GB2189142A - Relief of tonsillectomy pain - Google Patents

Abstract

Postoperative pain in human patients caused by tonsillectomy is relieved by the administration of a medicament selected from ibuprofen and a pharmaceutically acceptable salt of ibuprofen. The medicament may be administered before or after tonsillectomy, but is preferably administered after tonsillectomy. Oral administration is preferred. Preferred formulations for oral administration are viscous liquids, for example syrups or viscous suspensions.

Description

SPECIFICATION Analgesic method This invention relates to a method for relieving postoperative pain caused by tonsillectomy.

The operation of tonsillectomy in a human patient usually causes pain to such an extent that the patient requires analgesia in the postoperative period. Various analgesics have been used to relieve this pain, including aspirin, paracetamol, benzidamine hydrochloride, diclofenac and pentazocine.

We have now found that very efficacious relief of postoperative pain caused by tonsillectomy can be obtained by the use of ibuprofen. Ibuprofen, the chemical name of which is 2-(4isobutylphenyl)propionic acid, is a well-known medicament discovered by the Boots Company.

Ibuprofen has anti-inflammatory, analgesic and antipyretic properties but its use to relieve postoperative pain caused by tonsillectomy has not been proposed.

According to the present invention there is provided a method for relieving postoperative pain in a human patient caused by tonsillectomy which comprises administering ibuprofen or a pharmaceutically acceptable salt thereof to the patient.

The ibuprofen or pharmaceutically accepatable salt thereof may be administered prior to tonsillectomy and/or after tonsillectomy, but is prefereably administered after tonsillectomy. The adminstration may be enteral (i.e. oral or rectal) or parenteral (usually intramuscular). The preferred route of administration is enteral, especially oral. Pharmaceutically acceptable salts of ibuprofen include, for example, the sodium salt, potassium salt and aluminium salts.

In the method of the present invention, the ibuprofen or salt thereof is generally administered in the form of a pharmaceutical composition comprising the ibuprofen or salt thereof together with a pharmaceutically acceptable carrier. Such pharmaceutical compositions may take the form of any of the known pharmaceutical compositions for enteral or parenteral administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well-known in the art of pharmacy. Pharmaceutical compositions for use in the method of the present invention suitably contain 5-90% by weight of ibuprofen or pharmaceutically acceptable salt thereof and are often prepared in unit dosage form.

Compositions for oral administration are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the art of pharmacy.

Tablets may be prepared by mixing ibuprofen or a pharmaceutically acceptable salt thereof with a disintegrating agent, for example maize starch, and a lubricating agent, for example magnesium stearate or stearic acid and tableting the mixture by known methods. Such tablets may, if desired, be provided with a suitable coating, for example a sugar coating or film coating, by known methods. Similarly capsules, for example hard or soft gelatin capsules, containing ibuprofen or a pharmaceutically acceptable salt thereof with or without added excipients, may be prepared by conventional means. The tablets and capsules may conveniently contain 50-400 mg ibuprofen or a therapeutically equivalent amount of a pharmaceutically acceptable salt of ibuprofen.

Preferred compositions for use with the method of the present invention are liquids for oral administration, for example syrups and suspensions. Viscous liquids, for example syrups and viscous suspensions are especially preferred since their use causes some of the ibuprofen or pharmaceutically acceptable salt thereof to remain in the oropharynx to exert a local analgesic effect on post-tonsillectomy pain in addition to the relief provided by systemic absorption.

The syrups may be based on sucrose and contain ibuprofen or a pharmaceutically acceptable salt thereof dispersed or dissolved therein. Aqueous suspensions contain ibuprofen or a pharmaceutically acceptable salt thereof in an aqueous medium in the presence of a suitable suspending agent, for example sodium carboxymethylcellulose. Oily suspension may comprise a suitable vegetable oil, for example arachis oil.

Compositions suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with cocoa butter or polyethylene glycol bases.

Compositions suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous or oily media or sterile solutions in a suitable solvent.

The dosage of medicament used in the methof of the present invention is generally within the range 50-2400 mg ibuprofen (or the therapeutically equivalent amount of a pharmaceutically acceptable salt of ibuprofen) per day given in divided doses as directed by the physician.

Examples of formulations suitable for use with the method of the present invention are as follows.

FORMULATION 1 A syrup containing 2.0% w/v ibuprofen is prepared from the following ingredients.

% w/v Ibuprofen BP 2.00 Methyl hydroxybenzoate 3P 0.10 Propyl hydroxybenzoate BP 0.05 Sucrose BP 66.00 Citric acid BP, powder 0.25 Sodium benzoate BP 0.25 Agar BPC, powder 0.30 Glycerin BP 10.00 Sorbitol solution BPC 10.00 Sterilised light kaolin BP 1.00 Polysorbate 80 BPC 0.10 Sunset Yellow FC (colouring) 0.01 Orange Flavour D717* 0.25 (% v/v) Purified water BP to 100.00 *Manufactured by Bush Boake Allen Ltd. Blackhorse Lane, London E17 5QP, England.

The agar, sucrose, methyl hydroxybenzonate, propyl hydroxybenzonate and sodium benzonate are dissolved/dispersed at 95"C in purified water using a high speed stirrer. The citric acid, sorbitol solution and glycerin are then added and the resulting gel-syrup vehicle is allowed to cool. The ibuprofen and kaolin are mixed, deaggregated and dispersed into a solution of polysor bate 80 in purified water until a homogeneous suspension is obtained. The resulting suspension is stirred into the gel-syrup vehicle below 35"C. The colour and orange flavour are added to the stirred mixture.

FORMULATION 2 Tablets are prepared from the following ingredients.

parts by weight Ibuprofen BP 200.0 Maize Starch BP 128.0 Stearic Acid BP 1.6 The ibuprofen is wet granulated with an aqueous paste of some of the maize starch. The resulting granules are dried and mixed with the remainder of the maize starch and the stearic acid. The mixture is compressed into tablet cores each containing 200 mg ibuprofen. The tablet cores are then sugar coated with sucrose in a conventional manner to give tablets of weight 500 mg.

CLINICAL STUDY The following clinical study illustrates the method of the present invention. In this study, the effect of the oral administration of ibuprofen was compared with that of aspirin and placebo in post-tonsillectomy patients. In each case the dosage form was a syrup containing (a) ibuprofen, 100 mg per 5 ml, (b) aspirin, 100 mg per 5 ml, or (c) no medicament, i.e. placebo. The ibuprofen syrup was prepared as described in the above Formulation 1. The aspirin syrup was prepared in a similar way, except that the aspirin was added to the syrup immediately before use.

METHOD i) Design: The study was a double-blind, multiple dose, parallel group study of 6 days duration. Patients between the ages of 16 and 66 were entered if they requested analgesia for moderate to severe pain following tonsillectomy and gave informed consent.

ii) Drugs: The syrups were randomly allocated and matched for colour, taste and consistency, active syrups containing ibuprofen or aspirin, 100 mg per 5 mls. A 30 ml dose of either an active drug or placebo syrup was given up to four times a day if required, with at least 4 hours between doses. The maximum permitted daily dose for ibuprofen and aspirin was therefore 2400 mg, the normal therapeutic dose range for pain relief. Additional oral paracetamol or intramuscular analgesia was available if necessary.

iii) Records and Assessments: The INVESTIGATOR recorded: General demographic data and suitability for entry into the study, prior to operation.

On the second postoperative day (normally the day of discharge): a) Severity of the pain on a 9 point scale ranging from no pain to very severe pain.

b) Overall opinion of progress, on a 5 point scale-much better to much worse.

c) Side effects.

Eligible PATIENTS recorded: 1) Over the first 24 hours postoperatively: Baseline assessment of pain before medication taken. Then half an hour, one hour, two hours, three hours and four hours after medication: a) The degree of pain on a 9 point scale.

b) The degree of pain relief, on a 5 point scale with categories none/poor/fair/good/excellent.

c) The time of 50% pain relief by being asked the question "ls the pain at least half gone?".

d) Side effects.

2. For the following five days postoperatively the following information was recorded daily: a) The timing of maximum and minimum pain by recording the usual time period of each day when any pain was best and worst controlled.

b) Nocturnal pain relief graded on a five point scale from no relief to complete relief.

c) Side effects.

d) Trial medication and paracetamol consumption and timing.

DATA ANALYSIS Differences between the treatment groups were tested by Kruskal-Wallis method, described in Nonparametric Statistical Methods by Hollander, M and Wolfe, D.A., p. 115-129, published 1973 by Wiley, New York. When a significant difference was detected the paired comparisons of the treatment were tested using Dunn's multiple comparison procedure, described in Statistical Principles in Experimental Design, 2nd edition chapter 11, published in 1971 by MacGraw Hill, New York to determine which treatments were significantly different.

Aspirin treatment group: Because of the low stability of aspirin syrups (shelf life of 7 days stored at 5"C) supplies were prepared by the hospital pharmacy for individual patients immediately before use. However, assays undertaken on syrup samples from this treatment group showed varying concentrations and the preparation techniques therefore reassessed. As this pharmaceutical complication represents a potential difficulty whenever preparing and dispensing aspirin syrups, all patients who received aspirin have been analysed as a single group. Of the 50 patients entered in this group, 17 received aspirin syrup produced from the revised techniques.

RESULTS Of the 139 patients recruited 110 provided sufficient data for analysis. Of these, 44 received ibuprofen, 33 aspirin and 33 placebo. The treatment groups were well matched for sex but not for age where there were few patients over 30 years receiving placebo. The goups were well matched for the initial severity of post-tonsillectomy pain.

a) Pain relief: Results for perception of pain relief at half an hour and one hour after initial therapy showed ibuprofen to provide significantly more pain relief than placebo (put0.05) (Fig. 1). The difference between aspirin and placebo was not significant. Ibuprofen, but not aspirin took significantly less time than placebo for the patient to record the pain as having half gone (p < 0.05).

On the first postoperative night ibuprofen provided significantly better relief than placebo (put0.05) though on subsequent nights there was no difference between the three different groups.

c) Daily Dosage: The majority of patients on either aspirin or ibuprofen took either 3 or 4 doses each day, whereas comparatively few patients on placebo consumed this many doses. There were no recorded requests for intramuscular analgesia.

b) Side Effects The incidence of side effects on each of the three treatments is numerically similar, the highest figure of 8 being reported in the placebo group. None of the patients treated with ibuprofen withdrew from treatment (due to side effects) and only one patient withdrew on each of the alternative treatments because of side effects.

Claims (4)

1. Ibuprofen or a pharmaceutically acceptable salt thereof for use in a method of manufacture of a medicament for use in relieving postoperative pain in humans caused by tonsillectomy.

2. Ibuprofen or a pharmaceutically acceptable salt thereof for use in a method according to claim 1 in which the medicament is a liquid for oral administration.

3. Ibuprofen or a pharmaceuticaliy acceptable salt thereof for use in a method according to claim 2 in which the medicament is a syrup.

4. Ibuprofen for use in a method according to claim 3.