Methods for treating chronic or unresolvable pain and/or increasing the pain threshold in a subject and pharmaceutical compositions for use therein

Abstract

The invention relates to a method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms, as defined in the instant invention, comprising transdermally administering a pain-reducing amount of a composition comprising a bioactive androgen to a human subject on a daily basis. The invention further relates to a method of increasing the pain threshold of a human subject having symptoms of androgen deficiency comprising transdermally administering a composition comprising a pain threshold-increasing amount of a bioactive androgen to a human subject with androgen deficiency symptoms on a daily basis. The invention may be used to treat both a female subject and a male subject in order to either alleviate chronic inflammatory pain or to raise the subject's pain threshold. In addition, the invention also relates to increasing the levels of endogenous opioid peptides in a human subject by administering an androgen composition to the subject. The invention also encompasses administration of a composition consisting essentially of an androgen for the treatment of chronic inflammatory pain, and for increasing the pain-threshold in a subject. Chronic inflammatory pain has at least two factors that can predispose a subject to such pain. A subject can have low testosterone, be borderline testosterone-deficient, or be testosterone deficient. If this subject enters a stressor state, chronic inflammatory pain can occur. A subject with normal androgen levels can also enter a stressor state, and chronic inflammatory pain can occur.

What is claimed is: 
     
         1 . A method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms comprising:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state,   along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-reducing amount of an androgen to the human subject with androgen deficiency symptoms, wherein pain is reduced safely and effectively.   
     
     
         2 . The method of  claim 1 , wherein the subject's androgen serum levels are restored from the baseline to the middle or upper range of an appropriate reference range. 
     
     
         3 . The method of  claim 1 , wherein the subject is suffering from a condition selected from the group consisting of chronic pain and pain caused by an unresolvable stressor state. 
     
     
         4 . The method of  claim 3 , wherein the unresolvable stressor state is selected from the group consisting of post-traumatic stress disorder (PTSD), accident, trauma, surgery, autoimmune disease, chronic unresolved or acute viral infection, infectious disease, cancer, chronic exhaustion or physical distress, neuropathy, hyperalgesia, allodynia, grief, emotional distress, depression, dysthymia, surgical gonadectomy, and pharmacologic-induced gonadectomy. 
     
     
         5 . The method of  claim 3 , wherein the androgen is selected from the group consisting of testosterone, androstenedione, androstendiol, dehydroepiandrosterone, danazol, fluoxymesterone, oxandrolone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone, dihydrotestosterone, methyltestosterone, androgen precursors, and testosterone esters. 
     
     
         6 . The method of  claim 5 , wherein the testosterone ester is selected from the group consisting of testosterone enanthate and testosterone cypionate. 
     
     
         7 . The method of  claim 5 , wherein the androgen is testosterone. 
     
     
         8 . The method of  claim 5 , wherein the composition is administered in combination with an antidepressant selected from the group consisting of fluoxetine, duloxetine, sertraline, and a tricyclic antidepressant. 
     
     
         9 . The method of  claim 5 , wherein the subject is a female subject. 
     
     
         10 . The method of  claim 9 , wherein the composition is administered to deliver a daily unit dose of about 1.0 mg to about 12.8 mg of the androgen, wherein the administration results in steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety, wherein the administration is selected from the group consisting of transdermal administration, oral administration, parenteral administration, intramuscular administration, and buccal administration. 
     
     
         11 . The method of  claim 10 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel comprises the androgen and a pharmaceutically acceptable carrier. 
     
     
         12 . The method of  claim 11 , wherein the daily unit dose of the androgen is from about 2.5 mg to about 10.0 mg. 
     
     
         13 . The method of  claim 1 , wherein the daily unit dose of the androgen is from about 3.2 mg to about 9.6 mg. 
     
     
         14 . The method of  claim 13 , wherein the daily unit dose of the androgen is from about 6.0 mg to about 8.0 mg. 
     
     
         15 . The method of  claim 10 , wherein the daily unit dose of the androgen is selected to maintain steady state total androgen serum levels within a range of between about 0.9 ng/mL to about 1.4 ng/mL for at least 24 hours after administration. 
     
     
         16 . The method of  claim 10 , wherein free androgen serum levels and twenty-four hour free androgen AUC are not raised above levels required for therapeutic efficacy and safety. 
     
     
         17 . The method of  claim 16 , wherein the free androgen serum levels are raised to about 1.00 pg/mL to about 3.30 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 40 pg-h/mL to about 65 pg-h/mL. 
     
     
         18 . The method of  claim 10 , wherein the androgen is testosterone. 
     
     
         19 . The method of  claim 5 , wherein the subject is a male subject. 
     
     
         20 . The method of  claim 19 , wherein the composition androgen is administered to deliver a daily unit dose of about 35 mg to about 100 mg of the androgen, wherein the administration results in steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety, wherein the administration is selected from the group consisting of transdermal administration, oral administration, parenteral administration, intramuscular administration, and buccal administration. 
     
     
         21 . The method of  claim 20 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel comprises the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         22 . The method of  claim 20 , wherein the daily unit dose of the androgen is from about 50 mg to about 90 mg/day. 
     
     
         23 . The method of  claim 22 , wherein the daily unit dose of the androgen is from about 65 mg to about 85 mg. 
     
     
         24 . The method of  claim 20 , wherein the daily unit dose of the androgen is selected to maintain steady state total androgen serum levels within a range of between about 2.4 ng/mL to about 9.5 ng/mL for at least 24 hours after administration. 
     
     
         25 . The method of  claim 20 , wherein free androgen serum levels and twenty-four hour free androgen AUC are not raised above the levels required for therapeutic efficacy and safety. 
     
     
         26 . The method of  claim 25 , wherein the free androgen serum levels are raised to about 90 pg/mL to about 300 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 350 pg-h/mL to about 800 pg-h/mL. 
     
     
         27 . The method of  claim 26 , wherein the free androgen serum levels are raised to about 150 pg/mL to about 300 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 400 pg-h/mL to about 700 pg-h/mL. 
     
     
         28 . The method of  claim 20 , wherein the androgen is testosterone. 
     
     
         29 . The method of  claim 1 , wherein the composition consists essentially of the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         30 . A method of increasing the pain threshold of an androgen-deficient human subject comprising:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state, along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-threshold increasing amount of an androgen to a human subject with androgen deficiency, wherein the subject's pain-threshold is increased safely and effectively.   
     
     
         31 . The method of  claim 30 , wherein the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range 
     
     
         32 . The method of  claim 30 , wherein the subject is suffering from an unresolvable stressor state selected from the group consisting of post-traumatic stress disorder (PTSD), accident, trauma, surgery, autoimmune disease, chronic unresolved or acute viral infection, infectious disease, cancer, chronic exhaustion or physical distress, neuropathy, hyperalgesia, allodynia, grief, emotional distress, depression, dysthymia, surgical gonadectomy, and pharmacologic-induced gonadectomy. 
     
     
         33 . The method of  claim 30 , wherein the androgen is selected from the group consisting of testosterone, androstenedione, androstendiol, dehydroepiandrosterone, danazol, fluoxymesterone, oxandrolone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone, dihydrotestosterone, methyltestosterone, androgen precursors, and testosterone esters. 
     
     
         34 . The method of  claim 33 , wherein the testosterone ester is selected from the group consisting of testosterone enanthate and testosterone cypionate. 
     
     
         35 . The method of  claim 33 , wherein the androgen is testosterone 
     
     
         36 . The method of  claim 33 , wherein the subject is a female subject. 
     
     
         37 . The method of  claim 36 , wherein the composition is administered to deliver a daily unit dose of about 1.0 mg to about 12.8 mg of the androgen, wherein the administration results in steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety, wherein the administration is selected from the group consisting of transdermal administration, oral administration, parenteral administration, intramuscular administration, and buccal administration. 
     
     
         38 . The method of  claim 37 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel comprises the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         39 . The method of  claim 37 , wherein the daily unit dose of the androgen is from about 2.5 mg to about 10.0 mg. 
     
     
         40 . The method of  claim 39 , wherein the daily unit dose of the androgen is from about 3.2 mg to about 9.6 mg. 
     
     
         41 . The method of  claim 39 , wherein the daily unit dose of the androgen is from about 6.0 mg to about 8.0 mg. 
     
     
         42 . The method of  claim 37 , wherein the daily unit dose of the androgen is selected to maintain steady state total androgen serum levels within a range of between about 0.9 ng/mL to about 1.4 ng/mL for at least 24 hours after administration. 
     
     
         43 . The method of  claim 42 , wherein free androgen serum levels and twenty-four hour free androgen AUC are not raised above levels required for therapeutic efficacy and safety. 
     
     
         44 . The method of  claim 43 , wherein the free androgen serum levels are raised to about 1.00 pg/mL to about 3.30 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 40 pg-h/mL to about 65 pg-h/mL. 
     
     
         45 . The method of  claim 37 , wherein the androgen is testosterone. 
     
     
         46 . The method of  claim 37 , wherein the subject is a male subject. 
     
     
         47 . The method of  claim 46 , wherein the composition is administered to deliver a daily unit dose of about 35 mg to about 100 mg of the androgen, wherein the administration results in steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety, wherein the administration is selected from the group consisting of transdermal administration, oral administration, parenteral administration, intramuscular administration, and buccal administration. 
     
     
         48 . The method of  claim 47 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel comprises the androgen and a pharmaceutically acceptable carrier. 
     
     
         49 . The method of  claim 47 , wherein the daily unit dose of the androgen is from about 50 mg to about 90 mg/day. 
     
     
         50 . The method of  claim 49 , wherein the daily unit dose of the androgen is from about 65 mg to about 85 mg. 
     
     
         51 . The method of  claim 47 , wherein the daily unit dose of the androgen is selected to maintain steady state total androgen serum levels within a range of between about 2.4 ng/mL to about 9.5 ng/mL for at least 24 hours after administration. 
     
     
         52 . The method of  claim 51 , wherein free androgen serum levels and twenty-four hour free androgen AUC are not raised above the levels required for therapeutic efficacy and safety. 
     
     
         53 . The method of  claim 52 , wherein the free androgen serum levels are raised to about 90 pg/mL to about 300 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 350 pg-h/mL to about 800 pg-h/mL. 
     
     
         54 . The method of  claim 53 , wherein the free androgen serum levels are raised to about 125 pg/mL to about 250 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 400 pg-h/mL to about 900 pg-h/mL. 
     
     
         55 . The method of  claim 53  wherein the free androgen serum levels are raised to about 150 pg/mL to about 300 pg/mL and the twenty-four hour free androgen AUC levels are raised to about 400 pg-h/mL to about 700 pg-h/mL. 
     
     
         56 . The method of  claim 47  wherein the androgen is testosterone. 
     
     
         57 . The method of  claim 30 , wherein the composition consists essentially of the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         58 . A method for determining if a human subject would benefit from androgen administration comprising:
 testing for at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   testing the subject's pain threshold; and if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state,   along with androgen in the lower half of the appropriate reference range, and if the subject has androgen levels in the lower portion of the of the appropriate reference range and a low threshold of pain, determining that the subject would be a candidate for androgen therapy.   
     
     
         59 . The method of  claim 58 , further comprising.
 administering a composition comprising an androgen to the subject, wherein the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range.   
     
     
         60 . The method of  claim 58 , further comprising:
 administering a composition consisting essentially of an androgen to the subject, wherein the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range.   
     
     
         61 . The method of  claim 58 , wherein the subject is suffering from an unresolvable stressor state selected from the group consisting of post-traumatic stress disorder (PTSD), accident, trauma, surgery, autoimmune disease, chronic unresolved or acute viral infection, infectious disease, cancer, chronic exhaustion or physical distress, neuropathy, hyperalgesia, allodynia, grief, emotional distress, depression, dysthymia, surgical gonadectomy, and pharmacologic-induced gonadectomy. 
     
     
         62 . The method of  claim 61 , wherein the androgen is selected from the group consisting of testosterone, androstenedione, androstendiol, dehydroepiandrosterone, danazol, fluoxymesterone, oxandrolone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone, dihydrotestosterone, methyltestosterone, androgen precursors, and testosterone esters. 
     
     
         63 . The method of  claim 64 , wherein the testosterone ester is selected from the group consisting of testosterone enanthate and testosterone cypionate. 
     
     
         64 . The method of  claim 62 , wherein the androgen is testosterone 
     
     
         65 . The method of  claim 58 , wherein the subject is a female subject. 
     
     
         66 . The method of  claim 58 , wherein the subject is a male subject. 
     
     
         67 . The method of  claim 58 , wherein the administration of the composition results in steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety, wherein the administration is selected from the group consisting of transdermal administration, oral administration, parenteral administration, intramuscular administration, and buccal administration. 
     
     
         68 . The method of  claim 67 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel comprises the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         69 . The method of  claim 67 , wherein the composition is formulated as a gel for transdermal administration, wherein the gel consists essentially of the androgen and at least one pharmaceutical carrier. 
     
     
         70 . A kit for determining if a human subject would benefit from androgen administration comprising:
 instructions for diagnosing a subject as having symptoms of an androgen-deficiency treatable by administration of an androgen comprising:
 instructing a health care provider how to test the subject's androgen serum levels; 
 instructing the health care provider to determine if the subject has at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, or 
 e) an unresolved stressor state; 
 instructing the health care provider how to test the subject's pain threshold; and 
 instructing the health care provider to administer a composition comprising an androgen to the subject if the subject has androgen levels in the lower portion of the of the appropriate reference range, has a low threshold of pain, and at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, or 
 e) an unresolved stressor state; 
   so that the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range.   
     
     
         71 . The kit of  claim 70 , wherein the composition consists essentially of the androgen and at least one pharmaceutically acceptable carrier. 
     
     
         72 . The kit of  claim 70 , wherein the instructions further comprise instructing the health care provider not to administer an opioid concurrently with the composition. 
     
     
         73 . A method of increasing endogenous opioid peptide production an androgen-deficient, opioid peptide deficient human subject comprising:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   determining if the subject has low endogenous opioid peptide levels; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state, along with androgen levels in the lower half of the appropriate reference range and low endogenous opioid peptide levels;   administering a composition comprising an androgen to a human subject with androgen and opioid peptide deficiencies, wherein the subject's production of endogenous opioid peptides is increased.   
     
     
         74 . The method of  claim 73 , wherein the opioid peptides are selected from the group consisting of enkephalins, endorphins, dynorphins, adrenorphin, amidorphin, and opiorphin. 
     
     
         75 . The method of  claim 73 , wherein the endogenous opioid peptide levels are measured in cerebrospinal fluid. 
     
     
         76 . The method of  claim 73 , wherein the composition consists essentially of the androgen and a pharmaceutically acceptable carrier. 
     
     
         77 . A method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms consisting essentially of:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state,   along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-reducing amount of an androgen to the human subject with androgen deficiency symptoms, wherein pain is reduced safely and effectively.   
     
     
         78 . A method of increasing the pain threshold of an androgen-deficient human subject consisting essentially of:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or   e) an unresolved stressor state, along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-threshold increasing amount of an androgen to a human subject with androgen deficiency, wherein the subject's pain-threshold is increased safely and effectively.   
     
     
         79 . A method for determining if a human subject would benefit from androgen administration consisting essentially of:
 testing for at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   testing the subject's pain threshold; and if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state,   along with androgen in the lower half of the appropriate reference range, and if the subject has androgen levels in the lower portion of the of the appropriate reference range and a low threshold of pain, determining that the subject would be a candidate for androgen therapy.   
     
     
         80 . A kit for determining if a human subject would benefit from androgen administration comprising:
 instructions for diagnosing a subject as having symptoms of an androgen-deficiency treatable by administration of an androgen; wherein the instructions consist essentially of
 instructing a health care provider how to test the subject's androgen serum levels; 
 instructing the health care provider to determine if the subject has at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, or 
 e) an unresolved stressor state; 
 instructing the health care provider how to test the subject's pain threshold; and 
 instructing the health care provider to administer a composition comprising an androgen to the subject if the subject has androgen levels in the lower portion of the of the appropriate reference range, has a low threshold of pain, and at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, or 
 e) an unresolved stressor state; 
   so that the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range.   
     
     
         81 . A method of increasing endogenous opioid peptide production an androgen-deficient, opioid peptide deficient human subject consisting essentially of:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89, or   e) an unresolved stressor state;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   determining if the subject has low endogenous opioid peptide levels; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or   e) an unresolved stressor state, along with androgen levels in the lower half of the appropriate reference range and low endogenous opioid peptide levels;   administering a composition comprising an androgen to a human subject with androgen and opioid peptide deficiencies, wherein the subject's production of endogenous opioid peptides is increased.   
     
     
         82 . A method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms consisting essentially of:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state;   f) decreased endogenous opioid peptides; or   g) elevated Substance P levels;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state,   f) decreased endogenous opioid peptide levels; or   g) elevated Substance P levels   along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-reducing amount of an androgen to the human subject with androgen deficiency symptoms, wherein pain is reduced safely and effectively.   
     
     
         83 . A method of increasing the pain threshold of an androgen-deficient human subject comprising:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state;   f) decreased endogenous opioid peptide levels; or   g) elevated Substance P levels;   determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state;   f) decreased endogenous opioid peptide levels; or   g) elevated Substance P levels;   along with androgen levels in the lower half of the appropriate reference range;   administering a composition comprising a pain-threshold increasing amount of an androgen to a human subject with androgen deficiency, wherein the subject's pain-threshold is increased safely and effectively.   
     
     
         84 . A method for determining if a human subject would benefit from androgen administration comprising:
 testing for at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state;   f) decreased endogenous opioid peptide levels; or   g) elevated Substance P levels;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   testing the subject's pain threshold; and if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state,   f) decreased endogenous opioid peptide levels; or   g) elevated Substance P levels;   along with androgen in the lower half of the appropriate reference range, and if the subject has androgen levels in the lower portion of the of the appropriate reference range and a low threshold of pain, determining that the subject would be a candidate for androgen therapy.   
     
     
         85 . A kit for determining if a human subject would benefit from androgen administration comprising
 instructions for diagnosing a subject as having symptoms of an androgen-deficiency treatable by administration of an androgen; wherein the instructions consist essentially of
 instructing a health care provider how to test the subject's androgen serum levels; 
 instructing the health care provider to determine if the subject has at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, 
 e) an unresolved stressor state; 
 f) decreased endogenous opioid peptide levels; or 
 g) elevated Substance P levels; 
 instructing the health care provider how to test the subject's pain threshold; and 
 instructing the health care provider to administer a composition comprising an androgen to the subject if the subject has androgen levels in the lower portion of the of the appropriate reference range, has a low threshold of pain, and at least one of 
 a) elevated C-reactive protein, 
 b) elevated erythrocyte sedimentation rate, 
 c) DSM-IV disorder 307.80, 
 d) DSM-IV disorder 307.89, 
 e) an unresolved stressor state; 
 f) decreased endogenous opioid peptide levels; or 
 g) elevated Substance P levels; 
   so that the subject's androgen serum levels are restored to the middle-upper range of an appropriate reference range.   
     
     
         86 . A method of increasing endogenous opioid peptide production an androgen-deficient, opioid peptide deficient human subject consisting essentially of:
 diagnosing a human subject to have at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80,   d) DSM-IV disorder 307.89,   e) an unresolved stressor state; or   f) elevated Substance P levels;   determining if the subject has androgen levels in the lower half of the appropriate reference range;   determining if the subject has decreased endogenous opioid peptide levels; and, if the subject has at least one of   a) elevated C-reactive protein,   b) elevated erythrocyte sedimentation rate,   c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89,   e) an unresolved stressor state, or   f) elevated Substance P levels;   along with androgen levels in the lower half of the appropriate reference range and decreased endogenous opioid peptide levels;   administering a composition comprising an androgen to a human subject with androgen and opioid peptide deficiencies, wherein the subject's production of endogenous opioid peptides is increased.