used by para-dental workers (hygienists >, reduction of cross-infection risks and elimination of bleeding problems associated with injections in haematologically compromised patients. The total dose given to the patient can be reduced as on completion of the dental procedure the patch containing its remaining drug can be removed, allowing rapid recovery of sensation. The dose of lignocaine contained in the patches was similar to that used for a single dental block or infiltration (2 ml of 2% lignoCaine - 50 mg). However the maximum blood drug concentrations achieved with the patches (Fig. 2) (when kept in the mouth for 30 min) were 5 to 50 times less than maximum concentrations that have been reported following perioral injections (0.5-4.7 pg/ml) [ 7,8], indicating that very little of the dose in the patch was absorbed systemically. The concentrations were also well below those associated with antiarrhythmic activity (2-3 pg/ml) and systemic effects (5 fig/ml) [ 93. The two local reactions observed were attributed to mild lignocaine “chemical burns” (Fig. 3 > due to the high lignocaine concentration in contact with the epithelium. In both cases the subjects reported no discomfort and felt they would not have noticed the change in the epithelium had they not been told to check the area. Intra-oral soft tissue anaesthesia of similar distribution to that expected from a dental infiltration was achieved, except for reduced sensitivity of the tip of the tongue due to licking the edge of the patch (Fig. 4). Mucosal anaesthesia was achieved in a clinically acceptable time and recovery following removal of the patches was rapid (under 30 min ) compared to dental infiltration anaesthesia (60-120 min),
186
(m,ns)
TIllIt?
Fig. 2. Whole blood lignocaine concentration n=9. (mean (A) andrange (- - -)).
following application
of patches,
removal at 30 min (dashed
vertical line),
Fig. 3. Local reaction to patch occurred in two subjects at 24 h.
The patches altered the response of the teeth to electrical stimulation. The method of measurement used was by its nature imprecise [ 431; the conclusion can be drawn, however, that there was an analgesic effect on the pulps of teeth IlO] (Fig. 5). We feel this is sufficient to suggest that clinical trials to test the efficacy of the patches for pulpal analgesia are warranted.
All the subjects reported loss of proprioceptive feeling on biting the premolar teeth together suggesting analgesia of the periodontal membrane was achieved. This together with the profound anaesthesia of the gingival tissues indicates that the patches could be used in place of in~~tration anaesthesia for periodontal curettage and root planing procedures. This may
187
Anaesthesia
Fig. 4. Schematic
complication
of the mapped changes in soft tissue sensation
0
10
20
Fig. 5. Percentage change in the minimum threshold (A ) placebo: ( + 1 chi square= 19.6, d.f.8, P=O.Oll,
30
40
60
(no changes noted for placebo patches).
1 90
stimuli from baseline values (Mean and S.D. ): ( 0 ) lignocaine patch, d.f.8, P=O.O02.
( -I- + ) chi square=24.1,
188
be of particular importance in countries such as the United Kingdom where ancillary dental workers that carry out these periodontal procedures are not permitted to perform infiltration anaesthetic injections.
REFERENCES
1
2
CONCLUSIONS
3
The patches were easy to apply and well tolerated. The maximum plasma lignocaine levels achieved were well below those associated with systemic effects. Further clinical trials to establish the efficacy of the patch and study local toxicity are needed.
4
5
6
7
ACKNOWLEDGEMENT 8
We thank the staff of tbe Charles Clifford Dental Hospital who volunteered to participate in this study.
9
10
I.M. Brook and R. van Noort, Controlled delivery of drugs. A review of polymer based devices, Br. Dent. J., 157 (1984) 11. I.M. Brook and R. van Noort, Controlling drug release from acrylic polymers: In uitro studies with potential oral inserts, Biomaterials, 7 (1986) 292. R.N. Boyes, Information on file, Innovata Biomed. Ltd., 21A George St., St Albans, Her& AL8 4ES, Great Britain. G.T. Tucker and M.S. Lennard, Analysis of local anaesthetics, in: Analytical Methods in Human Toxicology, Part I, Macmillan Press, London, 1984, p. 170. J.M. Mumford and H. Bjorn, Problems in electric pulp testinganddental algesimetry, Int. Dent. J., 12 (1962) 161. B.N. Seale, D. Adams and R. Linden, Thresholds of vital and non-vital teeth to stimulation with electric pulp testers, Br. Dent. J., 137 (1974) 352. H. Cannell, H. Walters, AH. Bekett and A. Saunders, Circulating levels of lignocaine after peri-oral injections, Br. Dent. J., 138 (1975) 87. J.P. Rood and H. Cannell, Plasma levels of lignocaine after peri-oral injections of two different concentrations, Pharm. Ther. Dent., 3 (1978) 45. G.T. Tucker and L.E. Mather, Clinical pharmacokinetics of local anaesthetics, Clin. Pharmacokin., 4 (1979) 241. J. Gabka and R.K.J. Price, Tooth pulp stimulation: A method of de~rmining the analgesic efficacy of meptazinol in man, Br. J. Chn. Pharmacol., 14 (1982) 104.