WO2001000191A2

WO2001000191A2 - Use of fosphenytion for the treatment of acute neuropathic pain

Info

Publication number: WO2001000191A2
Application number: PCT/EP2000/006260
Authority: WO
Inventors: Gary John Mccleane
Original assignee: Warner-Lambert Company
Priority date: 1999-06-23
Filing date: 2000-06-22
Publication date: 2001-01-04
Also published as: AU5824800A; WO2001000191A3

Abstract

The invention concerns a method for the treatment of neuropathic pain and particularly acute neuropathic pain. The method comprises administering to a patient in need thereof an effective concentration of fosphenytoin over a prolonged period of time, particularly about 2250 mg (1500 mg PE) of fosphenytoin over a 24 hour period at the rate of about 90 mg (60 mg PE) per hour.

Description

USE OF FOSPHENYTOIN FOR THE TREATMENT OF ACUTE NEUROPATHIC PAIN

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Neuropathic pain is the result of functional abnormalities of the nervous system, peripheral or central. It usually develops after injury to the central nervous system. The sustaining mechanisms of two broad categories of neuropathic pain appear to involve reorganization of central somato-sensory processing. Deafferentiation pain is due to partial or complete interruption of peripheral or central afferent neural activity. Sympathetically maintained pain is dependent on efferent, sympathetic activity. Both are complex, and although presumably related pathogenetically, they differ substantially.

Neuropathic pain typically occurs following injury to elements of the nervous system (either peripheral of central). Neuropathic pain may produce deep aching, dysesthesias, burning and lancinating pain. Other abnormalities of perception of pain may occur as hyperesthesia, hyperalgesia and allodynia.

Because of the abrupt nature of the painful attacks in acute neuropathic pain, temporal profiles similar to those of seizures have been established. In the lancinating component of neuropathic pain, anticonvulsants have been used to reduce the frequency and strength of the attacks. However, dosage is extremely critical and unbearable side effects have often been observed. Furthermore, various analgesics such as opioids and corticosteroids have been used with a very limited rate of success. A typical anticonvulsant drug that has been used in the past to treat neuropathic pain is phenytoin. However, the major drawback with phenytoin is its potential for causing severe discomfort on intravenous injection, with the danger of tissue reaction if the infusion leaks from the vein. SUMMARY OF THE INVENTION

The inventor has discovered that appropriate dosages of fosphenytoin can be efficiently used for the treatment of acute neuropathic pain. In this regard, the present invention concerns a method for the treatment of neuropathic pain which comprises administering to a patient in need thereof, a steady state concentration of fosphenytoin over a period of 16 to 36 hours to provide sustained neuropathic pain relief over a period of time which in some instances, extends beyond the treatment itself. In some embodiments, this steady state administration is preceded by the administration of an initial loading dose of fosphenytoin, usually in the range of 300 to 600 mg PE (450 to 900 mg fosphenytoin).

The invention also concerns the use of fosphenytoin for the preparation of a medicament useful for preventing or treating acute neuropathic pain.

DETAILED DESCRIPTION OF THE INVENTION Fosphenytoin has been described in the literature as a phenytoin prodrug. It is a highly water-soluble ester of phenytoin. Although the literature generally describes no known pharmacological activity before the bio-conversion of fosphenytoin into phenytoin, the effect of the two drugs on certain diseases differ. For example, fosphenytoin was found to offer less protection against homocysteine dilactone-induced status epilepticus compared with phenytoin. Also, only phenytoin displays in vitro anti-arrhythmic activity against strophanthidin-induced arrhythmias in animals.

Using prolonged fosphenytoin administration rates and, in some embodiments, with a relatively important loading dose, the inventor has obtained spectacular results on patients from whom pain relief had in the past been demonstrated to be just about impossible to achieve. Efficient relief of severe neuropathic pain could be achieved through intravenous infusion of about 1100 to 1800, preferably 1300 to 1600 and more preferably about 1500 mg PE of fosphenytoin over a period of about 16 to 36 hours, preferably 20 to 28 hours and more preferably about 24 hours. Fosphenytoin is therefore administered at a steady- state rate ranging from about 45 to 75 mg PE per hour, preferably from about 55 to 65 mg PE per hour and more preferably at about 60 mg PE per hour.

At some of the preferred rates of administration, most patients develop side effects such as unsteadiness, dizziness and nausea. This appears to suggest that larger doses could be complicated by even more unacceptable side effects. Furthermore, the clinical investigation conducted by the inventor seems to show that between about 40 and 60 % of the patients treated experience symptom alleviation. This appears to suggest that smaller doses of fosphenytoin would reduce the percentage of patients gaining an advantage from such an infusion.

However, a very surprising effect has been obtained when this mode of administration of fosphenytoin was used. Indeed, for those patients who obtained pain relief from the treatment, it has been shown that the relief extends beyond the duration of the infusion and even beyond the serum half-life of fosphenytoin. For example, a 24 hour infusion can produce up to 10 days of pain relief.

Another aspect of the present invention is a pharmaceutical composition for the treatment or prevention of acute neuropathic pain which, in one of its preferred embodiments, comprises between about 1100 and 1800, preferably between 1300 and 1600 and more preferably about 1500 mg PE of fosphenytoin in admixture with a pharmaceutically acceptable excipient which allows a steady-state i.v. administration of fosphenytoin within a predetermined time period. This is the preferred embodiment of the composition of the present invention. However, any other type of pharmaceutical composition that can deliver a steady state amount of fosphenytoin, preferably a concentration of about 60 mg PE per hour over a period of approximately 24 hours, can be used. The composition of the invention can also take the form of a kit containing several (usually between 4 and 8) smaller sustained release doses of fosphenytoin to be administered to the patient at regular intervals to insure a steady-state delivery of fosphenytoin over the desired period of time.

Preferred formulations include the following :

1) Oral administration : various types of sustained release tablets can be made by the skilled person.

2) Intramuscular administration : for this type of administration, one can foresee the use of sustained-release gels as well as the use of sustained relief implants.

3) Intravenous administration : one can foresee the possibility of using at least two different types of i.v. compositions. The first group of i.v. compositions include classical i.v. infusions which can be administered at a steady state to the patient in order to deliver the appropriate fosphenytoin concentration over a determined period. The other possibility is the use of suspensions such as nanoparticular suspensions which can be used for the injection of sustained relief formulations, dispersed formulations and liposomes.

The following example is with provided to illustrate the present invention but should not be construed as restricting the scope of the invention to a specific embodiment.

Example 1

Patients with severe neuropathic pain received an intravenous infusion of 1500 mg PE units of fosphenytoin over a 24 hour period using a disposable intravenous infusor. The effect of the infusion has been examined in a double-blind, placebo controlled fashion and measuring the parameters of neuropathic pain. The result in terms of overall pain are highlighted in table 1 below. The pre-treatment mean pain score was 7.9.

TABLE 1

Claims

WHAT IS CLAIMED IS :

1) A method for the treatment of acute neuropathic pain, said method comprising administering to a patient in need thereof between about 45 and 75 mg PE per hour of fosphenytoin over a period of 16 to 36 hours.

2) A method according to claim 1 wherein about 1500 mg of phenytoin is administered over a period of about 24 hours.

3) A method according to claim 1 or 2 which further comprises administering an initial loading dose of about 300 to 600 mg PE of fosphenytoin to the patient. 4) A pharmaceutical composition for the treatment of acute neuropathic pain, said composition comprising between 1100 and 1800 mg PE of fosphenytoin in admixture with a pharmaceutically acceptable excipient, such composition allowing the steady- state delivery of fosphenytoin to a patient in need thereof at a rate of about 45 to 75 mg PE per hour. 5) A pharmaceutical composition according to claim 4, wherein the composition is a composition suitable for intravenous injection, such composition comprising between 1300 and 1600 mg PE of fosphenytoin in admixture with pharmaceutically acceptable i.v. excipient. 6) The use of 1 100 to 1800 mg PE of fosphenytoin for the preparation of a medicament for the treatment of acute neuropathic pain wherein said medicament can be used to deliver a steady state concentration of about 45 to 75 mg PE per hour of fosphenytoin to a patent in need thereof.