THE USE OF IFENPRODIL IN THE TREATMENT OF PAIN Field of the Invention This invention relates to the use of a known compound for the treatment of pain. BACKGROUND OF THE INVENTION N-ethyl-D-aspartate (NMDA) receptor antagonists have long been known to exhibit anti-nociceptive effects, and a number have proven effective in the treatment of a number of neuropathies, including neuralgia postherpetic, the central pain caused by spinal cord injury and pain of the chimeric member. The NMDA receptor antagonist, destrorfan is disclosed for the treatment of pain in EP-A-0615749 and also, together with a number of other such compounds (including ifenprodil), in WO-A-97/14415. Unfortunately, most agents that block the NMDA receptor also induce unacceptable side effects in analgesic doses, including memory impairment, ataxia, hallucinations and dysphoria, which prohibit its widespread use. Ifenprodil, ie 2- (4-benzylpiperidino) -1- (4-hydroxyphenyl) -1-propanol, selectively blocks NMDA receptors containing NR2B in a voltage-independent and non-competitive manner (Gallagher et al., 1996 , J. Biol. Chem. 271 (16): 9603-9611) and exhibits anti-nociceptive activity in animal models of
acute and chronic pain (Taniguchi et al., 1997, Brit. J. Pharmacol., 122, 809-812; Boyce et al., 1999, Neuropharmacology 38: 611-623). Ifenprodil (as ifenprodil tartrate) is commercially available as a racemic mixture of the diastereomer eri tro. Ifenprodil also exhibits potent binding properties of the alpha-1 adrenergic receptor (Chenard et al., 1991, J. Med. C, 34 (10): 3985-3090) which can cause hypotension and syncope in some receptors. It is also reported by Chenard et al. That the threo isomers of ifenprodil have selectivity for the NMDA receptor on the alpha-1 adrenoreceptor. WO03 / 092689 describes the utility of ifenprodil in the treatment of neuropathic pain. Intranasal administration (and another route, which preferably avoids first-pass metabolism) is described. Brief Description of the Invention The present invention is based on the discovery that ifenprodil has utility in the treatment of pain, especially in non-neuropathic pain conditions, including post-operative pain, acute pain, chronic benign pain and cancer. Therefore, ifenprodil can be used to reinforce analgesia during intermittently uncontrollable episodes (interruptions) found under certain conditions of the
pain, for example conditions known as episodic or interrupted pain. These conditions include chronic benign pain and cancer pain. The states of chronic benign pain can be classified as musculoskeletal, visceral and headache pain and include conditions such as osteoarthritis, chronic pancreatitis and chronic migraine. The pain conditions of cancer are associated with the malignant growth of both primary and metastatic tumors. The condition is believed to be associated with either pressure on normal tissue (invasion) or by the release of pro-nociceptive mediators in and around the tumor. The pain conditions that are treated also include those associated with inflammation, for example, as in osteoarthritis. Description of Preferred Modes The ifenprodil has two chiral centers. Any reference in the present to ifenprodil should be understood as a reference to any enantió or mixture of them. Any enantiomer may be substantially free of others, for example, in an enantiomeric excess of at least 80%, preferably at least 90% and more preferably at least 95%. Similarly, any mixture of diastereomers can be substantially free of the other. The threo form, and in particular the (-) -treo form, may be preferred in certain cases; the form (-) - erythro,
it may be preferred in others. The ifenprodil may be in the form of the pure base or any pharmaceutically acceptable salt, for example the citrate or tartrate, or in the form of a metabolite or prodrug. Such forms are known to those of ordinary skill in the art. The active agent can be administered by, for example, the oral, topical, dermal, ocular, intravenous, intraarticular, rectal, vaginal, inhalation, intranasal, sublingual or buccal route. The amount of active ingredient that is used can be chosen by the skilled person having considered the usual factors. For use, the active agent is typically formulated, for example, with a conventional diluent or carrier, or as a patch, as a medicament adapted to be delivered by the selected route. Such formulations are known to those skilled in the art and will be selected in accordance with the usual considerations such as the potency of the drug, the severity of the condition and the route of administration. The ifenprodil is preferably administered sublingually, intranasally, buccally or via the pulmonary route or any other route that avoids first-pass metabolism. Sublingual or nasal delivery, for example, can introduce significant concentrations of
ifenprodil and its isomers to NMDA receptors while reducing the side effects caused by unwanted alpha-1 adrenoreceptor binding activity. In this context, a typical daily dose is less than 60 mg, for example, 1 to 50 mg of ifenprodil; a higher dose, for example up to 500 mg, can be used, especially if the first pass metabolism is not avoided. In particular, it would be beneficial to administer ifenprodil in a manner that reduces peripheral vascular vascular smooth muscle exposure (minimizing the effect on vascular tone), while maximizing concentrations in the CNS (maximizing analgesia). This can be done by, for example, pulmonary, sublingual or nasal delivery, reducing the systemic load, while maximizing the concentration of the drug in the CNS. By way of example only, a composition for intranasal delivery comprises, in addition to ifenprodil, one or more of a solubility improver such as propylene glycol, a humectant such as mannitol, a buffer and water. A mucoadhesive agent can also be used. Ifenprodil has very poor pharmacokinetics, with very high first-pass metabolism (5% bioavailability and a short half-life, t? / 2 1 hour). Consequently, the administration of ifenprodil orally, to treat a chronic condition similar to neuropathic pain, can
require high and frequent doses. Dermal administration, for example, through the use of a dermal patch, allows the chronic dosage of this compound, while the first pass metabolism is avoided and thus the dose is lowered. Additionally, there is the potential to rapidly remove the dose from the circulation at the end of the treatment period. Another preferred route of administration is the sublingual. A formulation suitable for this purpose may contain components known to those skilled in the art. It will often be advantageous to use ifenprodil in combination with another drug used for pain therapy. Another drug of such kind may be an opiate or a non-opiate such as baclofen. The following Examples illustrate the invention. Example 1 This example is a composition suitable for intranasal delivery. In this Example, 1-10 mg of ifenprodil, preferably as (-) -treo-ifenprodil citrate, is included in 100 μl of: Excipient:% w / w Benzalkonium Chloride 0.02 Conservative Propylene Glycol 25 Solubility Enhancer
Mannitol 15 Moisturizer
Na2P04 (0.2 M) 25.2 Citric acid (0.1 M) 10.0 Deionized water 24.6 (buffer solution pH 6.5) Example 2 In a test on the effect of ifenprodil on paw withdrawal latency induced by intraplantar carrageenan in the rat, the racemate Ifenprodil erythro was shown to be remarkably analgesic when administered by both the intraperitoneal route (10 mg / kg and 30 g / kg) and the intranasal route (2.5 mg / rat and 7.5 mg / rat); see Figure 1. The intranasal route was proven to be at least equivalent if not superior to the intraperitoneal route. The (-) threo-ifenprodil has also been shown to have excellent efficacy in the latency of paw withdrawal induced by intraplantar carrageenan in the rat at low doses (0.1, 0.3, 1 and 3 mg / kg intravenously); see Figure 2. These results indicate that (-) threo-ifenprodil, when given through the nasal route, will have excellent efficacy in this pain model and in conditions of chronic pain. More particularly, Fig. 1 is a graph showing the effect of (-) threo-ifenprodil when given intranasally or intraperitoneally at 30 and 10 mg / kg on the% change in paw withdrawal latency induced by pressure on the leg administered with carrageenan
intraplantar in the rat (250 g). Fig. 2 is a graph showing the effect of
(-) treo-ifenprodil when given intravenously at 0.1 to 3 mg / kg in the% change in leg withdrawal latency induced by pressure on the leg administered with carrageenan intraplantar in the rat.