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Theramine®
Clinical Efficacy and Safety Information
Positioning Improved Pain Management
Nociceptive
• Involves the stimulation of nerves that sense
impending or actual tissue injury resulting
from trauma or disease.
• Tends to be localized and constant with a
throbbing or aching quality.
• Responds well to conventional analgesics.
• Examples include occupational trauma such as
los back pain, repetitive use injury, and
osteoarthritis.
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medical
foods2009;
Derived from Clark ME, Scholten JD, Walker RL, et al. Assessment and treatment of pain associated with combat-related
polytrauma.
Pain Med.
10:456-469; Sen D, Christie D. Chronic idiopathic pain syndromes. Best Pract Res Clin Rheumatol. 2006; 20:369-386
Neuropathic
• Arises from an injury to the peripheral or
central nervous system that damages normal
pain signaling pathways.
• Typically has a burning, tingling, electric, or
shooting quality.
• Often responds better to nonconventional
analgesics such as antidepressants and
anticonvulsants.
Better health through
medical
foods2009;
Derived from Clark ME, Scholten JD, Walker RL, et al. Assessment and treatment of pain associated with combat-related
polytrauma.
Pain Med.
10:456-469; Sen D, Christie D. Chronic idiopathic pain syndromes. Best Pract Res Clin Rheumatol. 2006; 20:369-386
Mixed
• Complex mixture of nociceptive and
neuropathic pain.
• Generally require multimodal therapy.
• Examples include stump pain at the site of
amputation, crush or burn injuries that
damage tissue and/or peripheral nerves, and
compartment syndrome.
Derived from Clark ME, Scholten JD, Walker RL, et al. Assessment and treatment of pain associated with combat-related
polytrauma. Pain Med. 2009; 10:456-469; Sen D, Christie D. Chronic idiopathic pain syndromes. Best Pract Res Clin
Rheumatol. 2006; 20:369-386
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Idiopathic
• Pain with no identifiable origin or that appears to
be excessive for its underlying pathology.
• Can be localized, regional, or diffuse.
• Can be triggered by tissue injury, trauma, and
psychological distress.
• Generally requires individualized multidisciplinary
care and rehabilitation.
• Examples include post-traumatic dystrophy, posttraumatic osteoporosis, complex regional pain
syndrome, and fibromyalgia.
Derived from Clark ME, Scholten JD, Walker RL, et al. Assessment and treatment of pain associated with combat-related polytrauma.
Pain Med. 2009; 10:456-469; Sen D, Christie D. Chronic idiopathic pain syndromes. Best Pract Res Clin Rheumatol. 2006; 20:369-386
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Nutrient Requirements of Pain
The neurotransmitter precursors involved in the
transmission and perception of nociceptive (pain)
are:
• Arginine
• Choline
• GABA
6
• Glutamine
• Histidine
• 5-hydroxytryptophan
• Serine
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Amino Acid Deficiencies and Chronic Pain
Change in Blood Concentration of Amino Acids
35
2010 Theramine and Ibuprofen Double Blind Clinical Trial for the treatment of chronic low back pain
30
n= 122
25
DAY 1
20
DAY 28
15
NORMAL
10
5
0
Arginine
Serine
Histadine
Histidine
Tryptophan
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 patients3
3. Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Wall K. Serum amino acids in fibrositis/fibromyalgia syndrome. J Rheumatol Suppl
1989;19:158-163
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Theramine®
Indication: for the dietary management of pain
syndromes and inflammatory conditions that
include:
• Chronic Pain
• Fibromyalgia
• Neuropathic Pain
• Inflammatory Pain
8
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Why is Theramine a Good Choice?
• No Adverse Side Effects
- No reported GI Bleeds
- No reported adverse CV effects
• Effective
- Reduces Chronic Back Pain*
- Reduces inflammation*
*Theamine/naproxen trial 2009, American Journal of Therapeutics;
Theramine ibuprofen trial 2010, Unpublished.
9
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Clinical Applications of Theramine
• Replace or Augment NSAID Therapies
- Some Patients
cannot take NSAIDs ( High BP, Over 65, CVD,
Taking Aspirin) CONTRAINDICATED
- Patients taking Theramine can take a very low dose NSAID
without loss of efficacy
• Replace or Reduce Narcotic Pain Meds
- Pair Theramine and low dose opiates to avoid attenuation
- Gradually replace opiates with Theramine to avoid addiction
10
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Theramine® - Advantages
• Effective as a stand alone medication
• Effective as an adjunct therapy
• Safe for long term use
• Potentially titrate dose of opioids and NSAIDs to
zero
• Works on ascending and descending pathways
and inflammatory processes associated with pain
11
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Theramine® Data
• 63,000,000 individual doses administered since
2003
• No reported GI bleeds
• No reported adverse cardiac events
• No reported kidney or liver abnormalities
• No reports of addiction
12
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2009 Double Blind Clinical Trial
Theramine and Naproxen (Theraproxen™)
•
•
•
•
•
•
•
•
•
•
13
127 patients
12 national sites
Established chronic back pain
VAS Scales
Likert Scales
Roland-Morris disability questionnaire
Oswestry back pain index
Inflammatory markers- hsCRP
Theramine – Two (2) capsules twice daily
Naproxen – One (1) 250mg tablet once daily
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Study Design
Inclusion Criteria:
• Back pain lasting greater than six weeks. Pain must
be present on at least 5 out of 7 days during each of
the two weeks prior to screening visit
• Analgesic medication used to treat pain at least 4 out
of last 7 days and at least 10 days in the last month
14
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Theraproxen™ Double Blind Trial – Roland Morris
The % Change in the Roland Morris index at Day 28
0.00
-10.00
-20.00
-11.88
-30.00
P<0.01
n=127
% Change
-40.00
-50.00
-60.00
-70.00
-80.00
-76.47
-90.00
-87.96
-100.00
Naproxen
15
theramine
theramine/naproxen
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Theraproxen™ Double Blind Trial – Walking on Flat Surface
Sequential Changes in Back Pain Walking on Flat Surface
5
4.5
n= 127
p<0.01
4
Likert Scale Units
3.5
3
2.5
2
1.5
1
0.5
0
Baseline
Naproxen
16
Day 7
theramine
Day 14
Day 28
theramine/naproxen
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Theraproxen™ Double Blind Trial – Oswestry Index
Percent Reduction of Oswestry Index at 28 Days
0.00
-10.00
Percent reduction (%)
-20.00
-30.00
-22.70
-40.00
n=127
p<0.01
-50.00
-60.00
-62.59
-70.00
-80.00
-90.00
-88.20
-100.00
Naproxen
17
Theramine
Naproxen/Theramine
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Theraproxen™ Double Blind Trial – Roland Morris
Effect of Theramine and Naproxen on Chronic Back Pain
14
Roland Morris Index
12
p<0.0001
n=127
10
before
8
after
6
4
2
0
naproxen
18
theramine
both
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Theraproxen™ Double Blind Trial – hsC-Reactive Protein
Change in hsCRP from Baseline at 28 Days
80
67.86
60
40
P<0.01
n=127
20
0
-20
-40
-33.33
-60
-64.79
-80
Naproxen
19
theramine
theramine/naproxen
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2010 Double Blind Clinical Trial
Theramine and Ibuprofen (Theraprofen™)
•
•
•
•
•
•
•
•
•
•
•
20
122 patients
12 national sites
Established chronic back pain
VAS Scales
Likert Scales
Roland-Morris disability questionnaire
Oswestry Back pain index
Inflammatory markers (hsC-Reactive Protein & Interleukins)
Amino Acid Turnover rates
Theramine – Two (2) capsules twice daily
Ibuprofen – One (1) 400mg tablet once daily
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Theraprofen™ Double Blind Trial– Oswestry Index
Oswestry Disability Index % Reduction
0
-10
-4.52
-20
p<0.01
-30
-40
-41.91
-50
-60
-62.15
-70
Ibuprofen n = 43
21
Theramine n = 41
Combination n = 38
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Theraprofen™ Double Blind Trial – Roland Morris Index
Roland-Morris Index % Change
10
0.73
0
-10
p<0.01
-20
-30
-40
-50
-50.3
-60
-63.1
-70
Ibuprofen n = 43
22
Theramine n = 41
Combination n = 38
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Theraprofen™ Double Blind Clinical Trial– hsCRP
hsC-Reactive Protein Change after 28 Days
80
60
60.1
40
p<0.01
20
0
-20
-40
-35.99
-47.05
-60
Ibuprofen n = 43
23
Theramine n = 41
Combination n = 38
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Theraprofen™ Double Blind Clinical Trial– IL-6
Interleukin- 6 Change after 28 Days
20
12.65
10
0
-10
-20
-23.55
-30
-40
-43.1
-50
Ibuprofen n = 43
24
Theramine n = 41
Combination n = 38
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Theramine® - Formulation
Proprietary Formulation of GRAS Ingredients in Specific Proportions
•
•
•
•
•
•
•
•
•
•
•
25
GABA
Choline Bitartrate
Whey Protein Hydrolysate (Milk Sourced Isolate)
L-Arginine
L-Histidine
L-Glutamine
Theobromine
Griffonia Seed Extract
Grape Seed Extract
L-Serine
Cinnamon Bark
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Mechanism of Action
The pharmacodynamic properties of Theramine are directly
related to the effects of the concentration of neurotransmitter
precursors on neurotransmitter activity which are responsible for
the induction, amplification, and mitigation of pain.
Amino Acid
Neurotransmitter
Functional Activity
Choline
Acetylcholine
Autonomic Regulation, NMDA Inhibition
L-Histidine
Histamine
Increases Glucorcorticoid Production
5-OHtryptophan
Serotonin
Decreases pain signals, NMDA inhibition
Serine
D-Serine
Sensitizes opioid receptors
Arginine
Nitric Oxide
Inhibits pain at low doses, GI protective
26
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Targeted Cellular Technology™
1. Neurotransmitter Precursor (Amino Acids)
2. Uptake Stimulator
3. Neuron Activator
4. Adenosine Brake Inhibitor
5. Attenuation Inhibitor
T
C
T
27
Uptake Stimulator
Cinnamon/Whey Protein Isolate
Neuron Activator
Glutamine Glutamate
Adenosine Brake Releaser
Theobromine
Attenuation Inhibitor
Grape Seed Extract
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Benefits of Targeted Cellular Technology™
• Promotes production of neurotransmitters from
precursors
• Precursors in milligram quantities not gram quantities
• Reduced Attenuation
• Potentially improve drug efficacy without elevating
drug dose
• Milligram quantities of amino acids are effective
28
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Free Amino Acid Absorption
• Absorbed in the intestines by specific transport molecules
• Released into the blood stream
• Distributed to tissues based on need
• Not destroyed or denatured by the stomach
• The liver deaminates unused amino acids
29
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Mechanism of GI Protection
Serotonin (5-HT)
• Indolamine with aggregating properties
• Considered a weak platelet agonist
• Can enhance the aggregating response of platelets to other
agonists, such as ADP.
Nitric Oxide
• Gastric Protection- potent inhibitor of leukocyte adherence to
vascular endothelium
• Mediates components of mucosal defense - Stimulates mucous
secretion in the gut, promotes healing and mucosal blood flow
• Performs many of the same GI protective functions as
prostaglandins
30
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Primary Chemicals Involved in Pain
• Adenosine
• Acetylcholine
• Glutamine/Glutamate
• GABA
• Histamine
31
• D-Serine
• NMDA receptors
• Serotonin
• Substance P
• Nitric Oxide
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NMDA Receptor
NMDA Receptors: N-methyl-D-aspartate
• Concentrated in the dorsal horn of the spine
• Responsible for potentiating nociception
• Activated by coagonist, Glutamate
• Facilitates and sustains pain signals
• Triggers release of Substance P
• Increase hyperalgesia
• Stimulates release of nitric oxide and prostaglandins in dorsal horn
32
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Substance P
Substance P: Sensory Neuropeptide
• Functions as a sensory afferent neurotransmitter
• Released from central terminals of spinal nociceptors
• Released in response to changes of NMDA electrical charge
• Mediates transmissions for longer periods than most
neurotransmitters
• Promotes vasodilation and swelling
• Stimulates release of histamine from mast cells
33
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Adenosine Brake Inhibition
Adenosine: Inhibitory Neurotransmitter
• Rapidly elevated in response to cellular damage (e.g. in
inflammatory or ischemic tissue).
• Cytoprotective, preventing tissue damage
• Inhibits neuronal firing
Theobromine: Uptake Stimulator
• Xanthine
• Inhibits function of Adenosine
• Promotes prolonged firing of neurons
• Enhance effects of amino acid precursors
34
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L-Glutamine, Glutamate, Glutathione
Glutamine: Amino Acid
• Promotes Production of Glutamate and Glutathione
• Facilitates uptake
Glutathione: Antioxidant, Immunomodulator
• Prevents
tissue oxidative damage due to inflammation
Glutamate: Excitatory Neurotransmitter
• Promotes Production of GABA
• NMDA co-agonist
• Modulates intensity of nociceptor response
• Deficiency contributes to prolonged pain states
• Pronociceptive activity
• Opposes effects of Acetylcholine
35
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Choline  Acetylcholine
Choline: Amino Acid
• Promotes production of Acetylcholine
• Prolonged deficiency triggers apoptosis
Acetylcholine: Inhibitory and Excitatory Neurotransmitter
• Stimulates synthesis and release of nitric oxide and serotonin
• Inhibits activity of receptors on peripheral afferent nerve terminals
• Inhibits dorsal horn neurons
• Decreases neuronal sensitivity and firing
• Inhibits NMDA receptor activity
• Inhibits production of Substance P
• Suppresses production of pro-inflammatory cytokines
• Stimulates parasympathetic response to suppress proinflammatory
response
36
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5-OH-Tryptophan  Serotonin
5-OH-Tryptophan: Essential Amino Acid
• Promotes production of Serotonin,
NAD+, and NADP
Serotonin: Excitatory/Inhibitory Neurotransmitter
• Decreases pain signals in the spinal cord and brain
• Inhibits NMDA receptor activity
• Inhibits the release of Substance P
• Acts synergistically with GABA and Acetylcholine
• Stimulates release of histamine from mast cells
• Aids in platelet aggregation in the gut
37
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GABA and D-Serine
GABA: Inhibitory Neurotransmitter
• Dampens pain signals in spinal cord and brain
• Inhibits NMDA receptor activity
• Inhibits release of Substance P and glutamate from dorsal horn
neurons
• Antinociceptive
D-Serine: Antinociceptive Neurotransmitter
• Regulates NMDA receptor activity in the brain
• Sensitizes opioid receptor systems to opioids and other analgesics
• Inhibit intracellular signaling
38
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Arginine Nitric Oxide
Arginine: Amino Acid
• Synthesized from glutamine and glutamate as well as
external sources
• Promotes synthesis of Nitric Oxide
Nitric Oxide: Inhibitory/Excitatory Neurotransmitter
• Antinociceptive, neuroprotective and anti-inflammatory
• Inhibits transmission of afferent pain signals in the spinal cord
• Activates natural opioids
• Protects mucosal lining of the gut
39
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Histamine and Receptors
Histamine: Excitatory Neurotransmitter
• Antinociceptive/ Pronociceptive and anti-inflammatory
• Synergistic with Nitric Oxide
• Stimulates production of glucocorticoids
• Inhibits NMDA receptor activity
H1 Receptor: Enhances nociception
H2 Receptor: Mediates antinociception and analgesia
H3 Receptor: Controls neurogenic inflammation
40
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