WO1990000390A1

WO1990000390A1 - New synergistic preparations containing dezocine and a local anaesthetic and a new method of alleviation of pain

Info

Publication number: WO1990000390A1
Application number: PCT/SE1989/000348
Authority: WO
Inventors: Claes Tomas Post
Original assignee: Aktiebolaget Astra
Priority date: 1988-07-08
Filing date: 1989-06-19
Publication date: 1990-01-25
Also published as: SE8802564D0; AU3856489A

Abstract

A pharmaceutical preparation for spinal analgesia, which alleviates postoperative or chronic pain containing dezocine or a physiologically acceptable salt thereof together with a local anaesthetic, such as bupivacaine or a physiologically acceptable salt thereof, a method for obtaining said preparation and a method of obtaining analgesia by administering said preparation to a patient in the need of analgesia.

Description

New synergistic preparations containing dezocine and a local anaesthetic and a new method of alleviation of pain.

Field of the Invention

The present invention is related to new synergistic pharmaceutical preparations, a method for their preparation and to a new method of alleviation of postoperative pain and pain related to pathophysiological changes in man, such as severe chronic pain, wherein the new pharmaceutical preparations are used.

Background of the Invention

The suffering from pain after operations, and that related to diseases as cancer and neurological diseases, has been the subject to treatment with e.g. conventional opiate analgesics. These have several severe draw-backs, as e.g. development of tolerance, addiction and sedation with risk for respiratory depression. There is thus a need for analgesic agents intended for pain relief post-operatively and for relief of severe pain of other origins, which do not have the mentioned draw-backs. The opiate agonist/antagonist analgesics have been shown to have several advantages in this respect. Another type of drug that has been used εpinally to treat pain, is the local anaesthetic compounds. Their disadvantage as analgesics is the undesired motor impairment that occurs at doses very close to those giving rise to analgesia. One possibility to avoid this is to combine an opiate agonistic/antagonistic drug with a local anaesthetic, in order to achieve an additive or synergistic analgesic effect thereof. Prior art

The compound dezocine, (-)-13β-amino-5,6,7,8,9,10,11,12- octahydro-5α-methyl-5,ll-methanobenzocyclodecen-3-ol, is described in e.g. US patent 4001331 and is known as an orally and parenterally active analgesic agent.

Outline of the Invention

According to the present invention it has been found that the known compound dezocine when administered together with a known local anaesthetic compound, e.g. bupivacaine, lidocaine, tetracaine or ropivacaine, gives an unexpected synergistic antinociceptive effect when administered intrathecally. The new preparations thus can be used to alleviate pain when administered intrathecally or epidurally.

Examples of physiologically acceptable salts, which are used according to this invention are hydrochloride, hydrobromide, lactate, acetate or sulphamate.

Especially preferred physiologically acceptable salts are the hydrochlorides of dezocine and bupivacaine.

The present invention thus provides new pharmaceutical preparations containing dezocine and a local anaesthetic agent, methods for preparing such preparations and methods for alleviating pain sensation wherein said pharmaceutical preparation is used in the post-operative period for the treatment of severe chronic pain. The pharmaceutical preparations are for spinal analgesia. They are preferably administered by intrathecal or epidural injection. In a preferred embodiment of this invention dezocine and bupivacaine are incorporated in a pharmaceutical preparation suitable for intrathecal or epidural injection.

In a further preferred embodiment of this invention dezocine HC1 is incorporated in a pharmaceutical preparation suitable for intrathecal injection together with bupivacaine HCl. A convenient route of administration of the new preparations is spinally i.e. intrathecally or epidurally, which will allow repeated administration over a long period of time. When administering the drug in this way intrathecally, a convenient way of restricting spread to segments more roεtrally than intended, would be to make the solution hyperbaric by adding i.e. glucose to the desired density. To restrict the elimination of the drugs from the site of injection, a vasoconstrictor such as adrenaline may be added to the solution.

The dosage of administration of dezocine and the local anaesthetic depend i.a. on the route of administration and the pharmaceutical formulation. A suitable dosage for obtaining analgesia by intrathecal or epidural administration is between 3 and 500 μg/kg of dezocine and between 0.1 and 1.5 mg/kg of bupivacaine.

Pharmaceutical preparations

In clinical practice the preparations will normally be injected intrathecally or epidurally. The preparations used are solutions which contain between 0.01 and 0.1 % by weight of dezocine between 0.1 and 1 % by weight of the local anaesthetic, and between 5-10 % by weight of glucose in order to increase the baricity of the solution. It is also possible to add a small amount of the vasoconstrictor adrenaline to the solution in order to restrict spreading. The preparations are made by dissolving the active ingredient or ingredients in a physiologically acceptable solvent.

Example 1

Dezocine HCl 0.6 mg/ml Bupivacaine HCl 5 mg/ml Sodium chloride 9 mg/ml Distilled water ad 100 ml

Example 2

Dezocine HCl 0.6 mg/ml Bupivacaine HCl 5 mg/ml Glucose 75 mg/ml

Sodium chloride 9 mg/ml Distilled water ad 100 ml

Example 3

Dezocine HCl 0.6 mg/ml Bupivacaine HCl 5 mg/ml Adrenaline 12.5 μg/ml Sodium chloride 9 mg/ml Distilled water ad 100 ml

Example 4

Dezocine HCl 0.6 mg/ml Lidocaine HCl 50 mg/ml Sodium chloride 9 mg/ml Distilled water ad 100 ml Example 5

Dezocine HCl 0.6 mg/ml

Ropivacaine HCl monohydrate 7.5 mg/ml Sodium chloride 9 mg/ml

Distilled water ad 100 ml

Example 1 is considered to represent the best mode of carrying out the invention known at present.

Pharmacological tests

The antinociceptive effect of the new preparations may be established by the hot plate and tail-flick test.

Testing of tail-flick was performed using an IITC inc. Mod. 33 Analgesiameter , with the light focused on the tip of the tail (d' mour, F.E and Smith, D.L. J. Pharmacol. Exp. Ther. 7_2, 74, 1941). The intensity of the beam was adjusted to give a reaction time of 3-4 sec. before intrathecal injection of the drug solutions. For the hot plate testing, a modification of the Eddy and Leimbach method (Eddy, N.B. and Leimbach, D.J. Pharmacol. Exp. Ther. 107, 385, 1952) was used. An IITC Inc. Mod. 35-D

^*p Analgesiameter was set at a temperature of 58+0.2°C. The criteria for a pain response was licking or kicking of either of the hindpaws. The cut-off time in the hot plate test was 30 sec. and in the tail-flick test 10 sec.

The pain responsiveness was examined in male NMRI mice in a weight range of 22-25 g. They were housed in groups of 10 in each cage for at least 4 days after delivery.

All drugs were administered by the lumbar puncture technique, essentially as that originally described by

Hylden and Wilcox, Eur. J. Pharmacol. 67, 313, 1980. In brief, a 30 G stainless steel cannula was inserted through the lumbar L4/L5 vertebral interspace, and the drug solution was delivered with a microsyringe, attached to the cannula by a PE 50 polyethylene tube. The drugs were delivered in a volume of 5 μl.

After the injections, the animals were tested for hot plate and tail-flick tests. The drugs were administered in a volume of 5 μl, and testing of hot plate and tail-flick reaction latencies took place at the intervals given in the tables. The animals were not tested until the local anaesthetic effect of bupivacaine had disappeared, which normally took between 10 and 15 minutes.

In the experiments with combinations of dezocine HCl and bupivacaine HCl, the results illustrate that the substances act in a synergistic way, cf. Tables 1A and IB. Although the effect of 3 μg dezocine, and also that of bupivacaine alone, completely had disappeared 2 hours after injection, a strong antinociceptive effect could be found for the new combination. In this study, the statistical difference was calculated for dezocine compared to dezocine injected together with bupivacaine. In the hot plate test, c.f. Table IB, some additive effect might have occured at 30 min after injection, since the animals injected with bupivacaine alone had a slight antinociceptive effect at this time. It is however obvious, from the Tables 1A and IB, that the contribution of dezocine to the antinociceptive effect of the preparation is more than additive. Regarding the local anesthesia, this appeared to be the same regardless whether bupivacaine HCl was injected alone or together with dezocine HCl. The duration of the motor blockade was thus between 15 and 20 min regardless of whether bupivacaine was injected alone or together with dezocine. Table 1A and IB

Antinociceptive effects of dezocine HCl at a dose of 3 μg alone or combined with 37.5 μg bupivacaine HCl in the tail-flick (A) or hot plate (B) tests. The cut-off time in the tail-flick test was 10 sec and in the hot plate test 30 sec. The values are reaction times (seconds) expressed as means + S.E.M. and represent the results from experiments performed in 10 mice. Note that the reaction time at 0 min represents the basal value for the animals, and that an increase from this value represents antinociception. The synergistic antinociceptive effects in animals injected with the combination of dezocine and bupivacaine is therefore, obvious at 60 and 120 min. in the tail-flick test and at 30 and 60 min. in the hot plate test (Mann-Whitney U-test) . ** P<0.01 when the difference between dezocine injected alone or together with bupivacaine is calculated.

Table 1A

Intrathecal administration of dezocine and/or bupivacaine tail-flick test mouse

Intrathecal administration of dezocine and/or bupivacaine hot late test mouse

Claims

1. A pharmaceutical preparation for spinal analgesia, characterized in that it contains dezocine or a physiologically acceptable salt thereof together with a local anaestetic agent or a physiologically acceptable salt thereof.

2. A pharmaceutical preparation according to claim 1 characterized in that it also contains glucose.

3. A pharmaceutical preparation according to claim 1 characterized in that it also contains adrenaline.

4. A pharmaceutical preparation according to claim 1 characterized in that it contains dezocine in an amount of between 0.01 and 0.1 % by weight and the local anaesthetic agent in an amount of between 0.1 and 1 % by weight.

5. A pharmaceutical preparation according to claims 1-4 characterized in that the local anaesthetic agent is bupivacaine or a physiologically acceptable salt thereo .

6. A pharmaceutical preparation according to claims 2 and 5 characterized in that it contains 0.06 % by weight of dezocine, 0.5 % by weight of bupivacaine and 5-10 % by weight of glucose.

7. A pharmaceutical preparation according to claim 1 characterized in that it contains 0.06 % by weight of dezocine and 1 % by weight of ropivacaine.

8. A method for the preparation of a pharmaceutical preparation according to claim 1 characterized in dissolving dezocine or a physiologically acceptable salt thereof together with a local anaesthetic agent or a physiologically acceptable salt thereof in a pharmaceutically acceptable solvent.

9. A method of obtaining analgesia comprising intrathecal or epidural injection to a patient in the need of analgesia an amount of dezocine or a physiologically acceptable salt thereof effective to obtain analgesia together with an amount of a local anaesthetic or a physiologically acceptable salt thereof effective to obtain local anaesthesia.

10. Use of dezocine together with a local anaesthetic in the manufacture of a pharmaceutical preparation with analgesic effect.