AU2014201782A1 - Improved medicinal compositions comprising buprenorphine and naltrexone - Google Patents

Abstract

An analgesic composition, in parenteral unit dosage form or in a unit dosage form suitable for delivery via the dermis or mucosa, comprises buprenorphine and an amount of naltrexone such that the ratio by 5 weight of buprenorphine to naltrexone delivered to or reaching the plasma of a patient is in the range 100:1 to 5000:1. The analgesic action of the buprenorphine is potentiated by the low dose of naltrexone. Also provided are a method of treatment of pain and the use of buprenorphine and naltrexone for the manufacture of a medicament.

Description

IMPROVED MEDICINAL COMPOSITIONS COMPRISING BUPRENORPHINE AND NALTREXONE The present invention relates to medicinal compositions 5 containing buprenorphine in coinbination with naltrexone; as well as to their use in the manufacture of such compositions and in clinical practice, as analgesics. Whilst opioids ar.e particularly effective in the 10 management of moderate to severe pain their use is limited by unpleasant and potentially dangerous adverse effects. Such adverse effects can include sedation, respiratory depression, nausea and gastrointestinal problems. Thus efforts have been made to minimise adverse effects. 15 There are many opioids and some produce more significant adverse , effects than others. Accordingly, careful selection of the opioid employed in an analgesic composition may itself reduce the incidence and severity 20 of adverse effects. One particularly suitable opioid is buprenorphine which has been shown to have both agonist (morphine-like) and antagonist properties without producing significant physical. dependence. 25 Buprenorphine (International Non-proprietary. Name for N cyclopropylmethyl-7 [alpha) - [l- (S) -hydroxy-1, 2, 2-trimethyl propyl)6,14-endoethano-6,7,8,14-tetrahydronororipavine) is a potent opiate partial agonist analgesic lacking the psychotomimetic effects found with other opiate 30 analgesics. However, buprenorphine suffers from side effects typical of opiate agonists such as nausea and vomiting, constipation and respiratory depression in some patients, although there is a ceiling to its effects on 2 respiratory depression as a direct consequence of its partial agonist properties. Attempts have also been made to enhance the analgesic 5 effect of opioids while minimising the incidence and severity of adverse effects by combining opioid treatment with other drugs.. One approach is the addition of a non-opioid analgesic to 10 the opioid treatment.' The rationale here is that lower levels of opioid should be required to achieve antinociception and thus. there should be a reduction of adverse effects. 15 Another approach is the co-administration of an opioid agonist and low doses of an opioid antagonist. One such antagonist, is naltrexone (International Non-proprietary Name for 1-N-cyclopropylmethyl-14-hydroxynordihydro morphinone) which is a pure opiate antagonist. Naltrexone 20 is also known for oral administration -(50 mg/day). as a maintenance drug for opiate addicts to block the effects of self-administered opiates and contribute to the extinction of drug craving. 25 In GB 2167663A there is disclosed an analgesic composition in parenteral or sublingual form comprising an active dose of buprenorphine and an amount of naltrexone sufficient to prove aversive to a narcotic addi'ct by parenteral administration but insufficient. to compromise the 30 analgesic action of the buprenorphine. The parenteral dosage form may contain -buprenorphine and naltrexone within the weight ratio of 12:1 to 3:1 and the sublingual form may contain buprenorphine and naltrexone within the 3 ratio 4:1 to 1:1. The testing in GB-A-2167663A was on rats. In EP 1242087A it is disclosed that parenteral and sub 5 lingual dosage forms of buprenorphine are potentiated and enhanced by low doses of naltrexone. Based on testing on rats, there is stated a suitable ratio by weight of buprenorphine to naltrexone of 12.5:1 to 22.5:1, preferably 15:1 to 20:1. 10 Human studies have now been carried out and have generated new findings for the combined use of buprenorphine, as opioid- agonist, and haltrexone, as opioid antagonist. These new ,findings extend our .,understanding of the 15 therapeutic doses which will give effective analgesia in humans. According to a first aspect of the present invention there is provided an analgesic composition, in parenteral unit 20 dosage form or in a unit dosage form suitable for delivery via the mucosa or dermis, the composition comprising buprenorphine and an amount of naltrexone such that the ratid by weight of buprenorphine to naltrexone delivered to or reaching the plasma of a patient is in the- range 25 100:1 to 5000:1. It is believed that the analgesic action ot buprenorpnine is potentiated by the relatively small level of naltrexone. 30 It is to be understood that the terms buprenorphine and naltrexone as used herein are intended to cover simple related, pharmaceutical compounds such as esters, bases 4 and salts, for example acid addition salts. Particularly preferred salts are the hydrochlorides. However the ratios and weights referred -to herein refer to buprenorphine and naltrexone per se, not salts, bases or 5 esters. The term parenteral is intended to encompass administration of the compositions by any way other than through the alimentary tract. i0 The term mucosa or mucosal is intended to encompass any mucous membrane and includes oral mucosa, rectal mucosa, vaginal mucosa and nasal mucosa. The term dermal denotes non-mucosal skin. 15 Administration may take a few minutes. Preferably it takes place over a period of at least one minute,. preferably at least two minutes, preferably at least three minutes. Preferably it takes place over a period of up to 20 ten minutes, preferably up to seven minutes, preferably up to five minutes. The unit dosage form for transdermal or transmucosal administration may, for example, be a tablet, film, spray, 25 patch, rub-in composition or lozenge. Administration, which will be further described in the second aspect, may comprise - the delivery of a medicament comprising buprenorphine and naltrexone, preferably 'in such a form. .30 .Transdermal administration may encompass any mode of administration trough the dermis. Transmucosal administration may encompass any mode of administration trough the mucosa, and sites of administration may 5 include, for example, vaginal and rectal mucosa and, preferably, mucosa of the oral-nasal cavity, for example nasal, throat, buccal and, sublingual sites. Nasal and sublingual administration is especially preferred. 5 Preferably the defined ratio of bupre'norphine to naltrexone is achieved within. sixty minutes after administration means herein ~within sixty minutes after administration being completed, that is, preferably at 10 some time within sixty minutes of administration being completed, the defined drug ratio in the plasma is achieved. Preferred compositions comprise buprenorphine and 15 naltrexone such' that the ratio by weight of buprenorphine to naltrexone provided delivered to or reaching the plasma of the patient is at least X:1 (X to 1) where X is 120, preferably 140, preferably 160. 20 Preferred compositions comprise. buprenorphine and naltrexone such that the ratio by weight of buprenorphine to naltrexone delivered to or reaching the plasma of the patient is no greater than Y:l (Y to 1) where Y is 1000, preferably 500, preferably 180. 25 The composition may comprise a parental unit dosage form and the ratio of buprenorphine to naltrexone within the parenteral composition may be substantially the same as that produced in the plasma of a patient upon application. 30 Thus the parenteral dosage form may comprise buprenorphine and naltrexone in any of the weight ratios stated above for the weight ratios in the plasma.

6 In a human being, as stated in EP 1242087B dosages of about 40 gag of buprenorphine -per kilogram of body weight are suitably required to obtain satisfactory pain relief in the absence of potentiation. Thus for typical body 5 weights of 50 to 80 kg, the buprenorphine dosage would be from 2 mg to 3.2 mg of buprenorphine per day. This would conveniently be administered as four unit doses. The amounts of buprenorphine which are required to be 10 effective in the compositions of - the invention are less than the amounts which are required to be effective in the absence of the potentiating effects of naltrexone. Importantly when equal doses of buprenorphine with and 15 without the potentiating effect of naltrexone are compared, the magnitude and duration of analgesia achieved by the former compositions (i.e. also containing naltrexone)., are markedly increased. Therefore the same analgesic performance can be achieved with. a lower 20 buprenorphine dose when combined with naltrexone. It is proposed that an increased analgesic effect can be achieved and/or reduced concentration of buprenorphine can be used, within or across the therapeutic range. 25 Suitably; unit doses of the compositions of the present invention (containing naltrexone) contain buprenorphine in an amount which is below that required to obtain corresponding pain relief in a unit dose of buprenorphine, without naltrexone. 30 Suitably, the compositions of the present invention comprise at least 10 pg of buprenorphine per unit dose, preferably at least 15 pg, preferably at least 20 pg, 7 preferably at least 30 pg, and most preferably at least 40 pg. These values reflect the benefit~ of the invention in achieving analgesia at low dosages. 5 Suitably, the compositions of the present invention may. contain any amount of buprenorphine, up to the upper end of conventional, clinical practice. Suitably, they may contain up to up to 32 mg buprenorphine per -unit dose, preferably up to 16 mg, preferably 8 mg, preferably up to 10 4 mg, preferably up to 2 mg, preferably up to 1 mg, preferably up to 600. pg, preferably up to 400 pg, preferably up to 200 pg, preferably up to 160 pg, preferably up to 100 pg. 15 Suitably, in accordance' with the present invention, a patient is administered at least 0.25 pg of buprenorphine per kg (of body weight) per 24 hours. Preferably the amount is at least 0.5 pg, preferably at least 1 pg, preferably at least 1.5 pg and most preferably at least 2 20 pg. Suitably, in accordance with the present. invention, a patient is administered up to 640 pg of buprenorphine per kg per 24 hours. Preferably the amount is up to 320 pg, 25. preferably up to 160 pg, preferably up to 80 pg, preferably up to 40 pg, preferably up to 20 pg, preferably up to 16 pg, and preferably up to 12 pg. Most preferably the amount is not greater than 8 pg. 30 Suitably by use of compositions of the present invention the amount of buprenorphine administered to a patient for the purpose of achieving relief from pain is at least 40 pg per 24 hours, preferably at least 60 pg, preferably at 8 least 80 pg, preferably at least 120 pg, and most preferably at least 160 pg. Suitably by use of compositions of the present invention 5 the amount of buprenorphine administered to a patient for the- purpose of achieving relief from pain is up to 32 mg, preferably up to 16 mg, preferably up to 8 mg, preferably up to 4 mg, preferably up to 2 mg, preferably up to 1 mg, preferably up to 800 pg, preferably up to 600 pg, 10 preferably up to 400 pg, preferably up to 200 pg, preferably up to 160 pg, preferably up to 100 pg. Suitably, a composition containing naltrexone comprises from 0.01 to 4 pg of naltrexone per unit dose, preferably 15 0.05 to 1.2 pg, most preferably 0.1 to 0.6 pg. Suitably the amount of naltrexone administered to -a patient is between 0.001 and 0.2 pg per kg body weight per 24 hours. Preferably the amount is at least 0.002 pg, and 20 preferably at least 0.004' pg, per kg body weight per 24 hours. Preferably the amount is not greater than 0.1 pg, preferably not greater than 0.05 pg, preferably not greater than 0.03 pg, preferably not greater than 0.015 pg, and most preferably not greater than 0.007 pg, per kg 25. body weight per 24 hours. Suitably the amount of naltrexone administered to a patient is in the range from 0.1 pg to 12 pg per 24 hours, preferably 0.2 to 5 pg, preferably 0.35 to 2.4 pg, and 30 most preferably 0.5 to 1.5 ucq.

9 References above to the amounts of compounds which may be administered to a patient are with reference to an adult patient. 5 Whatever the - absolute amounts of buprenorphine and naltrexone administered, the definition(s) stated herein of the ratio of buprenorphine to naltrexone must be satisfied. 10 It is preferable to formulate the compositions in unit dosage forms i'.e. physically discrete units containing the appropriate amounts of buprenorphine and naltrexone, together with pharmaceutically acceptable diluents and/or carriers. Such unit dosage forms for parenteral 15 administration are suitably in the form of ampoules. For delivery via the mucosa may for example be in the form of sublingual tablets, films or lozenges. Compositions of the invention may contain a buffer system, 20 for example an organic acid and a salt thereof, such as citric acid and sodium citrate. Compositions in the -form .. of sublingual dosage forms suitably contain soluble excipients selected from 25 materials such as lactose, mannitol, dextrose, sucrose or mixtures thereof. They suitably also contain granulating and disintegrating agents selected from materials such as starch, binding agents such as povidone or hydroxypropyl methyl cellulose and lubricating agents such as magnesium 30 stearate. Compositions intended for parenteral administration may comprise an isotonic solution of buprenorphine and .10 naltrexone in sterile water. Conveniently the solution may be made isotonic by use of dextrose , and sterilised by autoclaving 'or by filtration through a membrane filter. The compositions may be administered intramuscularly, 5 intradermally, intraperitonealy, intravenously, intraarterially, subcutaneously or by the epidural route. The compositions for parenteral administration, or for delivery via -the mucosa, such as by sublingual 10 administration, as detailed above, may be prepared by manufacturing techniques which are well known to those skilled in the art. According to a second aspect the present invention there 15 is provided a method for the treatment of pain in a human patient, which method comprises the- administration to a human patient,. by .a parenteral or dermal or mucosal route, of buprenorphine and naltrekone such that the ratio by weight of buprenorphine to naltrexone delivered to or 20. reaching the plasma of a patient is in the range: 100:1 to 5000:1. Preferred ratios of buprenorphine to naltrexone delivered to or reaching plasma of the patient are as defined above 25. with respect to the first aspect. Suitably, the method comprises delivery via the mucosa. The method may comprise delivery in a sublingual unit dosage form. 30 Suitably, the method comprises the administration of buprenorphine and, an amount of naltrexone for the purpose of potentiating the analgesic action of the buprenorphine 11 and in particular to optimising the balance between the analgesic action of the buprenorphine and the anti-abuse presence of the naltrexone. It will be appreciated that this balance is extremely important. The medicament must 5 be a potent analgesic for it to fulfil its intended function. At the same time in the present day it is vitally important that opioid medicaments discourage abuse by addicts. It is believed that the present invention is extremely effective in these respects. 10 Separate administration of buprenorphine and of naltrexone is not excluded in the method. Suitably, however, the method comprises administering a composition comprising buprenorphine and naltrexone, to a human. Suitably, the 15 method employs a composition according to the first - aspect. The definition's given above in relation -to the first aspect apply to the second aspect, noting however that the buprenorphine and naltrexone may in principle be administered separately in the second.aspect. 20 Suitably, the method comprises administering to the human or animal from 0.25 pg to 20 pg per kilogram of body weight of buprenorphine per day. 25 The method may comprise administering a dose of buprenorphine which would, if administered alone, produce minimal or no antinociception. The method may comprise administering to the human amounts of buprenorphine and naltrexone as 'stated above in -relation to the first aspect 30 of the invention. The method may comprise any feature as described in relation to the first aspect.

12 According to a third aspect of the present invention there is provided the use of buprenorphine and naltrexone in the manufacture of a medicament for the treatment of pain, 5 wherein the buprenorphine and naltrexone are' used in an amount such that the medicament is delivered to a patient at, or reaches in the plasma of a patient, a ratio by weight in the range 100:1 to 5000:1, buprenorphine:naltrexone. 10 Suitably this aspect comprises the use of buprenorphine and of naltrexone in the manufacture of a medicament for the treatment of pain, wherein buprenorphine is used for its analgesic effect, but at lower level than would be 15 needed, for a-given analgesic effect against a given pain in a given patient, in the absence of naltrexone. Thus the' naltrexone potentiates the analgesic effect of buprenorphine. Further, it renders the medicament less attractive to drug. addicts. 20 The use of buprenorphine and of naltrexone in the manufacture of a medicament according to the third aspect may comprise any feature as described in relation to the first or second aspect. 25 Suitably, the use of buprenorphine and of naltrexone in the manufacture of a medicament comprises the manufacture of a medicament comprising a composition according to the first aspect. However the use of buprenorphine and of 30 naltrexone in the manufacture of a medicament having two dosage units, containing buprenorphine and naltrexone respectively, is not excluded.

13 The present invention will now be illustrated by way of example with reference to the accompanying drawings in which: 5 Figure 1 comprises graphs showing pain tolerance for buprenorphine and combinations with naltrexone; Figure 2 comprises graphs showing pain tolerance for buprenorphine and combinations with naltrexone;. 10 Figure 3 comprises comparative graphs; -and Figure 4 is a comparative graph. 15 Methods Nociceptive testing The - cold pressor (CP) test was used to assess 20 antinociception. of buprenorphine and buprenorphine -and naltrexone combinations. The compound forms were buprenorphine as HCl -salt and naltrexone as HCl salt. The CP test utilised two plastic cylindrical containers, one of which was filled with warm. water and the other with a .25 combination of water and crushed ice to achieve a "slushy" consistency. The subject immersed the non-dominant forearm . . and hand into the warm water for exactly 2 minutes. At 1 minute 45 seconds,, a blood pressure cuff on the immersed arm was inflated to a pressure 20 mm Hg below the 30 diastolic blood-, pressure. The blood pressure cuff minimised the role of blood flow in determining the reaction to cold. At exactly 2 minutes, the forearm was transferred from the warm water to the cold water bath.

14 The subject's eyes were covered for the entire procedure to minimise distraction and cues for time. Upon immersion of the limb in the cold water bath, subjects were asked to indicate when they first experienced pain (pain threshold, 5 CPTHR), then asked to leave their arm submerged until they can no longer tolerate the pain ,(pain tolerance, CPTOL). Pain threshold and tolerance times were recorded in seconds from immersion in cold. An undisclosed cut-off of 180' seconds was imposed, after which time pain tolerance 10 can no longer be accurately assessed due ^to numbness. Pain tolerance (CPTOL) is the reported pain response parameter in the current investigations. For the present tests nociceptive testing was conducted in 15 the same environment, with minimal background noise, audible voices and no clock with audible ticking. Ambient room temperature and lighting was consistent. At no time did the experimenter discuss with the subject his/her performance on the test; or answer any questions related 20 to the average pain tolerance -time or any previous results. Screening 25 Before testing subjects were screened according to the inclusion and exclusion criteria based upon such factors as previous medical conditions and drug abuse. Test Procedure 30 Suitable screened subjects were tested according to the following procedure. Subjects provided a urine sample upon arrival on the day of testing, which was tested for 15 drugs of abuse opioidss, cannabinoids, benzodiazepines and sympathomimetic amines). and, for female subjects, pregnancy. A 22 gauge indwelling ven.ous catheter was inserted into the best available forearm vein on each arm 5 (above the CP immersion line for the non-doniinant arm) . A male luer lock adaptor injection site was attached to each catheter. One catheter was usec for blood, sampling throughout the testing day, and the other for infusions. The participant was then connected to a monitor, which was 10 set to continuously monitor physiological parameters for the duration of the testing session. On each testing day, subjects received a 30 minute unblinded intravenous infusion of saline, followed by one 15 or more 30 minute drug (or placebo) infusions. The purpose of the initial saline infusion was two-fold: to establish whether any changes in pain or physiological parameters would occur as a response to the infusion process itself, and to ensure that there was no 20 obstruction to venous access via the catheter and the infusion pump was operating correctly. Infusions- were administered using a Syringe Pump. Drugs and saline were prepared- in 30ml BD Plastipak syringes. 25 Infusions were run at a rate of 20ml per hour for 30 minutes. Each syringe was attached- to a minimum volume extension set (15.0cm tubing, female luer lock, male -luer lock, 0.SmL/30cm) The male luer lock was attached to a lever lock cannula. The extension set was primed with the 30 drug/saline, and. inserted into the injection site. In buprenorphine:antagonist ratio studies, BUP and antagonist were administered simultaneously. For the simultaneous infusion of two drugs (via one cannula), a Y-type catheter 16 extension set with two injection sites was attached to the catheter, and the lever lock cannulas (connected via the minimum volume extension set to each syringe) were inserted in each of the injection sites. S Testing sessions were conducted on numerous occasions during each testing day. Each testing session consisted of the following measures in, the order listed: nausea and sedation recorded, blood sample taken, physiological parameters recorded (pulse,' oxygen saturation and blood 10 pressure), nociceptive testing (as detailed , above) completed, and respiration recorded (breaths per minute counted. for one full minute during warm water component of CP). 15 Testing sessions were 'conducted at set intervals throughout each testing day. These were as follows: 1. Prior to the commencement of infusions; 2. Twenty minutes after the commencement of the 30 minute saline infusion; 3. Twenty minutes after the commencement of the 30 minute '20 drug infusion, and hourly following the cessation of the (last) drug infusion. This-is referred to as the washout period. The purpose of conducting the testing session 20 minutes after commencing each 30 minute infusion was to allow time for the testing to be completed before starting 25 the subsequent infusion. Comparison of results As baseline values were different between conditions, 30 CPTOL data were expressed as percent change from baseline in order to compare the effect associated with different drug combinations. Each participant's response at each time point for each condition was expressed as a percent 1-7 change from baseline response according to the equation below. Data are expressed as the mean (±SEM) of these values at each post-drug testing session for each condition. 5 Post-drug latency - baseline latency baseline latency This provided a value for percentage change CPTOL. Examples 10 Example 1 Four' healthy Caucasian participants (2 males, 2 females) ranging in age from 21 to 33 years (Mean±SEM, 26.0' ±5.3 15 years) were enrolled in the study.. Mean body weight was 74 kg (±13.3, range 57 - 89 kg) and mean CPTOL at screening was 30.7 seconds (±6.-9, range 25 - 39 seconds). There were no significant differences between males and females in terms of age (p=0.

7 8 2 ) or CPTOL at screening 20 (p=0.7 9 2 ). Subjects were administered buprenorphine and naltrexone in a ratio of 100:1 by IV infusion with buprenorphine administered at a dose of 0.5 pg/kg body weight. The 25 washout monitoring was performed for a period of 4 hours. The CPTOL results are presented in Figure 1. No adverse effects causing concern were noted. Example 2 - comparative 30 18 As a comparative example the same subjects from Example 1 were administered, on a separate day, buprenorphine and saline (referred to. subsequently as "BUP only") by IV infusion. Buprenorphine was again administered at a dose 5 of 0.5 pig/kg body weight and the washout monitoring performed over 4 hours. The CPTOL. results are presented in Figure 1. Example 3 10 The same subjects from Example 1 were administered, on a separate day, buprenorphine and naltrexone in a ratio of 133:1 by IV infusion with buprenorphine administered at a dose of 0.5 pg/kg body weight. The washout monitoring was 15 performed for a period of. 4 hours. The CPTOL results are presented in Figure 1. No adverse effects causing concern were noted. Example 4 20 The same subjects from Example 1 were administered, on a separate day, buprenorphine and naltrexone in a ratio of 166:1 by IV 'infusion with buprenorphine administered at a dose of 0.5 pg/kg body weight. The washout monitoring was 25 performed for a period of 4 hours. The CPTOL results are presented in Figure 1. No adverse effects causing concern were noted. Example 5 30 The same subjects . from Example 1 were administered, on a separate day, buprenorphine and naltrexone in a ratio. of 200:1 by IV infusion with buprenorphine administered at a 19 dose of 0.5 ptg/kg body weight.. The washout monitoring was performed for a period of 4 hours., The CPTOL results are presented in Figure 1. No adverse -effects causing concern were noted. 5 Example 6 Four healthy Caucasian volunteers (2 male, 2 female) participated in the, study. Mean age of participants was 10 23.3 (1.89, range 18-27), and CPTOL at screening ranged from 27 to 37' seconds (32.3±2.5 seconds) . Mean body weight was- 76.0 kg (±10.7, range 59-107 kg) . There was no significant difference between male and female subjects.in terms of. age (p=0.

3 1 2 ), however CPTOL at screening was 15 -higher among the females (36 and 37 seconds) compared to the males (27 and 29 seconds) (p=0.0 3 7 ). Subjects were administered buprenorphine and naltrexone in a ratio of 200:1 by IV. infusion with buprenorphine 20 administered at a dose of 0.5 ptg/kg body weight. The washout monitoring was performed for a period of 4 hours. The CPTOL results are presented in Figure 2. No adverse effects causing concern were noted. 25 Example 7 -. comparative As a comparative example the same subjects from Example 6 were administered, on a separate day, buprenorphine 'and saline (referred to subsequently as "BUP only") by IV 30 infusion. Buprenorphine was again administered at a dose of 0.5 pg/kg body weight and the washout monitoring 20 performed over 4 hours. The CPTOL results are presented in Figure 2. Example 8 5 The same subjects from Example 6,were administered,. on a separate day, buprenorphine and naltrexone in a ratio of 500:1 by IV infusion with buprenorphine administered at a dose of 0.5 jg/kg body weight. The washout monitoring was 10 performed for a period of 4 hours. The CPTOL results are presented in Figure 2. No adverse effects causing concern were noted. Example 9 15 The same subjects from Example 6 were administered, on a separate day, buprenorphine and naltrexone in a ratio of 1000:1 by IV infusion with buprenorphine administered at a dose of 0.5 pg/kg body weight.. The washout monitoring was 20 performed for a period of 4 hours. The CPTOL results are presented in Figure 2. No adverse effects causing concern were noted. Example 10 25 The same subjects from Example 6 were administered, on a separate day, buprenorphine and naltrexone in a ratio of 5000:1 by IV infusion with buprenorphine administered at a dose of 0.5 pg/kg body weight. The washout monitoring was 30 performed for a period of 4 hours. The CPTOL results ar.e presented in Figure 2. - No adverse effects causing concern were noted.

21 Comparison of Examples 1-10 The percentage change for CPTOL from the baseline was calculated for Examples 2, 4 and 5 and the results are 5 presented in Figure 3. It may be seen' that there was a benefit of the , buprenorphine and naltrexone combinations compared to buprenorphine alone. The percentage change for CPTOL from the baseline was 10 calculated for Examples 7 and 9 and the results are presented in Figure 4. It may be seen that there was a marked benefit, particularly early on, of the buprenorphine and naltrexone combination compared to buprenorphine alone. 15 Example 11 - Buprenorphine/Naltrexone parenteral composition 20 A parenteral formulation having the following composition: mg/ml. Buprenorphine as HCl salt 0.1 Naltrexone as HCl salt 0.0006 Anhydrous dextrose 50.0 Hydrochloric acid to pH 4.0 'Water for injection to 1.0 ml was prepared by dissolving dextrose, buprenorphine 25 hydrochloride and naltrexone hydrochloride in that order with stirring, in about 95% batch volume of water for injection. The acidity of the solution was adjusted to pH 22 4.0 by the addition of 0.1M hydrochloric acid, and the solution was made up to volume with water for injection. The solution was filtered through a membrane filter and transferred to sterilised 2 ml glass ampoules containing 2 5 ml of the solution. The ampoules were sealed and the product sterilised by, autoclaving.

Claims (7)

1. An analgesic composition, in parenteral unit dosage form or in a unit dosage form suitable fo- delivery via 5 the mucosa or dermis,, the composition comprising buprenorphine and an amount of naltrexone such that the ratio by weight of buprenorphine to naltrexone delivered to or reaching the plasma of a patient is in the range 100:1 to 5000:1. 10

2. A composition as claimed in claim 1, wherein the amount of buprenorphine in the unit dosage form is from 10 pg to 8mg. 15

3. A composition as claimed in claim 1 or 2, wherein the composition contains buprenorphine and naltrexone in a ratio of 120:1 to 1000:1, preferably 140:1 to 500:1, preferably 150:1 to 180:1. 20

4. A method for the treatment of pain in a human patient, which method comprises the administration to a human patient, by a parenteral or dermal or mucosal route, of buprenorphine and naltrexone such that the ratio by weight of buprenorphine to. naltrexone delivered to or reaching 25 the plasma of a patient is in the range: 100:1 to 5000:1.

5. Use of buprenorphine and naltrexone in the manufacture of a 'Medicament for the treatment of pain, wherein the buprenorphine and naltrexone are used in an amount- such 30 that the medicament is delivered to a patient at, or reaches in the plasma of a patient, . a. ratio by weight in the range: 100:1 to 5000:1, buprenorphine:naltrexone. 24

6. A method of use as claimed in claim 5 or 6 wherein the administration of buprenorphine is in the range 0.25 to 640 pg per kg of body weight per 24 hours. 5

7. A composition or method or use, substantially as hereinbefore described in accordance with the present invention 10