Presentation on "Curcumin on chronic pain" at the 8° international SIMPAR Congress held in Rome last April 7th to 9th.

1. SIMPAR (Study In Multidisciplinary PAin Research)

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Curcumin in chronic pain
Summary:
1. Chronic pain and inflammation
2. Curcumin from Turmeric
3. Active principles of turmeric
4. Curcumin and chronic pain
5. Mechanism of action (antinflammatory)
6. Mechanism of action (anti oxidant)
7. Epigenetic activity of curcumin
8. Absortion of curcumine
9. Curcumin and liver
10. Bio-avaliability and solutions
11. Curcumin tolerability
12. Take home messages

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Chronic and degenerative illness

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Chronic and degenerative illness
express high grade of inflammation
Cardiovascular diseases
INFLAMMATION
Cancer
Auto-immune
diseases
Neuro degenerative
diseases
Type II diabetes
High grade or Low grade

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Symptoms of Inflammation

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Acute pathological pain:
• Sharp, fast, pricking
• Occurs very rapidly
• Carried by large diameter myelinated Aδ fibers
• Usually alleviated with the help of professional
Chronic pathological pain:
• Burning, aching
• Gradually increases
• Carried by small diameter non-myelinated ‘C’ fibers
• Persistent pain that lasts many months to years
• Little apparent cause & not self limiting
• Pain often increases over time & is aggravated by many
factors

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Drugs used for pain management

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Most sold SOP and OTC in Italy 2011

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 Precautions in patients >70 years
 GI side effects
 Risks of gastic ulcers
 Attention in patients treated with
anti-coagulatns
 Risk of kidney impairment
Side effects and risks of NSAID’s
“Gli utilizzatori di FANS hanno
ulcere sintomatiche complicate 3-4
volte più frequentemente rispetto
ai non utilizzatori” 2
“Disturbi gastrici e intestinali
compaiono nel 10 - 30%
degli utilizzatori di FANS” 1
1-2Nederlandse Huisartsen Genootschap – pijnbestrijding: farmacotherapeutische richtlijn
3Cannon 2006, Chan 2006, Helin-Salmivaara 2006, Kearney 2006, McGettigan 2006

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 Curcuma longa
 Boswellia serrata
• Omega 3 (EPA and DHA)
 Zingiber officinale
Natural substances with anti-inflammatory activity

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• Rhizomatous, herbaceous,
perennial, plant
• Family Zingiberaceae
• Lives well with mild temperatures
(20°-30° C. and high rains
• Reach 1 m in hight
• Nice hermafrodite flowers in 20cm
inflorescence (August)
• Active sustances are concentrated
in rhizomes
Turmeric, the plant (Curcuma longa)

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Curcumin: THE active principle of turmeric
(1,7-bis (4-hydroxy-3-méthoxy-phényl) hepta-1,6-diène-3,5-dione)
Turmeric powder
contains 3-7% of Curcuminoids
essential oils and fibers

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8.770 studies shows pleiotroitropic effects
of curcumin (Pubmed)

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Inflammatory targets modulated by curcumin

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23
24
25
26
27
28
29
0
5
10
15
20
0
5
10
15
20
“Randomized, single blind study on efficacy and tolerability of
curcumin in patients with reumatoid poliarthritis “
Chandran et al. A Randomized, Pilot Study to Assess the Efficacy and Safety of Curcumin in Patients with Active Rheumatoid Arthritis. Phytother. Res. 2012;26:1719–
1725.
° n = 45 : curcumin n =15 ; diclofenac n = 15 ; curcumin and diclofenac n = 15
° 8 weeks , 1000 mg curcumin (BCM-95) e 100 mg diclofenac
Curcumin vs. NSAID’ (diclofenac )
Tassodisedimentazioneeritrocitaria(ESR)
- 11% - 8%
Significative reduction of
Disease Activity Score (DAS)
Significative reduction of
Joints pain
- 83%
- 69%
- 97% - 89%
Significative reduction of
Joints swelling
%Incidenza
%Incidenza
Curcumin
extract Diclofenac
1000 mg 100 mg
p < 0.05 p < 0.05 p < 0.05
Curcumin
extract Diclofenac
1000 mg 100 mg
Curcumin
extract Diclofenac
1000 mg 100 mg

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280
290
300
310
320
330
340
350
360
Ibuprofen Curcumina
° n = 367 : curcumin extract n = 182 ; ibuprofen n = 185
° After 4 weeks 1500 mg curcumin (2 capsuls 3x/die) e 1200 mg
ibuprofen (2 capsuls 3x/die).
° Simple turmeric extract
Mobility
Distance covered in 6 minutes
(Time 0 and after 4 weeks)
p = 0,010
Meterswalkedin6minutes
Chronic Pain
(Time 0 and after 4
weeks)
0
1
2
3
4
5
6
Ibuprofen Curcumina
p = 0,018
%Incidence
1200 mg 1500 mg 1200 mg 1500 mg
)
- 41%
+ 14% + 11%
Curcumin vs. NSAID’ (ibuprofen)
“Efficacy and safety of curcumin vs. Ibuprofen in patients
with knee arthrosis : a multicentric study“
Kuptniratsaikul V et al. Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee
osteoarthritis: a multicenter study. Clin Interv Aging. 2014 Mar 20;9:451-8.
- 39%

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Combination of Curcumin an ginger is effective as well as NSAID’S (indometacine)
Objective: measure effective of a blend of curcumin and ginger on pain
in patients with rheumatoid arthritis
3 groups NSAID’S (Indometacine) vs. 200 mg (CG) vs. 400 mg (CG)
Results:
Arthritic score
14d
Arthritic score
28d
Nsaid’s
(Indometacine)
 39.6%  50%
200 mg  41.7% 58.3%
400 mg  52.1%  78.6%
0
4
8
12
16
7 giorni 14 giorni 28 giorni
Controllo (dopo trattamento) Indometacina
200 mg curcumina +zenzero 400 mg curcumina+zenzero
- 78,6%- 52%Arthriticscore

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° n = 15 : curcumin 400 mg nimesulide 100mg achetominophen 1g
Cicle with 3 subtances with a wash out of 48 hour
Curcumin vs. Nimesulide and Acetoaminophene in acute pain
Comparative evaluation of the pain-relieving properties of
a lecithinized formulation of curcumin (Meriva®),
nimesulide, and acetaminophen
Di Pierro F1, Rapacioli G, Di Maio EA, Appendino G, Franceschi F, Togni S

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Curcumin studies in neuropatic pain in animal model
Zhao X, Xu Y, Zhao Q, Chen CR, Liu AM, et al. (2012)
Curcumin exerts antinociceptive effects in a mouse model of
neuropathic pain: descending monoamine system and opioid receptors
are differentially involved. Neuropharmacology 62: 843–854. 14.
Ji FT, Liang JJ, Liu L, Cao MH, Li F (2013)
Curcumin exerts antinociceptive effects by inhibiting the activation of
astrocytes in spinal dorsal horn and the intracellular extracellular signal-
regulated kinase signaling pathway in rat model of chronic constriction
injury.
Chin Med J (Engl) 126: 1125–1131

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Curcumin in cancer patients
Objective: Efficacy of curcumin in cancer patient ongoing chemio or radiotherapy
measured with Karnofsky Scale as developed by Karnofsky, Abelmann, Craver, and
Burchenal - 60 days with curcumin or placebo
Results:
Curcumin 100 mg
A Controlled Study of a Lecithinized
Delivery System of Curcumin to
alleviate the Adverse Effects of
Cancer Treatment

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23. Pubmed 18/11/2015
2367 publications
Curcumin anti-oxidant power is 10 time higher than Vit. E
- Direct activity on ROS
- Induction of NRF2
- Induce mitocondrial biogenesis
Curcumin is a powerful anti-oxidant

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Inflammatory targets modulated by curcumin

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Inflammatory targets modulated by curcumin

27. Epigenetic activity of Curcumin

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Epigenetic activity of curcumin
Molecular targets Activity Epigenetic and
anti-cancer
activity under
evaluation
DNA methylation,
HAT activities
Histone acetylation
(Acetil transferase/histone
deacetilase
HDAC isoenzymes (HDAC 1,3,4,5,8)
miRNA’s
miRNA’s target genes
Decrease
Decrease
Rebalance
Reduce
expression
Modulation
Regulation
Anti-oxidant,
anti-angiogenic,
antiproliferative
pro-apoptotic

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Bioavailability of Curcumin is very poor
Poor absorption
Max conc. 180 minutes
Liver cleverage Cit. P450

30. Curcuma polvere
Curcumina principio attivo (1)
Fitosoma (1)
Oli (1)
Ciclodestrina(1)
Forma micellare o Solubilizzata (2)
X 9,5 – 51,1
X 57,7
X 335
X 1350
X 7,3
Source:
• (1) Jäger et al, Nutrition Journal 2014, 13:11, comparative absorption of curcumin formulations.
• (2) Schiborr et al, Mol. Nutr. Food Res. 2014, 58, 516-527.
X 1
Biodisponibilità vs. Curcuma
Bioavailability of IMPROVED Curcumins

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• Curcuma longa is GRASS in the USA
Turmeric tolerability
• Curcumin is not carcinogenic
• No concerns of genotoxicity.
• ADI* of 3 mg/kg bw/day based on the NOAEL of 250-320
mg/kg bw/day
• Intake of curcumin from the normal diet amounts to less than
7% of the ADI of 3 mg/kg bw/day
• Possible weak interference with anti-coagulant that normally
do not require dosage adjustments.
*ADI = Accettable daily Intake

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Synergistic activity with:
• Nsaid’s
• Steroids
• Omega 3
• Boswellia
Inflammation
anc chronic pain
• Omega3
• Vit. B complex
• Ginko biloba
• Anti-oxidants
Peripheral
Neuropatic pain and
neurodegeneration
• Glutammine
• Probiotics
• Prebiotics
• Anti-oxidants
Gastrointestinal
health
• Glucosammine
• Chondroitine
• MSM
• Boswellia
Joints Health

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Ongoing
clinical
trials
with
curcumin

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D.A.I. Medicina Interna, Medicina Specialistica
U.O. Medicina Interna Universitaria “Cesare Frugoni”
Centro di Assistenza e Ricerca Sovraziendale per le Malattie Rare
Università Degli Studi “ALDO MORO” di Bari
Direttore: Prof. Carlo Sabbà
REGIONE PUGLIA
AZIENDA OSPEDALIERA
OSPEDALE POLICLINICO CONSORZIALE
Piazza Giulio Cesare, 11 – 70124 BARI
Testing 3 “levels” of curcumin activity
ANALYSYS OF GENIC EXPRESSION OF MONONUCLEATE BLOOD CELLS OF PATIENTS
WITH METABOLIC SYNDROME AND OSTEOARTHROSIS: POTENZIAL APPLICATIONS IN
DIAGNOSIS, MONITORING AND TREATMENT AFTER 3 MONTHS OF
SUPPLEMENTATION WITH CURCUDYN. (MSC/PBMC/CURCUMIN/15)
First Level
GENE EXPRESSION
• Quantitative analysis of (mRNA) PCR
Quantitative Real Time (RT-qPCR); RT-qPCR Primer
• SNP’s Genotyping on DNA
Second Level
INFLAMMATION’s MARKERS
• C Reactive Protein
• TNF alfa
• IL 6, IL 10
Third Level
SYMPTOMS AND LIFE QUALITY
• Chronic pain (Forms)
• Mobility
• Quality of Life (Form ILMA)

35. Take home messages
Curcumin is effective on chronic pain and inflammation
as NSAID’s
«Enhanced » curcumins have better bioavailability
Curcumin is safe, can be used with all patients

36. Contatti: msal37@gmail.com +39 3663461468
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Maurizio Salamone, biologist
Science Manager Metagenics Italia srl.
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