Centbucridine, A Newer Topical Anaesthetic Compared with Lignocaine: A Randomized Double Masked Single Drop Instillation Clinical Trial

 

NIHAR RANJAN BISWAS*, BASANT VERMA, SUPRIYO GHOSE,
GOPAL KRUSHNA DAS**, SARITA BERI*** AND
RAVINDRA MOHAN PANDEY****
Dr.  Rajendra Prasad Centre for Ophthalmic Sciences
and
* The Division of Ocular Pharmacology,
Dr.  Rajendra Prasad Centre for Ophthalmic Sciences,
AIIMS, New Delhi - 110 029
** Department of Ophthalmology,
UCMS & GTB Hospital, Delhi - 110 095,
*** Department of Ophthalmology,
LHMC & Smt.  S.K. Hospital, New Delhi - 110 001 and
****Department of Biostatistics,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi - 110 029

 (Received on April 20, 2002)

 

Abstract : A randomized double-masked single drop instillation clinical trial was conducted on 60 healthy volunteers divided into 3 equal groups to compare the efficacies of centbucridine and lignocaine.  One eye of each volunteer was instilled with a single drop of either 0.5% centbucridine hydrochloride, 1% centbucridine hydrochloride or 4% lignocaine hydrochloride, with the other eye as an unanaesthetized control - side effects, if any, were also recorded.  The onset of anaesthesia assessed both objectively and subjectively, was quickest with lignocaine 4% (P<0.001) followed by centbucridine 0.5% and 1%.  However, the period of peak activity as well as the total duration of surface anaesthesia, and also the depth of analgesia, were significantly highest with 1% centbucridine, followed by 0.5% centbucridine and 4% lignocaine respectively.  Minor side effects like burning sensations were longest with 1% centbucridine - no significant adverse effects, local or systemic, were observed.  Prolonged surface anaesthetic and analgesic actions of centbucridine 1% may be advantages for longer duration ophthalmic microsurgeries.

Key words : centbucridine, lignocaine, topical, anaesthetics, controlled, clinical trial

 

INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

INTRODUCTION

Since the initial observation of the topical anaesthetic effect of cocaine by Albert Neimann in 1860 (1), a large number of local anaesthetic agents (usually either amides or esters) have been analyzed both pharmacologically and clinically, especially in ophthalmic practice.  Lignocaine or lidocaine hydrochloride, an amide derivative, has found almost world wide acceptance as a local anaesthetic, though problems are still encountered with it including fatalities (2, 3).  The need of an even better and safer local anaesthetic, topical as well as injectable, is undeniable.

 

Centbucridine, a polymethyl quino compound, also of the amide group of local anaesthetics, is a newer drug, first synthesized by the Central Drug Research Institute (CDRI), at Lucknow, India (4).  Its chemical structure (Fig. 1) is 4-N-butylamino-1,2,3,4-tetrahydroacridine hydrochloride, or bucridine.  Earlier studies (5) and limited clinical trials (6) found it more, potent than lignocaine as an infiltration anaesthetic.  Other studies on its acute (7) and chronic (8) toxicities, teratogenicity (9), neurotoxicity (10) and clinical pharmacology (6) have demonstrated its wide margins of safety.  Injectable centbucridine in concentrations ranging from 0.2% - 0.5% has been used successfully for subarachnoid block (11), infiltration (12) as well as intravenous regional anaesthesia (13), and also tried for local blocks in similar concentrations of' 0.25 - 0.5% in ophthalmic surgery (14-16) and otherwise (17).

 However, only one work seems to be available mentioning briefly its clinical evaluation as an ocular surface anaesthetic (6).  Though the data collection and analysis are not, strictly speaking, very systematic from the ocular pharmacologic viewpoint and also does not comment on the analgesic effect, the authors do mention 2% concentration of centbucridine even with borate buffer produced signs of local irritation, and the effective concentration ranged from 0.25% to 1% (6).  Hence the, present study was undertaken.
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METHODS

Sixty normal "healthy" volunteers of either sex between 20-50 years of age, attending our Eye Centre's out patient department for eye strain, refractive error and routine intraocular pressure measurements were enrolled for this stud so long as any of the following exclusion criteria were not applicable to them.

A brief medical history was noted to rule out local and systemic factors which could affect corneal sensations, subject response, or the Bell's phenomenon, such as : diabetes, leprosy, neurological and endocrinal disorders; use of drugs like sedatives, tranquilizers and alcohol; contact lens wearing, previous viral keratitis, trachoma and other corneal diseases, dry eyes, glaucoma, thyroid ophthalmopathy; and use of local medications (especially timolol).  A complete ocular examination including intraocular pressure measurements, fundus examination and slit lamp biomicroscopy was done.  Informed consents were taken from all the subjects and ethical committee's approval of our Institution was obtained for the study.  Any subject was allowed to withdraw from the study at any time without being asked for any explanation.

Three groups comprising 20 subjects each were selected for single drop instillation of the drug solutions in distilled water (DW), in randomly selected one eye of the subjects, while the opposite eye served as the unanaesthetized control.  No drug, vehicle or placebo was instilled in the control eye, and no data as such were drawn from the control eyes except baseline parameters identical in the paired control and study eyes of the same subjects.  The untouched control eye therefore permitted both objective evaluations by us for any overt signs in the study eye, as well as subjective comparisons by the volunteer as for ocular comfort etc.

Drug formulation and installation

0.5% and 1% centbucridine hydrochloride (Unichem Labs, Mumbai) in distilled water and lignocaine hydrochloride (Xylocaine ® ASTRA IDL, Bangalore) also in distilled water of identical colour and volume were dispensed from the Ocular Pharmacy of our Eye Centre in identical vials.  Our trials were double masked, ensured by assigning random code number to all these identical vials.  Neither the ophthalmologists nor the patients know which or what drug they were using.  A number of similar looking, droppers were tested for the drop size derived.  From these, droppers were selected which gave a drop size of' approximately 30 ± 2.5 /ml.  A single drop of a drug solution was instilled into the lower conjunctival fornix by gently pulling the lower eyelid in all subjects.

Testing for corneal anaesthesia, analgesia and side effects of drug solutions

Subjects were made to lie down comfortably facing the uniform background of the white ceiling of the examination room.  Drug solutions were instilled; corneal tactile sensations were tested with a fine cotton wisp brought in from the lateral side (6, 18-20).  To obviate unwanted reflex stimulation as far as possible, care was taken not to touch the eye lashes or the cotton being seen by the subjects.  The uniform and large background helped to render the cotton wisp less noticeable.  The tactile sensations were tested over the central 3 mm of cornea at 10 seconds intervals after instillation of drug to note the earliest decrease in corneal sensation denoting the onset of anaesthesia when compared to response similarly elicited from the unanaesthetized contralateral eye.  All subjects were instructed beforehand to report burning or any ocular irritation felt after instillation and also the moment it ceased.

After every 5 minutes intervals, tactile. sensations were tested at three predetermined sites - the central 3 mm of cornea, temporal peripheral cornea 1 mm inside the limbus, and temporal conjuctiva 3 mm outside the limbus.  Both objective and subjective responses of the cornea were graded separately for all the three different sites by assigning scores of 0-3 each, standardized after preliminary pilots (Table I); thus a maximum score of 9 (3+3+3) could be achieved.  Correlation of time periods elapsed and depth of ocular surface anaesthesia were noted, till anaesthesia went off completely with the control eye being used as a reference (Table I).

 

Table I click to see full view

Table I: Grading of subjects responses on testing for ocular surface anaesthesia with cotton wisps.

 

Analgesia was tested at 5 minutes intervals by gently clasping the temporal conjunctiva 5 mm away from the limbus, with a pair of nontoothed forceps, similar to the method reported by Linn and Vey (18). The subjects’ responses were graded by scoring from 0-2: Grade 0 (score = 0) was given when the response was "painful", Grade 1 (score = 1) when there was "no pain but subject felt it or complained of slight discomfort", and Grade 2 (score = 2) when no pain was felt by subject with no discomfort at all; thus a maximum score of 2 was obtainable from any study eye.

Other ocular side effects like itching, irritation, foreign body sensation, grittiness, watering, pain, eyeache or headache, diminution of vision, persistent congestion, chemosis, lid oedema and corneal epithelial defects were especially asked for and ruled out using slit lamp biomicroscopy and fluorescein staining.  Visual acuity, and pupillary size and reactions were noted, and intraocular pressure (IOP) was measured by non-contact tonometer (without any necessity of topical anaesthesia).  Systemic side effects like drowsiness, change in mood and dizziness if any, along with pulse rate and blood pressure or any respiratory or neurological difficulties were also noted. 

Statistical analysis 

Observations were recorded according to code of drug and entered into Excel software.  One-way analysis of variance (ANOVA) was applied to detect the statistically significant differences between the mean values.  In case of significant difference shown by ANOVA, post-analysis variance (i.e. multiple range test) was applied to detect the statistically significant difference on various pairs of group means (21).  The analysis was done using STATA 6.0 intercooled version package.  After the analysis was performed, vials were decoded and results were accordingly interpreted.
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RESULTS 

Subjects of all the groups were age and sex matched.  Both objective and subjective criteria were tabulated for grading the subject responses to tactile sensation.  The objective criteria were primarily used for scoring and the subjective responses were utilized to decide the score only in equivocal situations.  A subject's request to repeat the test was interpreted as 'no score' and graded accordingly. 

In our study the onset of anaesthesia was quickest with 4% lignocaine in DW followed by 0.5% centbucridine in DW and then by 1% in DW (Table II).  With 1% centbucridine, the peak achievement and peak duration surface anaesthesia and also its maintenance for the longest period were supported by its highest score for depth of anaesthesia as well as depth of analgesia the corresponding values for 0.5% centbucridine in DW were lower, followed finally by 4% lignocaine in DW (Table II), with differences being statistically significant (P<0.001). Burning sensations were noted with all three drug solutions, the period of burning being longest (over 2 minutes) for 1% centbucridine drops in DW (Table II).  No other ocular and systemic side effects were noted with any of these drug solutions on single drop instillations.

Table II click to see full view

Table II: Ocular surface anaesthesia efficacies of centbucridine 0.5% & lignocaine 4% drops.

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DISCUSSION

The testing for the effect of any anaesthetic agent calls for a safe, objective and standardized method in clinical situations which can give reproducible results.

Anaesthesiometers have disadvantages of stimulation of pain receptors along with the touch receptors and the fact that their higher stimulus strength can cause corneal epithelial abrasions, thus obviating its use in clinical situations (17, 22).  Therefore, cotton wisp was used as a suitable and adequate stimulus to test corneal and conjunctival tactile sensations, and subject responses were graded rather than grading the stimulus.  The non-contrasting background rendered the cotton wisp less noticeable, and bringing in the stimulus from a non-seeing to a seeing area further helped.

The qualities of an ideal ocular surface anaesthetic agent (so important for many ophthalmic procedures), include : good epithelial penetration good potency, satisfactory onset of action, short latent period, no secondary effect on pupillary size and intraocular pressure, no tissue allergic reaction, no systemic toxicity, no inhibition of healing process, good solubility in water and saline, a pH close to that of tears, easy sterilization, chemical stability in solution, and preferably low cost (18, 23, 24).  At present no drug fulfils all these diverse criteria, indicating the need of a continuous search in this regard.

Lignocaine hydrochloride used as a control drug in this study is the most commonly used anaesthetic drug in this part of the world.  However, more so in the West, lignocaine is not the favoured drug especially for topical anaesthesia, and side effects including fatal reactions had been reported from its injectable use (3).  Secondly, though onset of lignocaine maybe quicker, it has a relatively shorter duration of action maybe because of its intrinsic vasodilator activity (25).

Centbucridine, a quinoline derivative anaesthetic agent, has been found to have potent anaesthetic activity (5-17).  It has been tried by subarachnoid (11), intravenous regional (13), as well as for infiltration anaesthesia (14-17) including our earlier study (16), and proved to have good anaesthetic activity with wide margin of safety.  It has again been demonstrated that action of injectable centbucridine was concentration dependent, a higher concentration giving more anaesthetic activity (15).  It was shown that centbucridine was 4-5 times more potent than lignocaine dose to dose.

Though various experimental and clinical studies including topical anaesthesia (6) have been conducted on centbucridine, to the best of our knowledge, no study as ours has been carried out earlier to evaluate its comparative efficacy in different strengths by using single drop topical application to evaluate different parameters (Table II).  We observed that, centbucridine's topical anaesthetic action was also concentration dependent, i.e. centbucridine 1% showed maximum peak as well as duration of anaesthetic and analgesic activities.  Another interesting result of our study was that, with centbucridine in both the concentrations (0.5% and 1%), longer durations of anaesthesia (Table II) were obtained as compared to 4% lignocaine (which is the latter's usual strength used to obtain ocular surface anaesthesia in clinical ophthalmic settings).  The increased duration of anaesthetic action of centbucridine may be of greater value in clinical and operative ophthalmology, where more time may be required in modern day procedures and microtechniques.  Centbucridine in higher concentration (1%) produces temporary burning sensations for a slightly longer period as compared to 0.5% centbucridine and 4% lignocaine hydrochloride - however, this did not reduce the clinical applicability or efficacy of 1% as well as 0.5% centbucridine, and no other serious side effects like corneal epithelial defect were observed from either of these.

Our study was the initial step to evaluate different clinicopharmacological parameters of topical centbucridine as compared to lignocaine by single drop application.  We are in the process of further analyses including multiple drop studies and comparison of effectivity of centbucridine using different vehicles and pH values, so that along with our earlier proven efficacy of this newer agent as an infiltration anaesthetic (16), centbucridine with its greater potency and wide safety margins can be then considered both for topical and injectable use in ophthalmic and all other surgeries.

ACKNOWLEDGEMENTS

The study was supported by a research grant from the All India Institute of Medical Sciences (AIIMS) New Delhi, India.  We are grateful to Mrs. S. Jhingan, Pharmacist for preparing centbucridine and lignocaine eye drops and Mr. Alok K. Ravi for help in preparing the manuscript.
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REFERENCES  

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6.       Gupta PP, Tangri AN, Saxena RC, Dhawan BN.  Clinical Pharmacology studies of 4-N-Butylamino-1,2,3,4-Tetrahydroacridine Hydrochloride (Centbucridine) A new local anaesthetic agent.  Ind J Expt Biol 1982; 20: 344-346.

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14.    Dhir SP, Sharma PL, Jain IS, Zafrulla KM.  Comparative double blind clinical trial of centbucridine and lignocaine hydrochloride in ocular surgery.  Bull PGI (Chandigarh, India) 1977; 11(4): 163-165.

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