Uploaded by Andrey Cherednichenko

Theramine Supplement

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Theramine
Innovative Pain Solutions
Theramine®
for the dietary management of pain syndromes
Non-Addictive
No Reported GI Bleeds
Improve Pain Perception
Over 38 million Individual Doses Administered
without a Reported GI Bleed
1
Improve Clinical Outcomes
Percent Reduction in CRP Levels
*
Reduction of Chronic Back Pain*
14
67.86
12
60
p<0.01
n=127
% Change
40
20
0
-20
Roland Morris Index
80
10
p<0.001
n=111
8
Before
6
After
4
-40
2
-60
-64.79
-80
Naproxen
Theramine
0
Naproxen
Theramine
Double Blind Randomized Control Study - 28 days of therapy
In this double blind multicenter trial of 127 subjects with chronic established back pain, a statistically relevant decrease in CRP was
measured among subjects taking Theramine compared to those taking naprosyn (250mg) once daily.*
In a 28 day double blind multicenter trial of 127 subjects with chronic established back pain, subjects taking Theramine experienced a
76% reduction in pain compared to once daily naprosyn (250mg)1 as measured by the Roland Morris Index.*
*Shell, et al. Theramine and naproxen double blind clinical trial American Journal of Therapeutics; 2012 108-114
Safety Information
Theramine® is contraindicated in an extremely small number of patients with hypersensitivity to any of the nutritional components of Theramine.
ADVERSE REACTIONS: Ingestion of L-Tryptophan, L-Arginine, or Choline at high doses of up to 15 grams daily is generally well tolerated. The most common adverse
reactions of higher doses — from 15 to 30 grams daily — are nausea, abdominal cramps, and diarrhea. Theramine contains less than 1 gram per dose of amino
acids however, some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each Theramine capsule does not
exceed 300 mg.
DRUG INTERACTIONS: Theramine
Theramine may allow for lowering the dose of co-administered drugs under physician supervision.
Theramine® and Targeted Cellular Technology
TM
Theramine is driven by Targeted Cellular Technology
1
Neurotransmitter Precursors
Choline bitartrate, L-arginine, L-glutamine, L-histidine, 5-HTP, L-serine
2
Neuron Uptake Stimulator
Cinnamon, Whey Protein Isolate
3
Neuron Activator
Glutamine
4
Adenosine Antagonist
Metabromine
5
Attenuation Inhibitor
Grape-seed extract
Amino Acids, Biogenic Amines, & Other Nutrients
Rx Medical Food
Per Recommended Dose** (Theramine)
Gamma Aminobutyric Acid (GABA)
200 mg
Choline Bitartrate (Choline Bitartrate from natural L(+)-tartaric acid)
125 mg
Whey Protein Isolate (90%+ protein by weight)
75 mg
L-Arginine HCL (Produced from plant derived materials)
75 mg
L-Histidine HCL (Produced from plant derived materials)
50 mg
L-Glutamine (Produced from plant derived materials)
50 mg
(seed) (95% 5-HTP) (Standardized Extract)
32 mg
L-Serine (Produced from plant derived materials)
25 mg
Cocoa Extract (fruit) (6% theobromine) (Standardized Extract)
50 mg
Grape Seed Extract (85% polyphenols) (Standardized Extract)
25 mg
Cinnamon (bark) (Botanical Powder)
25 mg
* Ingredient claims are based on current market availability. Actual claims may vary. Individual results, including those for microbiology, pesticides, and heavy metals including arsenic, cadmium, lead, and mercury are available
to practitioners upon request. If you would like to learn more or provide feedback please email [email protected]
Theramine should be taken without food to increase the absorption of key ingredients.
Theramine
®
/ŶĚŝĐĂƟŽŶ͗
Theramine is indicated for the dietary management of pain syndromes that include chronic pain,
ĮďƌŽŵLJĂůŐŝĂ͕ŶĞƵƌŽƉĂƚŚŝĐƉĂŝŶ͕ĂŶĚŝŶŇĂŵŵĂƚŽƌLJƉĂŝŶ͘Theramine is an Rx only GRAS/GRAE
ŵĞĚŝĐĂůĨŽŽĚ͘
WŚĂƌŵĂĐŽĚLJŶĂŵŝĐƐ͗
dŚĞƉŚĂƌŵĂĐŽĚLJŶĂŵŝĐƉƌŽƉĞƌƟĞƐŽĨ TheramineĂƌĞĚŝƌĞĐƚůLJƌĞůĂƚĞĚƚŽƚŚĞĞīĞĐƚƐŽĨƚŚĞĂŵŝŶŽ
ĂĐŝĚƉƌĞĐƵƌƐŽƌƐŽŶŶĞƵƌŽƚƌĂŶƐŵŝƩĞƌĂĐƟǀŝƚLJǁŚŝĐŚĂƌĞƌĞƐƉŽŶƐŝďůĞĨŽƌƚŚĞŝŶĚƵĐƟŽŶ͕
ĂŵƉůŝĮĐĂƟŽŶ͕ĂŶĚŵŝƟŐĂƟŽŶŽĨƉĂŝŶ͘
ŽƐŝŶŐ͗
The recommended dose of Theramine ŝƐϭŽƌϮĐĂƉƐƵůĞƐ͕ƚĂŬĞŶϭƚŽϰƟŵĞƐĚĂŝůLJĂƐĚŝƌĞĐƚĞĚďLJ
ĂƉŚLJƐŝĐŝĂŶ͘
/ŶŐƌĞĚŝĞŶƚƐ͗
'͕ŚŽůŝŶĞŝƚĂƌƚƌĂƚĞ͕>ͲĂƌŐŝŶŝŶĞ͕tŚĞLJƉƌŽƚĞŝŶŚLJĚƌŽůLJƐĂƚĞ͕>ͲŚŝƐƟĚŝŶĞ͕>ͲŐůƵƚĂŵŝŶĞ͕DĞƚĂďƌŽŵŝŶĞ͕
ϱͲ,LJĚƌŽdžLJƚƌLJƉƚŽƉŚĂŶ͕'ƌĂƉĞ^ĞĞĚdžƚƌĂĐƚ͕>Ͳ^ĞƌŝŶĞ͕ŝŶŶĂŵŽŶďĂƌŬ͘
WƌĞĐĂƵƟŽŶƐĂŶĚŽŶƚƌĂŝŶĚŝĐĂƟŽŶƐ͗
Theramine ŝƐĐŽŶƚƌĂŝŶĚŝĐĂƚĞĚŝŶĂŶĞdžƚƌĞŵĞůLJƐŵĂůůŶƵŵďĞƌŽĨƉĂƟĞŶƚƐǁŝƚŚŚLJƉĞƌƐĞŶƐŝƟǀŝƚLJƚŽĂŶLJŽĨƚŚĞŶƵƚƌŝƟŽŶĂů
components of Theramine͘
ADVERSE REACTIONS
/ŶŐĞƐƟŽŶŽĨ>ͲdƌLJƉƚŽƉŚĂŶ͕>ͲƌŐŝŶŝŶĞ͕ŽƌŚŽůŝŶĞĂƚŚŝŐŚĚŽƐĞƐŽĨƵƉƚŽϭϱŐƌĂŵƐĚĂŝůLJŝƐŐĞŶĞƌĂůůLJǁĞůůƚŽůĞƌĂƚĞĚ͘dŚĞ
ŵŽƐƚĐŽŵŵŽŶĂĚǀĞƌƐĞƌĞĂĐƟŽŶƐŽĨŚŝŐŚĞƌĚŽƐĞƐͶĨƌŽŵϭϱƚŽϯϬŐƌĂŵƐĚĂŝůLJͶĂƌĞŶĂƵƐĞĂ͕ĂďĚŽŵŝŶĂůĐƌĂŵƉƐ͕ĂŶĚ
ĚŝĂƌƌŚĞĂ͘Theramine ĐŽŶƚĂŝŶƐůĞƐƐƚŚĂŶϭŐƌĂŵƉĞƌĚŽƐĞŽĨĂŵŝŶŽĂĐŝĚƐŚŽǁĞǀĞƌ͕ƐŽŵĞƉĂƟĞŶƚƐŵĂLJĞdžƉĞƌŝĞŶĐĞƚŚĞƐĞ
ƐLJŵƉƚŽŵƐĂƚůŽǁĞƌĚŽƐĞƐ͘dŚĞƚŽƚĂůĐŽŵďŝŶĞĚĂŵŽƵŶƚŽĨĂŵŝŶŽĂĐŝĚƐŝŶĞĂĐŚdŚĞƌĂŵŝŶĞĐĂƉƐƵůĞĚŽĞƐŶŽƚĞdžĐĞĞĚϯϬϬŵŐ͘
DRUG INTERACTIONS
Theramine ĚŽĞƐŶŽƚĚŝƌĞĐƚůLJŝŶŇƵĞŶĐĞƚŚĞƉŚĂƌŵĂĐŽŬŝŶĞƟĐƐŽĨƉƌĞƐĐƌŝƉƟŽŶĚƌƵŐƐ͘ůŝŶŝĐĂůĞdžƉĞƌŝĞŶĐĞŚĂƐƐŚŽǁŶƚŚĂƚ
ĂĚŵŝŶŝƐƚƌĂƟŽŶŽĨTheramine ŵĂLJĂůůŽǁĨŽƌůŽǁĞƌŝŶŐƚŚĞĚŽƐĞŽĨĐŽͲĂĚŵŝŶŝƐƚĞƌĞĚĚƌƵŐƐƵŶĚĞƌƉŚLJƐŝĐŝĂŶƐƵƉĞƌǀŝƐŝŽŶ͘
OVERDOSE
dŚĞƌĞŝƐĂŶĞŐůŝŐŝďůĞƌŝƐŬŽĨŽǀĞƌĚŽƐĞǁŝƚŚTheramine as the total amount of amino acids in a one month supply
;ϵϬĐĂƉƐƵůĞƐͿŝƐůĞƐƐƚŚĂŶϯϬŐƌĂŵƐ͘KǀĞƌĚŽƐĞƐLJŵƉƚŽŵƐŵĂLJŝŶĐůƵĚĞĚŝĂƌƌŚĞĂ͕ǁĞĂŬŶĞƐƐ͕ĂŶĚŶĂƵƐĞĂ͘
For more information, please visit
www.ptlcentral.com
Copyright © 2012 Physician Therapeutics®, a division of Targeted Medical Pharma Inc. All Rights Reserved.
Ref Booklet 1 April 2012
Theramine
®
ŵŝŶŽĐŝĚƐ͕ŝŽŐĞŶŝĐŵŝŶĞƐ͕ĂŶĚKƚŚĞƌEƵƚƌŝĞŶƚƐ
ƉĞƌĂƉƐƵůĞ;нͬͲϭϬйͿ
Gamma Aminobutyric Acid (GABA)
100 mg
Choline Bitartrate (Choline Bitartrate from natural L(+)-tartaric acid)
62.5 mg
Whey Protein Isolate (90%+ protein by weight)
37.5 mg
L-Arginine HCL (Produced from plant derived materials)
37.5 mg
>Ͳ,ŝƐƟĚŝŶĞ,> (Produced from plant derived materials)
25 mg
L-Glutamine (Produced from plant derived materials)
25 mg
'ƌŝīŽŶŝĂdžƚƌĂĐƚ'ƌŝīŽŶŝĂ^ŝŵƉůŝĐŝĨŽůŝĂ(seed) (95% 5-HTP) (Standardized extract)
16 mg
L-Serine (Produced from plant derived materials)
12.5 mg
ĚĚŝƟŽŶĂůŽƚĂŶŝĐĂůƐ
ƉĞƌĂƉƐƵůĞ;нͬͲϭϬйͿ
Cocoa Extract dŚĞŽďƌŽŵĂĐĂĐĂŽ (fruit) (6% theobromine) (Standardized extract)
25 mg
Grape Seed Extract sŝƚƵƐǀŝŶŝĨĞƌĂ (85% polyphenols) (Standardized extract)
12.5 mg
Cinnamon ŝŶŶĂŵŽŵƵŵ͘ĐĂƐƐŝĂ (bark) (Botanical powder)
12.5 mg
*Ingredient claims are based on current market availability. Actual claims may vary. Individual results,
ŝŶĐůƵĚŝŶŐƚŚŽƐĞĨŽƌŵŝĐƌŽďŝŽůŽŐLJ͕ƉĞƐƟĐŝĚĞƐ͕ĂŶĚŚĞĂǀLJŵĞƚĂůƐŝŶĐůƵĚŝŶŐĂƌƐĞŶŝĐ͕ĐĂĚŵŝƵŵ͕ůĞĂĚ͕ĂŶĚ
ŵĞƌĐƵƌLJĂƌĞĂǀĂŝůĂďůĞƚŽƉƌĂĐƟƟŽŶĞƌƐƵƉŽŶƌĞƋƵĞƐƚ͘/ĨLJŽƵǁŽƵůĚůŝŬĞƚŽůĞĂƌŶŵŽƌĞŽƌƉƌŽǀŝĚĞĨĞĞĚďĂĐŬ
please email [email protected]
For more information, please visit
www.ptlcentral.com
Copyright © 2012 Physician Therapeutics®, a division of Targeted Medical Pharma Inc. All Rights Reserved.
Ref Booklet 1 April 2012
www.ptlcentral.com
®
1
Acute Pain
Chronic Pain
Fibromyalgia
Neuropathic Pain
Inflammatory Pain
www.ptlcentral.com
Recommended
R
d d Dosing:
D i
2 capsules b.i.d.
•
•
•
•
•
Theramine® is intended for the dietary management
of pain syndromes that include:
Indication & Dosing
2
1.
2.
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RussellIJ,MichalekJE,VipraioGA,FletcherEM,WallK.Serumaminoacidsinfibrositis/fibromyalgiasyndrome.JRheumatolSuppl1989;19:158Ͳ163
Shelletal.TheramineandIbuprofendoubleblindclinicaltrial,2010.Publicationpending.
3
In a double blind, multicenter trial, subjects with pain syndromes showed decreased levels of the amino
acids required for production of pain modulating neurotransmitters, despite having a sufficient intake of
1
protein indicating that the need for these amino acids are selectively increased in these patients.
Theramine® Improves Amino Acid Levels
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1.Shell,etal.Theramineandnaproxendoubleblindclinicaltrial;AmericanJournalofTherapeutics;2012108Ͳ114
4
In a 28 day double blind, randomized, controlled, multicenter trial of 127 subjects with chronic
established back pain, subjects taking Theramine experienced a 76% reduction in pain compared to
1
once daily naprosyn (250mg)
Theramine® can Significantly Reduce Pain
www.ptlcentral.com
1.Shell,etal.TheramineandnaproxendoubleblindclinicaltrialAmericanJournalofTherapeutics;2012108Ͳ114
Data from a 2009, 28 day double blind randomized controlled trial of 127 subjects with chronic
established back
pain shows that a low dose NSAID can be effective when co-administered with
1
Theramine.
Effective as a Standalone Medication
and as an Adjunct to a Low Dose NSAID
Theramine®
5
www.ptlcentral.com
1. Shell, et al. Theramine and naproxen double blind clinical trial American Journal of Therapeutics; 2012 108-114
In this double blind multicenter trial of 127 subjects with chronic established back pain, a marked
decrease in CRP was measured among subjects taking Theramine compared to subjects taking
1
naprosyn (250mg) once daily
daily.
6
Theramine® is Effective at Reducing Inflammation
1.
www.ptlcentral.com
Shell et al. Theramine and Ibuprofen double blind clinical trial, 2010. Publication pending.
In this double blind multicenter trial of 122 subjects with chronic established back pain, a marked
decrease in CRP was measured among subjects taking Theramine compared to subjects taking
1
Ibuprofen(400mg) once daily
daily.
7
Theramine® is Effective at Reducing Inflammation
1.
www.ptlcentral.com
Shell et al. Theramine and Ibuprofen double blind clinical trial, 2010. Publication pending.
In this double blind multicenter trial of 122 subjects with chronic established back pain, a marked
decrease in IL-6 was measured among subjects taking Theramine compared to subjects taking
1
Ibuprofen(400mg) once daily
daily.
8
Theramine® is Effective at Reducing Inflammation
* administrations is defined as number of pills sold since 2004
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1. Shell, et al. American Journal of Therapeutics; 2012 108-114 ; Theramine ibuprofen trial 2010, Unpublished.
• Reduces inflammation1
• Reduces chronic back pain1
Effective Non-Addictive Pain Medication
• No reported adverse CV effects
• No reported GI bleeds
No reported side effects in over 38 million
administrations
administrations*
Why is Theramine® a Good Choice?
9
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1. Shell, et al. American Journal of Therapeutics; 2012 108-114 ; Theramine ibuprofen trial 2010, Unpublished.
• Theramine can be used as a replacement therapy
10
• Theramine can be used as an adjunct to a low dose opiate
Replace or Reduce Narcotic Pain Meds
• Patients taking
g Theramine can take a veryy low dose NSAID
without loss of efficacy1
• Patients unable to take NSAIDs ( High BP
BP, Over 65
65, CVD
CVD,
Taking Aspirin) Contraindicated
Replace or Augment NSAID Therapies
Clinical Applications of Theramine®
Pain syndromes increase metabolic demand and the usual rate of
synthesis is no longer sufficient and nonessential nutrients become
conditionally essential, requiring that supplemental amounts be
consumed.
consumed
•
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11
(CH3)3N+CH2CH2OHXо
These patients require additional amounts of arginine, choline,
GABA glutamine,
GABA,
glutamine histidine
histidine, 5
5-hydroxytryptophan,
hydroxytryptophan and serine to
restore homeostasis.
•
Example:IncreaseddemandsforCholine areassociatedwithpaindisordersandinflammation;normal
p
g
y
y
amountsofcholineproducedendogenouslyareinsufficientandmustbeadministeredenterally.
Theramine is a source of amino acids, biogenic amines, and other
nutrients formulated for patients with certain types of pain
y
syndromes.
•
Theramine® (Nutritional Requirements)
Theramine is formulated with Targeted Cellular Technology™ (TCT)
ap
patented integrated
g
molecular system
y
that delivers milligram
g
quantities of amino acids and other ingredients to targeted cells in a
time sensitive manner and in specific ratios efficiently promote
neurotransmitter production.
•
12
The use off Theramine
Th
Th
i in
i managementt off pain
i syndromes
d
iis
supported by experimental and clinical data which have identified
specific roles for each ingredient in the mechanism of pain reduction.
•
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The Pharmacodynamic properties of Theramine® are directly related
to the effects of amino acid and other precursors on neurotransmitter
activity which are responsible for the induction, amplification, and
mitigation of pain.
•
Pharmacodynamics
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13
Ingestion of L-Tryptophan, L-Arginine, or Choline at high doses of up to 15
grams daily is generally well tolerated. The most common adverse reactions of
higher doses — from 15 to 30 grams daily — are nausea, abdominal cramps,
diarrhea Theramine contains less than 1 gram per dose of amino acids
and diarrhea.
however, some patients may experience these symptoms at lower doses. The
total combined amount of amino acids in each Theramine capsule does not
exceed 300 mg.
ADVERSE REACTIONS
Theramine® is contraindicated in an extremely small number of patients with
hypersensitivity to any of the nutritional components of Theramine.
PRECAUTIONS AND CONTRAINDICATIONS
Safety Information
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14
There is a negligible
g g
risk of overdose with Theramine as the total amount of
amino acids in a one month supply (90 capsules) is less than 30 grams.
Overdose symptoms may include diarrhea, weakness, and nausea.
OVERDOSE
Theramine® does not directly influence the pharmacokinetics of prescription
drugs. Clinical experience has shown that administration of Theramine may
allow for lowering the dose of co-administered drugs under physician
supervision.
supervision
DRUG INTERACTIONS
Safety Information Cont.
29.
30.
31.
32.
33.
24.
25.
26.
27.
28.
19.
20.
21.
22.
23.
17.
18.
15.
16.
14.
12.
13.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
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15
Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991;14:219-245.
Schaible HG, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann N Y Acad Sci 2002;966:343-354.
Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;429:23-37.
Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999;57:1-164.
Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002;966:290-303.
Cuninkova L, Brown SA. Peripheral circadian oscillators: interesting mechanisms and powerful tools. Ann N Y Acad Sci 2008;1129:358
2008;1129:358-370.
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McGinty D, Szymusiak R. The sleep-wake switch: A neuronal alarm clock. Nat Med 2000;6:510-511.
Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 2006;21:482-493.
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Neurosci 2001;21:2015-2027.
Farber L, Haus U, Spath M, Drechsler S. Physiology and pathophysiology of the 5-HT3 receptor. Scand J Rheumatol Suppl 2004;2-8.
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Pelligrino DA, Baughman VL, Koenig HM. Nitric oxide and the brain. Int Anesthesiol Clin 1996;34:113-132.
Cerra FB. Nutrient modulation of inflammatory and immune function. Am J Surg 1991;161:230-234.
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American Journal of Therapeutics 0, 000–000 (2010)
A Double-Blind Controlled Trial of a Single Dose
Naproxen and an Amino Acid Medical Food
Theramine for the Treatment of Low Back Pain
William E. Shell, MD,1* Elizabeth H. Charuvastra, RN,1 Marcus A. DeWood, MD,2
Lawrence A. May, MD,2 Debora H. Bullias, BS, CRA,1 and David S. Silver, MD2
To study the safety and efficacy of a new medical food (Theramine) in the treatment of low back pain,
we performed a 28-day double-blind randomized controlled trial in 129 patients. Back pain was
present for at least 6 weeks and was not mild. Patients were randomly assigned to receive medical
food alone (n = 43), naproxen alone (250 mg/d, n = 42), or both medical food and naproxen (n = 44).
All patients were assessed by using Roland–Morris Disability Questionnaire, Oswestry Low Back
Pain Scale, Visual Analog Scale Evaluation and laboratory analysis performed at baseline and at 28
days for assessing the safety and impact on inflammatory markers, which included complete blood
counts, C-Reactive protein (CRP), and liver function (alkaline phosphatase, aspartate transaminase,
and alanine transaminase). At baseline, there were no statistically significant differences in low back
pain when assessed by Roland–Morris function or Oswestry assessments nor were there differences
in the blood indices of inflammation. At day 28, both the medical food group and combined therapy
group (medical food with naproxen) were statistically significantly superior to the naproxen-alone
group (P , 0.05). The medical food and naproxen group showed functional improvement when
compared to the naproxen-alone group. The naproxen-alone group showed significant elevations in
CRP, alanine transaminase, and aspartate transaminase when compared with the other groups.
Medical food alone or with naproxen showed no significant change in liver function tests or CRP,
with medical food potentially mitigating the effects seen with naproxen alone. The medical food
(Theramine) appeared to be effective in relieving back pain without causing any significant side
effects and may provide a safe alternative to presently available therapies.
Keywords: amino acid formulation, Theramine, pain, NSAIDs, C-reactive protein, naproxen, medical
food, low back pain, neurotransmitter, nitric oxide
INTRODUCTION
A large percentage of the population will experience
low back pain during their lifetime.1 Low back pain can
become chronic with considerable pain and debilitation. Long-term treatment adds additional costs to the
healthcare system and time out of work is frequent and
costly to society.2,3
1
Physician Therapeutics, Los Angeles, CA; and 2UCLA School of
Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
*Address for correspondence: 2980 Beverly Glen Circle, Suite 301,
Los Angeles, CA 90077. E-mail: [email protected]
1075–2765 Ó 2010 Lippincott Williams & Wilkins
The treatments for both acute and chronic back pain
include nonsteroidal anti-inflammatory agents(NSAIDS),
cetaminophen, narcotics, surgical interventions, and
physical therapy.4,5 Many of the drug treatment modalities have significant side effects, including gastrointestinal (GI) hemorrhage, kidney, and heart disease. The side
effects of NSAIDS are related to the magnitude and
frequency of the dose.6,7
Theramine, an amino acid formulation (AAF), has
been developed and is used as a prescription medical
food for the clinical dietary management of the
metabolic processes associated with pain and inflammation.8 The formulation is designed to increase the
production of serotonin,9–11 nitric oxide (NO),12–15
www.americantherapeutics.com
2
histamine,16–18 and gamma-aminobutyric acid by providing precursors to these neurotransmitters. The
neurotransmitters addressed in this formulation have
well-defined and specific roles in the modulation of
pain and inflammation. For example, gut serotonin
alters platelet aggregation, whereas gut NO specifically
reduces erosions induced by NSAIDS.19–21 The formulation contains ingredients that are generally recognized as safe (GRAS) and is regulated by the Food and
Drug Administration in the medical food category.22–24
A medical food that is GRAS and effective for its
intended use and that has shown the ability to allow
a reduction in the dose of NSAIDS used in the
treatment of back pain, thereby reducing the side
effects of these agents, would be of substantial use. The
purpose of this randomized double-blind controlled
clinical trial was to compare the effects of the AAF with
and without low-dose naproxen in a 28-day study of
129 patients with chronic low back pain.
MATERIALS AND METHODS
The study involved 129 patients in a 3-arm doubleblind randomized trial comparing naproxen alone (n =
42), AAF alone (n = 43), or the combined use of AAF
and naproxen (n = 44). During the washout period,
patients taking oral anti-inflammatory or other analgesic medicines discontinued their medication for 5
half lives before randomization. Aspirin ingestion
(#325 mg/d) for nonarthritic conditions was allowed
and used as a stable background drug. Only acetaminophen (650–1000 mg every 4–6 hours) was used as
rescue therapy for pain but never exceeded 4 gm daily.
Protocol
The study was conducted at 12 sites. At each site,
informed consent was obtained, screening procedures
were performed, and a washout period was begun.
After the washout period, there was a baseline day-1
visit. At that time, a baseline Roland–Morris Disability
Questionnaire, an Oswestry Low Back Pain Scale, and
a Visual Analog Scale (VAS) evaluation were obtained.
In addition, blood was sampled for assessing Creactive protein (CRP), blood count, and blood
chemistries.
On the day-1 visit, the patients were randomized to
1 of 3 groups: (1) naproxen-alone group, which was
treated for 28 days with a 2-capsule dose of an amino
acid–like placebo twice daily and naproxen 250 mg/d
in the morning (2) AAF-alone group, which was
treated with the active AAF at a 2-capsule dose twice
daily and a single naproxen-like placebo in the
morning, and (3) the combined group (both AAF and
American Journal of Therapeutics (2010) 0(0)
Shell et al
naproxen), which was treated with active AAF at
a 2-capsule dose twice daily and 250 mg of an active
naproxen in the morning. The active and naproxen
tablets were identical, and the AAF active and placebo
capsules were identical.
On days 7 and 14, the evaluation of VAS and patient
medication usage was completed.
On day 28, a Roland–Morris Disability Questionnaire, an Oswestry Low Back Pain Scale, a VAS
Evaluation, and a patient medication usage evaluation
were completed. Blood was again sampled for
estimating CRP, blood count, and blood chemistries.
Primary endpoints
The primary endpoints of the study were pain and
disability as measured by the Roland–Morris pain
questionnaire and the Oswestry Disability Index.25–29
Patient selection
Patients were identified in 12 separate physicians’
offices. Men and nonpregnant, nonlactating women
aged between 18 and 75 years were recruited for the
study. To be included in the study, patients were
required to have back pain lasting ,6 weeks, with pain
present on 5 of 7 days during each of the 2 weeks before
screening. Patients with a Roland–Morris back pain
index .40 of 100 mm on the VAS were included.
Finally, patients being treated with psychoactive
medication were considered eligible to participate
provided the dose remained stable for 3 months before
study entry.
Exclusion criteria
Patients with surgery in the previous 6 months were
excluded as were patients with neurologic impairment.
Patients with fracture of the spine within the past year
and patients receiving oral, intramuscular, or soft tissue
injection of corticosteroids within 1 month before
screening were excluded. Patients were also excluded
if they had a history of GI bleeding, gastric or duodenal
ulcer as were patients receiving an epidural injection
within 3 months before screening. Patients were also
excluded for participation in a prior clinical trial within
1 month of screening for the present study. Finally,
patients who used controlled substances or opiate
analgesics for .5 days in the month before screening
were considered ineligible to participate.
Statistical analysis
The primary measure of efficacy was the change in
awakening stiffness and pain scores obtained from the
Roland–Morris Lower Back Pain Scale and the
Oswestry Disability Index questionnaire evaluation.25–30 Scores were assigned on study entry (day 0)
www.americantherapeutics.com
A Double-Blind Trial for Treatment of Back Pain
and at study end (day 28). Assuming that larger values
are worse, a negative value for the change from
baseline score indicates an improvement in the score,
and positive values indicate a worsening in the score in
percent.
Analysis of variance was used (ANOVA) to determine statistical differences among the 3 groups on
the study entry and at the completion of treatment.
Statistical significance was defined as P # 0.05. An
intension to treat analysis was utilized.
Of the 129 patients who entered the trial, 126
completed the study. Patients who did not complete
were carried forward as an intention to treat. As is
shown in Table 1, none of the 3 study groups was
statistically different on entry into the trial. Likewise,
the laboratory responses assessed in each of the 3 study
groups we measured, including CRP and hemoglobin
(Hgb), alkaline phosphatase (alk phos), aspartate
transaminase (AST), and alanine transaminase (ALT),
were not statistically significantly different (Table 1) at
baseline. CRP was chosen because it is an acute phase
marker of inflammation. The liver enzymes (alk phos,
AST, and ALT) were monitored to assess possible liver
toxicity due to NSAIDs.
Safety
There were no adverse events or complications among
any of the groups during this 28-day study. There were
no GI side effects observed in this cohort.
RESULTS
3
For example, The Roland–Morris Index if fell by 65%,
and the Oswestry Disability index fell 61% between
baseline and day 28 in the AAF/naproxen group. In the
AAF-alone group, there was a significant reduction in
back pain. Thus, if the AAF was used as either primary
therapy or an adjunct to naproxen, low back pain was
significantly improved. Low-dose naproxen had no
appreciable effect on chronic back pain in 28 days.
Similar results were seen on using the VAS scale.
C-Reactive protein
In the single daily dose of naproxen (Table 3), CRP rose
significantly (P , 0.001). In the AAF-alone group, the
CRP level fell by 16.7% (P , 0.05). In the group treated
with both the AAF and single daily dose of 250 mg of
naproxen, CRP fell 78.6% (P , 0.001).
Laboratory measurements
For participants of the study, no significant differences
were found in Hgb, Alk Phos, alanine transaminase,
aspartate transaminase among the 3 groups, as shown
in Table 1. Throughout the study (Table 3), neither Hgb
nor Alk Phos changed significantly among the groups.
Both ALT and AST values rose significantly in the
naproxen-alone group compared with those in the AAF
alone group or the AAF/naproxen-treated cohort.
Although there was no clinical deterioration evident,
there was laboratory evidence of hepatocellular inflammation if naproxen was used in the absence of
active AAF.
DISCUSSION
Significant changes were observed among the 3 groups
after 28 days (Table 2). The Naproxen group remained
unchanged from baseline to 28 days when assessed
by either the Oswestry Low Back Pain Scale or the
Roland–Morris rating scale. There were significant
differences in pain reduction in both the AAF-alone
group and the amino acid/naproxen treated groups.
The data in this study indicate that addressing the
dietary management of pain syndromes could allow
for the dose reduction of NSAIDs without affecting
therapeutic efficacy. Dietary management of disease is
an underappreciated option for patients, although it
has been in existence for .100 years. Osler31
Table 1. Clinical characteristics at study entry.
Mean 6 SD
Naproxen alone (n = 42)
Oswestry Disability Index
Roland–Morris Pain Scale
Hgb
CRP
Alk. Phos.
ALT
AST
www.americantherapeutics.com
29.19
12.90
13.61
1.9
75.04
24.85
20.85
6
6
6
6
6
6
6
7.49
5.14
3.92
1.90
27.1
10.64
7.49
AAF alone (n = 43)
24.21
10.97
13.93
2.36
73.7
25.69
21.84
6 8.09
6 5.42
61.52
6 3.3
6 29.99
6 15.46
6 11.3
Both (n = 44)
P value
6
6
6
6
6
6
6
NS
NS
NS
NS
NS
NS
NS
27.13
12.38
13.85
3.53
74.2
30.53
25.69
8.19
5.31
1.51
5.73
19.16
28.13
15.46
American Journal of Therapeutics (2010) 0(0)
4
Shell et al
Table 2. Primary endpoints percent change
from baseline.
% Change from baseline
Oswestry
disability index
Roland–Morris
Pain index
23.4
232.94
260.47
,0.05
2.95
244
265
,0.05
Naproxen
AAF
Both
P value ANOVA
prominently emphasized the value of nutrition in his
textbooks. Advances in science mandate inclusion of
nutrient management of symptoms and disease.
Because nutrient management of disease has existed
since therapeutic medicine began, evidence-based examples of more modern observations would be useful.
For example, Tepaske et al32 administered an
arginine-based preparation to patients before cardiac
surgery. The clinical outcomes were found to be
improved, specifically postoperative creatine clearance
and immune function. Fonarow and coworkers33 and
Tepaske et al32 demonstrated that administration of
amino acid neurotransmitter precursors in patients
with congestive heart failure improved clinical outcomes. These are 2 examples of recent observations of
the importance of nutrient management of disease.
The AAF of neurotransmitter precursors used in this
study is designed to elicit neurotransmitter production.
The amino acid precursors support the production of
neurotransmitters that modulate pain and inflammation. The precursors of serotonin, NO, histamine, and
gamma-aminobutyric acid are supplied in this formulation as 5-hydroxytryptophan, arginine, histidine, and
glutamine, respectively. These neurotransmitters modulate nociception and inflammation.34–48 Histidine, for
example, is converted to histamine, which elicits
adrenocorticotropic hormone/cortisol release.49,50
In this study, a single daily dose of 250 mg of
naproxen had no effect on chronic back pain over 28
days, a nonsignificant 2.95% increase in the Roland–
Morris Index measure of pain was found. The AAF
Table 3. Toxicity data percent change from baseline.
% Change from baseline
CRP
Naproxen
184.5
AAF
216.7
Both
278.6
P value ANOVA ,0.01
HB
Alk Phos
21.6
21
21.49
,0.01
1.68
4.75
0.51
NS
American Journal of Therapeutics (2010) 0(0)
ALT
AST
7.4 20.24
2
1.37
214.1
9.96
,0.05 ,0.05
alone produced a 44% reduction in the Roland–Morris
Index and a 33% reduction in the Oswestry index. The
AAF with 250 mg of naproxen administered once a day
resulted in a 65% reduction in the Roland–Morris Index
and a 61% reduction in the Oswestry Index.
Back pain is a common concern, affecting up to 90%
of people during their lifetime. Nonsteroidal antiinflammatory drugs are the most commonly used
drugs in the treatment of pain and inflammation.51–59
However, their use is limited by adverse drug side
effects notably GI toxicity.6,60,61–64 The adverse effects
of NSAIDS are dose related.65–72 The current advice of
the American Geriatrics Society is to restrict or even
eliminate NSAIDS in older people. This demographic
with the highest incidence of osteoarthritis, back pain,
and spinal stenosis is at greatest risk for adverse events.
For many of these patients, the only alternative to
NSAIDS may be addictive narcotics.
The study included 129 patients from 12 sites. The
differences in the data were highly statistically
significant, but the subjects were limited to 129
patients. Because the ingredients of the AAF are GRAS,
a large safety trial would appear to be unnecessary. The
single daily dose of naproxen is unlikely to cause liver
or kidney damage. Whether the low dose of naproxen
would be cardioprotective or whether the low dose of
naproxen combined with the AAF would reduce the
incidence of GI side effects was not examined. It is
interesting to note that tryptophan induces an increase
in platelet aggregability, and NO production in the
GI tract is known to reduce NSAID-induced mucosal
erosion.
Anti-inflammatory nonsteroidal drugs with NOproducing precursors attached (NO–NSAIDs) are
a new class of drugs.73–77 These compounds have been
shown to retain the anti-inflammatory, analgesic, and
antipyretic activity with reduced GI toxicity.20,73,78 The
use of an NO moiety with an NSAID has been shown in
studies to inhibit in vitro T-cell proliferation79 and
cytokine production.79 Moreover, NO–NSAIDS have
been shown to be GI protective in several models. The
AAF used in our study produces NO similarly to
the NO–NSAIDS. If the reduction of inflammation and
the alteration of nociception in chronic back pain
syndromes seen in this study are also associated with
the reduction of GI side effects associated with the NO–
NSAIDS, the use of an AAF, with or without low-dose
naproxen therapy may be useful in the management of
back pain.
A single daily dose of naproxen increased the CRP
by 185%, whereas the administration of AAF reduced
the CRP. The AAF administered with naproxen
reversed the elevation of CRP. There is a paucity of
reported data on the effects of low-dose naproxen on
www.americantherapeutics.com
A Double-Blind Trial for Treatment of Back Pain
CRP. NSAIDs alter the prostaglandin inflammatory
cascade but have little effect on other components such
as cytokine release and T-cell activation.
The ingredients in the AAF are defined by the Food
and Drug Administration as GRAS, and in this
formulation, the doses fall within the acceptable daily
dose for GRAS. The study, however, is underpowered
to detect any potential deleterious interaction between
the amino acids and naproxen. We could only detect an
event of 1 in 129 exposures. We have examined a large
number of subjects exposed to the AAF and various
NSAIDS, and this manuscript is in preparation. In
addition, additional double-blind trials will be necessary to detect potential deleterious interactions.
There are limited data, however, to indicate that the
provision of neurotransmitter precursors alters the
efficiency of pharmaceuticals. The data in this study
indicate that the provision of amino acid precursors in
a formulation to facilitate neurotransmitter production
results in improving the efficiency of pharmaceutical
therapy. We postulate that the mechanism is related to
improving intracellular metabolic function rather than
having any effect on the drug itself. This may be a new
approach to a long-standing therapy.
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American Journal of Therapeutics (2010) 0(0)
David S. Silver et al. / Journal of Pharmacy Research 2012,5(5),2806-2809
Research Article
ISSN: 0974-6943
Available online through
www.jpronline.info
Theramine (A Medical Food) Versus Non-Steroidal Anti Inflammatory
Agents in Elderly Patients: A Pharmacoeconomic Analysis
*David S. Silver MD,Elizabeth H. Charuvastra RN,Lawrence May MD,Stephanie L. Pavlik CRA,William E. Shell MD
Targeted Medical Pharma,2980 N. Beverly Glen Circle,Suite 301,Los Angeles, CA 90077, USA
Received on:11-01-2012; Revised on: 17-02-2012; Accepted on:19-04-2012
ABSTRACT
Non-steroidal anti-inflammatory drugs are the leading cause of drug induced morbidity and mortality in the United States. Gastrointestinal hemorrhage is
the most common concern, with hypertension, edema, renal complication and cardiovascular risk other considerations. These complications occur at higher
rates in elderly patients. Strategies to reduce these risks have had mixed results. Theramine, a prescription only medical food, is used to treat pain and
inflammation without risk of gastrointestinal or other side effects. We undertook a pharmacoeconomic analysis of Theramine versus NSAIDs in elderly
patients; specifically examining the additional cost burden of the strategies to prevent GI side effects and complications. The higher acquisition costs for
Theramine are offset by the reduction in side effects and need for testing and other protective medications in patients over the age of sixty-five taking
NSAIDs. Theramine should be the preferred choice over NSAIDs in elderly patients.
Key words: Theramine, NSAIDs, Side effects, Cost Analysis, Elderly population, Pain management
INTRODUCTION
Non-steroidal anti-inflammatory drugs (NSAIDs) are a mainstay treatment
of pain from a variety of inflammatory and non-inflammatory conditions.
They are a recommended treatment for a wide variety of disease states such
as, rheumatoid arthritis, systemic lupus erythematosis, and osteoarthritis, as
well as nonsystemic acute and chronic muscle, joint and ligament discomforts. With more than 100 million prescriptions annually, NSAIDs are the
most commonly prescribed drug class (1). Concerns regarding safety have
led to reduced use in older and high-risk patients, who are often the patients
most in need of pain relief. Billions of dollars are spent each year on NSAIDs,
the majority over the counter purchases with approximately 10% by prescription.
The introduction of COX-2 inhibitors in the late 1990’s was intended to
reduce the incidence of NSAID induced bleeds while preserving equivalent
efficacy (6,7). Although COX-2 inhibitors did show a reduction in gastrointestinal side effects, the incremental cost and concerns about cardiovascular safety have limited their use (8,9). Two popular agents (Vioxx and
Bextra) were voluntarily withdrawn from the market. Further investigation
revealed that the COX-2 inhibitors were probably no different from non
selective NSAIDs in terms of cardiovascular risk (10, 11, 12). Physician and
public awareness of the potential toxicity of the class was increased. These
drugs simply provide symptomatic relief making the search for alternative
agents imperative.
NSAIDs are associated with significant drug induced morbidity and mortality. In the late 1990’s it was estimated 16,500 died and over 100,000 were
hospitalized from NSAID induced GI bleeds (2). This complication accounted for a third of the total cost of arthritis care (3, 4). Patients over the
age of 65, with concomitant medications and disease states are the most
likely to suffer serious consequence side effects (5).
NSAIDs are associated with other toxicities as well. Patients with impaired
renal or hepatic function must exercise caution when taking NSAIDs or
should not take them at all. NSAIDs precipitate blood pressure elevation
and fluid retention. Approximately a fifth of the population cannot tolerate
NSAIDs due to esophageal reflux, dyspepsia or diarrhea and GI side effects
independent of hemorrhage (5,13).
Table 1. Risk factors for NSAID induced upper gastrointestinal bleed
The addition of proton pump inhibitors to NSAIDs has been shown to
decrease GI bleeds and dyspepsia by up to 50% (14). However, the additional cost and other potential complications such as pneumonic reduced
calcium absorption, resulting in osteoporosis, (15) and B12 deficiency from
changes in gut flora are problematic (16, 17). Reduced compliance occurs due
to the number of pills taken and frequency in dosing (18-20). New agents
combining a NSAID with a Nitric Oxide moiety reduce GI bleeds by 20-30%
and lower the risk of hypertension, but have yet to be approved by the FDA
and will be costly if they reach the market (21).









Age of 65 years and over.
Previous history of gastroduodenal ulcer and gastrointestinal bleeding.
Concomitant use of medications that are known to increase the likelihood of uppergastrointestinal adverse events (anticoagulants, aspirin, including low-dose aspirin,
and corticosteroids).
Presence of serious co-morbidity, such as cardiovascular disease, renal or hepatic impairment, diabetes, or hypertension.
Prolonged duration of NSAID use.
Use of the maximum recommended doses of NSAIDs.
The presence of Helicobacter pylori infection.
Alcohol use.
Smoking.
*Corresponding author.
David S. Silver MD,
Targeted Medical Pharma,
2980 N. Beverly Glen Circle,
Suite 301,Los Angeles,
CA 90077, USA
Alternatives to NSAIDs for pain management also have challenges. Narcotic
analgesics, although effective, are sedating, cause constipation, urinary retention and have potential for addiction. Tricyclic antidepressants, dual reuptake
inhibitors, anti epileptics, and others have a separate set of side effects and
can also be costly.
Theramine
Theramine is intended for use in the management of pain syndromes including
Journal of Pharmacy Research Vol.5 Issue 5.May 2012
2806-2809
David S. Silver et al. / Journal of Pharmacy Research 2012,5(5),2806-2809
fibromyalgia, acute and chronic, neuropathic or inflammatory pain. Theramine
is a medical food that must be used under the active or ongoing supervision of
a physician. Medical foods address the altered physiologic requirements and
distinctive nutritional needs resulting from metabolic disorders, chronic
diseases, injuries, premature birth, other medical conditions or drug therapies.
(22)
The nutrient requirements that are most crucial for patients with pain syndromes are the amino acids which are essential for the synthesis of neurotransmitters which transmit pain signals and mediate their perception. (23)
The concept that nutrient requirements are modified in disease has long been
recognized, and is supported by studies of plasma, urinary, and tissue levels
of nutrients associated with changes in physiological endpoints, symptoms
or decreases. (24). These requirements can be estimated by determining the
level of intake at which a physiological response is normalized, indicating
that the balance between intake and metabolic demand has been restored. For
example, improvement in perceived intensity of back pain following consumption of supplemental amounts of 5-hydroxytryptophan, arginine, and
glutamine from Theramine suggests an additional need for tryptophan, arginine, and glutamate in individuals suffering with pain syndromes. (25-28)
Many peer-reviewed publications support increased requirements of arginine,
tryptophan, choline, glutamine, serine, and histidine in pain syndromes.
Patients suffering with pain syndromes have decreased blood levels of these
amino acids despite sufficient protein intake indicating amino acid needs are
selectively increased in pain patients. (29 -31) This observation may be
explained by the competitive demands for these amino acids by metabolic
pathways which decrease the supply available to moderate the pain process.
Low blood levels of tryptophan and/or altered tryptophan metabolism are
reported in patients with pain disorders. (32) These patients also exhibit
reduced blood levels of 5-hydroxytryptophan (5-HTP), arginine, choline,
GABA, histidine, and serine. (33 - 35) Moreover, they respond to oral
administration of amino acid formulations by showing favorable changes in
physiologic endpoints and improvements in clinical symptoms supporting a
need for increased amounts of those amino acids which are reduced in the
blood of patients with pain disorders. (36,37).
Theramine Clinical Trials
Two double blind multicenter randomized trials which compared Theramine
to low dose Naproxen and Ibuprofen respectively have been performed
(38,39). Each study involved 120 patients in 12 centers around the US.
Patients were randomized to receive Theramine alone, 2 capsules twice daily,
NSAID, or a combination of both. In both studies, Theramine showed
statistically significantly greater pain relief than either Naproxen, 250mg
daily or Ibuprofen 400mg daily. The combination of Theramine and NSAID
produced better pain relief than either alone. Importantly, Theramine lowered
CRP while increased CRP was seen in the Naproxen and Ibuprofen groups.
No side effects from Theramine were reported in either trial.
The available clinical data estimates 1-4% of patients over the age of 65
taking NSAIDs will experience a GI bleed annually (40-42). A significant
percentage of patients in this age group will take aspirin 81mg every day or
every other day for cardiovascular prophylaxis, further increasing the risk
(43). The estimated cost of hospitalization for a GI bleed is $50,000 (44). It
is recommended that high risk patients take proton pump inhibitors (PPIs)
with the NSAID to prevent GI events (45-47). This includes patients over
the age of 65 or patients with a previous history of ulcer or GI hemorrhage
which represent over half of all chronic users of NSAIDS. The costs of
additional PPIs are approximately $120 per month. Compliance with
combination therapy, especially in populations with already complicated
medical regimens, is diminished. Most commonly, if patients are
asymptomatic, they will continue to take the NSAID for pain relief and not
take the PPI, although a preparation that combines naproxyn with prilosec is
available in a single pill. Alternatively, the use of Celecoxib, the only available
COX-2 selective inhibitor, would cost approximately $200.
These costs do not account for the other complications including renal,
hepatic, and others associated with the use of NSAIDs. Biannual blood
screening to monitor potential side effects of NSAIDs is estimated at $100
and must be considered as well. Finally, evaluation costs for patients who
present with dyspepsia and undergo gastroenterological workup. Estimates
range from 25-50% of all patients taking NSAIDs will have evidence of
endoscopic ulceration in the stomach or duodenum, but only a fraction of
them will be scoped in clinical settings (48,49).
The following assumptions are based on clinical evidence available with an
implied bias in favor of NSAIDs, as they are presently the preferred treatment.
1.
2.
3.
4.
5.
6.
Observational reporting after over 60,000,000 doses of Theramine revealed
no GI bleeds. Although underreporting may have occurred, the data implies
GI risk in patients taking Theramine is unlikely. Therefore, an increased risk
of gastrointestinal bleeds based on the formulation would not be expected.
7.
8.
Cost Analysis
Pharmacy and therapeutic formulary committees are charged with balancing
efficacy and safety concerns versus cost of medication acquisition. Analysis
of economic factors is necessary before placing a more expensive medication
on formulary. In an ideal world, only safety and efficacy would drive decisions.
The burden of escalating health care costs and limited resources demand a
pharmacoeconomic analysis. The costs of side effects can be challenging to
quantify but must be undertaken to determine cost benefit rates of Theramine
compared to a generic NSAID.
9.
The annual risk of GI bleed in patients over the age of 65 taking
regular NSAIDs is 2.5%.
Theramine does not cause gastrointestinal bleeds.
The cost of generic NSAID is $10 per month. The insurance
reimbursement of Theramine averages $176 per month at the most
commonly and clinical trial dose. The dollar amount is based on the
average insurance reimbursement for Theramine.
Laboratory screen of complete blood count (CBC) and complete
metabolic panel semi-annually costs $100 total per year.
Estimate of 40-65% of NSAID users are considered at high GI risk
for bleed and should receive a PPI or COX-2 inhibitor. All patients
in the 65 and older age group are considered at high risk. It is
recommended that high risk patients should be either on a COX-2
inhibitor or a PPI with a standard NSAID. The average cost
estimate would be $40 to $120 per month per patient and will
prevent 50% of all NSAID induced GI bleeds.
Assume 10% of patients taking NSAIDs will require GI work up
for dyspepsia costing $1200 for upper endoscopy, Helicobacter
Pylori testing, consultation and endoscopies.
Mortality for upper gastrointestinal bleed is approximately 16%
in high risk patients (2,49).
Calculations of cost per 100 patients treated per year will be
performed as well as cost per life saved. The additional costs of
cardiovascular, renal and hepatic toxicity due to NSAIDs may be
substantial but have not been calculated.
The figures do not include patients in whom NSAID therapy is
contraindicated, specifically patients with renal insufficiency,
previous history of GI bleed, congestive heart failure, peripheral
edema, hepatic failure, poorly controlled hypertension and aspirin
sensitivity. These patients now have an option for non-narcotic
pain relief.
Journal of Pharmacy Research Vol.5 Issue 5.May 2012
2806-2809
David S. Silver et al. / Journal of Pharmacy Research 2012,5(5),2806-2809
MATERIALS AND METHODS
Risk data and rates of gastrointestinal bleeding, morbidity and mortality data
were derived from the Medicare database and peer reviewed literature.
Medication acquisition costs were determined based on listed average wholesale
pricing (AWP). Procedural and hospitalization rates were obtained from the
Medicare fee schedule.
RESULTS
The annual cost of Theramine for 100 patients treated is $211,200. A generic
NSAID for 100 patients would be $12,000 if all patients were given generic
NSAID’s; the cost of branded prescription NSAIDs would obviously add to
this cost. The additional costs include: $75,000 for costs of GI bleeds per
100 patients treated per year, medication acquisition costs of $144,000 for
high risk patients, laboratory testing of $10,000 for all patients, cost of GI
evaluation of symptomatic patients $14,500. Excluding cost of treatment for
hepatic, renal and cardiovascular side effects generic NSAIDs will cost
$241,500 per 100 patients treated. When examining actual costs, Theramine
is cost savings when comparing total impact of NSAIDs. Cost per life saved
analysis was not performed as there is no incremental overall cost increase to
use of Theramine.
DISCUSSION
NSAIDs are the most commonly utilized drug class. Despite efficacy in
treating symptoms of inflammatory and non inflammatory conditions, their
use has been reduced greatly due to the side effect profile. Physicians must
make difficult decisions either accepting the risk or prescribing as needed
with therapeutic efficacy reduced. Patients are either exposed to significant
side effects or suffer with inadequate pain relief. Recent guidelines for pain
management in the elderly have recommended only rare use of NSAIDS,
despite the fact that over 50% of individuals over the age of 65 suffer from
chronic pain (50).
Efforts to diminish the GI side effects of NSAIDs include co-administration
of a PPI or use of COX-2 inhibitor increase cost. They do not eliminate the
gastrointestinal effects or impact hepatic, renal and cardiovascular toxicities
at all.
Theramine, a prescription only medical food, has been shown to be an effective
and safe anti-inflammatory pain reliever without the concerning side effects
of NSAIDs. Although more expensive than generic NSAIDs, the use of
Theramine is cost neutral using conservative estimates of the economic impact
of NSAID side effects based on best care practice guidelines. Cost neutrality
favors the use of Theramine because of the reduction in morbidity and
mortality.
Theramine, unlike generic NSAIDs plus a PPI or COX-2 inhibitors, eliminates
all NSAID induced side effects. Despite the initial upfront costs, even when
low risk patients are included, Theramine lowers cost of care, and there is no
risk of GI bleed, renal or hepatic toxicity, hypertension, peripheral edema or
heart attack. Based on this analysis, Theramine should be preferred in all
cases instead of NSAIDs. If Theramine does not provide adequate therapeutic
response, use of NSAIDs can be considered and administered at the lowest
dose and for the shortest time when added to Theramine. The economic
reducibility or likely cost saving in addition to the reduced burden of morbidity
and mortality make Theramine preferred over NSAID for treatment of pain
syndromes.
ACKNOWLEDGEMENTS
During the preparation of this manuscript, Elizabeth Charuvastra passed
away after a brief but brave battle with pancreatic cancer. Her contributions
to this paper, and the development of safer and more effective medical
treatments and her tireless devotion to patients are incalculable. She will be
sorely missed by all that have known and worked with her.
Conflict of Interest
The authors of this manuscript are owners, employees or consultants of
Targeted Medical Pharma, Inc. (TMP). TMP has been the sponsor for all
data compilation and preparation related to this manuscript.
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-60
-40
-20
0
20
40
60
80
-70
-60
-50
-40
-30
-20
-10
0
10
-50.3
-63.1
p<0.01 for the
comparison of
Theramine or
combination versus
ibuprofen
Combination n = 38
Theramine n = 41
Ibuprofen n = 43
60.1
-35.99
-50
-40
-30
-20
-10
0
10
20
-70
-60
-50
-40
-30
-20
-10
0
12.65
-4.5
-62.2
-23.55
-43.1
Figure 4. Interleukin- 6
-41.9
Figure 2. Oswestry Pain Index
Percent
Change
in Amino
AcidAcid
Blood
Concentration
DayDay
1 and
28
Figure
5. Percent
Change
in Amino
Serum
Concentrationatfrom
1 to Day
Day 28
Versus Normal
-47.05
p<0.01 for the
comparison of
Theramine or
combination versus
ibuprofen.
Combination n = 38
Theramine n = 41
Ibuprofen n = 43
Figure 3. High Sensitivity C-Reactive Protein
0.73
Figure 1. Roland-Morris Pain Scale
Results
Affiliation: Targeted Medical Pharma, Inc.
p<0.01 for the comparison
of Theramine and
combination versus
ibuprofen
Combination n = 38
Theramine n = 41
Ibuprofen n = 43
p<0.01 for the
comparison of
Theramine or
combination versus
ibuprofen.
Ibuprofen n = 43
Theramine n = 41
Combination n = 38
Ibuprofen
77
Theramine
19
Combination
12
Figure 6. Percent Subject Use of Rescue Medication (APAP 6501000mg prn) at Study Completion
p<0.01
n=122
Combination
Theramine
Ibuprofen
* All authors are employees of Targeted Medical Pharma, Inc. which
manufactures and distributes the medical food, Theramine under
subsidiary brand Physician Therapeutics.
ƒ Theramine is an effective analgesic in the treatment of
chronic back pain.
ƒ Theramine reduces inflammatory markers.
ƒ Theramine may provide a safer pharmacologic
alternative to traditional pharmaceuticals prescribed in
the management of chronic back pain.
Conclusions
ƒ Both the Theramine alone group and the combination
group showed statistically significant reductions in pain
when compared to baseline. (p<0.01) The ibuprofen
group alone showed no difference. (Figures 1 and 2)
ƒ Laboratory blood tests confirmed Theramine reduced
inflammatory markers as measured by hsCRP and Il-6.
(Figures 3 and 4)
ƒ Administration of Theramine resulted in an increase in
blood concentrations of the amino acids associated with
the neurotransmitters involved in the modulation of pain.
(Figure 5)
ƒ Theramine subjects required statistically significantly
less rescue medications when compared to ibuprofen.
(p<0.01) (Figure 6)
0
10
20
30
40
50
60
70
80
90
Publication pending . Previous study entitled, “A Double Blind Placebo Study to determine the effectiveness of Theramine on the management of chronic back pain”, American Journal of Therapeutics (2011)
ƒ A total of 127 patients were randomized (122
completed) to one of three treatment arms: ibuprofen
400mg (n=42); Theramine (n=42); or the combination
of Theramine and ibuprofen (n=43) for a 28-day
period.
ƒ Pain was assessed using the Roland-Morris Pain
Scale, Oswestry Disability Index and Visual Analog
Scale.
ƒ Blood samples were taken at baseline and Day 28 to
measure Complete Blood Count (CBC) and liver
function.
ƒ The inflammatory markers high sensitivity CReactive Protein (hsCRP) and Interleukin-6 (Il-6)
were measured at baseline and Day 28.
ƒ 25 subjects were randomly selected for serum amino
acid level sampling, measured at baseline and Day 28.
Materials & Methods
condition. Many current drug treatments such as
non-steroidal anti-inflammatory drugs (NSAIDs) and
narcotic analgesics are associated with significant
side effects, including gastrointestinal (GI)
hemorrhage, renal and cardiovascular complications
and have an increased potential for addiction.
ƒ The primary objective of this study was to compare
prescription-only Theramine, an amino-acid based
prescription medical food/old drug, to low dose
ibuprofen in the treatment of chronic low back pain.
ƒ Theramine has been shown in a previous double
blind clinical trial to be effective in the treatment of
chronic low back pain when compared with
naproxen, as well as reducing levels of inflammatory
mediators.
ƒ Chronic low back pain is a common debilitating
Background
Authors: William E. Shell M.D., David S. Silver M.D., Fred McCall-Perez Ph.D., Stephanie Pavlik C.R.A.*
THERAMINE VERSUS IBUPROFEN FOR THE SAFE AND EFFECTIVE MANAGEMENT OF
CHRONIC LOW BACK PAIN AND INFLAMMATION
Percent Change
Percent Change
Percent Change
Percent Change
Percent Change
Theramine® Product Information
Theramine®ProductInformation
Indication
Theramine® is intended for use in the management of pain syndromes that include acute pain, chronic
pain, fibromyalgia, neuropathic pain, and inflammatory pain. Theramine is a medical food that must
be used under the active or ongoing supervision of a physician. Medical foods are developed to address
the different or altered physiologic requirements that may exist for individuals with distinctive nutritional
needs arising from metabolic disorders, chronic diseases, injuries, premature birth associated with
inflammation and other medical conditions, as well as from pharmaceutical therapies.1
Pain is a complex process initiated by pain-inducing or noxious stimuli interacting with pain receptors
(nociceptors) which triggers a series of action potentials that are transmitted by neurotransmitters from
peripheral afferent neurons to the spinal cord and higher nerve centers in the brain. The presence of
inflammation exacerbates the intensity of signals from these stimuli by sensitization of the peripheral
neurons in the surrounding area. Patients with pain syndromes benefit from increased availability of
choline, arginine, glutamine, histidine, 5-hydroxytryptophan, and serine to restore homeostasis.
Theramine is designed to provide a balance of neurotransmitters with well-defined roles in the
modulation of pain and a blend of antioxidants, anti-inflammatory agents, and immunomodulators to
moderate the effects of inflammation on the pain response.
Ingredients
Theramine is a proprietary blend of neurotransmitters (gamma-aminobutyric acid [GABA], Lglutamate, L-glutamine) and neurotransmitter precursors (choline bitartrate, L-arginine, L-glutamine,
L-histidine, 5-hydroxytryptophan, and L-serine); stimulators of precursor uptake (cinnamon);
polyphenolic antioxidants (grape seed extract, cinnamon bark, cocoa powder); anti-inflammatory and
immunomodulatory peptides (whey protein hydrolysate); adenosine antagonists (cocoa powder,
metabromine); and an inhibitor of the attenuation of neurotransmitter production associated with
precursor administration (grape-seed extract). The neurotransmitters and neurotransmitter precursors have
been carefully selected based on scientific support for their roles in the physiological processes involved
in reduction of pain. These roles are summarized in this monograph in the section, Scientific Support for
Use of Theramine in Management of Pain Syndromes. The other ingredients in the formulation are
involved in neurotransmitter metabolism or are functional components of the Targeted Cellular
Technology® system.
All of the ingredients included in Theramine are classified as generally recognized as safe (GRAS) by
the United States Food and Drug Administration (FDA). To qualify for GRAS status, a substance that is
added to a food, including a medical food, has to be supported by data demonstrating that it is safe when
consumed in amounts from these foods, as they are typically ingested or prescribed.
1
As defined in the guidelines issued by the Center for Food Safety and Nutrition, United States Food and Drug
Administration (FDA).
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Theramine® Product Information
TargetedCellularTechnology®
Theramine has been formulated using Targeted Cellular Technology, an integrated molecular system
that facilitates the uptake and utilization of neurotransmitter precursors by target cells within the nervous
system. This 5-component patented system consists of (1) specific neurotransmitter precursors; (2) a
stimulus for the neuronal uptake of these precursors by specific neurons; (3) an adenosine antagonist that
blocks the inhibitory effect of adenosine on neuronal activity (adenosine brake); (4) a stimulus to trigger
the release of the required neurotransmitters from targeted neurons; and (5) a mechanism to prevent
attenuation of the precursor response, a well known phenomenon associated with precursor
administration.
Use of Targeted Cellular Technology improves the metabolic efficiency of neurotransmitter synthesis,
thereby reducing the amounts of precursors needed to correct neurotransmitter imbalances. Use of
Targeted Cellular Technology also ensures that the appropriate amounts of neurotransmitter precursors
are delivered to the target neurons with the appropriate timing. As such, Targeted Cellular Technology
synchronizes the availability of the precursor supply with the fluctuating demand for the corresponding
neurotransmitters, which is especially important for processes which are regulated by circadian rhythms
and are therefore sensitive to the timing of the synthesis and release of neurotransmitters such as
acetylcholine, serotonin, nitric oxide, and histamine (1-5).
Previous attempts to provide an exogenous source of precursor amino acids and other biogenic amines in
the quantities required to support neurotransmitter synthesis for individuals with specific needs
necessitated that large amounts of amino acids be added to the formulations. For patients whose precursor
requirements were considerably higher than normal, the amounts of exogenous amino acids that were
needed were not practical to consume on a daily basis. Moreover, ingestion of large quantities of amino
acids increases the potential for adverse effects. Metabolic efficiency is also decreased when large
amounts of amino acids are delivered to the cells at one time because intestinal membrane transport
receptors would be rapidly saturated resulting in a reduction in fractional amino acid absorption and thus
attenuation of the tissue response to the supplemental amounts provided. Improving metabolic efficiency
in uptake and utilization of neurotransmitter precursors by target neurons with Targeted Cellular
Technology allows ingestion of smaller amounts of amino acids to elicit the same responseas larger
amounts, making daily dosing more feasible and reducing the potential for tolerance. Unlike
pharmaceutical agents which are not innate components of the pain process, and thus may lose their
effectiveness in a relatively short period of time, the effectiveness of Theramine is not attenuated.
Metabolism
Theramine is a source of amino acids,biogenic amines, and other nutrients formulated for patients
with certain types of pain syndromes. These patients require additional amounts of arginine, choline,
GABA, glutamine, histidine, 5-hydroxytryptophan, and serine to restore homeostasis. Under normal
physiological conditions, glutamine, arginine, serine, and choline are considered nonessential because
endogenous synthesis is sufficient to satisfy metabolic demand. When needs are altered by conditions that
increase metabolic demand, the usual rate of synthesis is no longer sufficient and these nutrients become
conditionally essential, requiring that supplemental amounts be consumed. Histidine has also been
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Theramine® Product Information
considered a nonessential amino acid for adults because blood levels can be maintained by breakdown of
skeletal muscle and hemoglobin; however, there is no evidence of de novo histidine synthesis in
mammalian tissues and thus an exogenous supply is important, especially during times of increased need
to preserve muscle mass and plasma hemoglobin concentration.
In contrast to the nutrients which are nonessential under normal conditions, tryptophan is an essential
amino acid that must always be consumed from exogenous sources, as the enzymes required for its
synthesis are absent in humans. Because it is an essential amino acid, the amount of tryptophan consumed
determines the amount available for utilization by multiple pathways. Tryptophan is a precursor of the
neurotransmitter serotonin, as well as of the coenzymes nicotinamide adenine dinucleotide (NAD+) and
nicotinamide adenine dinucleotide phosphate (NADP) (Figure 1). The competition between these and
other metabolic pathways for the supply of tryptophan available restricts the amount of serotonin that can
be produced from supplemental amounts of the amino acid.
Figure 1. Competing Pathways of Tryptophan Metabolism
To overcome this limitation, Theramine provides 5 hydroxytryptophan, an intermediate metabolite in
the pathway of tryptophan conversion to serotonin, thus bypassing the rate-limiting step dependent on
tryptophan availability (6) (Figure 2). Unlike tryptophan, this intermediate cannot be shunted into
production of niacin or protein which eliminates competition by other metabolic pathways for the amount
available. Consequently, an increase in 5-hydroxytryptophan lessens the dependence of serotonin levels
on the amount of tryptophan consumed. By facilitating production of serotonin without requiring
consumption of large amounts of tryptophan, Theramine ensures that adequate amounts of serotonin
are produced without compromising synthesis of other important compounds derived from tryptophan,
thus improving metabolic efficiency.
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Theramine® Product Information
Figure 2. Structure of 5-Hydroxytryptophan
As nonessential amino acids, glutamine, arginine, and serine are not normally dependent on exogenous
sources, thus metabolic competition for these amino acids develops only under conditions of increased
demand. Under normal conditions, glutamine is synthesized from glutamate in virtually all tissues by the
transfer of an amino group. Glutamine can therefore function as a carrier of amino groups which are
utilized in the synthesis of a number of cellular compounds including the antioxidant glutathione
(Ȗ-glutamylcysteinylglycine) as well as purines, pyrimidines, and urea (Figure 3). Deamination of
glutamine regenerates glutamate, the major excitatory neurotransmitter of the central nervous system
which is also utilized as a precursor for the synthesis GABA, the major inhibitory neurotransmitter of the
central nervous system. In addition, glutamine also functions as a neurotransmitter at NMDA receptor
sites in the brain.
Figure 3. Competing Pathways of Glutamine Metabolism
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Theramine® Product Information
For individuals with inflammatory pain, the requirement for glutamine is greater than normal because
additional amounts are needed to support the increase in demands for glutamate and GABA. The
competition for glutamine by other pathways that utilize it will limit the amount of glutamate that can be
produced, and subsequently, the amount of GABA. A decrease in the supply of glutamine will draw on
the available supply of glutamate and thus can compromise other important glutamate-dependent
functions. Theramine improves metabolic efficiency by providing supplemental glutamine to ensure
that there will be sufficient glutamate available to support its metabolic activity without drawing from the
supply of glutamine needed by competing pathways. Additional GABA further ensures that there is a
sufficient amount of this neurotransmitter while conserving the available supplies of both glutamate and
glutamine.
The metabolic pathways which generate arginine are also normally sufficient to ensure an adequate
supply of this amino acid. Because arginine can be synthesized from glutamine and glutamate, it is not
considered an essential nutrient. A critical role for arginine is utilization as precursor of nitric oxide, a
neurotransmitter which also functions as a vasodilator, immunomodulator, and intercellular/intracellular
messenger. Arginine is also utilized as a precursor of polyamines, urea, and the high-energy storage
compounds creatine and creatine phosphate (Figure 4). When the demand for nitric oxide is increased,
arginine is diverted away from the synthesis of these other compounds. To compensate a decrease in
arginine available for utilization by competing pathways, glutamate and glutamine are metabolized to
ornithine and citrulline which are then converted to arginine in the urea cycle. Theramine improves
metabolic efficiency by ensuring that there is a sufficient amount of arginine available to satisfy the
demands of competing pathways and prevent depletion of the glutamate body pool which would upset
neurotransmitter balance (nitric oxide, glutamate, and GABA). Supplemental arginine will also ensure
that there is sufficient glutamine available to conserve the existing supply of glutamate.
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Theramine® Product Information
Figure 4. Competing Pathways of Arginine Metabolism
Choline is also considered a nonessential nutrient under normal physiological conditions. When the
demand for choline is increased to supply precursor for synthesis of acetylcholine, supplemental amounts
of choline are needed. Acetylcholine is produced from choline in an acetylation reaction catalyzed by
choline acetyltransferase with acetyl coenzyme A (CoA) as the acetyl group donor (Figure 5).
Figure 5. Biosynthesis of Acetylcholine
The primary source of choline normally utilized in the synthesis of acetylcholine is phosphatidylcholine
(lecithin), a membrane phospholipid which serves as a reservoir to supply choline for short-term needs
(Figure 6). When the demand for acetylcholine exceeds the amount of choline that can be supplied by the
hydrolysis of phosphatidylcholine from the membrane pool, dietary choline becomes an increasingly
more important source. Theramine provides additional amounts of choline to meet the increased
needs for acetylcholine when demand is elevated for an extended time period. By supplying an exogenous
6|P a g e Revised03Mar2011
Theramine® Product Information
source of choline, Theramine prevents the depletion of membrane phosphatidylcholine and thus
preserves the structural integrity of the cell.
Figure 6. Sources of Acetylcholine
Serine is a nonessential amino acid which functions as a neurotransmitter/neuromodulator in the brain and
spinal cord in its D isomeric form (5). Since amino acids can only be incorporated into human protein as
L isomers, D-serine is utilized solely as a neurotransmitter. Adequate amounts of L-serine are normally
synthesized from 3-phosphoglycerate, an intermediate of glucose metabolism. To produce the
neurotransmitter, L-serine is converted to D-serine by serine racemase which is localized primarily in
specific neurons in the central nervous system (Figure 7).These neurons normally obtain L-serine from
the plasma because they lack the enzyme needed for the synthesis of this amino acid. When demand for
D-serine is high, plasma L-serine levels may not be adequate to provide sufficient quantities of precursor
to these neurons, thus additional amounts must be obtained from nearby astrocytes. As a result, astrocyte
production of L-serine becomes rate-limiting to the supply of D-serine during periods of increased needs.
Theramine provides additional L-serine to ensure that there is sufficient D-serine available to meet
these needs.
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Theramine® Product Information
Figure 7. Conversion of L-Serine to D-Serine
Dosage
The recommended dose of Theramine is 1 or 2 capsules, taken 1 to 4 times daily as directed by a
physician. Theramine is designed to reduce pain and support the function of pain medications by
minimizing side effects. Patients who are taking pharmaceutical agents to relieve pain may continue to
take these medications with Theramine. As with any medical food, the best dosing protocol should be
determined by assessment of individual needs.
There are no known interactions between Theramine and any medication.
Theramine can be taken with pain medications such as once daily low dose aspirin (32 mg) or other
nonsteroidal anti-inflammatory drugs (NSAIDs) such as low dose naproxen (250 mg) or tramadol (50 mg
daily). If pain relief is obtained when Theramine is taken in combination with other pain medications,
the drug dosage may be further tapered to lower levels under medical supervision.
Theramine can also be used to manage the effective dose and dose-related side effects of pain
medications. A randomized crossover study of patients with pain syndromes who were treated with
naproxen in combination with Theramine demonstrated a 75% decrease in the effective dose of
naproxen needed to achieve the same degree of pain reduction from 4 times to once daily. This study is
described in greater detail in this monograph in the section, Clinical Validation of Theramine.
The amounts of each ingredient consumed at the recommended doses of Theramine for pain reduction
are provided in Table 1.
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Theramine® Product Information
Table 1.
Theramine Composition
mg/kg body weight1
Ingredient
1
į-aminobutyric acid (GABA)
1.5 – 12.0
choline bitartrate
1.0 – 7.7
L-arginine
0.6 – 4.6
Whey protein hydrolysate
0.6 – 4.6
L-histidine
0.4 – 3.1
L-glutamine
0.4 – 3.1
Metabromine
0.4 – 3.1
5-Hydroxytryptophan
(griffonia seed, 95% w/w)
0.2– 1.9
Grape seed extract
0.2 – 1.5
L-serine
0.2 – 1.5
Cinnamon bark
0.2 – 1.5
Cocoa powder
0.2 – 1.5
Dosing range of 1 to 4 capsules daily
SideEffectsandContraindications
As with any amino acid therapy, headache, upset stomach, or dry mouth may be experienced in some
people after beginning treatment with Theramine. These symptoms are mild and temporary, and
readily managed by increasing fluid intake. The development of side effects from Theramine can be
minimized by careful titration of the dosage. The ingredients in Theramine are regularly consumed in
amounts normally found in foods or dietary supplements; therefore, adverse reactions associated with
administration of Theramine are not expected to occur.
Theramine is contraindicated in patients who may be hypersensitive to any component of an argininecontaining preparation. Theramine contains L-arginine which has been associated with side effects
when consumed as a supplement; however, these effects are not observed when consumed at low doses as
part of a formulation containing other amino acids. The adverse effects associated with L-arginine
supplementation also appear to be dependent on the dosage regimen and are not observed when doses are
divided instead of given as a single dose (7). A 2-capsule dose of Theramine contains 126 mg of
L-arginine provided in a balanced formula with other amino acids and dietary factors.
Side effects specific to oral supplementation with L-arginine have been reported at doses between 3 and
100 g/d, approximately 12 to 400 times the amount provided in Theramine in the recommended daily
dose (126 mg/2 capsules) (7). L-arginine is generally well-tolerated at intakes of up to 15 g/d. The most
common adverse reactions have been observed at the range of intakes between 15 30 g/d and include
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Theramine® Product Information
nausea, abdominal cramps, diarrhea, and vomiting. Some patients may experience symptoms at lower
doses. Most of the side effects associated with L-arginine supplements have been reported at single doses
>9 g (>140 mg/kg), particularly when consumed in regimens where total daily doses amount to >30 g/d.
L-arginine supplements must not be taken alone by patients testing positive for HIV-1 infection, but may
be consumed by these patients in combination with other amino acids and dietary factors as provided in
Theramine. Long-term safety studies have not been conducted with L- arginine. Because it may
stimulate growth hormone production, pregnant women and nursing mothers should avoid L-arginine
supplementation. Individuals with renal or hepatic failure should also exercise caution with the use of
supplemental L-arginine. Oral supplements of arginine and citrulline can increase local nitric oxide
production in the small intestine which may be harmful under certain circumstances.
AbbreviationsandDefinitionofTerms
The abbreviations and terms used frequently in this monograph are summarized in Table 2.
Table 2.
Abbreviations and Definitions of Terms
Term/Abbreviation
Definition
Adenosine
Ubiquitous homeostatic neuromodulator; responsible for fine tuning neuronal function; exerts
inhibitory effects on neuronal activity
Anti-inflammatory
Inhibitory effect on the synthesis and release of chemical and hormonal stimuli which initiate
and sustain inflammation
Antinociceptive
Moderates nociceptor responsiveness to noxious stimuli which reduces pain
Antioxidants
Molecules or enzyme systems that inhibit injury to cells from reactive oxygen or nitrogen
species
Biogenic amine
Biologically active substance that contains an amine group but does not have the
characteristic structure of an amino acid, i.e., alpha carbon binding both an amino and
carboxyl group
Central sensitization
Increased responsiveness of the spinal cord to all incoming signals which contributes to
hyperexcitability of spinal cord neurons; originates from the release of excessive amounts of
neurotransmitters from sensitized peripheral neurons
C-fibers
Small diameter afferents in peripheral nerves which convey information about pain and
temperature to the dorsal horn of the spinal cord
Cholinergic
Neurons that synthesize, package, and release acetylcholine
Dorsal horn
Section of the spinal cord which is the primary center for processing nociceptive information;
receives input from peripheral afferent fibers where it is encoded and transmitted for
processing by higher nerve centers in the thalamus and cortex
Excitatory
Neurotransmitters
Molecules released from presynaptic cells at terminal nerve endings which transmit action
potentials to adjacent neurons by depolarization of postsynaptic cell membranes resulting in a
decreased stimulus threshold for firing which increases the frequency and rate of transmission
of action potentials
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Theramine® Product Information
Term/Abbreviation
Definition
GABAergic
Neurons that synthesize, package, and release gamma-aminobutyric acid
Glutamatergic
Neurons that synthesize, package, and release glutamate
Glutathione
Potent cellular antioxidant synthesized from glutamate, cysteine, and glycine
Inflammatory Mediators
Serum proteins and cellular products released from activated inflammatory cells
(lymphocytes, leukocytes, platelets) and damaged tissues which modulate the inflammatory
response, e.g, cytokines and prostaglandins
Inhibitory
Neurotransmitters
Molecules released from presynaptic cells at terminal nerve endings which transmit action
potentials to adjacent neurons by hyperpolarization of postsynaptic cell membranes resulting
in a increased stimulus threshold for firing which decreases the frequency and rate of
transmission of action potentials
Neuropeptides
Polypeptides which function as neurotransmitters but are more widely diffused and have
longer-lasting effects; may also function as hormones, e.g., prolactin, vasopressin
Neurotransmitters
Amino acids, biogenic amines, and other molecules that facilitate communication between the
peripheral nervous system, spinal cord, and brain by generating a series of action potentials
which are transmitted between neurons
NMDA Receptors
N-methyl-D-aspartate; subfamily of glutamatergic receptors which require a co-agonist for
activation; implicated in generation and maintenance of central (spinal) states of
hypersensitivity through enhancing transmission of nociceptive information; mediates events
that are critical components of pathological and/or prolonged pain states
Nociception
Initiation, transmission, processing, and perception of pain
Nociceptors
Receptors at the terminal endings of peripheral afferent nerves which transduce noxious
stimuli to receptor potentials
Noxious stimuli
Chemical, physical, or electrical signals that stimulate nociceptors in the area of tissue
damage to initiate the sequence of electrochemical events that send the nociceptive
information over afferent pathways to the brain
Neuropeptides
Polypeptides which function as neurotransmitters but are more widely diffused and have
longer-lasting effects; may also function as hormones, e.g., prolactin, vasopressin
Peripheral sensitization
Increased responsiveness of primary afferent neurons as a consequence of factors that lower
the threshold level for nociceptive stimulation
Pronociceptive
Effect that enhances the intensity and duration of pain by increasing nociceptor
responsiveness to noxious stimuli
Prostaglandins
Inflammatory mediators synthesized from 20-carbon fatty acids by COX enzymes; may have
proinflammatory (omega-6 fatty acids) or anti-inflammatory (omega-3 fatty acids)
Serotoninergic
Neurons that synthesize, package, and release serotonin (5-hydroxytryptamine)
Substance P
Sensory neuropeptide released from NMDA receptors at the terminal ending of C-fibers in
response to increased electrical activity in nociceptors
Targeted Cellular
Technology™
A patented process that facilitates endogenous production, uptake, and utilization of
neurotransmitter precursors
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Theramine® Product Information
MechanismofAction
Theramine has been formulated to provide a balance of neurotransmitters with well-defined roles in
the physiological mechanisms underlying the initiation and perception of pain. Pain is a sensory response
to tissue damage which protects the area from additional stimulation in order to optimize healing and
prevent infection. It is the outcome of a complex series of events originating with an interaction between
unspecialized nerve endings (nociceptors) and noxious stimuli at or near the site of the injury (8-9). The
noxious stimuli are transduced to receptor potentials by the nociceptors triggering a series of action
potentials that are transmitted over peripheral afferent pathways to the spinal cord and higher nerve
centers in the brain (8-12). The presence of inflammation increases the intensity of pain by sensitizing the
nociceptors in the surrounding area to noxious stimuli causing them to fire more rapidly and frequently
(11, 13-14). Transmission of nociceptive information by peripheral afferent fibers to the pain processing
centers in the dorsal horn of the spinal cord is mediated by neurotransmitters. In the dorsal horn, these
signals are encoded and output transmitted to the higher nerve centers in the thalamus and cerebral cortex.
Neurotransmitters are amino acids, biogenic amines, or amino acid derivatives which function as
mediators of physiological responses to physical, chemical, or electrical stimuli. Neurotransmitters are
released from storage vesicles in presynaptic neurons in response to action potentials at the distal nerve
endings where they bind to receptors on postsynaptic neurons (Figure 8). Neurotransmitter binding alters
the resting membrane potential of postsynaptic neurons generating an action potential which is
transmitted to the terminal ending of the neuron where the sequence of electrochemical events is repeated
until the signal reaches specific processing centers in the brain. The same mechanism of neurotransmittermediated electrochemical events is involved in transmission of output from the brain to the target effector
tissues or organs, and in transmission of signals originating within different regions of brain over the
internal circuits between these regions.
Figure 8. Neurotransmitter Activity in Presynaptic and Postsynaptic Neurons
The rate of signal transmission between presynaptic and postsynaptic neurons in the central and
peripheral nervous systems is dependent on the chemical nature of the neurotransmitter involved.
Excitatory neurotransmitters released from presynaptic nerve terminals depolarize postsynaptic cell
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Theramine® Product Information
membranes which lowers the stimulus threshold for firing and increases the frequency and rate of
transmission. Inhibitory neurotransmitters have the opposite effect of hyperpolarizing postsynaptic
membranes which raises the stimulus threshold and decreases the frequency and rate of transmission.
Although neurotransmitters can be classified as excitatory or inhibitory based on the primary effects they
have on resting membrane potentials, these classifications do not always predict the response of the
effector tissue or organ. Excitatory neurotransmitters can suppress a response by activation of inhibitory
mechanisms and inhibitory neurotransmitters can activate a response by suppression of these
mechanisms. Imbalances caused by deficiencies in one or more of the excitatory and inhibitory
neurotransmitters, or changes in their binding affinities to postsynaptic receptors, will determine the
intensity and duration of the signals transmitted (16-20).
The primary neurotransmitters involved in the transmission of nociceptive signals are glutamate, GABA
nitric oxide, acetylcholine, histamine, and D-serine. Glutamate is the major excitatory neurotransmitter of
the central nervous system while GABA is the primary inhibitory neurotransmitter. Serotonin has
excitatory activity while acetylcholine, nitric oxide and histamine can each exhibit both excitatory and
inhibitory effects in the central and peripheral nervous systems depending upon the specific type and
location of the respective receptors. D-serine influences nociceptive and inflammatory processes as an
excitatory neurotransmitter in the brain. Imbalances caused by deficiencies in one or more of the
excitatory and inhibitory neurotransmitters, or changes in their binding affinities to postsynaptic
receptors, will determine the intensity and duration of the nociceptive signals generated (21-24).
The amount of pain experienced resulting from tissue injury is influenced by nociceptor activity at or near
the site of the injury. The responsiveness of neurons to pain signals is amplified by the presence of
chemical or electrical phenomena which sensitize them to incoming signals (25-29). The accumulation of
leukocytes, lymphocytes, and platelets at the site of tissue damage triggers the release of inflammatory
mediators (cytokines and prostaglandins) which activates the corresponding receptors in a proportion of
nerve fibers (13-14, 27, 30-31). Maintenance of inflammation after tissue damage has been repaired will
ultimately lead to peripheral sensitization, which lowers the threshold level for nociceptive stimulation.
Within the first hour after onset of inflammation, sensitization of peripheral neurons occurs and can
persist over weeks in chronic inflammation (10).
Sensitization of the central nervous system arises from the release of excessive amounts of
neurotransmitters from sensitized peripheral neurons (11-12, 28, 32). The responsiveness of the spinal
cord to all incoming signals is then amplified which contributes to hyperexcitability of spinal cord
neurons. This hyperexcitable state potentiates the responsiveness of dorsal horn neurons to noxious
mechanical and chemical stimuli (hyperalgesia), reduces the pain threshold of spinal nociceptors
(allodynia), and increases the sensitivity of normal tissue to mechanical stimulation (8, 25-27, 32-35).
Central sensitization is mediated by various transmitter/receptor systems on spinal cord neurons which
include N-methyl-D-aspartate (NMDA) receptors.
NMDA receptors are a subfamily of glutamatergic receptors concentrated in the dorsal horn of the spinal
cord which increase hyperalgesia following tissue damage, nerve dysfunction, and surgery by potentiating
spinal nociception (23, 31). NMDA receptors differ from other nociceptive receptors in that the ion
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channels involved in generation of action potentials are blocked by magnesium and therefore cannot be
activated until the block is removed. Activation of NMDA receptors requires a co-agonist such as
glutamate or acetylcholine to remove the magnesium block which triggers a massive depolarization that
markedly increases neuron excitability resulting in enhancement of nociceptive signal transmission (23,
36). Although not directly involved in transmission of nociceptive information, NMDA receptors
facilitate and sustain transmission of these signals and thus NMDA-mediated events are important
contributors to pathological and/or prolonged pain states. Since the effects of NMDA receptor activity are
slow and long-lasting, they contribute to all persistent clinically important types of pain including
neuropathic and inflammatory pain.
The activation of NMDA receptors is the key event in the development and maintenance of peripheral and
central sensitization and a factor in modulation of the intensity of the nociceptor response to noxious
stimuli (11-13, 28, 35, 37). Sensitized neurons establish the physiological basis for persistent or ongoing
pain by spontaneously discharging at greater frequencies over extended periods. Persistent pain is an
outcome of the hyperexcitability of dorsal horn neurons originating with severe or prolonged tissue or
nerve injury (11, 27-28, 35, 38). Activation of nociceptors by sensitizing agents not only amplifies
cellular responsiveness to pain stimuli, but also attenuates neuron sensitivity to antinociceptive receptor
stimulants such as endogenous opioids (endorphins, dynorphins, and enkephalins) or exogenously
administered opiates such as morphine (39-43).
NMDA receptor activation further enhances the transmission of nociceptive information in the spinal cord
by stimulating the release of nitric oxide and prostaglandins in the dorsal horn (29, 34, 40, 44). D-serine
influences central nociceptive activity by effects on NMDA receptor activity in the brain (45-46). The
release of glutamate following the activation of NMDA receptors increases the neuronal discharge rate
and stimulates the release of substance P from the central terminals of spinal nociceptors. The release of
substance P is triggered in response to an increase in electrical activity of NMDA receptors on the
terminals of C-fibers, which are small-diameter peripheral afferents that receive input from peripheral
nociceptors (32, 34, 37, 47-51). Substance P is a sensory neuropeptide which functions as a primary
afferent neurotransmitter and mediator of central transmission with effects that are more widely diffused
and longer-lasting than those of other neurotransmitters (32, 34, 37, 47, 49-50, 52-53). It facilitates the
expression of nociceptive inputs which signal the intensity of noxious or aversive stimuli, promotes
vasodilation and swelling, and stimulates the release of histamine from mast cells, which prolongs pain by
sustaining inflammation-mediated neuron sensitivity (34, 37, 47, 49-53). Substance P is also believed to
be an integral part of central nervous system pathways involved in pain associated with psychological
stress (39, 50, 52).
Central sensitization which is mediated by NMDA receptor activity is enhanced by increased levels of
substance P and proinflammatory prostaglandin E2 (PGE2) in the spinal cord (37 49, 51-52, 54).
Prostaglandins enhance the sensitivity of high threshold pain fibers by increasing neuron excitability,
lowering the pain threshold, and potentiating the action of pain-producing stimuli (55-56). PGE2 is the
dominant prostaglandin in the spinal nociceptive pathway (57). PGE2 binds to receptors at presynaptic
endings of primary afferent neurons promoting the release of substance P and to receptors on postsynaptic
spinal cord neurons where it produces changes in spinal cord responsiveness similar to peripheral
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inflammation (Schaible 2002 9). The release of pronociceptive neurotransmitters triggered by PGE2
binding depolarizes spinal cord neurons and blocks the effects of inhibitory neurotransmitters (57-58).
Binding of prostaglandins to receptors on peripheral terminals of primary sensory nerves increases the
sensitivity of high threshold pain fibers by enhancing neuron excitability which lowers the pain threshold
thus potentiating the action of pain-producing stimuli. PGE2 levels are regulated by changes in the activity
of the inducible form of cyclooxygenase (COX-2), which is increased by macrophages at sites of
inflammation (56, 58-59). COX-2 is also expressed constitutively in small amounts in the central nervous
system by glutamatergic neurons where it may participate in glutamate-mediated neurotransmission (57,
59).
The effects of NMDA receptor activation and the release of substance P on induction, enhancement, and
maintenance of pain suggest that treatments which target these effects may be useful in ameliorating
persistent pain (28, 43, 47, 60-62). Central sensitization of the responses of spinothalamic tract neurons
can be prevented by spinal cord administration of NMDA-glutamate receptor antagonists or substance P
receptor antagonists (32). Achieving balance between excitatory and inhibitory neurotransmitters such as
nitric oxide, glutamate, and D-serine can also prevent the sensitization of nerve fibers triggered by
NMDA stimulation of spinal nociceptors (23). Because central sensitization facilitates efferent neuronal
processes through which the nervous system influences the inflammatory response, regulation of NMDA
receptor activity can be effective in management of pain resulting from inflammation.
Successful pain management is complicated by the multifaceted relationships among different
neurotransmitters and further complicated by the different types of pain often present in various
combinations in different pain syndromes. Acute pain is a nociceptive phenomenon comprising visceral,
somatic, and referred pain mechanisms whereas chronic pain is non-nociceptive dominated by
neuropathic and psychogenic mechanisms which contribute to the physical and mental suffering and
disability characteristic of this type of pain syndrome (10, 34, 63-65). The transformation of acute pain to
chronic pain involves changes in neuronal pathways (plasticity) which include sensitization to stimuli and
increased signal transmission in the central nervous system (12, 44, 66).
Oral agents such as gabapentin which target GABAergic activity have been proven effective in treating
neurogenic pain states (67-69). GABAergic receptors are concentrated in the pain-processing areas of the
thalamus where they are expressed by approximately 10-25% of the neuron population (13, 68).
Gabapentin is a widely prescribed analgesic which exerts its antinociceptive effects by selectively acting
on NMDA receptors located in GABAergic neurons, thereby increasing the inhibitory activity of GABA.
Selective serotonin reuptake inhibitors, which increase serotoninergic activity, have also been used for
treatment of neurogenic pain, while D-serine facilitates analgesic effects by sensitizing opioid receptor
systems to opioids, opioid-like agents, and other analgesics (8, 45, 69).
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The Inflammatory Cascade
Inflammation is a response to cellular injury initiated by infection or trauma and
mediated by serum proteins and cellular products released from accumulated
phagocytic leukocytes, platelets, and lymphocytes at the site of the injury. Among
these cellular products are cytokines (bradykinin), lymphokines, (interleukins and
interferons), eicosanoids (prostaglandins and leukotrienes), histamine, chemotaxins,
platelet aggregating factors, and neuropeptides. These substances are responsible for a
wide range of effects including changes in vascular permeability and modification of
the electrochemical properties of cell membranes which contribute to the cellular and
physiological effects of inflammation. Clinical manifestations of inflammation are
redness, swelling, loss of function, and increased body temperature.
Inflammation is a part of the normal innate immune response, but can cause excessive
damage to host tissue when it is uncontrolled and sustained after tissue repair is
complete. Hyperexpression of cellular adhesion molecules, sequestration of
leukocytes in areas where they are not normally found, and overproduction of
inflammatory mediators are responsible for the destructive effects of inflammation.
Although intended to be protective as an acute response, chronic inflammation is
implicated in the pathology of autoimmune diseases (multiple sclerosis, rheumatoid
arthritis, type I diabetes, lupus erythematous), cardiovascular disorders (angioplasty
re-stenosis, by-pass graft occlusion, transplant vasculopathy), and other disorders
(fibromyalgia, asthma, inflammatory bowel disease, and transplant rejection).
ScientificSupportforUseofTheramineinManagementofPainSyndromes
The use of Theramine in management of pain syndromes is supported by experimental and clinical
data which have identified specific roles for each ingredient in the mechanism of pain reduction. An
optimal balance between the activities of excitatory and inhibitory neurotransmitters involved in the
transmission of nociceptive information is essential to management of pain (23, 25). Inflammation
disrupts this equilibrium by chemical modification of nociceptive activity which recalibrates the levels of
neurotransmitters required to achieve balance. The relationship between the excitatory effects of
glutamate and inhibitory effects of GABA are primary determinants of the level of pain transmission. To
reduce pain, the balance between neurotransmitters with pronociceptive effects and those with the
opposing antinociceptive effects must be restored (23).
Recent evidence suggests that central pain originating with central nervous system damage may be
attributed to a derangement in neurotransmission between the sensory thalamus and sensory cortical areas
involving GABA (24). In addition, loss of GABAergic activity in spinal cord neurons contributes to the
allodynia and hyperalgesia observed after peripheral nerve injury (68). Central pain attributed to relative
hypofunction of GABAergic inhibition at both the thalamic and cortical levels may be controlled by
either potentiating GABAergic neurotransmission or by inhibiting the opposing effects of glutamatemediated transmission. If enhanced nociceptor sensitivity to noxious stimuli is not due to increased
activity of excitatory neurotransmitters such as glutamate, loss of inhibitory controls would be the likely
factor involved (23). Apoptosis of neurons in the peripheral and central nervous systems induced by loss
of inhibitory systems and the resultant neuronal sensitization is often an outcome of nerve injury
(neuropathic) and other nervous system diseases (neurogenic) (12). The spread of local nerve injuries to
distant parts of the peripheral and central nervous systems is facilitated by attenuation of central pain
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inhibitory mechanisms in addition to upregulation of nitric oxide synthesis in axotomized neurons,
deafferentation hypersensitivity of spinal neurons following afferent cell death, and long-term
potentiation of spinal synaptic transmission.
The nociceptive effects of neurotransmitters co-localized within the same neurons are also influenced by
balance in the relative amounts released (38, 64). Some of these neurotransmitters may act as co-agonists
with synergies that amplify the effects of each and others may act as antagonists with opposing activities
that mitigate these effects. Balance is also important in the regulation of neurotransmitter activity by
mechanisms involving feedback inhibition. The increase in nociceptor sensitivity to noxious stimuli
which is mediated by release of glutamate from NMDA receptors in the spinal cord and brain is
controlled by the subsequent increase GABAergic activity also mediated by glutamate (38, 67, 70). This
increase in GABAergic activity inhibits the release of substance P from NMDA receptors as well as the
additional release of glutamate from NMDA receptors (34, 47, 64, 70).
Pain reduction is optimized by achieving a balance between the pronociceptive effects of excitatory
neurotransmitters which are normally opposed by the antinociceptive effects of inhibitory
neurotransmitters (64). The loss of inhibitory controls may enhance nociceptor sensitivity to noxious
stimuli even in the absence of increased excitatory activity. Different pain states may not respond
similarly to changes in inhibitory transmitter systems since the activity of these systems can be influenced
by variations in opioid, adenosine, and GABA transmission in the spinal cord. For example, hyperalgesia
might be balanced by inhibitory effects of neurotransmitter systems in inflammatory conditions, but not in
neuropathic states associated with nerve damage.
The effects of serotonin on nociceptive transmission are largely mediated by the activity of the 5-HT3
receptor in the central and peripheral nervous systems which modulates the release of acetylcholine,
GABA and substance P, as well as serotonin itself (22, 71). The pronociceptive activity of serotonin
results from stimulation of peripheral afferent fibers and enhancement of the transmission of nociceptive
information to the spinal cord and pain perception centers in the brain (34, 72-73). The antinociceptive
effects of serotonin are mediated by inhibition of the release of substance P and amplified by stimulation
of GABA, acetylcholine activity, and the release of adenosine from peripheral afferent fibers (C-fibers)
(13, 22, 28, 47, 74-76). Adenosine receptors in the spinal cord exhibit antinociceptive activity in acute
nociceptive, inflammatory, and neuropathic pain tests (77). Endogenous adenosine systems also
contribute to the antinociceptive properties of caffeine, opioids, noradrenalin, tricyclic antidepressants,
and transcutaneous electrical nerve stimulation.
The antinociceptive activity of acetylcholine is due in part to cholinergic-mediated stimulation of the
synthesis and release of serotonin (64, 78). Acetylcholine also inhibits the activity of receptors localized
on peripheral afferent nerve terminals and intrinsic dorsal horn neurons, decreases neuronal sensitivity
and firing, inhibits NMDA receptor activity and production of substance P, and suppresses the production
of proinflammatory cytokines by stimulating the parasympathetic nervous system (34, 37, 64). The
parasympathetic-cholinergic anti-inflammatory pathway represents a physiological neuroimmune
mechanism for regulation of innate immune function and control of inflammation (78).
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The effects of nitric oxide on nociception are dose-dependent with exacerbation of pain at high doses and
inhibition at low doses (79). Nitric oxide is synthesized from arginine in a hydrolytic reaction catalyzed
by one of three isoforms of nitric oxide synthase (NOS); however, inducible NOS (iNOS) is the only
isoform which is active in inflammatory processes (26, 80-84). The activity of this enzyme is induced in
neurons by inflammatory mediators concentrated in the area of inflammation (79). The synthesis of nitric
oxide in dorsal horn neurons is increased by the induction of iNOS by NMDA receptor-mediated
stimulation of C fibers and neuronal nitric oxide synthase (nNOS) (34, 40). The amount of nitric oxide
produced by NOS is dependent upon the amount of arginine available to the enzyme and is controlled by
upregulation of arginine transport and the extent of competition between this enzyme and arginase (Figure
4) (82-83).
Nitric oxide modulates spinal cord nociception through effects on the transmission of pain signals from
dorsal horn neurons to cerebral centers in the brain (85). It blocks the transmission of afferent pain signals
in the spinal cord, activates natural opioids, and stimulates the production of anti-inflammatory
prostaglandins (26, 82, 85-86). Pain can thus be modulated by NMDA-mediated changes in neuronal
NOS activity which control nitric oxide production (13). Nitric oxide also influences the regulation,
proliferation, survival, and differentiation of neurons (82). Although at high concentrations nitric oxide is
deleterious to all cells, physiological amounts have anti-inflammatory effects and potent cytoprotective
effects which are especially pronounced in neurons (87-90). While nitric oxide influences the efficiency
of NMDA-mediated synaptic transmission, a deficiency blocks the neurotrophic and neuroprotective
effects of NMDA receptor activity which has a profound impact on neuronal function.
Glutamine plays an important role in modulation of pain as a precursor of glutamate especially during
periods of increased demand because elevated levels of glutamate can be toxic to the central nervous
system (91-93). This function of glutamine is particularly critical if nerve damage is present since
extracellular glutamate levels are further increased by the additional glutamate which is released into the
extracellular space from the damaged nerves. Glutamine also modulates the inflammatory response by
attenuation of pro-inflammatory cytokine production (94). Glutamine and glutamate are also utilized as
precursors of glutathione, a major intercellular antioxidant which protects against DNA damage from
accumulation of the large amounts of reactive oxygen species produced by inflammatory cells during
cytotoxic activities (95). Under certain conditions, glutathione can serve as an intracellular reservoir of
nitric oxide in its nitrosylated form (S-nitrosoglutathione).
Glutamate exhibits nociceptive effects in the brain and dorsal horn and modulates inflammatory processes
through activation of the hypothalamus-pituitary-adrenal (HPA) axis which triggers the synthesis and
release of glucocorticoids (54, 59, 95). Interactions between glutamate and acetylcholine have been
identified in mediation of many neurological functions (21, 36, 96-100). Glutamatergic neurons in the
central nervous system are concentrated in areas of high cholinergic activity. Under conditions where
glutamatergic receptor activity is inhibited, cholinergic transmission is stimulated and its receptors
upregulated in the hypothalamus (36).
Histamine has both antinociceptive and pronociceptive activity as well as proinflammatory and antiinflammatory effects depending upon the particular histamine receptor involved (3, 101-102). Histamine
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is produced from histidine in a decarboxylation reaction catalyzed by histidine decarboxylase. Many
neuropeptides rely on histaminergic transmission by H2 receptors for their analgesic effects and H1
receptors for nociceptive effects (13). Antinociception and stress-induced analgesia in the central
histamine system are mediated by activation of H2 and H3 receptors. Histamine decreases nociceptive
signal transmission by inhibition of NMDA receptor activity and acting synergistically with nitric oxide
while it promotes nociception by stimulating the release of substance P from peripheral afferent nerve
terminals (103). Neurogenic inflammation is also controlled by the H3 receptor through local feedback
loops linking neurons to mast cells (3, 104).
Whey protein hydrolysate comprises several proteins and peptides with anti-inflammatory,
immunomodulatory, and antioxidant properties (105-106). In particular, Į-lactalbumin and ȕlactoglobulin interact with opioid receptors indicating that these proteins also have anti-nociceptive
effects (105-107). Whey is a high biological value protein derived from milk which contains all 22 amino
acids necessary for human protein synthesis and metabolism including the neurotransmitter precursors,
tryptophan, arginine, and histidine.
A summary of the roles of these and other ingredients provided in Theramine in the management of
pain, is presented in Table 3.
Table 3.
Ingredient
Effector
Molecule
GABA
Role of Theramine Ingredients in Nociception
Effects
Roles
GABA
Inhibitory
neurotransmitter;
Antinociceptive
Dampens pain signals in the spinal cord and brain;
inhibits NMDA receptor activity; inhibits release of
substance P and glutamate from dorsal horn
neurons
Choline
Acetylcholine
Inhibitory
neurotransmitter;
Antinociceptive;
Anti-inflammatory
Promotes synthesis and potentiates the effects of
nitric oxide and serotonin; inhibits peripheral
afferent nerve terminal receptor activity; reduces
neuronal sensitivity and firing; inhibits NMDA
receptor activity and production of substance P;
suppresses proinflammatory cytokines by activation
of the parasympathetic nervous system
Glutamine
Glutamine
Facilitator of
neurotransmitter
precursor uptake
Promotes synthesis of neurotransmitters; source of
glutamate; protects against neurotoxicity by
preventing extracellular glutamate accumulation in
the central nervous system
Glutamate
Excitatory
neurotransmitter;
Pronociceptive
Primary neurotransmitter of the NMDA receptor;
Inhibits NMDA receptors through activation of
GABAergic receptors; precursor of GABA ;
interacts with acetylcholine
Glutathione
Antioxidant;
Immunomodulator
Prevents tissue oxidative damage due to the effects
of inflammation
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Ingredient
Effector
Molecule
Effects
Roles
5-OH-tryptophan
Serotonin
Excitatory
neurotransmitter;
Antinociceptive;
Pronociceptive
Decreases pain signals in the spinal cord and brain;
stimulates nociceptive peripheral afferent fibers; ;
inhibits NMDA receptor activity; inhibits release of
substance P; increases adenosine production by
C-fibers which release substance P; acts
synergistically with GABA and acetylcholine to
amplify antinociception; stimulates release of
histamine and serotonin from mast cells
Serine
D-Serine
Neurotransmitter;
Antinociceptive
Regulates NMDA receptor activity in the brain;
sensitizes opioid receptor systems to opioids,
opioid-like agents, and other analgesics (natural
opioids include endorphins, enkephalins, and
dynorphins and synthetic opioids include morphine)
Arginine
Nitric Oxide
Inhibitory and excitatory
neurotransmitter;
Antinociceptive;
Pronociceptive;
Neuroprotective;
Anti-inflammatory
Inhibits pain at low doses and exacerbates pain at
high doses; inhibits transmission of afferent pain
signals in the spinal cord; inhibits NMDA receptor
activity; activates natural opioids; stimulates
production of anti-inflammatory prostaglandins;
neuroprotective at physiological levels
Histidine
Histamine
Excitatory
neurotransmitter;
Antinociceptive;
Proinflammatory;
Anti-inflammatory
Receptor dependent effects on nociception; active
in the spinal cord and brain; stimulates NMDA
receptor activity; acts synergistically with nitric
oxide; modulates inflammation through increasing
production of glucocorticoids
Cocoa Powder
Caffeine
Adenosine antagonist
Binds to adenosine receptors to disinhibit the
adenosine brake which promotes the inhibitory
effect of adenosine on neuronal activity (76, 108111)
Grape seed extract
Polyphenols
Antioxidant;
Anti-inflammatory
Protects against tissue oxidant damage due to
inflammation; prevents attenuation of the response
to increased availability of neurotransmitter
precursors (112 -115)
Whey Protein
Hydrolysate
Į-lactalbumin,
ȕ-Lactoglobulin,
Glycomacropeptide,
Lactoferrin
Antinociceptive
Immunomodulator
Antioxidant
Anti-inflammatory
Į-lactalbumin and ȕ-lactoglobulin reduce pain
through interactions with opioid receptors; other
peptides reduce the effects of inflammation on pain
(105-107, 109-111)
Metabromine
Caffeine,
Theobromine,
Procyanidins
Adenosine antagonist
Interacts with adenosine receptors localized on axon
terminals of excitatory neurons; disinhibits the
adenosine brake which promotes the inhibitory
effects of adenosine on neuronal activity (108-110)
NutritionalRequirementsinPainSyndromes
The nutritional requirements of most interest to patients with pain syndromes are the nutrients and dietary
factors which support the synthesis and activities of neurotransmitters involved in the transmission and
perception of nociceptive information (38, 110, 116-120). These include arginine, choline, GABA,
glutamine, histidine, 5-hydroxytryptophan, and serine which modulate nociceptor responsiveness to
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noxious stimuli. Theramine is formulated to ensure the availability of the neurotransmitters
acetylcholine, nitric oxide, glutamate, serotonin, D-serine, histamine that modulate pain by optimizing
nociceptive activity in the central and peripheral nervous systems using Targeted Cellular Technology to
control the timing of the release of these ingredients. Balance in production and release of
neurotransmitters is important to neurotransmission because it is the highly integrated functions of these
neurotransmitters and the complexity of the multiple feedback loops between them that determine the net
input received by the brain. These interactions explain why an imbalance in the intake of a nutrient or
dietary factor which supports the synthesis or activity of any one neurotransmitter can influence the
activities of the others, potentially inducing absolute and relative deficiencies (121-124).
The concept that nutrient requirements are modified by disease has been recognized for more than 30
years, and is supported by studies which have shown changes in plasma, urinary, and tissue levels of
nutrients with modified intakes of these nutrients that correspond to changes in physiological endpoints
reflective of specific pathologies (Table 4) (125). These requirements can be estimated by determining the
level of intake at which a physiological response is improved indicating that the balance between intake
and metabolic demand has been favorably modified. The nature of the pathological characteristics of a
disease will determine the relative amounts of nutrients needed to restore balance between intake and
demand (118 -120, 125-129). For example, improvement in perceived intensity of back pain following
consumption of supplemental amounts of 5-hydroxytryptophan, arginine, and glutamine from
Theramine suggests that additional allowances for tryptophan and the other amino acids are needed by
individuals with pain syndromes (Figure 9). (4, 124-129). The degree of coordination between the
activities of different neurotransmitters is an important consideration in assessing the amounts of dietary
precursor needed (110, 119, 130-134).
Diseases with pathologies that involve imbalances in neurotransmitters will increase the requirements for
certain amino acids and other dietary precursors to restore homeostasis (4, 120, 125 131). For most
amino acids and dietary precursors of neurotransmitters, neuronal uptake is a concentration-driven
process; therefore, intakes of precursors must be high enough to increase the extracellular to intracellular
ratio to a level that will drive a rapid rate of uptake (116, 120, 130, 131- 132, 135-136). The rate of
precursor uptake by target neurons is important to neurotransmitter synthesis because the enzymes
involved are found only in these neurons and thus the amount of substrate available is the limiting factor
in neurotransmitter production (120, 136). As blood levels of dietary precursors rise in response to
increased intakes, the concentration-dependent rate of precursor uptake by target neurons is increased,
making more substrate available for neurotransmitter production and subsequent release (132, 137-139).
Changes in intakes of dietary precursors of these neurotransmitters will therefore influence physiological
responses by affecting neurotransmitter availability (116, 121-122, 126, 128-129, 132, 135-142).
A large body of peer-reviewed published data supports the basis for increased requirements of choline
(120, 143-144), arginine (83, 86, 145-146, 148-149), tryptophan (117, 127, 150-151), glutamine (144,
149), serine (148, 152), and histidine (150, 153-154) in conditions which depend on neurotransmitter
balance. Patients with pain disorders show decreased blood levels of specific amino acids despite having a
sufficient intake of protein indicating that the needs for these amino acids are selectively increased in
these patients (117, 149, 155-159). This observation may be explained by the competitive demands for
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certain amino acids by different metabolic pathways which decreases the supply of neurotransmitters
available to function in the pain process (See Section on Metabolism in this monograph).
Certain physiologic and biochemical mechanisms must exist in order for nutrient consumption to affect
neurotransmitter synthesis (136). These conditions are listed below. The extent to which neurotransmitter
synthesis in any particular aminergic neuron is affected by changes in precursor availability will vary
directly with the firing frequency of the neuron. Consequently, precursor administration can produce
selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons
potentially capable of utilizing the precursor for the particular effect. It is also useful in predicting when
administering the precursor might be useful for amplifying a physiologic process, or for treating a
pathologic state.
Conditions that Support Effects of Dietary Precursors on
Neurotransmitter Synthesis
1.
Absence of significant feedback control of plasma precursor
levels
2.
Ability of plasma precursor levels to control influx into or
efflux from the central nervous system
3.
Presence of a low-affinity (unsaturated) transport system
mediating the flux of precursor between blood and brain
4.
Low-affinity kinetics of enzyme that initiates conversion of
precursor to neurotransmitter
5.
Lack of in vivo end-product enzyme inhibition by the
neurotransmitter
Syndromes associated with musculoskeletal pain have been the most extensively studied with regard to
identifying the increased needs for certain amino acids in moderation of pain. Patients with these
syndromes and other types of pain disorders exhibit reduced blood levels of tryptophan, arginine,
glutamate, histidine, and serine (117, 142, 154, 158). Measurements of total serum tryptophan (p = 0.002)
as well as 6 other amino acids including histidine (p = 0.001) and serine (p = 0.028) yielded significantly
lower values for patients with fibromyalgia (fibrositis syndrome) than for controls (117). Plasma histidine
and serine levels were also found to be significantly lower (p < 0.01) in another study of patients with this
condition (151). Fibromyalgia patients also had significantly lower plasma levels of total essential amino
acids compared with controls suggesting that a generalized defect in amino acid homeostasis may be
present among affected individuals (157).
The possibility that relative deficiencies in certain amino acid precursors are associated with pain
syndromes is also supported by clinical observations. In a study of patients with secondary fibromyalgia
syndrome, individual measures of pain intensity assessed by the tender point index (TPI), an examinationbased measure, co-varied with glutamine levels (158). Severe neurological symptoms attributable to
deficiencies in serine have also been reported underscoring the importance of this amino acid in brain
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tissue, particularly as a precursor of phospholipids and D-serine (152). Low blood levels of tryptophan
accompanied by altered tryptophan metabolism have been frequently reported in patients with pain
disorders and have also been associated with decreased brain serotonin concentration (127, 130, 137-138,
150, 155-156, 160-161, 163-165). These patients also commonly exhibit reduced blood levels of 5hydroxytryptophan, arginine, choline, GABA, histidine, and serine. Moreover, they respond to oral intake
of amino acids with favorable changes in physiologic endpoints and improvements in clinical symptoms
associated with pain, thus supporting the increased need for specific amino acids to normalize blood
levels in patients with pain disorders (3, 86, 119-120, 125, 137-138, 143, 149, 156-157, 159-161, 163165).
In conditions where tryptophan metabolism is altered, intake of 5-hydroxytryptophan, the metabolic
intermediate in the conversion pathway of tryptophan to serotonin, would be a more effective approach
for restoring balance in serotonin levels than administration of tryptophan (Figure 1) (See section on
Metabolism in this monograph). Therapeutic administration of 5-hydroxytryptophan has been shown to be
effective in treating a wide variety of conditions that involve serotoninergic activity including depression
and insomnia (6). Oral 5-hydroxytryptophan is well-absorbed with approximately 70% of the dose
measured in blood following intake. This molecule crosses the blood-brain barrier and effectively
increases central nervous system synthesis of serotonin. The appearance in cerebrospinal fluid of
increased amounts of 5-hydoxyindolacetic acid, the primary metabolite of the breakdown of serotonin,
following oral-administration of 5-hydroxytryptophan confirms that supplemental intake of this precursor
not only increases production of serotonin but that the neurotransmitter is released by serotoninergic
neurons (129, 137-138). By affecting the production and release of neurotransmitters, changes in intakes
of precursor nutrients can influence the physiological functions dependent on these neurotransmitters
(116, 120, 123, 126, 128-133, 135, 138, 143, 149, 152,166-169). Some dietary precursors such as arginine
which depend on membrane transporters for cellular uptake are not as affected by extracellular
concentrations as those dependent on a favorable concentration gradient, but instead depend on factors
that compete for binding sites on the transport proteins (126, 147, 169).
The primary determinant of plasma arginine levels and thus nitric oxide production is dietary arginine
because endogenous synthesis does not increase sufficiently to compensate for depletion, increased
turnover, increased requirement, or inadequate supply of the amino acid (148, 170-171). Arginine
requirements are therefore influenced by metabolic utilization and factors that affect rates of de novo
synthesis (30-31, 89, 147, 166). Utilization of arginine is increased by citrulline which upregulates iNOS
and eNOS activity and by glutamate which increases iNOS and nNOS activity in the brain and other
nervous system tissues (85). In a study of stable short-bowel patients, a decrease in plasma arginine levels
was observed after 5 days of consuming an arginine-free diet and was accompanied by a decrease in
levels of citrulline, indicating that synthesis of arginine from citrulline in the urea cycle had been
increased, but the rate was not sufficient to maintain plasma arginine levels when intake was inadequate
(147, 172). Thus an increase in the demand for arginine to support increased nitric oxide synthesis would
require an increase in arginine intake to satisfy the demand.
The arginine body pool is also influenced by intake of glutamine and glutamate which contribute to levels
of ornithine and citrulline, intermediates of the urea cycle which can be converted to arginine (Figure 3
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and Figure 4). Glutamine also plays a role in regulation of whole body arginine homeostasis through
inhibitory effects on arginine utilization that reduce nitric oxide synthesis (172). It also increases in
arginine utilization for synthesis of urea as the primary donor of amino groups to arginine. Despite being
the most abundant amino acid in the blood, glutamine levels are rapidly depleted by catabolic processes.
Plasma glutamine levels do not appear to be affected by the accelerated release of glutamine from skeletal
muscle during periods of increased demand which suggests that glutamine availability is reduced by
competition for tissue uptake and dietary intake becomes rate limiting for glutamine-dependent processes
(94, 173).
Although a clearly defined glutamine deficiency syndrome has not been described, endogenous
production is not sufficient to meet the increased and altered tissue demands imposed by trauma, sepsis,
infection, and inflammation (94). Since most naturally-occurring food proteins contain 4% to 8% of their
amino acid residues as glutamine, an average of less than 10 g of dietary glutamine is likely to be
consumed daily. Studies in stressed patients indicate that considerably larger amounts of glutamine (2040 g/day) may be necessary to maintain glutamine homeostasis (173). The need for glutamine is also
increased by a demand for glutathione to protect against the increased production of reactive oxygen
during inflammatory activities. As a precursor of glutathione, glutamine supports the activity of the
glutathione peroxidase antioxidant enzyme system (174-175). Supplemental glutamine is important for
maintenance of tissue glutathione levels that protects against cellular damage from oxidative stress (175).
Supplemental glutamine is also protective against damage due to oxidative stress by effects that inhibit
inflammation.
The need for supplemental histidine intake is also increased by inflammation to satisfy the increased
demand for histamine production. After 8 weeks of consuming a low histidine (10 mg/day), low nitrogen
(6.3 g/day) diet, a significant decrease in 24-hour urinary free histidine was observed in 7 healthy men
associated with a reduction in serum hemoglobin concentration indicating that the contribution of
hemoglobin to the histidine body pool is limited (167). Addition of histidine to the diet resulted in an
increase in serum hemoglobin concentration to baseline levels within 2 weeks associated with a
corresponding increase in urinary histidine.
Acetylcholine is produced in the terminal endings of cholinergic neurons and in regions of the brain
where choline acetyltransferase is concentrated (Figure 5). Under steady state conditions, the brain
enzyme is not completely saturated, thus the rate of acetylcholine production is driven by the availability
of choline and acetyl CoA (139, 176). Dietary choline is the primary contributor to plasma choline levels
accounting for a greater proportion of the plasma concentration than de novo synthesis (155, 161, 163,
168, 177-178). The rate of choline transport across the blood brain barrier is increased by an amount
proportional to the increase in serum concentration and is followed by an increase in the release of
acetylcholine from cholinergic neurons (139).
In the brain, choline is incorporated into the membrane phosphatidylcholine pool and released when the
demand for acetylcholine is increased; however, the appearance of choline in cerebrospinal fluid confirms
that there is a pool of free choline in the brain (179-180). In a normal physiological state, most of the
choline utilized for acetylcholine synthesis is obtained from hydrolysis of phosphatidylcholine (179,
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181-183). When demand for acetylcholine is increased over prolonged periods, dietary choline becomes
an increasingly more important source of precursor. If a supplemental source of choline is not provided to
meet these increased demands, loss of membrane phosphatidylcholine will eventually compromise cell
membrane function and trigger apoptosis (178-179, 182-187).
The importance of dietary precursor intake to plasma levels and thus availability of precursor for
neurotransmitter synthesis was demonstrated by a study showing an increase in serum choline
concentration following treatment with choline chloride. Other studies have confirmed that exogenous
choline can be utilized by central cholinergic neurons as a precursor for acetylcholine synthesis (180). An
increase in plasma choline promotes the expression of high affinity choline transporters on cholinergic
neurons which regulate the synaptic availability of choline and facilitate the release of acetylcholine from
these neurons (155, 178-179). Synaptic acetylcholine levels are regulated by a negative feedback
mechanism in which accumulation of the neurotransmitter inhibits transporter activity on cholinergic
neurons to prevent further uptake of choline. Anticholinergic drugs such as chlorpromazine, atropine, and
cholinesterase inhibitors decrease acetylcholine release by inhibition of these transporters (183, 188-189).
Although serum choline levels are decreased by a choline-free diet, brain choline levels remain relatively
stable indicating that the brain is given metabolic priority at the expense of other tissues when the amount
of free choline available is limited (180). Brain phosphatidylcholine levels decrease in parallel with the
decrease in serum choline which further suggests that brain choline concentration is maintained within
narrow limits at the expense of larger tissue pools of phosphatidylcholine and other phospholipid
precursors (serine and ethanolamine) (168, 177, 179, 182). Data from an experimental study in rats
showed that brain choline concentration increased within 5 hours following oral administration of choline
chloride (180). The consumption of a choline-free diet for 7 days lowered serum choline and brain
phosphatidylcholine concentration suggesting that choline kinase, the controlling enzyme in phospholipid
synthesis, is unsaturated with substrate in vivo and thus may serve as a modulator of the response of brain
choline concentrations to alterations in the supply of circulating choline.
Clinical evidence of a human choline deficiency was first reported in adults receiving total parenteral
nutrition (TPN) (190-191). These patients exhibited hepatic morphologic and aminotransferase
abnormalities which were reversed by choline-supplemented TPN. The effects of inadequate choline
intakes on physiological endpoints are rapidly observed. Low blood levels of choline indicate that the
requirements for the dietary precursors are not being met at current levels of intake (116, 139, 177, 179).
Clinical signs of deficiency were documented in men with otherwise normal nutritional status after
consuming a choline-deficient diet for a period of < 3 weeks (192). Changes in blood and urine markers
of organ dysfunction (muscle and liver enzymes) were also been reported in these men. Decreases in
plasma levels of choline and phosphatidylcholine accompanied by elevated alanine aminotransferase, a
biochemical marker of liver damage, and elevated creatine kinase, a biological marker of muscle damage,
have also been observed with a dietary choline deficiency (185, 192 -196). Serum choline levels are more
responsive to increased choline intake than to a choline deficiency with increases of as much as 52%
observed with choline supplementation compared with decreases of 20% with a choline-deficient diet
(126, 179).
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Specific neurotransmitter deficiency syndromes related to inadequate intakes of amino acid precursors
have been identified for GABA and serotonin. A syndrome characterized by a basic depressive state,
sleep disorders, nuchal headache, and other clinical symptoms was attributed to a GABA deficiency based
on the observation of a rapid reversal of these symptoms following administration of an enzyme inhibitor
of GABA catabolism (197). Several findings also raise the possibility that inadequate intakes of
tryptophan may be related to a brain serotonin deficiency in patients with fibromyalgia/fibrositis. An
inverse relationship between blood tryptophan concentration and severity of musculoskeletal pain which
was accompanied by significantly lower levels of serum tryptophan (p = 0.002) has been reported in
patients with these conditions compared with healthy adults suggesting that a functional deficiency of
serotonin may be involved in the pathology of fibromyalgia-related pain (150-151).
A possible link between inadequate intake of tryptophan and a deficiency of serotonin is also supported
by evidence of altered tryptophan metabolism associated with low blood tryptophan levels (170). A trend
towards lower levels of plasma tryptophan was associated with a significantly lower tryptophan
membrane transport ratio (p<0.01) in patients with primary fibromyalgia/fibrositis compared with
controls indicating that insufficient amounts of tryptophan were reaching target tissues when plasma
levels were below normal (151). A specific neuroendocrine response (i.e., prolactin release with
tryptophan infusion) suggestive of postsynaptic serotonin receptor supersensitivity was associated with a
15 to 20% reduction in fasting total plasma tryptophan levels in 22 healthy subjects consuming a
tryptophan-restricted diet (198).
A summary of the scientific support for the increased requirements of specific amino acids for patients
with pain disorders is found in Table 4.
Table 4.
Observations Supporting Increased Nutrient Needs in Pain Disorders
Clinical Observations and Associated
Biochemical Findings
Nutrient
Blood/Tissue/Urinary Levels
Glutamine/Glutamate
Low blood levels
Increased pain intensity in patients with secondary
fibromyalgia; low tissue glutathione levels; GABA
deficiency characterized by a basic depressive state,
sleep disorders, nuchal headache; loss of synaptic
inhibition; seizures
Tryptophan
Low blood and brain levels
Low membrane transport ratio; postsynaptic serotonin
receptor supersensitivity; inverse relationship with
severity of musculoskeletal pain; depression,
behavioral changes, fibromyalgia/fibrositis syndrome;
increased serotonin metabolites in cerebrospinal fluid
following supplementation; serotonin deficiency
Arginine
Low plasma levels
Low serum levels of arginine metabolites (e.g.,
ornithine, citrulline); decreased rate of nitric oxide
synthesis; increase in plasma arginine and nitrates, and
exhaled nitric oxide with supplementation
Histidine
Low 24-hour urine levels
Decreased serum hemoglobin (source of histidine);
fibromyalgia/fibrositis syndrome
Low blood levels
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Clinical Observations and Associated
Biochemical Findings
Nutrient
Blood/Tissue/Urinary Levels
Serine
Low blood levels
Loss of sensitivity to both natural and synthetic
inhibitors of pain
Choline
Low plasma levels
Decreased activity of NMDA receptors; diminished
responses to GABA and serotonin; decreased
parasympathetic autonomic nervous system activity;
increased creatine phosphokinase and alanine
transaminase; myocyte and lymphocyte apoptosis
ClinicalValidationofTheramine The relationship between intakes of dietary precursors and production of the corresponding
neurotransmitters has been validated by observations of improvements in neurotransmitter-mediated
clinical outcomes with supplemental intakes of these dietary factors (38, 119, 126-128, 133, 137-139,
143, 155, 198-204). A change in the levels of a neurotransmitter in the blood and/or its metabolites in
cerebrospinal fluid following ingestion of a dietary precursor from a medical food reflect the uptake and
utilization of the nutrient or dietary factor for synthesis of the neurotransmitter by target cells, thus
demonstrating the biological availability of dietary precursors and the clinical utility of the medical food
as a source of these precursors (118 -122, 125, 132-134, 137-138, 143-144, 149, 155-156, 160-163, 165,
177-178, 180, 182, 184-187, 203-210).
The clinical benefits which may be obtained from medical foods can be validated by the observed
changes in biological, physiological, and clinical endpoints following ingestion by individuals with
specific conditions. If an individual with a chronic pain disorder ingesting a medical food containing 5hydroxytryptophan shows an increase in serum levels of the molecule following ingestion (biological
availability) which is associated with increased concentrations of serotonin metabolites in cerebrospinal
fluid (physiological response) and an improvement in pain measurement (clinical response), the clinical
benefit of this medical food as a source of precursors for serotonin production has been validated.
Theramine has been formulated with specific ratios of arginine, choline, GABA, glutamine, histidine,
5-hydroxytryptophan, and serine using Targeted Cellular Technology to control the timing of the release
of each ingredient. If sufficient amounts of these nutrients are not available, or their availability is not
well-synchronized with demand, imbalances in neurotransmitter activity contributing to acute and chronic
pain disorders may result (21-24).
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Theramine® Product Information
BiologicalAvailability
The biological availability of 5-hydroxytryptophan and L-arginine which are provided in Theramine
has been demonstrated by changes in blood levels of the respective neurotransmitters observed following
ingestion of these supplemental amino acids. Within 60 minutes after administration of 2000 mg of
5-hydroxytryptophan, blood serotonin levels increased by more than 3-fold, confirming that
5-hydroxytryptophan is well-utilized by target tissues as a precursor of serotonin (Figure 9).
Figure 9. Effect of 5-Hydroxytryptophan Supplementation on Blood Serotonin Levels
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The biological availability of supplemental arginine has also been demonstrated by assessment of the
appearance of nitric oxide in expired air following ingestion of a 15 mg dose. Within 15 minutes of
administration, nitric oxide concentration in expired air increased 50% from baseline levels (Figure 10).
This finding confirms that supplemental arginine is utilized as a precursor in the synthesis of nitric oxide.
Figure 10. Effect of Supplemental Arginine on % Change in Nitric Oxide
Concentration in Expired Air
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Theramine® Product Information
ClinicalResponse
Theramine has been clinically tested in crossover studies of patients with fibromyalgia, trigeminal
neuralgia, back pain, headache, osteoarthritis, tendonitis, and post herpetic neuropathic pain. Physiologic
and symptomatic pain was assessed in a controlled crossover study of 14 patients using visual analogue
scales and Likert numeric scales as outcome measures. After 3 days of treatment with Theramine,
patients reported a statistically significantly reduction in symptoms of back pain compared with the period
prior to treatment (p<0.01) (Figure 11). Based on the results assessed by the Likert scale, symptoms were
reduced by more than half in these patients after treatment with Theramine.
Figure 11. Effects of Theramine Administration on Back Pain
SelectedReferences
1.
Borgonio A, Witte K, Stahrenberg R, Lemmer B. Influence of circadian time, ageing, and hypertension on
the urinary excretion of nitric oxide metabolites in rats. Mech Ageing Dev 1999;111:23-37.
2.
Tangphao O, Chalon S, Coulston AM et al. L-arginine and nitric oxide-related compounds in plasma:
comparison of normal and arginine-free diets in a 24-h crossover study. Vasc Med 1999;4:27-32.
3.
Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001;63:637-672.
4.
Brown DW. Abnormal fluctuations of acetylcholine and serotonin. Med Hypotheses 1993;40:309-310.
5.
Wolosker H, Dumin E, Balan L, Foltyn VN. D-amino acids in the brain: D-serine in neurotransmission
and neurodegeneration. FEBS J 2008;275:3514-3526.
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