Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-25
2001-01-30
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227800, C514S230800, C514S231200, C514S231500, C514S235500, C514S235800, C514S236200, C514S236800, C514S239500, C514S282000
Reexamination Certificate
active
06180624
ABSTRACT:
This invention relates to the treatment or prevention of pain or nociception by the administration of a combination of a tachykinin antagonist, in particular an NK-1 receptor antagonist, and an opioid analgesic.
Pain has been defined as the sensory experience perceived by nerve tissue distinct from sensations of touch, pressure, heat and cold. It is often described by sufferers by such terms as bright, dull, aching, pricking, cutting, burning, etc. This range of sensations, as well as the variation in perception of pain by different individuals, renders a precise definition of pain near impossible. Pain as suffering, however, is generally considered to include both the original sensation and the reaction to that sensation. Where pain is “caused” by the stimulation of nociceptive receptors and transmitted over intact neural pathways, this is termed nociceptive pain. Alternatively, pain may be caused by damage to neural structures, often manifesting itself as neural supersensitivity, and is classed as neuropathic pain.
The level of stimulation at which pain is perceived is referred to as the “pain threshold”. Where the pain threshold is raised, for instance, by the administration of an analgesic drug, a greater intensity or more prolonged stimulus is required before pain is experienced. Analgesics are a class of pharmaceutical agent which, following administration to a patient in need of such treatment, relieve pain without loss of consciousness. This is in contrast to other pain-relieving drugs, for example, general anaesthetics which obtund pain by producing a hiatus in consciousness, or local anaesthetics which block transmission in peripheral nerve fibres thereby preventing pain.
Tachykinin antagonists have been reported to induce antinociception in animals, which is believed to be analogous to analgesia in man (for review see Maggi et al,
J. Auton. Pharmacol.
(1993) 13, 23-93). In particular, non-peptide NK-1 receptor antagonists have been shown to produce such analgesia, thus, for example, in classical tests of chemo-nociception (phenylbenzoquinone-induced writhing and formalin test) the NK-1 receptor antagonist RP 67,580 produced analgesia with potency comparable to that of morphine (Garret et al,
Proc. Natl. Acad. Sci. USA
(1993) 88, 10208-10212).
The opioid analgesics are a well-established class of analgesic agent. They are also sometimes referred to as opiates although this term should be reserved for chemical relatives of morphine. The term opioid is generally accepted to refer in a generic sense to all drugs, natural or synthestic, with morphine-like actions. The synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans. Pharmacologically these compounds have diverse activities, thus some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g. nalbuphine); and yet others are partial agonists (e.g. nalorphine). Whilst an opioid partial agonist such as nalorphine, (the N-alkyl analogue of morphine) will antagonise the analgesic effects of morphine, when given alone it can be a potent analgesic in its own right.
Of all of the opioid analgesics, morphine remains the most widely used and is a suitable archetype compound. Unfortunately, apart from its useful therapeutic properties, morphine also has a number of drawbacks including respiratory depression, decreased gastrointestinal motility (resulting in constipation) and, in some individuals, nausea and vomiting may occur. Another characteristic is the development of tolerance and physical dependence which may limit the clinical use of such compounds. There is therefore a need to develop methods which enable the clinician to use lower doses of opioid analgesics such as morphine, thereby reducing the likelihood of tolerance and dependence, and thus avoiding the major problem of drug withdrawal associated with cessation of administration.
Morphine-induced emesis may be effectively blocked by the administration of a potent, non-peptide NK-1 receptor antagonist (Bountra et al.,
Eur. J. Pharmacol.,
(1993) 249, R3-R4). It is therefore surprising to find that other effects of morphine, notably morphine-induced analgesia, are not blocked by an NK-1 receptor antagonist. Thus, treatment with morphine and an NK-1 receptor antagonist relieves pain without reduction of the morphine analgesic activity, and with the added benefit of enabling lower doses of morphine to be used, as well as reducing the likelihood of nausea and vomiting.
The present invention accordingly provides the use of a tachykinin antagonist and an opioid analgesic for the manufacture of a medicament for the treatment or prevention of pain or nociception.
The present invention also provides a method for the treatment or prevention of pain or nociception, which method comprises administration to a patient in need of such treatment an amount of a tachykinin antagonist and an amount of an opioid analgesic such that together they give effective pain relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a tachykinin antagonist and an opioid analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the tachykinin antagonist and opioid analgesic may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of pain. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a tachykinin antagonist and an opioid analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
The compositions of the present invention are useful for the treatment of pain of any eitiology, including acute and chronic pain and any pain with an inflammatory component. Examples of acute pain include, in particular, post-operative pain, migraine, headache and trigeminal neuralgia. Examples of chronic pain include, in particular, pain associated with musculo-skeletal disorders such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism and peri-articular disorders, and pain associated with cancer, peripheral neuropathy and post-herpetic neuralgia. Examples of pain with an inflammatory component (in addition to some of those described above) include rheumatic pain, dental pain and dysmenorrhoea.
The compositions of the present invention are especially useful for the treatment of pain where the use of an opioid analgesic is generally prescribed. By the use of a combination of a tachykinin antagonist and an opioid analgesic in accordance with the present invention, it is now possible to treat pain with a sub-maximal dose of an opioid analgesic thereby reducing the likelihood of side-effects associated with opioid analgesic usage (e.g. respiratory depression, constipation, nausea and vomiting, and tolerance and dependence and the associated problem of drug withdrawal).
A particularly preferred use for a composition of the present invention is in the treatment or prevention of post-operative pain.
The tachykinin antagonists of use in the present invention may be any tachykinin antagonist known from the art. Preferably, the tachykinin antagonist is an NK-1 or NK-2 receptor antagonist, especially an NK-1 receptor antagonist.
NK-1 receptor antagonists of use in the present invention are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538 and 0 610 793; and in International Patent Specification Nos. 90/05525
Jarvis William R. A.
Merck Sharp & Dohme Limited
Rose David L.
Thies J. Eric
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