Method for treating tension-type headache

Abstract

NMDA receptor antagonists, especially mirtazapine, can be used to treat tension-type headaches.

1 . A method for treatment or prevention of tension-type headache in a person in need of such treatment, comprising administering an amount of an agent effective to interact with neuronal transmission connected with pain perception, so as to prevent or reduce central sensitization, with the proviso that said interaction is not performed by administering ethyl 2-amino-6-(4-fluorobeznylamino)-3-pyridylcarbamate or an arylglycinamide derivative as defined herein.  
     
     
         2 . A method according to  claim 1  for treatment of tension-type headache in a person in need of such treatment, comprising administering an amount of an agent effective to interact with neuronal transmission connected with pain perception, so as to prevent or reduce central sensitization.  
     
     
         3 . A method according to  claim 1  for prevention of tension-tape headache in a person in need of such treatment, comprising administering an amount of an agent effective to interact with neuronal transmission connected with pain perception, so as to prevent or reduce central sensitization.  
     
     
         4 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially normalizing a pathological qualitatively altered stimulus-response function.  
     
     
         5 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially normalizing a pathological abnormally low pain threshold.  
     
     
         6 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially reducing a pathological increased pericranial muscle hardness.  
     
     
         7 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially reducing a pathological increased pericranial myofascial tenderness.  
     
     
         8 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing pain, tenderness or hardness in pericranial muscle induced by experimental tonic muscle contraction, or normalizing a qualitatively altered stimulus-response function induced by experimental tonic muscle contraction, or normalizing a reduced pain threshold induced by experimental tonic muscle contraction.  
     
     
         9 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing pain, tenderness or hardness in pericranial muscle induced by intra muscular infusion of algogenic substances, or preventing or normalizing a qualitatively altered stimulus-response function induced by intra muscular infusion of algogenic substances or normalizing a reduced pain threshold induced by intra muscular infusion of algogenic substances.  
     
     
         10 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing pain, tenderness or hardness in pericranial muscle induced by stimulation of nociceptive afferents in myofascial tissues or preventing or normalizing a qualitatively altered stimulus-response function induced by stimulation of nociceptive afferents in myofascial tissues or normalizing a reduced pain threshold induced by stimulation of nociceptive afferents in myofascial tissues.  
     
     
         11 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing secondary allodynia or secondary hyperalgesia induced by stimulation of nociceptive afferents in myofascial tissues.  
     
     
         12 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing wind-up induced by repetitive stimulation of nociceptive afferents in the pericranial region.  
     
     
         13 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing secondary allodynia or secondary hyperalgesia induced by nociceptive input in an experimental animal model.  
     
     
         14 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing wind-up induced by repetitive stimulation of nociceptive afferents in an experimental animal model.  
     
     
         15 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing increased receptive field size of second order neurons induced by nociceptive input in an experimental animal model.  
     
     
         16 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing an increased excitability of the flexion reflex induced by nociceptive input in an experimental animal model.  
     
     
         17 . A method according to  claim 1 , wherein the agent is an agent which is capable of substantially preventing or reducing central sensitization induced by nociceptive input in an experimental animal model.  
     
     
         18 . A method according to  claim 1  for treatment or prevention of tension-type headache in a person in need of such treatment, the patient having a qualitatively altered stimulus/response function in connection with nociception, comprising administering an amount of an agent effective to interact with neuronal transmission connected with pain perception, so as to obtain a substantial normalization of an otherwise qualitatively altered stimulus/response function in connection with nociception.  
     
     
         19 . A method according to  claim 1 , wherein the treatment or prevention of tension-type headache is not accompanied by a substantial reduction of muscle tension.  
     
     
         20 . A method according to  claim 1 , wherein the interaction comprises interaction with neuronal transmission connected with second order nociceptive neurons.  
     
     
         21 . A method according to  claim 1 , wherein the interaction comprises a reduction of input to second order nociceptive neurons.  
     
     
         22 . A method for treating tension-type headache in a person which comprises administering an agent in an amount effective to alleviate said headache, said agent being an agent capable of altering the relationship of pain intensity to pressure intensity when the trapezoid muscle is palpated at different pressure intensities in said person.  
     
     
         23 . A method according to  claim 22  wherein the relationship is substantially linear in the untreated persons, and substantially non-linear in the treated persons.  
     
     
         24 . A method according to  claim 23 , wherein the relationship is positively accelerating in the treated person.  
     
     
         25 . A method according to  claim 24 , wherein the rate of acceleration of pain intensity with pressure intensity is substantially constant.  
     
     
         26 . A method according to  claim 25 , wherein the relationship in the treated persons is substantially the same as in control persons who did not have tension-type headache and who were treated with a placebo.  
     
     
         27 . A method according to  claim 1 , wherein the interaction is one which in a panel of test persons suffering from increased myofascial tenderness with disorder of pericranial muscle in connection with tension-type headache still transform a substantially linear pain intensity perception in response to pressure intensity in trapezius muscle into a curve (C) of which the values of pain intensity are lower than the linear pain intensity perception and wherein the curve (C) can be described substantially as a power function and is a curve which is substantially linear in a double logarithmic plot and wherein substantially each of the values of curve (C) is at the most 20% higher than the value of the corresponding curve produced for a test panel of healthy controls.  
     
     
         28 . A method according to  claim 27 , wherein substantially each of the values of curve (C) is at the most 10% higher than the value of the corresponding curve produced for a test panel of healthy controls.  
     
     
         29 . A method according to  claim 1 , wherein the interaction is effected by administering an effective amount of an agent interacting with neuronal transmission connected with pain perception, the administration being performed substantially at least once daily and being continued for a period of at least one month.  
     
     
         30 . A method according to  claim 29 , wherein the administration is being continued for a period of at least one month and less than 10 years.  
     
     
         31 . A method according to  claim 29 , wherein the administration is being continued for a period of at least one month and less than 5 years.  
     
     
         32 . A method according to  claim 29 , wherein the administration is being continued for a period of at least one month and less than 2 years.  
     
     
         33 . A method according to  claim 29 , wherein the administration is being continued for a period of at least one month and less than 1 year.  
     
     
         34 . A method for treatment or prevention of tension-type headache in a person in need of such treatment comprising administering an amount of an agent which, in the peripheral and/or central nervous system, is effective to specifically interact with neuronal transmission connected with pain perception by 
 a) substantially antagonizing the action of glutamate, 5-HT, GABA, nitric oxide, nitric oxide synthase, guanylate cyclase, cyclic guanylate monophosphate (cGMP), CGRP, substance P, neurokinin A, neurokinin B, bradykinin, PACAB, adenosine, glycine, his tin, neurotrophins, Na +  ions or Ca 2+  ion channels,    or by    b) substantially potentiating the action of adenosine, galanine or norepinephrine,    with the proviso that said agent is not ethyl 2-amino-6-(4-fluorobenzylamino)-3-pyridylcarbamate.    
     
     
         35 . A method according to  claim 34 , wherein the agent is an agent capable of interacting with neuronal transmission connected with pain perception, so as to prevent or reduce central sensitization.  
     
     
         36 . A method according to  claim 34 , wherein the agent is an agent capable of interacting with neuronal transmission connected with pain perception, so as to obtain a substantial normalization of a qualitatively altered stimulus/response function in connection with nociception.  
     
     
         37 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of glutamate or substantially inhibiting the release of glutamate or substantially counteracting the action of glutamate or substantially inhibiting the binding of glutamate to receptors for glutamate.  
     
     
         38 . A method according to  claim 34 , wherein the agent comprises a glutamate receptor antagonist.  
     
     
         39 . A method according to  claim 37 , wherein the agent comprises a glutamate receptor antagonist.  
     
     
         40 . A method according to  claim 39 , wherein the agent comprises an NMDA glutamate receptor antagonist.  
     
     
         41 . A method according to  claim 40 , wherein the agent comprises a competitive NMDA glutamate receptor antagonist.  
     
     
         42 . A method according to  claim 41 , wherein the agent comprises a nitrogen-containing heterocyclic compound selected from the group consisting of diacidic piperidines, diacidic piperazines and phosphono amino acids or derivatives of any of the above which are competitive NMDA antagonists or prodrugs thereof.  
     
     
         43 . A method according to  claim 40 , wherein the agent comprises a non-competitive NMDA glutamate receptor antagonist.  
     
     
         44 . A method according to  claim 43 , wherein the agent is selected from a group consisting of polycyclic amines, tricyclic antidepressants, adamantanamines, arylcyclohexylamines, arylcyclohexylamines, opioid derivatives, glycylamides, piperidinylethanols, piperidinylethanols, diguanidines, g-aminobutyric acid derivatives, polycyclic amines or derivatives of any of the above which are non-competitive NMDA antagonists or prodrugs thereof.  
     
     
         45 . A method according to  claim 40 , wherein the agent comprises a tricyclic antidepressant or derivatives thereof which are NMDA glutamate receptor antagonists or prodrugs thereof.  
     
     
         46 . A method according to  claim 40 , wherein the agent is a selected from the group consisting of γ-aminobutyric acid derivatives, polycyclic amines or derivatives of any of the above which are NMDA glutamate receptor antagonists or prodrugs thereof.  
     
     
         47 . A method according to  claim 39 , wherein the agent comprises a non-NMDA glutamate receptor antagonist.  
     
     
         48 . A method according to  claim 47 , wherein the agent comprises a competitive non-NMDA glutamate receptor antagonist.  
     
     
         49 . A method according to  claim 47 , wherein the agent comprises a non-competitive non-NMDA glutamate receptor antagonist.  
     
     
         50 . A method according to  claim 47 , wherein the agent comprises an AMPA glutamate receptor antagonist.  
     
     
         51 . A method according to  claim 47 , wherein the agent is a competitive AMPA glutamate receptor antagonist.  
     
     
         52 . A method according to  claim 51 , wherein the agent is selected from the group consisting of quinoxalinediones, dihydraquinolones, diacidic decahydroisoquinolines, amino acid isoxazoles, indoleoximes or derivatives of any of the above which are competitive AMPA receptor antagonists or prodrugs thereof.  
     
     
         53 . A method according to  claim 47 , wherein the agent comprises a non-competitive AMPA glutamate receptor antagonist.  
     
     
         54 . A method according to  claim 53 , wherein the agent is selected from the group consisting of 2,3-benzodiazepines, phthalazines or derivatives of any of the above which are non-competitive AMPA receptor antagonists or prodrugs thereof.  
     
     
         55 . A method according to  claim 47 , wherein the agent comprises a kainic acid receptor antagonist.  
     
     
         56 . A method according to  claim 55 , wherein the agent comprises a competitive kainic acid receptor antagonist.  
     
     
         57 . A method according to  claim 56 , wherein the agent comprises an indoleoxime or derivatives thereof which are competitive kainic acid receptor antagonists or prodrugs thereof.  
     
     
         58 . A method according to  claim 55 , wherein the agent comprises a non-competitive kainic acid receptor antagonist.  
     
     
         59 . A method according to  claim 47 , wherein the agent comprises a metabotropic glutamate receptor antagonist.  
     
     
         60 . A method according to  claim 59 , wherein the agent comprises a competitive metabotropic glutamate receptor antagonist.  
     
     
         61 . A method according to  claim 59 , wherein the agent comprises a non-competitive metabotropic glutamate receptor antagonist.  
     
     
         62 . A method according to  claim 37 , wherein the agent comprises a metabotropic glutamate receptor agonist.  
     
     
         63 . A method according to  claim 62 , wherein the agent is selected from the group consisting of phenylglycines, amino acid indanes, phosphono amino acids or derivatives of any of the above which are metabotropic glutamate receptor agonists or prodrugs thereof.  
     
     
         64 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of 5-HT or substantially inhibiting the release of 5-HT or substantially counteracting the action of 5-HT or substantially inhibiting binding of 5-HT to 5H 2,3  receptors.  
     
     
         65 . A method according to  claim 34 , wherein the agent comprises a 5-HT 2,3  receptor antagonist.  
     
     
         66 . A method according to  claim 64 , wherein the agent comprises a 5-HT 2,3  receptor antagonist.  
     
     
         67 . A method according to  claim 66 , wherein the agent is selected from the group consisting of tropan derivatives, polycyclic amines or derivatives of any of the above which are 5-HT 2,3  receptor antagonists or prodrugs thereof.  
     
     
         68 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially enhancing the production of GABA or substantially enhancing the release of GABA or substantially enhancing the action of GABA or substantially activating receptors for GABA.  
     
     
         69 . A method according to  claim 68 , wherein the agent comprises a GABA activity enhancer.  
     
     
         70 . A method according to  claim 69 , wherein the agent comprises a benzodiazepine or a derivative thereof which is a GABA activity enhancer or prodrugs thereof.  
     
     
         71 . A method according to  claim 34 , wherein the agent comprises a GABA uptake inhibitor.  
     
     
         72 . A method according to  claim 70 , wherein the agent comprises a GABA uptake inhibitor.  
     
     
         73 . A method according to  claim 72 , wherein the agent is selected from the group consisting of carboxypiperidine derivatives, carboxypyridine derivatives, 3-hydroxyisoxazoles, nipecotic acid derivatives, guvacine derivatives or derivatives of any if the above which are GABA uptake inhibitors or prodrugs thereof.  
     
     
         74 . A method according to  claim 68 , wherein the agent comprises a GABA-A agonist.  
     
     
         75 . A method according to  claim 74 , wherein the agent is selected form the group consisting of γ-aminobutyric acid derivatives, 3-hydroxyisoxazoles or derivatives of any of the above which are GABA-A agonists or prodrugs thereof.  
     
     
         76 . A method according to  claim 68 , wherein the agent comprises a GABA transaminase inhibitor.  
     
     
         77 . A method according to  claim 76 , wherein the agent comprises a g-aminobutyric acid derivative or derivatives thereof which are GABA transaminase inhibitors or prodrugs thereof.  
     
     
         78 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system is capable of substantially inhibiting the production of nitric oxide or substantially counteracting the action of nitric oxide or substantially inhibiting the production of nitric oxide synthase (NOS) or substantially counteracting the action of nitric oxide synthase (NOS).  
     
     
         79 . A method according to  claim 34 , wherein the agent comprises a nitric oxide inhibitor.  
     
     
         80 . A method according to  claim 78 , wherein the agent comprises a nitric oxide inhibitor.  
     
     
         81 . A method according to  claim 34 , wherein the agent comprises an NOS inhibitor.  
     
     
         82 . A method according to claim  8 D, wherein the agent comprises an NOS inhibitor.  
     
     
         83 . A method according to  claim 82 , wherein the agent is selected from the group consisting of arginine derivatives, citrulline derivatives, indazoles, imidazolin-N-oxides, phenylimidazoles, 21-aminosteroids, biphenyls, piperidine derivatives or derivatives of any of the above which are NOS inhibitors or prodrugs thereof.  
     
     
         84 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of guanylate cyclase or substantially counteracting the action of guanylate cyclase or substantially inhibiting the production of cyclic guanylate monophosphate (cGMP) or substantially counteracting the action of cyclic guanylate monophosphate (cGMP) or substantially inhibiting any further steps in the reaction induced by cyclic guanylate monophosphate (cGMP).  
     
     
         85 . A method according to  claim 34 , wherein the agent comprises a guanylate cyclase inhibitor.  
     
     
         86 . A method according to  claim 84 , wherein the agent comprises a guanylate cyclase inhibitor.  
     
     
         87 . A method according to  claim 86 , wherein the agent comprises a quinoxaline or derivatives thereof which are guanylate cyclase inhibitors.  
     
     
         88 . A method according to  claim 84 , wherein the agent comprises a cGMP inhibitor.  
     
     
         89 . A method according to  claim 84 , wherein the agent comprises capable of substantially counteracting the action of protein kinase C.  
     
     
         90 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of CGRP or substantially inhibiting the release of CGRP or substantially counteracting the action of CGRP or substantially inhibiting the binding of CGRP to receptors for CGRP.  
     
     
         91 . A method according to  claim 34 , wherein the agent comprises a CORP inhibitor.  
     
     
         92 . A method according to  claim 90 , wherein the agent comprises a CGRP inhibitor.  
     
     
         93 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of substance P or substantially inhibiting the release of substance P or substantially counteracting the action of substance P or substantially inhibiting the binding of substance P to receptors for substance P.  
     
     
         94 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of neurokinin A or substantially inhibiting the release of neurokinin A or substantially counteracting the action of neurokinin A or substantially inhibiting the binding of neurokinin A to receptors for neurokinin A.  
     
     
         95 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of neurokinin B or substantially inhibiting the release of neurokinin B or substantially counteracting the action of neurokinin B or substantially inhibiting binding of neurokinin B to receptors for neurokinin B.  
     
     
         96 . A method according to  claim 95 , wherein the agent comprises an NK2 receptor antagonist.  
     
     
         97 . A method according to  claim 96 , wherein the agent comprises a peptidomimetic or derivatives thereof which are NK2 receptor antagonists or prodrugs thereof.  
     
     
         98 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of bradykinin or substantially inhibiting the release of bradykinin or substantially counteracting the action of bradykinin or substantially inhibiting binding of bradykinin to receptors for bradykinin.  
     
     
         99 . A method according to  claim 34 , wherein the agent comprises a bradykinin antagonist.  
     
     
         100 . A method according to  claim 95 , wherein the agent comprises a bradykinin antagonist.  
     
     
         101 . A method according to  claim 100 , wherein the agent comprises a peptidomimetic or derivatives thereof which are bradykinin receptor antagonists or prodrugs thereof.  
     
     
         102 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of PACAB or substantially inhibiting the release of PACAB or substantially counteracting the action of PACAB or substantially inhibiting binding of PACAB to receptors for PACAB.  
     
     
         103 . A method according to  claim 34 , wherein the agent comprises a PACAB inhibitor.  
     
     
         104 . A method according to  claim 102 , wherein the agent comprises a PACAB inhibitor.  
     
     
         105 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of adenosine or substantially inhibiting the release of adenosine or substantially counteracting the action of adenosine or substantially inhibiting binding of adenosine to adenosine A2 receptors.  
     
     
         106 . A method according to  claim 34 , wherein the agent comprises an A receptor antagonist.  
     
     
         107 . A method according to  claim 105 , wherein the agent comprises an A2 receptor antagonist.  
     
     
         108 . A method according to  claim 107 , wherein the agent comprises a xanthine derivative or derivatives thereof which are A2 receptor antagonists or prodrugs thereof.  
     
     
         109 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially enhancing the production of adenosine or substantially enhancing the release of adenosine or substantially enhancing the action of adenosine or substantially activating adenosine A1 receptors.  
     
     
         110 . A method according to  claim 34 , wherein the agent comprises an adenosine uptake inhibitor.  
     
     
         111 . A method according to  claim 109 , wherein the agent comprises an adenosine uptake inhibitor.  
     
     
         112 . A method according to  claim 111 , wherein the agent comprises a pyrimidine derivative or homopiperazine derivative or derivatives of any of the above which are adenosine uptake inhibitors or prodrugs thereof.  
     
     
         113 . A method according to  claim 34 , wherein the agent comprises an A1 receptor agonist.  
     
     
         114 . A method according to  claim 109 , wherein the agent comprises an A1 receptor agonist.  
     
     
         115 . A method according to  claim 114 , wherein the agent is selected from the group consisting of adenosine derivatives, adeninglucosides or derivatives thereof which are A1 receptor agonists or prodrugs thereof.  
     
     
         116 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral-and/or central nervous system, is capable of substantially enhancing the production of galanine or substantially enhancing the release of galanine or substantially enhancing the action of galanine or substantially activating receptors for galanine.  
     
     
         117 . A method according to  claim 34 , wherein the agent comprises a galanine receptor agonist.  
     
     
         118 . A method according to  claim 116 , wherein the agent comprises a galanine receptor agonist.  
     
     
         119 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially enhancing the production of norepinephrine or substantially enhancing the release of norepinephrine or substantially enhancing the action of norepinephrine or substantially activating receptors for norepinephrine.  
     
     
         120 . A method according to  claim 34 , wherein the agent comprises an norepinephrine receptor agonist.  
     
     
         121 . A method according to  claim 119 , wherein the agent comprises an norepinephrine receptor agonist.  
     
     
         122 . A method according to  claim 121 , wherein the agent comprises an a-2 receptor agonist.  
     
     
         123 . A method according to  claim 122 , wherein the agent is selected from the group consisting of aminoimidazolines, thiazinamines, imidazoles, or derivatives of any of the above which are a-2 receptor agonists or prodrugs thereof.  
     
     
         124 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of glycine or substantially inhibiting the release of glycine or substantially counteracting the action of glycine or substantially inhibiting binding of glycine to receptors for glycine.  
     
     
         125 . A method according to  claim 34 , wherein the agent comprises a glycine antagonist.  
     
     
         126 . A method according to  claim 124 , wherein the agent comprises a glycine antagonist.  
     
     
         127 . A method according to  claim 126 , wherein the agent is selected from the group consisting of aminopyrrolidinones, kynurenic acid derivatives, tetrahydroquinolines, kynurenic acid derivatives, indoles, glycine derivatives, quinoxalinediones, dicarbamates or derivatives of any of the above which are glycine antagonists or prodrugs thereof.  
     
     
         128 . A method according to  claim 1 , wherein the agent is an agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of histamin or substantially inhibiting the release of histamin or substantially counteracting the action of histamin or substantially inhibiting binding of histamine to receptors for histamin.  
     
     
         129 . A method according to  claim 1 , wherein the agent is a agent which, in the peripheral and/or central nervous system, is capable of substantially inhibiting the production of neurotrophins or substantially inhibiting the release of neurotrophins or substantially counteracting the action of neurotrophins or substantially inhibiting binding of neurotrophins to receptors for neurotrophins.  
     
     
         130 . A method according to  claim 34 , wherein the agent comprises a neurotrophin receptor antagonist.  
     
     
         131 . A method according to  claim 129 , wherein the agent comprises a neurotrophin receptor antagonist.  
     
     
         132 . A method according to  claim 1 , wherein the agent is capable of substantially inhibiting the action of Na +  ion channels in the peripheral and/or central nervous system.  
     
     
         133 . A method according to  claim 34 , wherein the agent comprises a Na +  channel blocker.  
     
     
         134 . A method according to  claim 132 , wherein the agent comprises a Na +  channel blocker.  
     
     
         135 . A method according to  claim 134 , wherein the agent is selected from the group consisting of triazines, diphenylmethylpiperazines, hydantoins, aminopiperidines, benzthiazoles, dibenzazepines, phenylamides, aminoethylanisoles or derivatives of any of the above which are Na +  channel blockers or prodrugs thereof.  
     
     
         136 . A method according to  claim 1 , wherein the agent is capable of substantially inhibiting the action of Ca 2+  ion channels in the peripheral and/or central nervous system.  
     
     
         137 . A method according to  claim 34 , wherein the agent comprises a Ca 2+  channel blocker.  
     
     
         138 . A method according to  claim 136 , wherein the agent is a Ca 2+  channel blocker.  
     
     
         139 . A method according to  claim 138 , wherein the agent is selected from the group consisting of diphenylmethylpiperazines, arylphosphonic esters or derivatives of any of the above which are Ca 2+  channel blockers or prodrugs thereof.  
     
     
         140 . A method of treatment of tension-type headache comprising administering to a person in need of such treatment an effective amount of an agent which is capable of substantially inhibiting the action of the enzyme nitric oxide synthase (NOS) and thereby reduces chronic pain in connection with tension-type headache.  
     
     
         141 . A method according to  claim 140 , wherein the agent is selected from the group consisting of arginine derivatives, citrulline derivatives, indazoles, imidazolin-N-oxides, phenylimidazoles, biphenyls, piperidine derivatives or derivatives of any of the above which are NOS inhibitors or prodrugs thereof.  
     
     
         142 . A method of screening a drug for the ability to alleviate a tension-type headache which comprises comparing the relationship of pain intensity to pressure intensity when the trapezoid muscle is palpated at different pressure intensities for (a) persons having tension-type headaches after treatment with the drug, and (b) persons having tension-type headaches, treated with a placebo, and determining if the relationship is altered.