MXPA01002234A - Treatment of persistent pain - Google Patents

Abstract

A method of using N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine to treat persistent pain.

Description

THE USE OF DULOXETIN TO TREAT PERSISTENT PAIN FIELD OF THE INVENTION The invention relates to a method for using N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (hereinafter referred to as 'duloxetine') for the treatment of persistent pain.

BACKGROUND OF THE INVENTION For some years, it has been recognized that the chemistry of serotonin and norepinephrine is extremely important in neurological processes, and pharmacologists and medical researchers have been very actively studying the mechanisms of those neurotransmitters in the brain. Concomitantly, the synthesis and study of pharmacists which affect the processes of serotonin and norepinephrine in the brain are of great interest and are also intensively studied by pharmaceutical chemists and by medical researchers as well. Duloxetine inhibits the reincorporation of REF. : 127235 both serotonin and norepinephrine, and is investigated for being used as an antidepressant. 3-aryloxy-3-substituted propanamines, such as duloxetine, have been described in U.S. Patent No. 5,023,269 for being used for the treatment of pain. This patent, however, does not specify what forms of pain are treated. PCT / US95 / 13289 discloses that duloxetine is used for the treatment and prevention of neuropathic pain and migraine. As stated herein, 'nuropathic pain, as distinct from other varieties of pain, is emanating specifically from a neurological source, such as from a nerve, which is unnaturally stressed, compressed or otherwise injured, does not include the pain emanating of an injury or inflammation of the bone, muscle or other tissue. "PCT / US95 / 13289 defines migraine" as a headache, particularly a very severe headache, which occurs repetitively in patients subject to the condition. They have been treated with partial events with vasoconstrictors, but no treatment of migraine in the prior art, is certainly successful. "For clinical purposes, pain can be divided into two categories: acute and persistent pain.Acute pain is caused by harmful or damaging stimulation produced by injury and / or skin disease, deep somatic structures or viscera, or abnormal function of the muscle or viscera that do not cause damage to the current tissue, otherwise, the persistent pain can be defined as the pain that persists beyond the usual course of an acute condition or a reasonable time due to a health injury, or that is associated with a chronic pathological process that causes continuous pain or pain repeated at intervals for months or years. still present after a cure has been made, it is considered persistent pain For the purposes of the present invention, pain persists It can be chronic not mitigated or recurrent. The difference in the definition between acute and persistent pain is not merely semantic, but it has an important clinical relevance. For example, a simple fracture of the wrist usually remains painful for a week up to 10 days. If the pain is still present beyond the typical course of treatment, it is likely that the patient is developing a reflex of sympathetic dystrophy, a persistent pain syndrome that requires immediate effective therapy. Early and effective intervention potentially prevents undue disability and suffering, and prevents the potential development of a condition that becomes intractable with therapy. Acute and chronic pain differs in etiology, mechanisms, pathophysiology, symptomatology, diagnosis, therapy, and physiological responses. In contrast to the transient nature of acute pain, persistent pain is caused by chronic pathological processes in somatic or visceral structures, by prolonged and sometimes permanent dysfunction of the central or peripheral nervous system, or both. As well, persistent pain can sometimes be attributed to psychological mechanisms and / or environmental factors. Persistent pain is a state of suffering that is one of the most important health problems in industrialized nations around the world. Persistent pain and suffering, despite the cause, has a serious physical, behavioral, mental, psychological, social and economic effect on both the patient and the family, and is very costly to society. The mental effects of persistent or prolonged pain are mainly influenced by the duration, intensity, and periodicity of persistent pain, by the personality and psychological characteristics of the individual, and by various sociological and economic factors. The duration of persistent pain is an important factor in determining the mental effects; but while the average individual may briefly carry, both psychologically and physiologically, even the most severe pain, if such pain is prolonged, it exerts effects which cause mental and physical deterioration. Prolonged, persistent and intense pain interferes with the reasoning processes and dominates the entire organism. The impact of persistent pain in society is equally devastating as its effects on the victim. Patients develop problems with their families and friends, and, as previously mentioned, they decrease their social interactions. Domestic routines, (cooking, care for a sick child, etc.) social and family obligations, are often canceled. Some patients are unable to work, some are ineffective at work, others are not encouraged to work, and still others lose their jobs due to frequent absences. In effect, the unemployment ratio of some chronic pain conditions can be 4-5 times higher than the average unemployment rate in the United States. These profound social effects can give the patient an economic disadvantage instead of an advantage. Current therapies for persistent pain include opiates, drugs such as barbiturate such as sodium thiopental, and surgical procedures such as neurectomy, rhizotomy, cordotomy, and cordectomy. These therapies have significant disadvantages. Opiates and drugs such as barbiturate have side effects that are limiting and addictive. Tricyclic antidepressants and anticonvulsants are marginally effective, and are also associated with some limiting side effects. Electrical stimulation for example, TENS has limited events in chronic pain. Surgical procedures are costly, irreversible and often fail to provide long term assistance for persistent pain. Faced with suboptimal therapy for persistent pain, patients suffer more, complain more, and become more desperate and dissatisfied with their health care. As a consequence, the patient seeks and consumes more direct and indirect means of health care. In view of these realities, there is a demand for more effective analgesic agents, specifically targets for persistent pain, which have superior safety and tolerability profile and are not addictive. Ideal analgesics may reduce pain awareness, produce analgesia over a wide range of pain types, act satisfactorily if given orally or parenterally, produce minimal or no side effects, and are free from a tendency to produce tolerance and dependence on the drug . The present invention addresses the need for a safe and effective treatment of persistent pain by providing a persistent pain treatment method.

DESCRIPTION OF THE INVENTION According to the present invention, there is provided a persistent pain treatment method comprising the administration to a patient in need of such treatment, of an effective amount of duloxetine.

The present invention also provides the use of duloxetine for the manufacture of a medicament for the treatment of persistent pain. In addition, the present invention provides the use of duloxetine for the treatment of persistent pain. The term "treatment" for purposes of the present invention includes the prophylaxis or prevention, amelioration or elimination of a named condition once the condition has been established.The term "patient" for purposes of the present invention is defined as any warm-blooded animal, such as, but not limited to, a mouse, guinea pig, dog, horse or human.

Preferably, the patient is a human. For purposes of the present invention, the term 'acute pain' is defined as a pain which is caused by the damaging stimulation caused by injury and / or skin disease, deep somatic structures or viscera, or abnormal muscle function. or viscera, which do not cause damage to the current tissue.The term "persistent pain" as used herein, is defined as a pain that persists beyond the usual course of an acute state or reasonable time for damage to the greeting or that is associated with a chronic pathological process that causes continuous pain or pain repeated at intervals for months or years. If the pain is still present after a cure has been made or beyond a typical course of treatment, it is considered persistent pain. The length of time that could pass before the pain is persistent depends on the nature of the pain and the typical course of treatment associated with the pain. The pain is persistent if it is lasting beyond a typical course of treatment. Persistent pain includes, but is not limited to, tension-type headaches, skeletal muscle pain, pain associated with somatoform disorders, visceral pain, painful diabetic neuropathy, vascular pain, arthritic pain, back pain, neck pain , shoulder pain, pain from cancer, pain associated with AIDS, post-operative pain, and post-burn pain. Duloxetine is effective in the treatment of persistent pain as defined above. Also, duloxetine is useful in the treatment of other conditions where there is hypersensitivity to painful signals, hyperalgesia, allodynia, increased pain perception and increased pain memory. Duloxetine will be improved by mimicking pain. Tension-type headache is the most common form of primary or idiopathic headaches, that is, those that are not related to an identifiable cause. Two types of tension-type headaches are recognized; the type episodic tension and chronic tension type. 'chronic tension type headaches' as used here, are defined by the criteria of the International Headache Society (Cephalalgia 1988; 8 . { Suppl 7): 1-96) as recurrent pains that are present for at least 15 days in a month, for at least 6 months. The headache is usually insistent / severe in quality, medium or moderate in severity, bilateral and does not worsen with physical activity. Nausea, photophobia or phonophobia may occur. "Chronic tension type headache (TTH) occurs in 2-3% of the population. The severity of TTH pain, other than episodic TTH, is usually moderate to severe. Chronic TTH is differentiated from migraine clinically based on the following characteristics: bilaterality of pain; non-pulsating quality; often from varied locations of pain; infrequent association with sensitivity of both light (phototrophy) and noise (phonophobia). In addition, sensitivity to odor (osmophobia) is not a symptom of TTH; the absence of neurological accompaniments such as visual or sensory auras. "Somatoform alterations" as used in the present invention, are defined as having, as a common feature, the presence of physical symptoms suggesting a general medical condition, which is not completely explained by a general medical condition, by the direct effects of a substance, or by other mental alterations. (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, p.445) Somatoform alterations include functional somatic syndromes, including those referenced in Barsky AJ, Borusn JF. So atic Syndromes, Ann Intern Med 1999; 130: 910-921, such as, but not limited to, multiple chemical sensitivity, disease construction syndrome, repetitive stress injury, chronic whiplash, chronic calcium conditions, side effects of silicone breast implants, hypersensitivity to candidiasis, Gulf War Syndrome, food allergies, prolapse of the to mitral valve, and hypoglycemia. The term "musculoskeletal pain" as used herein, includes but is not limited to, myofacial pain, trauma-induced pain, and chronic regional pain syndrome.The term "myofascial pain" as used herein, includes but is not limited to a, suffering from temporo-mandibular junctions (TMJ) and fibromyalgia with or without chronic fatigue syndrome. The term 'fibromyalgia', for purposes of the present invention includes but is not limited to, that pain which is defined by the American College or Rheumatology (ACR) classification (olf F, et al., The American College of Rheumatology 1990 Criteria for the classification of fibrosis and pain: Report of the Multicenter Criteria Committee, Arthritis Rheu 33: 160-172, 1990. Fibromyalgia is a clinical syndrome characterized by chronic muscle pain, stiffness or inflexibility, fatigue, non-renovating sleep, and localized weaknesses The ACR criteria for fibromyalgia is: 1) pain extended in all four quadrants and the axial skeleton for more than the last 3 months, and 2) pain in 11 or more than 18 points under examination by digital pressure For the purposes of the present invention, 'painful diabetic neuropathy' is pain which is secondary to nerve injuries as a complication of diabetes mellitus. itus The nerve injuries in diabetes mellitus are caused at least in part by decreased blood flow and high blood sugar levels. Some diabetics will not develop neuropathy, while others may develop this condition relatively early. Diabetic neuropathies can be classified into mononeuropathies that involve one or more focal sites and generalized polyneuropathies which can be diffuse, symmetric, and often predominantly involve sensory modalities [Merrit's Texbook of Neurology, 9th ed., Ed by LP Rowland, Williams and Wilkins, 1995, p. 669]. The manifestations of diabetic neuropathy can include autonomic nerve dysfunction that results in dysregulation of vital functions including the heart, soft muscles and glands. Low blood pressure, diarrhea, constipation, and sexual impotence also result from autonomic neuropathies. Cranial neuropathies can affect vision. Sensory neuropathies affect the nerves that carry sensory information from the skin and other brain-sensitive organs. The loss of sensation of touch, pressure, vibration and temperature to a part of the body or area, can result from sensory neuropathies. Diabetic neuropathies are sometimes, but not always, accompanied by pain. Painful diabetic neuropathy tends to develop in stages. Early, intermittent and tingling pain can be felt in the extremities of the nerve endings fields, particularly the foot in the case of autonomic or sensory neuropathy, or in the face and around the eye in the case of cranial neuropathy. In the final states, the most intense and constant pain. Finally, a painless neuropathy develops when the sensation of pain is lost in one area, which greatly increases the risk of severe tissue injury without pain as an indicator of injury. "The term" visceral pain "includes, but is not limits that pain associated with irritable bowel syndrome (IBS) with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis.

The term "vascular pain" for purposes of the present invention is that pain produced by one or more of the following pathophysiological factors: (a) inadequate perfusion of tissues with consequential temporal or continuous ischemia such as occurs in the muscles of the limb during exercise, ischemia of the skin that produces pain that remains, and ischemia of a viscera such as the heart or gastrointestinal tract, (b) secondary changes such as ulcerations or gangrene in the skin or abdominal viscera, (c) accelerated changes or sudden in the vascular dimension of the large vessels as occurs with aneurism; (d) rupture of the aorta with the consequent shedding of the blood that stimulates the nociceptive fibers in the parietal peritoneum or parietal pleura; (e) intense spasm consistent with the intra-arterial injection of severe irritants in the artery endothelium, and (f) deterioration of the venous return with consequent massive edema that rapidly e dilates the fascial compartments. " (JJ Bonica et al., The Management of Pain Vol. 1 (2nd ed., Philadelphia: Read &Febiger 1990) Examples include, but are not limited to, obliteration or fading of arteriosclerosis, obliteration or fading of thromboangitis, acute arterial occlusion, embolism, congenital arteriovenous aneurysm, vasospatic disease, Raynaud's disease, acrocyanosis, acute venous occlusion, thromboplebitis, varicose veins and lymphoedema The term 'arthritic pain' includes but is not limited to, osteoarthritis, arthritis rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, gout, pseudogout, infectious arthritis, tendonitis, bursitis, bone lesions and inflammation of the soft tissue joints. For purposes of the present invention, 'nociceptive pain' is the pain caused by a process of tissue damage that excites the nociceptive attractants or afferents of pain, which is caused by the prolonged excitement of the nociceptors. The persistent pain which is reached from a nociceptive pain, can be due to the persistent harmful stimulation of the nociceptors or their sensitizations or both, or it can be initiated by these factors and prolonged by its persistence, by several reflex mechanisms and by other factors. The term 'nociception', as used here, refers to the neural mechanisms by which the damaging stimulus is detected.Nociception involves two stages: transductions of the damaging stimulus by the peripheral nerve endings and the transmission of these signals to the central nervous system. The present invention is employed for the treatment of nociceptive pain or pain that is achieved from a combination of nociceptive and neuropathic etiologies, It is preferred that the pain to be treated be nociceptive pain It is also believed by those of ordinary skill in the art that central sensitization contributes to the expression of persistent pain The term 'central sensitization' as used herein is defined as the hyperexcitability of spinal neurons. Duloxetine, N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) pronanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first shown by U.S. Patent No. 4,956,388, which shows this high potency in the inhibition of serotonin and norepinephrine uptake. The term "duloxetine" as used herein, refers to any acidic addition salt or free base of the molecule.

Duloxetine is a safe drug, and its use in the treatment of persistent pain is a superior treatment because of its improved safety. The compound is particularly effective, having a few if any, physiological effects behind those in the processing of norepinephrine and serotonin, and therefore are free of side effects and unintended activities, distinctly limiting the side effects of other drugs. similar ones used for the treatment of persistent pain. further, they are effective at relatively low doses, as discussed above, and can safely and effectively be administered once a day. In addition, the difficulties created by multiple dosages of patients are completely avoided. The effective amount or dose of duloxetine for the treatment of persistent pain is in the range of about 1 mg / day to about 200 mg / day. The preferred adult dose is in the range of about 40 to about 150 mg / day, and a more highly preferred adult dose is about 60 to about 120 mg / day. The optimal dose for each patient as always, could be exposed by the specialist in charge of the case, taking into account the size of the patient, other medications which the patient requires, severity of the persistent pain and all the other circumstances of the patient. Since duloxetine is readily absorbed orally and requires only one administration / day, there is little or no reason to administer it in any form other than oral. It is produced in the form of a stable, clean glass, and is also easily formulated in oral dosage forms, such as tablets, capsules, suspensions, and the like. The usual methods of pharmaceutical scientists are applicable. They can be usefully administered if there is any reason to do so in particular circumstances, in other pharmaceutical forms, such as but not limited to, injectable solutions, injections in containers, suppositories and the like, which are well known to and understood by pharmaceutical scientists. It will be substantially always preferred, however, to administer duloxetine as a tablet or capsule and such dosage forms are recommended.

An enteral formulation of the preferred duloxetine is as described in Patent No. 5,508,074, which is hereby incorporated by reference, is a pellet formulation comprising a) a center consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separation layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. The following example demonstrates the preparation of such a preferred formulation.

Example Duloxetine base 10 mg / capsule List of materials Perlillas Sucrose - uncut starch, Mesh 20-25 60.28 mg Duloxetine layer Duloxetine 11.21 mg Hydroxypropylmethylcellulose 3.74 mg Separation layer Hydroxypropylmethylcellulose 2.51 mg Sucrose 5.00 mg Talc, mesh 500 10.03 mg Enteric layer HPMCAS, grade LF, Shin-Etsu 25.05 mg Co., Tokyo, Japan Triethyl citrate 5.00 mg Talc, mesh 500 7.52 mg Finishing layer Hydroxypropylmethylcellulose 8.44 mg Titanium dioxide 2.81 mg Talc Rastro 141.60 mg The duloxetine layer was made completely by the suspension of duloxetine in a solution of 4% w / w of the hydroxypropylmethylcellulose in water, and the grinding of the suspension with a CoBall mill (Fryma Mashinen AG, Rheinfelden, Switzerland) model MS- 12 A fluid bed dryer with a Wurster column was used to make this product, at a batch size of 1.0 kg. The separation layer was added from a 4% w / w solution of the hydroxypropylmethylcellulose in water, in which the sucrose was also dissolved.

In order to prepare the enteric coating suspension, purified with water and cooled to 10 ° C and polysorbate, tiethyl citrate and silicone emulsion were added and dispersed or dissolved. Then HPMCAS and talc were added and stirred until homogeneity was obtained, and HPMCAS was completely neutralized by the addition of ammonium hydroxide until the polymer solution was complete. To this suspension, an aqueous solution of carboxymethylcellulose, 0.5% w / w, was added uniformly. The enteric suspension was maintained at 20 ° C during the coating process. The enteric suspension was then added to the partially finished pellets in the Wurster column at an atomization rate of approximately 15 ml / min, maintaining the air inlet temperature at approximately 50 ° C. The dry product in the Wurster at 50 ° C when the enteric suspension has been fully added, and then dried on a tray for 3 hours in a dry room at 60 ° C. A finishing layer was then applied, which consists of a 4.5% w / w hydroxypropylmethylcellulose solution containing titanium dioxide and propylene glycol as the plasticizer. The pellets were completely dried in the fluidized bed dryer and then loaded into gelatin capsules of 3 sizes.

Example I The analgesic effect of duloxetine for the treatment of persistent nociceptive pain was demonstrated using the well-known "formalin test" The formalin test is a model of persistent nociceptive activation induced by a skin lesion which can lead to sensitization central (Shibata, M., Ohkubo, T., Takahashi, H., and Inoki, R., 'Modified formalin test: Characteristic biphasic pain response, "Pain (1989) 38: 347-352; and Tjolsen, A. , Bergen, OG, Hunskaar, S., Rosland, J.H., and Hole, K., 'The formalin test: an evaluation of the method, "Pain (1992) 51: 5-17). The effect of duloxetine on the paw licking behavior induced by formalin in the rat was investigated as the persistent noceceptive activation index. In this test, the injection of formalin under the skin on the dorsal lateral surface of the hind paw of the rats causes an immediate and intense increase in the spontaneous activity of attractants or afferents of the fiber C.

This activation evokes a distinctly quantifiable behavior indicative of pain, such as smacking, leaning back, staying or biting the injected paw. The response related to behavior to formalin is biphasic, with an early phase that is short-lived, followed by an extended tonic response or late phase of persistent nociceptive activation. The mechanisms that cause the late phase response, such as sensitization of pain transmitting neurons, are currently believed to contribute to several types of persistent pain. 'Male Sprague-Dawley Rats (200-250 g; Charles River, Portage, MI) were kept at constant temperature and light (12h light / 12h dark) for 4-7 days before the studies. The animals had free access to feed and water every time before the day of the experiment. The formalin test was carried out in Plexiglas® boxes of 25x25x20 cm (length x amplitude x height) in size elaborated as usual. A mirror placed on the back of the box allowed unobstructed observation of the legs injected with formalin. The rats were acclimatized individually in the cubicles at least 1 hour before the experiment. All tests were conducted between 08:00 and 14:00 hours and the test room temperature was maintained at 21-23 ° C. The test compound was administered 30 or 60 minutes before injection with formalin. Formalin (50 μl of a 5% solution in saline) was injected subcutaneously into the dorsal lateral surface of the right hind paw with a measuring needle 27. Observation started immediately after injection with formalin. Formalin-induced pain was quantified by recording at 5-minute intervals the number of paw licking events injected with formalin and the number of seconds of each last licking event. These records were made for 50 minutes after the injection of formalin. After the experiment, the animals were sacrificed with an overdose of C02. (Euthanasia protocol, Eli Lilly Animal Use and Care Committee). Records in the formalin test were made in accordance with Goderre et al., 1993b and Abbott et al., 1995. (Coederre TJ, Fundytus ME, McKenna JE, Dalal S. and Melzack R. 'The Formalin test: a validation of the weighted-scores method of behavioral pain rating ", Pain (1993b) 54: 43-50, and Abbott FV, Franklin KBJ and Westbrook RF 'The formalin test: scoring properties of the first and second phases of the pain response in rats', Pain (1995) 60: 91-102) The sum of the time consumed from licking in seconds from time 0 to 5 seconds the early phase was considered, while the last phase was taken as the sum of the seconds consumed from the licking from 15 to 40 minutes.

The data were presented as the mean with standard errors of means (+ SEM). Data were evaluated by one-way analysis of variance (ANOVA) and appropriate contrasts were analyzed by the Tukey test and Dunnett's 't' test by two lateral comparisons.

Treatment Early phase Late phase Vehicle (i.p. 31.33 ± 8.04 386.22 + 40.13 Duloxetine (i.p.) * (-30 min) 3 mg / kg 32.78 ± 15.97 254.00 ± 45.87 mg / kg 17.00 ± 5.83 163.89 ± 54.14 *** mg / kg 29.56 ± 16.30 80.44 ± 36.22 *** Vehicle (p.o.) ** 10.71 ± 3.17 376.71 ± 36.93 Duloxetine (p.o.) ** (- 60 min) 3 mg / kg 21.78 ± 5.14 393.56 ± 26.74 10 mg / kg 20.22 ± 5.29 255.78 ± 38.22 *** 20 mg / kg 12.67 ± 3.61 161.11 ± 31.77 *** * (i.p.): intraperitoneal ** (p.o.): oral *** p < 0.05 significantly different compared to the group control vehicle.

As illustrated above, duloxetine blocks the late phase response to formalin in a dose-dependent manner. These results demonstrate that duloxetine is effective in the treatment of nociceptive pain which is persistent.

Example II The tendency of duloxetine to induce ataxia or neuromuscular effects at analgesic doses was investigated using the well-known rotary test.

Male Sprague-Dawley rats (200-250 g, Charles River, Portage, MI) were kept at constant temperature and light (12h light / 12h dark) for 4-7 days before the studies. The animals had free access to food and water every time before the day of the experiment.

An automated accelerator turner (Omnitech Electronics Inc., Columbus, OH) connected to an IBM PC computer was used. For the purposes of testing and training, the spinner was placed until the acceleration of 17 r.p.m in 5 seconds and such speed was maintained for 40 seconds. The rats were given 3 training trials to learn how to maintain posture on the turner before the current day of the drug test. The next day, the turntable test was conducted at either 30 or 80 minutes per i.p. and at 60 and 110 minutes for p.o, after administration of the drug or compound. The animals that maintained the position and did not fall on the spinner gave a maximum record of 40 seconds.

All data were analyzed using a JMP statistical program. The data were presented as the means with the standard errors of the means (+ SEM). The data were evaluated by one way variance analysis (ANOVA) and the appropriate contrasts were analyzed by the Tukey test and the Dunnett 't' test by two lateral comparisons. * (i.p.): Intraperi toneal ** (p.o.): oral As demonstrated above, duloxetine did not show ataxia or neuromuscular effects in the spinner test at doses that cause analgesia.

Example III The analgesic effect of duloxetine for the treatment of neuropathic pain is demonstrated using the well-known 'Seltzer Model', which involves the partial ligation of the sciatic nerve.

(Seltzer, Z., Dubner, R. and Shir, Y., 'A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury', Pain, 43 (1990) 205-218). This model mimics the major clinical symptoms of causalgia, which are the rapid onset of hyperalgesia and allodynia. Young male Sprague Dawley rats from Harian (Indianapolis, IN) weighing 135-155 g, were housed in groups of 3-4 in plastic cages with soft straw under a 12 / 12h day / night cycle. The rats were placed in an upside down position under anesthesia by gaseous isoflurane. Surgery was performed on the upper right thigh as described by Seltzere et al., 1990. The sciatic nerve was carefully exposed by the separation of the anterior muscles with a small retractor. The third dorsal to the middle of the nerve was tightly ligated with a silk 4.0 suture to a distal view to the point at which the posterior bicept-semitendinous nerve branches. The wound site was subsequently sutured in accordance with animal protocol procedures. The animals were then allowed to recover and were subsequently placed in their cages. The rats recovered sufficiently from the surgical procedures to return to normal activity within 30 minutes after the termination of gas anesthesia. Beginning 24 hours after recovery from surgery, pain sensitivity of the hind paw was analyzed using Frey von filaments applied to both surgical and contralateral leg surfaces. In this method, the removal of the live foot was measured in response to the normally iniquitous mechanical stimulus. (Kim, SH and Chung, JM, 'An experimental model for neuropathy produced by segmental spinal nerve ligation in the rat', Pain, 50 (1992) 355-363.) The iniquitous mechanical stimulus was applied to the von Frey filaments. forces of different inclination (corresponding to grams of force varying from 1-15 g) The rat was placed in a Plexiglas box with a metal mesh floor and the von Frey filaments were applied to the surface of the plant A Frey von filament was applied perpendicularly to the surface of the sole of the foot with sufficient force to cause slight opposition against the leg, and was maintained for 2-3 seconds on each hind leg.A positive response was noted if the leg The threshold (gram force) to cause foot withdrawals in response to the filament was expressed as Response (g) and the calculations to carry this out were based on the method of Dixon, WJ, Efficient analysis of experimental observations. , Ann. Rev. Pharmacol. Toxicol 20: 441-462, 1980. Stimulation of normal human skin with weak Frey von (4.3 nM) and strong (5.18 nM) filaments respectively stimulated a weak sensation of touch and a feeling of pressure. Therefore, a significant change in the threshold sensor that causes removal of the live foot in response to these harmless mechanical stimuli is due to the development of mechanical allodynia due to nerve ligation. The response (g) (mechanical stimulus) was scored against the test doses of the drug or vehicle. While the paw on the surgical sides developed mechanical allodynia, the paw in the non-surgical contralaterals remained normal and served as a control. All data were analyzed using the JMP statistical program. The data were presented as means with standard errors of means (+ _ SEM). The data were evaluated by one way variance analysis (ANOVA) and the appropriate contrasts were analyzed by the Tukey test and the Dunnett 't' test by two lateral comparisons.

Treatment Response to Allodynia (g) No nerve ligation Vehicle (ip *, po **) 15 ± 0.0 (without allodynia) Nerve ligation 2.18 ± 0.31 Vehicle (ip *) Duloxetine (15 mg / kg, 57 ± 1.72 ^ ip *, 1 hour pretratamie) vehicle (po **) 3.45 ± 0.56 duloxetine (20 mg / kg, .53 + 1.66 ^ po **, 1 hour pretreatment) duloxetine (20 mg / kg x 4 9.18 ± 2.95 *** days, po **, sub-chronic pretreatment) intraperitoneal (ip) * or oral (po) ** and then oral sub-chronic dosages of duloxetine once a day for four consecutive days. *** p < 0.05 significantly different compared to the group control vehicle.

As illustrated above, duloxetine attenuates the developed allodynia after partial ligation of the sciatic nerve after acute or sub-chronic systemic administration. These results demonstrate that duloxetine is effective in the treatment of neuropathic pain.

It is noted that in relation to this date, the best method known by the present invention to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (17)

1. A method of treating persistent pain, characterized in that it comprises administering to a patient in need of said treatment, an effective amount of duloxetine.

2. A method of claim 1, characterized in that the persistent pain is the nociceptive pain.

3. A method of treating chronic tension type headache, characterized in that it comprises administering to a patient in need of said treatment, an effective amount of duloxetine.

4. A method of treating fibromyalgia, characterized in that it comprises administering to a patient in need of said treatment, an effective amount of duloxetine.

5. A method of treating pain associated with diabetic neuropathy, characterized in that it comprises administering to a patient in need of said treatment, an effective amount of duloxetine.

6. A method of treating pain associated with disorders of somatoforms, characterized in that it comprises administering to a patient in need of said treatment, an effective amount of duloxetine.

7. The use of duloxetine for the manufacture of a medication for the treatment of persistent pain.

8. The use of duloxetine for the manufacture of a medication for the treatment of chronic tension type headache.

9. The use of duloxetine for the manufacture of a medicament for the treatment of fibromyalgia.

10. The use of duloxetine for the manufacture of a medicament for the treatment of pain associated with diabetic neuropathy.

11. The use of duloxetine for the manufacture of a medicament for the treatment of pain associated with somatoform disorders.

12. The use of duloxetine for the treatment of persistent pain.

13. The use of duloxetine for the treatment of chronic tension type headache.

14. The use of duloxetine for the treatment of fibromyalgia.

15. The use of duloxetine for the treatment of pain associated with diabetic neuropathy.

16. The use of duloxetine for the treatment of pain associated with somatoform disorders.

17. A method of any of claims 1 to 16, characterized in that the duloxetine is (+) - N -methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine hydrochloride. SUMMARY OF THE INVENTION A method for using N-methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine to treat persistent pain.