Abstract:
The present invention is directed to compositions comprising N-L-alpha-aspartyl-L-phenylalanine and esters thereof as well as to method of treating pain which comprises administering such a composition to a patient in need thereof.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a 371 of PCT/US96/10716 filed Jun. 21, 1996 and a continuation-in-part of U.S. application Ser. No. 08/590,409 filed Jan. 25, 1996, now issued as U.S. Pat. No. 5,654,334, which claims the benefit of copending U.S. Provisional Application No. 60/000,479 filed Jun. 23, 1995. 
    
    
     TECHNICAL FIELD 
     The present invention relates to pain relieving composition and a method for use. 
     BACKGROUND OF THE INVENTION 
     Pain is the most common symptom for which patients seek medical assistance. In the case of incurable diseases, treatment for pain may last for extended periods of time. Pain is both a physical and an emotional experience which differs greatly from one individual to another. Although subjective, most pain is associated with tissue damage and has a physiological basis. 
     Pain can be either acute or chronic. Acute pain is generally caused by sudden injury, tissue damage, or infection for which the cause is easily found. Chronic pain, however, is the pain of pathological conditions and often difficult to isolate and treat. Chronic pain is routinely defined as pain of over six months duration. 
     For patients suffering from chronic pain, the autonomic nervous system adapts to the pain and evidences of autonomic hyperactivity such as tachycardia, hypertension, diaphoresis, mydriasis, and pallor disappear, leaving the physician to rely on the patient&#39;s subjective complaints in assessing chronic pain. 
     In the management of chronic pain, some types of pain permit treatment of the underlying disorder, i.e., radiation treatment for pain caused by bone cancer. In some cases, a particular treatment is given for a specific type of pain, i.e., treatment of trigeminal neuralgia or glossopharyngeal neuralgia with carbamazepine, reflex sympathetic dystrophies with local anesthetic, postherpetic neuralgia with direct stimulation. 
     In many patients, however, the pain is chronic and the physician can neither treat the underlying disturbance nor prescribe a specific therapy for that type of pain. For example, osteoarthritis is a joint disease characterized by degeneration and loss of articular cartilage and by osteophyte formation, or bony outgrowth of subchondral bone. The disease is slowly progressive, leading to chronic pain and stiffness and gradually to increasing dysfunction of the affected joint. The incidence of the disease increases with age and affects three times as many women as men. 
     Chronic joint pain, swelling, creaking, and stiffness are the most prominent symptoms of osteoarthritis. The disease commonly affects the distal interphalangeal joints of the hands, resulting in bone enlargements often accompanied by inflammation and pain. Weight bearing joints such as the neck, lower back, knees and hips are often affected by this type of arthritis. 
     Another major symptom of osteoarthritis is loss of articulation of the joint. Weakness and shrinkage of surrounding muscles may occur if pain prevents the joint from being used regularly. As movement of an affected joint becomes severely limited, the sufferer experiences loss of functionality of the joint. In the case of osteoarthritis of the hip or knees, ambulation becomes impaired. 
     Although osteoarthritis is the most common of the rheumatic diseases, its pathogenesis is not well understood, and currently there is no treatment that will retard or reverse pathological processes in the disease. The only treatment available to osteoarthritis sufferers has involved symptomatic treatment through analgesics for pain and nonsteroidal anti-inflammatory agents for reduction of joint inflammation. An injection of a corticosteroid may also be administered to a painful joint. 
     Chronic pain is also associated with multiple sclerosis (MS), also known as disseminated or insular sclerosis, a disease of the central nervous system (CNS) characterized by widespread patches of demyelination in the brain and spinal cord. The disease occurs worldwide in about 10-60 persons per 100,000 with the age at onset occurring at about 20-40 years, and appears to affect females more often than males. While MS is generally chronic and relapsing, fulminating attacks occur, and as many as 30% of the patients progress steadily from the onset. 
     Although multiple sclerosis is the most common demyelinating disease, its cause is unknown, and there is no treatment to retard or reverse the pathological processes of the disease. There is no specific therapy recommended because spontaneous remissions make treatment difficult to evaluate. The only treatment available to multiple sclerosis patients includes corticosteroid therapy (e.g., prednisone or dexamethasone) until manifestations remit, and symptomatic treatment such as baclofen for spasticity and pain relievers such as analgesics and opiates. 
     There are several types of drugs used to decrease chronic pain. Analgesics are drugs used to decrease pain without causing loss of consciousness or sensory perception. There are two basic classes of analgesics: anti-inflammatory, routinely prescribed for short-term pain relief and for modest pain, and opioids used for either short-term or long term pain relief of severe pain. The anti-inflammatory analgesics generally provide analgesia, anti-inflammation, and antipyretic action. It has been reported that the mechanism of action may be to provide inhibition of the synthesis of prostaglandins. W. W. Douglas, &#34;Polypeptides--angiotensin, plasma kinins, and other vasoactive agents; prostaglandins,&#34; The Pharmacological Basis of Therapeutics, 9th edition, L. S. Goodman and A. Gilman (eds.), MacMillan Publishing Co., Inc., N.Y., 1975. 
     Prolonged use of anti-inflammatory analgesics have been known to cause gastrointestinal problems. 
     The opioid analgesics, or narcotics, include all natural or synthetic chemical compounds closely related to morphine and are thought to activate one or more receptors on brain neurons. Opioid analgesics have serious side effects and thus are used with discrimination. These side effects include: 1) tolerance, which requires gradually increasing doses to maintain analgesia; 2) physical dependence, which means that the narcotics must be withdrawn gradually if they are discontinued after prolonged use; 3) constipation, which requires careful attention to bowel function, including use of stool softeners, laxatives, and enemas; and 4) various degrees of somnolence, or drowsiness, which requires adjustments in dosages and dose scheduling, or possibly varying the type of narcotic to find one better tolerated by the patient. 
     It has been reported that various treatments for pain are additive and should be used together rather than separately. For example, the combination of aspirin or acetaminophen and codeine is often prescribed to provide pain relief stronger than codeine by itself. Certain antidepressants prescribed for depression have been recommended as an analgesic adjuvant. 
     While pain management has been a problem faced by physicians for many years, available pain medications have ameliorated, but not alleviated the problem of pain treatment. A significant problem remains in that detrimental side effects are often caused by pain-relieving medications as detailed above. Thus, there remains a continuing need for alternative pain therapy regimens which would address the need for pain reduction but also reduce these side effects. 
     Surprisingly, it has now been discovered that N-L-α-aspartyl-L-phenylalanine 1-methyl ester and derivatives have analgesic properties, relieving pain and restoring function of soft tissues, muscles, ligaments, tendons, bones, and joints. Further, when taken in combination with other analgesic agents, N-L-α-aspartyl-L-phenylalanine 1-methyl ester provides an additive analgesic effect. The detrimental side effects inherent in pain therapy known to the art can be reduced through the use of N-L-α-aspartyl-L-phenylalanine 1-methyl ester in pain therapy and management. 
     SUMMARY OF THE INVENTION 
     In one aspect of the invention, N-L-α-aspartyl-L-phenylalanine 1-methyl ester or its derivatives or both are used in a method for decreasing pain in a mammal. 
     In another aspect, N-L-α-aspartyl-L-phenylalanine 1-methyl ester or its derivatives or both are used in combination with an anti-inflammatory analgesic drug of other composition in a pain treatment regimen. 
     In another aspect, N-L-α-aspartyl-L-phenylalanine 1-methyl ester or its derivatives or both are used in combination with an opioid analgesic in a pain treatment regimen. 
     In yet another aspect, N-L-α-aspartyl-L-phenylalanine 1-methyl ester or its derivatives or both are used in treating osteoarthritis. 
     Another aspect of the invention concerns pharmaceutical dosage form containing N-L-α-aspartyl-L-phenylalanine 1-methyl ester or its derivatives or both. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a graph depicting the average time required to ascend and descend stairs for the APM and control treatment groups measured over time. 
     FIG. 2 is a graph depicting the average pain experienced by the APM and control treatment groups upon ascending and descending stairs measured over time. 
     FIG. 3 is a graph depicting the average rest pain experienced by the APM and control treatment groups taken after a one hour rest period following ascending and descending stairs measured over time. 
     FIG. 4 is a graph depicting the difference between stair pain and rest pain experienced by the APM and control treatment groups upon ascending and descending stairs measured over time. 
     FIG. 5 is a graph depicting the average distance walked by the APM and control treatment groups measured over time. 
     FIG. 6 is a graph depicting the average pain experienced by the APM and control treatment groups upon walking for five minutes measured over time. 
     FIG. 7 is a graph depicting the average grip strength for the APM and control treatment groups measured over time. 
     FIG. 8 is a graph depicting the average gripping pain experienced by the APM and control treatment groups measured over time. 
     FIG. 9 is a graph depicting the average bleeding time before and after treatment with APM or placebo. 
     FIG. 10 is a graph depicting the average amount of blood loss before and after treatment with APM or placebo. 
    
    
     DETAILED DESCRIPTION 
     Chronic pain has been shown to be associated with various pathological conditions such as osteoarthritis, inflammation, multiple sclerosis, and myocardial infarction. It has now been found that N-L-α-aspartyl-L-phenylalanine 1-methyl ester (APM), which has been sold under the trade name of ASPARTAME™ (G.D. Searle &amp; Company, Chicago, Ill.) and its derivatives offers medicinal qualities beneficial in the treatment of chronic pain in mammals. One can use an effective amount of APM to effect a reduction in perceived pain by the recipient within one hour of dosage. An effective amount of APM which car effect pain relief after one dose is from about 40 milligrams to about 540 milligrams A preferred range is from about 80 milligrams to about 320 milligrams. A more preferred range is from about 80 milligrams to about 160 milligrams. Most preferred is about 160 milligrams. The dosage can be repeated over time for continued relief, preferably at 160 milligrams every 4 hours. APM can also be administered together with other analgesics such as acetaminophen, phenacetin, aspirin, ibuprofen, phenylbutazone, indomethacin and derivatives, opiates and derivatives, piroxacam, and steroidal and nonsteroidal anti-inflammatory agents, providing additive analgesic properties. 
     APM can be administered orally, parenterally, intraperitoneally, or sublingually. It can be administered via ingestion of a food substance containing APM in a volume sufficient to achieve therapeutic levels. Alternatively, it can be enclosed in capsules, compressed into tablets, microencapsulated, entrapped in liposomes, in solution or suspension, alone or in combination with a substrate immobilizing material such as starch or poorly absorbable salts. Pharmaceutically compatible binding agents and/or adjuvant materials can be used as part of a composition. Tablets or capsules can contain any of the following ingredients, or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; an integrating agent such as alginic acid or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and additional sweetening and flavoring agents. When a capsule form is used the liquid carrier such as a fatty oil may be used. Capsules and tablets can be coated with sugar, shellac and other enteric agents as is known. APM can also be in a controlled-release formulation. 
     APM is available commercially. Its preparation is also disclosed in U.S. Pat. No. 3,492,131. It is believed that various modifications can be made to the APM molecule and the resulting derivatives will also have utility in the claimed invention. Since the 1-methyl ester portion of the molecule is not believed to contribute to the analgesic activity of the molecule, N-L-α-aspartyl-L-phenylalanine itself or other lower alkyl esters are believed to be effective. Other possible analgesic physiologically acceptable derivatives are believed to include N-acyl-L-(beta-substituted)-aspartyl-L-phenylalanine lower alkyl esters and N-acyl-L-(beta-substituted)-aspartyl-L-phenylalanine. Chemical modifications made to the APM molecule which do not reduce the analgesic physiologically active properties disclosed herein thus fall within the scope of this invention. 
     EXAMPLE 1 
     Osteoarthritis 
     In a well-controlled double-blind crossover study, patients suffering from osteoarthritis were given the tasks of climbing stairs, walking, and hand gripping, all of which are known to cause chronic pain in osteoarthritic patients, following treatment with either APM or a placebo. The study was performed twice for all patients, and prior to each study, all other analgesics were withheld for twenty-four hours. During the first study, one test group of eleven patients were randomly administered 4 tablets of either aspartame (76 milligrams; 19 milligrams/tablet) or placebo, and another test group of nine patients were randomly given 8 tablets of either aspartame (152 milligrams; 19 milligrams/tablet) or placebo. During the second study, each patient was given the same number of tablets but were given the opposite medication from what they had received in the first study. Following each test, data analysis of the recovered information was completed using non-parametric analyses of variance and distribution free assessments of the measured variable. 
     Stair Climbing 
     Twenty osteoarthritic patients divided into groups of nine and eleven each were asked to ascend and descend one flight of stairs, making a total of three trips with one-hour rest periods between trips. Right after the first baseline trip, patients were administered the test medication. All patients then made three subsequent trips up and down the stairs. Table I and FIG. 1 present an objective measurement of performance with respect to the time required for each patient to ascend and descend one flight of stairs. The mean results show that over time the 4-tablet APM group decreased the stair time, with a 9.6% decrease for the last trip. For the 8-tablet APM group, a decrease of 11.9% was observed for the second trip after dosing and 6.9% for the last trip. After administration of the placebo, the 4-tablet placebo group showed a decrease in stair time of 6.5% for the first and second trips after dosing, and 3.7% for the last trip. The 8-tablet placebo group showed a gradual increase in stair time with a maximum increase of 2% for the last trip. 
     A subjective measurement of stair pain was made by administering a visual analog pain assessment to the patients. A baseline assessment for various joints, usually three joints, was taken one hour prior to the first baseline trip, and the assessment was then 
     
                       TABLE I______________________________________Stair Time with and without APM       Stair Climb Time (min)  Hours after TreatmentSubject #   0      1          2    3______________________________________Control group - 4 tablets placebo  1             1.04   0.59     0.59 1.01  2 0.92 0.99 0.97 0.96  3 1.19 1.12 1.10 1.15  4 1.00 1.03 1.04 1.04  5 0.90 0.91 0.94 0.98  6 2.09 1.50 1.51 1.56  7 0.79 0.79 0.80 0.81  8 1.28 1.27 1.23 1.24  9 1.25 1.26 1.26 1.26  10 0.72 1.02 1.01 0.80  11 0.56 0.58 0.54 0.55mean        1.07   1.00       1.00 1.03APM group - 4 tablets APM  1             1.05   1.01     1.00 1.01  2 0.96 0.96 0.93 0.88  3 1.10 1.08 1.04 1.02  4 1.10 1.10 1.07 1.06  5 0.90 0.91 0.89 0.92  6 2.07 2.10 2.16 1.54  7 0.78 0.79 0.79 0.78  8 1.36 1.30 1.28 1.33  9 1.23 1.25 1.24 1.25  10 1.01 1.02 1.02 1.02  11 1.07 1.03 1.01 0.59mean        1.15   1.14       1.13 1.04Control group - 8 tablets placebo  12            0.94   0.94     0.91 0.93  13 0.90 0.92 0.90 0.96  14 1.44 1.43 1.51 1.56  15 0.49 0.51 0.54 0.58  16 1.24 1.25 1.25 1.22  17 1.07 1.07 1.13 1.13  18 1.14 1.11 1.09 1.10  19 0.81 0.84 0.83 0.84  20 1.15 1.08 1.08 1.05  mean 1.02 1.02 1.03 1.04APM group - 8 tablets APM  12            0.94   0.92     0.89 0.86  13 0.87 0.88 0.89 0.90  14 1.45 1.42 1.35 1.44  15 0.50 0.55 0.56 0.51  16 1.33 1.25 1.27 1.25  17 1.00 1.03 0.55 0.59  18 1.14 1.16 1.08 1.08  19 0.84 0.88 0.86 0.83  20 1.06 1.02 0.58 1.00  mean 1.01 1.01 0.89 0.94Total mean score by treatment group  Control       1.05   1.01     1.01 1.04  APM 1.09 1.08 1.02 0.99______________________________________ 
    
     repeated for each of the four trips. Each patient made an assessment under a nurse&#39;s supervision (same nurse throughout study) as to the amount of pain involved on a scale marked with increments for none, a little, more, a lot, and most. A numerical conversion of the marks on the scale in millimeters taken as the distance from the absence of pain mark was made. The representation of this assessment scale where the lower the number the lesser the pain, and the higher the number, the greater the pain is given in Table II and FIG. 2 as an average value for all rated joints. Referring to the mean, there was a marked decrease in the amount of pain associated with ascending and descending stairs in the APM groups in comparison to that in the placebo groups. The 4-tablet placebo group showed increased pain over the pre-climbing baseline assessment for each trip; however, while the 4-tablet APM group also experienced increased pain over the pre-climbing baseline assessment for the first two trips, they had decreased pain below or just above the pre-climbing baseline assessment for the last two trips. 
     Table III provides pain assessment measurements for the most sensitive joint for some of the patients taken at one hour and two hours after treatment. For the 4-tablet treatment groups, the placebo group showed a slight increase in pain (2.2%), while the APM group experienced a 52.2% decrease in pain. The 8-tablet APM group also experienced a significant decrease in pain 
     
                       TABLE II______________________________________Stair Pain with and without APM   Stair Pain (relative numerical scale)  Hours after TreatmentSubject #   -1       0        1      2      3______________________________________Control group - 4 tablets placebo  1         27       49     33     42     36  2 62 102 119 91 74  3 51 85 67 110 73  4 31 73 25 32 31  5 42 59 38 73 58  6 93 117 118 126 127  7 24 81 97 89 88  8 41 22 31 28 21  9 31 46 64 45 75  10 55 72 78 88 85  11 36 48 50 31 36mean    44.82    68.55    65.45  68.64  64.00APM group - 4 tablets APM  1         45       47     48     36     22  2 24 80 91 32 38  3 106 130 130 73 73  4 79 63 70 40 42  5 41 71 56 56 44  6 46 95 130 101 130  7 28 87 87 56 74  8 59 28 30 28 62  9 94 56 47 30 30  10 67 83 96 91 105  11 36 45 49 52 24mean    56.82    71.36    75.82  54.09  58.55Control group - 8 tablets placebo  12        33       66     60     51     59  13 22 40 26 30 24  14 35 74 115 116 118  15 45 74 21 33 50  16 50 52 50 51 56  17 22 28 26 22 21  18 62 74 92 77 74  19 8 49 63 49 83  20 43 45 33 20 21  mean 35.56 55.78 54.00 49.89 56.22APM group - 8 tablets APM  12        42       72     71     51     53  13 31 31 39 31 31  14 69 97 84 85 117  15 33 35 23 31 33  16 53 52 54 53 54  17 39 31 15 21 17  18 25 48 65 49 56  19 57 78 63 72 74  20 34 37 26 14 14  mean 42.56 53.44 48.89 45.22 49.89Total mean score by treatment group  Control   40.65    62.80  60.30  60.20  60.50  APM 50.40 63.30 63.70 50.10 54.65______________________________________ 
    
     
                       TABLE III______________________________________Stair Pain of Most Sensitive Joint  with and without APM       Stair Pain (relative numerical scale)  Hours after TreatmentSubject #   1           2______________________________________Control group - 4 tablets placebo  1             24          43  2 113 105  3 63 92  4 25 32  5 21 57  6 149 149  7 97 77  8 16 21  9 73 3510          --          --11          33          17mean        61.40       62.80APM group - 4 tablets APM  1             53          35  2 107 53  3 130 16  4 104 46  5 56 22  6 150 106  7 75 39  8 45 26  9 73 3710          --          --11          32          14mean        82.50       39.40Control group - 8 tablets placebo  12            48          39  13 26 3814          --          --  15 -- --  16 -- --  17 -- --18          129         93  19 86 58  20 33 15  mean 64.40 48.60APM group - 8 tablets APM  12            71          11  13 55 3914          --          --  15 -- --  16 -- --  17 -- --18          32          15  19 86 72  20 36 8  mean 56.00 29.00Total mean score by treatment group  Control       62.40       58.07  APM 73.67 35.93______________________________________ 
    
     (48.2%), compared to a 24.5% decrease in pain for the 8-tablet placebo group. 
     An evaluation of pain was also measured using the visual analog pain assessment method by the patient at the end of each rest period (Table IV and FIG. 3). While the average rest pain generally increased for both placebo groups, the 4-tablet APM group experienced a 12.2%, 16.5%, and 10.4% decrease in rest pain from pretreatment over time, while the 8-tablet APM group, a 2.3%, 36.8% and 14.6% decrease. In Table V and FIG. 4, the mean difference between stair pain and rest pain for each patient at each time period is given, showing that the mean difference of the APM groups was lower than the placebo groups. As indicated by the negative numbers, some patients in both groups experienced greater rest pain than stair climb pain. 
     Walking Distance 
     Chronic pain was examined in respect to distance walking at a comfortable speed for a five minute period. A pre-walking baseline pain assessment was performed. After establishing a baseline walking distance, the 4- and 8-tablet APM groups were given 76 milligrams and 152 milligrams APM, respectively, while the 4- and 8-tablet control groups were given the appropriate number of placebo tablets. After resting for one hour, the patients repeated the 5-minute walking procedure three times with one hour rest 
     
                       TABLE IV______________________________________Rest Pain with and without APM     Rest Pain (relative numerical scale)  Hours after TreatmentSubject # 0       1           2     3______________________________________Control group - 4 tablets placebo  1           27      31        32    45  2 62 79 36 48  3 51 10 30 15  4 31 46 30 30  5 42 54 40 41  6 93 116 127 129  7 24 39 42 40  8 41 35 23 16  9 31 31 48 58  10 55 70 73 80  11 36 35 32 25mean      44.82   49.64       46.64 47.91APM group - 4 tablets APM  1           45      37        45    17  2 24 50 77 78  3 106 25 14 30  4 79 68 56 40  5 41 40 39 41  6 46 77 94 99  7 28 9 8 39  8 59 49 25 27  9 94 77 32 24  10 67 80 89 96  11 36 38 43 69mean      56.82   50.00       47.45 50.91Control group - 8 tablets placebo  12          33      34        16    14  13 22 24 28 32  14 35 78 115 118  15 45 19 32 32  16 50 53 50 50  17 22 19 18 24  18 62 35 30 34  19 8 8 8 10  20 43 36 26 24  mean 35.56 34.00 35.89 37.56APM group - 8 tablets APM  12          42      58        32    38  13 31 32 28 33  14 69 73 53 86  15 33 20 19 27  16 53 54 52 52  17 39 35 20 16  18 25 33 12 20  19 57 39 9 39  20 34 30 17 16  mean 42.56 41.56 26.89 36.33Total mean score by treatment group  Control     40.65   42.60     41.80 43.25  APM 50.40 46.20 38.20 44.35______________________________________ 
    
     
                       TABLE V______________________________________Stair Pain v. Rest Pain with and without APM     Stair Pain Minus Rest Pain  Hours after TreatmentSubject # 0       1           2     3______________________________________Control groups - 4 or 8 tablets placebo  1           22      1         10    -9  2 40 40 55 26  3 34 57 80 58  4 42 -21 2 1  5 17 -16 33 17  6 24 2 -1 -2  7 57 58 47 48  8 -19 -4 5 5  9 15 33 -3 17  10 17 8 15 5  11 12 15 -1 11  12 33 26 35 45  13 18 2 2 -8  14 39 37 1 0  15 29 2 1 18  16 20 -3 1 6  17 6 7 4 -3  18 12 57 47 40  19 41 55 41 73  20 2 -3 -6 -3mean      23.05   17.65       18.40 17.25APM groups - 4 or 8 tablets APM  1           2       11        -9    5  2 56 41 -45 -40  3 24 105 59 43  4 -16 2 -16 2  5 30 16 17 3  6 49 53 7 31  7 59 78 48 35  8 -31 -19 -2 35  9 -38 -30 -2 -4  10 16 16 2 9  11 9 11 9 -45  12 30 13 19 15  13 0 7 3 -2  14 28 11 84 116  15 2 3 12 6  16 -1 0 1 2  17 -8 -20 1 1  18 23 32 37 36  19 21 25 74 35  20 3 -4 -3 -2mean      12.90   17.55       14.78 14.06______________________________________ 
    
     periods between trips. Table VI and FIG. 5 show the total distance walked in terms of feet traveled. The average distance walked in the control groups decreased slightly over time, with the mean varying from -0.5% to -2.2% from baseline. Comparatively, the average distance walked in the APM groups varied from -0.4% to 1.8% from baseline. Although the average distance walked decreased at one hour from baseline, there was an increase at 3 hours from baseline for both APM groups. 
     Walking distance pain was recorded via the visual analog pain assessment. A baseline assessment was taken one hour prior to the first baseline trip. The assessment was then repeated for each of the four trips. A relative numerical representation of this assessment scale where the lower the number the lesser the pain, and the higher the number, the greater the pain is given in Table VII and FIG. 6. The average distance pain after the four walks increased over the pre-walking baseline assessment by 22.7 to 42.8% for the 4-tablet control group, and 20.6% to 35.6% for the 8-tablet control group. Comparatively, the patients in the 4-tablet APM group showed an increase in average distance pain after the baseline walk (23.0%) and the first walk after dosing (21.8%), while the average distance pain decreased below the pre-walking baseline assessment by 1.1% after the second walk after dosing and then increased to 11.4% above the pre-walking 
     
                       TABLE VI______________________________________Walking Distance with and without APM     Walking Distance (feet)  Hours after TreatmentSubject # 0       1           2     3______________________________________Control group - 4 tablets placebo  1           1035    1040      1055  1045  2 895 875 895 825  3 1000 980 1030 1000  4 1010 980 970 990  5 1100 1095 1095 1120  6 800 775 810 800  7 1325 1295 1310 1295  8 865 900 920 890  9 840 865 850 810  10 1175 1110 1085 1100  11 1150 1125 1105 1100mean      1017.73 1003.64     1011.36                               997.73APM group - 4 tablets APM  1           990     1000      1000  1000  2 880 840 835 870  3 1025 1080 1090 1100  4 910 885 900 910  5 1075 1075 1070 1060  6 755 770 785 810  7 1320 1320 1325 1310  8 820 825 890 885  9 830 810 850 880  10 1300 1235 1245 1220  11 1010 1000 1025 1070mean      992.27  985.45      1001.36                               1010.45Control group - 8 tablets placebo  12          935     930       920   910  13 1150 1160 1145 1120  14 780 785 760 770  15 1230 1250 1240 1170  16 900 930 940 920  17 1065 1025 995 1000  18 1095 1070 1085 1120  19 1350 1305 1300 1260  20 710 705 720 735  mean 1023.89 1017.78 1011.67 1000.56APM group - 8 tablets APM  12          980     930       910   1000  13 1120 1140 1115 1120  14 790 795 825 740  15 1210 1270 1260 1260  16 890 900 925 905  17 1000 995 960 1045  18 1075 1060 1070 1100  19 1285 1250 1250 1250  20 790 765 780 780  mean 1015.56 1011.67 1010.56 1022.22Total mean score by treatment group  Control     1020.50 1010.00   1011.50                                 999.00  APM 1002.75 997.25 1005.50 1015.75______________________________________ 
    
     
                       TABLE VII______________________________________Walking Pain with and without APM   Walking Pain (relative numerical scale)  Hours after TreatmentSubject #   -1       0        1      2      3______________________________________Control group - 4 tablets placebo  1         27       43     49     43     37  2 62 81 80 53 53  3 51 83 25 16 53  4 31 46 38 22 22  5 42 87 87 71 39  6 93 95 116 128 128  7 24 57 57 77 76  8 41 63 43 35 56  9 31 39 57 56 65  10 55 70 70 70 73  11 36 40 38 34 33mean    44.82    64.00    60.00  55.00  57.73APM group - 4 tablets APM  1         45       60     53     33     35  2 24 50 62 42 99  3 106 118 94 32 13  4 79 51 63 54 59  5 41 71 71 73 74  6 46 81 93 100 100  7 28 58 40 37 42  8 59 71 86 65 85  9 94 83 49 29 30  10 67 74 86 90 100  11 36 52 64 63 59mean    56.82    69.91    69.18  56.18  63.27Control group - 8 tablets placebo  12        33       68     17     21     18  13 22 29 43 57 47  14 35 55 95 114 114  15 45 75 32 49 55  16 50 51 60 61 72  17 22 26 27 30 28  18 62 87 52 59 42  19 8 8 41 8 38  20 43 35 19 20 17  mean 35.56 48.22 42.89 46.56 47.89APM group - 8 tablets APM  12        42       41     30     40     40  13 31 47 48 47 46  14 69 95 84 84 96  15 33 38 31 36 27  16 53 54 61 54 56  17 39 35 28 27 24  18 25 49 55 29 44  19 57 75 11 40 39  20 34 44 24 16 13  mean 42.56 53.11 41.33 41.44 42.78Total mean score by treatment group  Control   40.65    56.90  52.30  51.20  53.30  APM 50.40 62.35 56.65 49.55 54.05______________________________________ 
    
     baseline assessment after the last walk. For the 8-tablet APM group, the average distance pain after the baseline walk increased over the pre-walking assessment by 24.8%; however, the average distance pain for the remaining three walks was right at or below the pre-walking baseline assessment. 
     Grip Strength 
     Grip strength was measured by placing the cuff into a cloth bag and filling with air to a resting pressure of 20 mmHg for easy gripping. Each patient gripped the cloth bag, and the increase in pressure registered as change in mmHg on the cuff was recorded. Following a baseline gripping measurement, the 4- and 8-tablet APM groups were given 76 milligrams and 152 milligrams APM, respectively, while the 4- and 8-tablet control groups were given the appropriate number of placebo tablets. After a one hour rest period, the gripping measurement was repeated three more times with a one hour rest period between each measurement. As shown in Table VIII and FIG. 7, both APM groups and the 4-tablet control group basically showed increasing grip strength over time. The 8-tablet control varied about 2% to 3% above and below baseline. 
     To determine average grip pain, a visual analog pain assessment was performed prior to the baseline gripping measurement and then repeated after each subsequent gripping measurement. In Table IX and FIG. 8, the mean data shows that within 2 hours after treatment, grip pain for both APM groups fell at or 
     
                       TABLE VIII______________________________________Grip Strength with and without APM    Grip Strength (mmHg)  Hours after TreatmentSubject #    0       1           2     3______________________________________Control group - 4 tablets placebo  1          275     280       265   260  2 135 110 105 105  3 175 170 180 170  4 165 180 160 170  5 170 195 195 180  6 140 155 145 200  7 95 80 95 95  8 225 235 245 275  9 195 205 205 245  10   230 230 235 225  11  155 160 145 160  mean 178.18 181.82 179.55 189.67APM group - 4 tablets APM  1          240     235       255   250  2 65 85 80 105  3 75 135 155 180  4 115 135 165 145  5 140 165 170 160  6 120 100 140 160  7 95 110 95 105  8 190 240 215 210  9 270 275 295 265  10   170 165 155 155  11  180 170 170 170  mean 150.91 165.00 172.27 173.18Control group - 8 tablets placebo  12         85      90        100   100  13 155 155 170 160  14 165 160 145 135  15 150 140 145 140  16 230 210 210 215  17 180 180 190 225  18 165 150 170 165  19 85 90 105 85  20 55 75 90 90  mean 141.11 138.89 147.22 146.11APM group - 8 tablets APM  12         80      90        95    95  13 145 160 160 165  14 125 125 120 135  15 155 165 165 170  16 235 230 220 225  17 185 190 195 220  18 110 130 160 180  19 110 115 100 95  20 75 90 85 80  mean 135.56 143.89 144.44 151.67Total mean score by treatment group  Control    161.50  162.50    165.00                                170.00  APM 144.00 155.50 159.75 163.50______________________________________ 
    
     
                       TABLE IX______________________________________Grip Pain with and without APM   Grip Pain (relative numerical scale)  Hours after TreatmentSubject #   -1       0        1      2      3______________________________________Control group - 4 tablets placebo  1         48       79     50     59     51  2 --  --  --  --  --  3 85 25 22 84 84  4 46 59 21 21 15  5 --  --  --  --  --  6 47 82 105 86 82  7 75 76 76 100 77  8 19 19 18 17 16  9 24 42 42 41 25  10  43 70 80 87 85  11  37 54 45 35 45  mean 47.11 56.22 51.00 58.89 53.33APM group - 4 tablets APM  1         17       45     55     22     19  2 --  --  --  --  --  3 106 106 40 20 10  4 47 49 33 30 35  5 --  --  --  --  --  6 46 82 106 105 93  7 40 58 75 75 73  8 16 19 19 20 17  9 41 42 23 24 22  10  71 81 91 95 107  11  50 53 59 50 63  mean 48.22 59.44 55.67 49.00 48.78Control group - 8 tablets placebo  12        16       48     46     38     17  13 23 49 36 23 51  14 35 71 92 132 97  15 64 66 27 32 57  16 48 47 47 48 51  17 14 8 11 8 8  18 103 128 94 101 84  19 41 72 73 40 57  20 43 51 41 40 16  mean 43.00 60.00 51.89 51.33 48.67APM group - 8 tablets APM  12        16       43     74     39     15  13 23 23 22 20 20  14 34 31 71 71 72  15 32 35 40 48 56  16 18 17 16 20 17  17 9 13 21 24 7  18 88 75 90 47 71  19 98 97 72 74 73  20 75 70 36 22 17  mean 43.67 44.89 49.11 40.56 38.67Total mean score by treatment group  Control   45.06    58.11  51.44  55.11  51.00  APM 45.94 52.17 52.39 44.78 43.72______________________________________ 
    
     below the pre-gripping baseline assessment, while both control groups stayed at least 8% higher than the pre-gripping baseline assessment. 
     Overall, this study documents that use of APM was successful in relieving pain and that performance was measurably improved. Statistical assessments of measured variables suggests that the inference that the observed differences were due to chance is improbable at p&lt;0.05 to p&lt;0.01 or more. 
     EXAMPLE 2 
     Osteoarthritis--Pain Alleviation 
     The analgesic properties of APM given over time was demonstrated in one osteoarthritic patient engaged in viewing a football game. The patient was in severe pain at the beginning of the game. However, upon consumption of six diet soft drinks through the course of the game (approximately 1 g APM over 3 hours), the patient experienced substantial pain relief and markedly increased joint mobility. 
     EXAMPLE 3 
     Multiple Sclerosis--Pain Alleviation 
     In one example of the analgesic properties of APM in combination with other analgesic agents in relieving pain associated with multiple sclerosis, four tablets each containing 19.5 milligrams of APM were ingested by a patient with multiple sclerosis. The dosage was repeated at 100-120 milligrams every six hours. Upon administration of the APM, the patient&#39;s need for opiates for relief from pain dropped by 50%: one-half tablet Percocet (Du Pont Pharmaceuticals, Wilmington, Del.; each tablet containing 5 mg oxycodone hydrochloride and 325 mg acetaminophen) taken 2-3 times a day rather than one tablet taken 4 times a day. By combining APM with the opiate analgesic, the required dosage of the opiate analgesic was decreased, thereby lessening the negative side effects of the opiate analgesic such as constipation experienced by the patient. 
     EXAMPLE 4 
     Alleviation of Pain Associated with Injury 
     APM provided pain relief for a 48 year old female (non-arthritic) who injured her heel and associated tendons and ligaments to the arch of the foot while running along rough terrain. At 12 hours after the injury, the patient walked with a severe limp. Approximately 4 packets (about 0.15 grams) APM mixed in orange juice was given to the patient on an empty stomach. Approximately 50 minutes later, the patient participated in a one mile hike without noticeable limp. A second 4-packet dose in orange juice was administered 5 hours later. Eight hours after start of treatment, the patient was walking without pain. The following morning, there was tenderness to thumb pressure but no pain while walking. Thirty-six hours after treatment, there was no pain and very little tenderness. 
     EXAMPLE 5 
     Alleviation of Pain Associated with Back Surgery 
     Enrolled in a blind study, an osteoarthritis patient was taking a study compound for pain relief. Prior to back surgery, the patient discontinued using the study compound, but postoperatively, he resumed taking five tablets of the study compound unprescribed three times a day. On Day 1 after surgery, the patient took only one prescribed p.r.n. pain tablet and discontinued use of a prescribed PCA pump narcotic pain reliever because he reported a lack of need. Despite continued access to prescribed pain relievers, the patient declined due to lack of need. The patient was walking on Day 1, went home on Day 3, and resumed normal routine without pain on Day 10. The blinded study compound was APM (19.5 milligrams per tablet). 
     EXAMPLE 6 
     Myocardial Infarction--Pain Alleviation 
     Pain associated with myocardial infarction has been associated with platelet aggregation. Since the pain reliever effects of APM show properties in common with aspirin and other nonsteroidal anti-inflammatory agents, APM was further evaluated for possible anticoagulant properties. 
     A preliminary study of bleeding times in twelve normal subjects was performed. After baseline bleeding times were measured using the Simplate bleeding technique according to manufacturer&#39;s instructions (General Diagnostics, Organon Technica, Oklahoma City, Okla.), each subject ingested four tablets of aspartame (76 milligrams; 19 milligrams/tablet). Two hours after the oral ingestion of APM, repeat bleeding times were determined. The initial data demonstrated that a clinical response occurred in subjects with bleeding times of less than six minutes. Bleeding times longer than six minutes were thought to represent limits from commonly ingested dietary substances with properties similar to APM. 
     Since the preliminary data indicated possible clinical effects of APM on bleeding times, a double blind crossover study of 34 volunteers was conducted using the Simplate bleeding technique. All seventeen volunteers receiving placebo and seventeen receiving APM completed the study without complication. After a baseline bleeding time determination, each volunteer was given either four tablets of APM (76 milligrams; 19 milligrams/tablet) or four tablets of placebo. 
     Two hours after dosing, the bleeding time was repeated. Each bleeding time determination used pre-weighed blotting paper to collect blood droplets. The blotting paper was weighed on an analytical balance after the bleeding stopped. The time required for the bleeding to stop was measured with a stop watch. The data for the APM and placebo volunteers are given in Table X and Table XI, respectively. The effects of APM on bleeding time is summarized in Table XII and in FIG. 9 and FIG. 10. The results show a slight prolongation of bleeding time with APM which is similar to the 
     
                                           TABLE X__________________________________________________________________________Bleeding Times Before and After APMBefore APM             After APMBleeding      Pre-  Post- Blood                       Bleeding                             Pre-  Post- Blood   Time bleeding bleeding loss Time bleeding bleeding loss  Subject (min) Wt (gram) Wt (gram) (gram) (min) Wt (gram) Wt (gram)                                         (gram)__________________________________________________________________________1    4.460 4.669 4.769 0.120                       4.430 4.692 4.850 0.158  2 5.150 4.728 4.819 0.091 4.420 4.726 4.890 0.164  3 3.430 4.720 4.811 0.091 5.140 7.991 8.142 0.151  4 3.220 4.285 4.333 0.048 4.000 4.764 4.831 0.067  5 5.030 4.781 4.889 0.108 5.250 4.803 4.884 0.081  6 5.340 4.781 4.978 0.197 4.060 4.704 4.778 0.074  7 3.540 4.790 4.841 0.051 4.250 4.748 4.848 0.100  8 5.060 5.608 5.723 0.115 6.070 5.200 5.307 0.107  9 5.320 5.189 5.309 0.120 6.450 5.466 5.950 0.484  10 4.270 5.215 5.325 0.110 5.490 5.166 5.464 0.298  11 4.330 5.400 5.550 0.150 5.290 5.418 5.578 0.160  12 4.440 5.595 5.727 0.132 5.090 5.735 5.873 0.138  13 2.370 5.442 5.451 0.009 2.050 5.586 5.605 0.019  14 3.320 5.508 5.548 0.040 3.380 5.361 5.372 0.011  15 3.380 6.015 6.040 0.025 4.060 5.792 5.825 0.033  16 4.220 5.532 5.640 0.108 5.020 5.608 5.819 0.211  17 4.220 8.053 8.087 0.034 6.270 7.971 8.432 0.461  Average 4.182   0.091 4.748   0.160__________________________________________________________________________ 
    
     
                                           TABLE XI__________________________________________________________________________Bleeding Times Before and After PlaceboBefore Placebo         After PlaceboBleeding      Pre-  Post- Blood                       Bleeding                             Pre-  Post- Blood   Time bleeding bleeding loss Time bleeding bleeding loss  Subject (min) Wt (gram) Wt (gram) (gram) (min) Wt (gram) Wt (gram)                                         (gram)__________________________________________________________________________1    3.270 4.690 4.735 0.045                       4.530 4.656 4.755 0.099  2 4.480 4.735 4.858 0.123 3.270 4.731 4.793 0.062  3 3.550 4.707 4.771 0.064 3.360 4.691 4.726 0.035  4 4.300 5.404 5.461 0.057 4.040 5.927 5.960 0.033  5 4.510 4.766 4.952 0.186 6.440 4.731 5.171 0.545.sup.a   3.747 3.852  6 4.560 5.545 5.643 0.098 4.180 4.723 4.788 0.065  7 5.230 5.480 5.609 0.129 5.180 5.658 5.789 0.131  8 4.500 5.403 5.479 0.076 4.040 5.366 5.426 0.060  9 3.160 5.325 5.417 0.092 3.380 5.354 5.505 0.151  10 3.420 5.418 5.515 0.097 3.430 5.251 5.388 0.137  11 4.270 5.375 5.510 0.135 3.440 5.434 5.500 0.066  12 2.470 5.328 5.380 0.052 2.220   0.000.sup.b  13 3.180 5.208 5.284 0.076 5.120 5.473 5.572 0.099  14 4.280 5.648 5.696 0.048 4.580 5.424 5.519 0.095  15 3.490 5.917 5.974 0.057 5.450 6.066 6.148 0.082  16 5.070 5.857 6.035 0.178 4.200 5.897 5.971 0.074  17 4.320 7.962 8.145 0.183 3.350 8.047 8.149 0.102  Average 4.004   0.100 4.130   0.080__________________________________________________________________________ .sup.a Two separate blotter papers used to absorb volunteer&#39;s blood; sinc total blood loss was outside of normal range, blood loss value not included in mean analysis. .sup.b Volunteer did not bleed. 
    
     
                       TABLE XII______________________________________Summary of Bleeding Time by Event  and Mean Values               Number of Patients                   Increased                            Decreased  Treatment Bleeding Time Bleeding BleedingGroup     Before  After     Time   Time______________________________________APM       4.18    4.78      13     4  Placebo 4.04 4.13 8 9______________________________________ 
    
     effect associated with aspirin. In the APM group, 13 volunteers had increased bleeding time, compared to 8 volunteers in the placebo group. By increasing bleeding time, APM may be used to control platelet aggregation and alleviate pain associated with myocardial infarction. 
     EXAMPLE 7 
     Use of APM as a Veterinary Pain Reliever 
     A fifteen year old German shepherd dog experiencing osteoarthritic symptoms was given 5-10 tablets APM (95-190 milligrams; 19 milligrams/tablet) twice a day. Three days later, the dog had resumed normal activities. When the treatment was subsequently discontinued, the dog again exhibited osteoarthritic symptoms and lack of appetite. Treatment with APM was resumed, and the dog again resumed normal activity.