3/24/10

Case
study:
IBS
and
joint
pain


Nutri&onal
basis
of
pain


Ann
Walker
PhD


College of Practitioners of Phytotherapy

Continuing Professional Development Seminars

Glucosamine
for
pain
relief
in
osteoarthri&s

  Glucosamine
found
naturally
in
the
body
as
a
precursor
for

glycosaminoglycan
–
a
major
component
of
joint
car&lage

  Posi&ve
studies:‐



Supplementary
Metabolites
 ›  A
3‐year,
RCT
212
people
with
knee
OA:

those
on
glucosamine
had

less
pain
compared
to
placebo


•  Reginster
JY
et
al.
Lancet.
2001;
357:
251

›  Other
RCTs
with
a
total
of
more
than
1,000
people
have
shown
similar

results


•  E.g.
Pavelka
K

et
al.
Arch
Intern
Med.
2002;
162:
2113


›  Other
RCTs
with
a
total
of
>
400
people
found
glucosamine
equally

effec&ve
as
the
ibuprofen

•  e.g.

Thie
NM
et
al
.
J
Rheumatol.
2001;
28:
1347

  No‐effect
studies:‐

›  Several
recent
studies
based
in
the
USA
have
failed
to
show

glucosamine
improved
OA
symptoms


•  e.g.

Rozendaal
RM
et
al.
Ann
Intern
Med.
2008;
148:
268


Combining
omega‐3
faay
acids
with
glucosamine
may
give
more

Glucosamine:

&ssue
repair
 support
for
joint
health
than
glucosamine
alone

J.
Gruenwald
et
al
2010
Advances
in
Therapy;
26:

858


•  A
3‐year
RCT
of
212
people
found
improvement
in

pain
and
mobility
x‐rays
showed
that
glucosamine
 •  177
people
with
moderate‐to‐severe
hip
or

prevented
progressive
damage
to
the
knee
joint

»  Reginster
JY
et
al.
Lancet.
2001;
357:
251

 knee
osteoarthri&s
received
daily
either

•  Another
large,
3‐year
study
with
202
people
found
 glucosamine
(1500
mg)
or
glucosamine
plus

similar
results

 200
mg
omega‐3

»  Pavelka
K
et
al.
Arch
Intern
Med.
2002;
162:
2113


•  A
follow‐up
on
the
study
above
indicated
that
 •  Ader
26
weeks
the
WOMAC
score
showed
no

glucosamine
might
reduce
the
need
for
knee
 difference
in
20%
pain
reduc&on
(primary

replacement
surgery

 outcome)
between
groups,
but
a
significant

»  Bruyere
O
et
al.
Osteoarthri8s
Car8lage.
2007


difference
in
80%
pain
reduc&on
(a
secondary

outcome)
in
the
group
with
omega‐3


1
 3/24/10

Acetyl‐L‐carni&ne
for
diabe&c
neuropathy
 5‐HTP

•  Acetyl‐L‐carni&ne
(ALC)
can
cross
the
blood‐brain
 •  5‐Hydroxytryptophan
(5‐HTP)
is
a
precurser

barrier
where
it
acts
as
an
an&oxidant

 for
serotonin

•  Review
of
studies
on
ALC
for
the
treatment
of

•  When
5‐HTP
is
taken
as
a
supplement,

diabe&c
peripheral
neuropathy

serotonin
produc&on
may
be
increased



–  Two
large
clinical
studies
with
1679
subjects
were

included



 •  Dosage:
400
mg
to
600
mg
daily

–  Those
receiving
≥
2
g
daily
of
ALC
showed

decrease
in
pain
scores


Evans JD et al Ann Pharmacother. 2008 ; 42: 1686

5‐HTP
and
migraine
 SAMe
and
fibromyalgia

•  In
a
6‐month
trial
of
124
people,
5‐HTP
(600
 •  S‐adenosylmethionine:

derived
from
a
combina&on

of
methionine
and
adenosine
triphosphate
(ATP)

mg
daily)
was
equally
effec&ve
to
the
drug
 •  Four
double‐blind
trials
of
intravenous
SAMe
for

methysergide
for
reducing
the
intensity
and
 fibromyalgia,
three
found
it
helpful

dura&on
of
migraines

 •  One
double‐blind
study
of
oral
SAMe
:

44
people

•  Titus
F
et
al.
Eur
Neurol.
1986;25:327

with
fibromyalgia
took
800
mg
of
SAMe
or
placebo

for
6
weeks:‐



•  Similarly
posi&ve
effects
were
seen
in
another
 –  
Compared
with
placebo,
those
taking
SAMe
had

improvements
in
pain
at
rest,
fa&gue,
and
morning

equivalence
study
with
a
different
drug
or
5‐ s&ffness,
and
in
one
measurement
of
mood


HTP
(400
mg
daily)


•  Bono
G
et
al.
Adv
Neurol.
1982;33:357

Jacobsen S et al. Scand J Rheumatol. 1991; 20: 294

Omega‐3
&
rheumatoid
arthri&s


•  The
results
of
numerous
small
 Essen&al‐nutrient

double‐blind
trials
indicate
that

omega‐3
fish
oil
can
help
reduce
the
 supplementa&on

symptoms
of
rheumatoid
arthri&s

•  E.g.
Adam
O,
et
al.
Rheumatol
Int.
2003;23:27


2
 3/24/10

Omega‐3
and
dysmenorrhea
 Vitamin
E
and
dysmenorrhoea


•  In
a
4‐month
cross‐over
study,
women
 •  In
a
RCT,
100
women
given
either
500
IU
vitamin
E
or

received
1800
mg/d
of
DHA
+
EPA
or
placebo
 placebo
for
5
days
(from
2
days
before
menstrua&on)

for
2
months
 for
two
menstrual
cycles:

pain
was
less
in
the

vitamin
E
group

•  There
was
reduced
menstrual
pain
while
 •  
Ziaei
S,
et
al.
BJOG
2001;108:1181

taking
fish
oil

 •  In
another
RCT,
278
adolescents
took
either
placebo

•  Harel
Z
et
al.
Am
J
Obstet
Gynecol.
1996;174:1335
 or
400
IU
of
vitamin
E
for
5
days
(from
2
days
before

menstrua&on):
vitamin
E
was
more
effec&ve
than

placebo


•  Ziaei
S,
et
al.
BJOG.
2005;112:466



Mg
and
dysmenorrhoea


 Magnesium
&
Migraine

•  A
6‐month
RCT
of
50
women:

Mg
 •  A
12‐week
RCT
with
81
people
taking
either

supplementa&on
reduced
pain
and
levels
of
 600
mg
of
Mg/d
(as
citrate)
or
placebo:


the

prostaglandin
F2
alpha,
one
of
the
 frequency
of
migraine
was
reduced
by
41.6%

prostaglandins
involved
in
menstrual
pain

 for
Mg
compared
to
15.8%
for
placebo

•  Seifert
B,
et
al.
Zentralbl
Gynakol.
1989;111:755

 •  Peikert
A,
et
al.
Cephalalgia.
1996;16:257



•  Similarly
posi&ve
results
were
seen
in
a
RCT
of
 •  Similar
results
have
been
seen
in
other

21
women
 double‐blind
studies

•  Fontana‐Klaiber
H
&
Hogg
B.
Schweiz
Rundsch
Med
Prax.

•  E.g.
Wang
F,
et
al.
Headache.
2003;43:601


1990;79:491



Vitamin
D
supplementa&on:



 Vitamin
D
recommenda&ons


Pain
relief
ader
3
months
in
open
studies
 in
mcg
per
day

1 mcg vitamin D = 40 IU (International Units
•  Glerup
et
al
2000

–  55
women
with
bone
and
muscle
pain:

 Year Population USA UK 1991
significant
reduc&on
in
pain
 1997 Adults to 50 yrs 5 None
•  Al
Faraj
&
AL
Mutairi
2003
 Adults >50 yrs 10 10
–  360
women
with
back
pain:

symptoms
 2005 Children, adults 25 0-5
improved
in
95%
of
pa&ents
 Adults with pain* 50 None
(in addition to any in
•  De
la
Jara
et
al
2006
 a multivit/min)
–  33
women
with
chronic
back
pain:

symptoms

Table adapted from: pain-topics.org
disappeared
in
66%
of
women

*Leavitt, SB (2008) Review available from pain-topic.org/VitaminD

3
 3/24/10

%
UK
adults
failing
to
achieve
RNI
–
top
 Bruce
Ames’

Triage
Theory 

Low
micronutrient
intake
may
accelerate
the
degenera&ve

ten
nutrients
 diseases
of
aging
through
alloca&on
of
scarce
micronutrients
by

triage


“Inadequate dietary intakes of vitamins and minerals are widespread,

most likely due to excessive consumption of energy-rich, micronutrient-poor,
refined food. Inadequate intakes may result in chronic metabolic disruption,
including mitochondrial decay. Deficiencies in many micronutrients cause DNA
damage, such as chromosome breaks, in cultured human cells or in vivo.
Some of these deficiencies also cause mitochondrial decay with oxidant
leakage and cellular aging and are associated with late onset diseases such as
cancer. I propose DNA damage and late onset disease are consequences of a
triage allocation response to micronutrient scarcity. Episodic shortages of
micronutrients were common during evolution. Natural selection favors short-
term survival at the expense of long-term health. I hypothesize that short-term
survival was achieved by allocating scarce micronutrients by triage, in part
through an adjustment of the binding affinity of proteins for required
micronutrients. If this hypothesis is correct, micronutrient deficiencies that
trigger the triage response would accelerate cancer, aging, and neural decay
but would leave critical metabolic functions, such as ATP production, intact. ….
NDNS Survey 19-64 yrs (2003) A multivitamin-mineral supplement is one low-cost way to ensure intake of the
Recommended Dietary Allowance of micronutrients throughout life.”

Vitamin
K:

a
test
of
the
triage
theory


The
Triage
Theory

•  Of
the
16
known
vitamin‐K‐dependent
proteins:‐

•  Some
func&ons
of
micronutrients
are
 –  5
are
made
in
the
liver
and
required
for
coagula&on

and
are

essen&al
for
foetal
development



restricted
during
deficiency
because
func&on
 –  5
non‐hepa&c
proteins
have
less
cri&cal
func&ons
[e.g.

for
short‐term
survival
takes
precedence
 osteocalcin,
matrix
Gla
protein
(Mgp)]
and
without
them

animals
survive
at
least
un&l
weaned


over
less
essen&al
func&on



 •  When
vitamin
K
is
limi&ng
there
is
preferen&al

•  In
the
long
term,
the
adverse
changes
 distribu&on
to
the
liver
to
preserve
coagula&on
func&on

caused
by
nutrient
restric&on
increase
the
 •  In
humans,
vitamin
K
deficiency
is
linked
to
age‐related

condi&ons:

bone
fragility
ader
oestrogen
loss

risk
of
chronic
diseases
 (osteocalcin)
and
arterial
calcifica&on
linked
to

cardiovascular
disease
(Mgp)




McCann JC & Ames BN Am J Clin Nutr. 2009; 90: 889

Evidence
that
a
daily
mul&vitamin/mineral
(MVM)
 Theories
of
pain

reduces
risk
of
chronic
disease

•  Classifica&on
by
ae&ology:


"somatogenic"
versus

•  Maternal
MVM:

reduced
risk
of
neuroblastoma

–  Olshan,
AF
et
al
(2002)
Epidemiology
13:
575
 "psychogenic”

•  Reduced
risk
of
colon
cancer
 •  Somatogenic
pain
classed
as
"nocicep&ve“
or


»  Giovannucci,
E.,
et
al.
(1998)
Ann.
Intern.
Med.
129:
517

"neuropathic“


•  Reduced
rate
of
infec&on
and
increased
quality
of
life

 –  Nocicep&ve
pains
may
be
classified
into
"superficial"
and

»  Barringer,
TA

et
al
(2003)
Ann.
Intern.
Med.
138:
365

"deep",
and
deep
pains
into
"deep
soma&c”
and
"visceral"


•  Reduced
risk
of
heart
aaack

»  Holmquist
,C

et
al
(2003)
J.
Nutr.
133:
2650
 –  Neuropathic
pain
is
divided
into
"peripheral“
and
"central“


•  MVM
for
chronic
disease
preven&on
in
adults:
review

 –  Peripheral
neuropathic
pain
is
oden
described
as

»  Fairfield,
KM
&
Fletcher,
RH
(2002)
J.
Am.
Med.
Assoc.
287:
3116
 “burning,”
“&ngling,”
“electrical,”
“stabbing,”
or
“pins
and

needles”


Ames, BN 2004 J Nutr 134, 3164S

4
 3/24/10

“Law
of
Pain”
proposed
by
 Omoigui’s
Treatment
of
Pain
Syndromes


Dr
Sota
Omoigui


•  Determine
the
inflammatory
profile
of
the
pain

•  All
pain
syndromes
share
the
common
origin
of
 syndrome

inflamma&on
 •  Inhibit
or
suppress
the
produc&on
of
the
appropriate

•  Biochemical
mediators
include
cytokines,
 inflammatory
mediators

neuropep&des,
growth
factors
and
neurotransmiaers
 –  e.g.
with
inflammatory
mediator
blockers
or
surgical

generated
by
inflamma&on
according
to
&ssue:‐
 interven&on

–  From
immune
cells:

prostaglandin,
nitric
oxide,
TNF‐α,
IL
1‐
 •  Inhibit
or
suppress
the
neuronal
afferent
and
efferent

α,
IL
1‐β,
IL‐4,
IL‐6
and
IL‐8,
histamine,
serotonin
 (motor)
transmission


–  From
nerve
cells:

Substance
P,
glutamate,
calcitonin
gene‐ –  e.g.
with
an&‐seizure
drugs
or
local
anaesthe&c
blocks

related
pep&de
(CGRP)
neurokinin
A
and
vasoac&ve

 •  Modulate
neuronal
transmission
e.g.
with
opioid

intes&nal
pep&de
 medica&on

•  A
successful
outcome
is
one
that
results
in
less

inflamma&on
and
thus
less
pain

Omoigui S Med Hypotheses. 2007;69(1):70

Inflamma&on
–
what
is
it?
 Minor
health
problems
which

indicate
a
pro‐inflammatory

•  The
body’s
normal
response
to
infec&on,
irrita&on
or
 response
of
the
body

other
injury


•  The
key
features
are
redness,
warmth,
swelling
and
pain
 •  Catarrh
 •  Headaches

•  The
inflammatory
process
inevitably
causes
&ssue

damage
due
to
free
radicals
but
in
acute
disease
it
is

•  Wheezing
 •  Period
pain

normally
followed
by
healing
and
repair
 •  Dry
skin
 •  Breast
pain

•  But
inflamma&on
can
persist
and
result
in
chronic
 •  Eczema
 •  Fa&gue

disease

•  Hayfever
 •  Fluid
reten&on

•  Joint
pain
 •  Allergies


Case
study:
scia&ca


Personal
details:


 Lifestyle:



Caucasian
male,
28
yrs
 Past
heavy
smoker
and
drinker
–
given

purchasing
manager
for
TV
 both
up.


His
poor
health
and
diagnosis

systems.

Diagnosed
with
type
I
 of
type
1
diabetes
a
huge
shock.

Had

diabetes
2000.

Difficulty
 advice
from
the
die&&an
and
now
ea&ng

driving.
 a
healthy
diet.

Main

Presenta2on:


 Other
health
problems:



Neuropathy:

difficulty
walking
 Weight
loss
due
to
prescribed
drugs.


into
my
office,
could
not
 Low
vitality.

Throat
and
mouth
thrush.


tolerate
shoes
on
feet
for
 Dry
eczema
(lower
legs)
&
blistering

dura&on
of
appointment.


 eczema
between
fingers.
Walked
on
heels.

5
 3/24/10

Regime
 Components
of
integrated
medicine

Drugs
 Co‐dydramol,
Paracetamol,
Dihydrocodeine,
Gabapen&n,
 Date
 Appe&te
 BMI
 Foot
 Inflam‐ Walking
 Vitality

Clonazepam,
Carbamepine,
Insulin
 pain

 ma&on
 ability

(1‐5)
 (1‐5)

Supplements
per
 Vitamin
E
1,000
iu,
Vitamin
C
1g,
high‐potency
Mul&,
Omega
3


day
 (DHA+EPA)
500
mg,
Ru&n

360
mg
 Jul
‘00
 poor
 17
 5
 5
 none
 low

Herbal
medicine

 Ginkgo,
Ginkgo
biloba
 1st
visit

Yellow
jasmine,
Gelsemium
sempervirens

Aug
‘00
 beaer
 18
 5
 4.5
 beaer
 beaer

Bilberries,
Vaccinium
myr8llus

Hawthorn,

Crataegus
laevegata

Oct
‘00
 good
 19
 2
 0.5
 good
 beaer

Devil’s
claw,

Harpagophytum
procumbens

Periwinkle,

Vinca
major

Jan
‘01
 good
 20
 1
 0
 walks
well
 "feels

St
John’s
wort,
Hypericum
perforatum

good"

External

 St
John’s
wort
infused
oil
+
eol
of
ginger,
black
pepper,
rosewood,

(eol,
essen&al
oil)
 lavender.


Rub
well
into
feet
bid.

Chickweed
+
chamomile
cream

for
eczema.


Oxida&ve
stress
in
the
pathogenesis
of

diabe&c
neuropathy

TW’s
leaer
26/5/01

•  Animal
and
cell
culture
studies,
as
well
as
clinical

•  “You…warned
that
it
would
take
about
3
 trials
of
an&oxidants,
strongly
implicate
oxida&ve

months…”
 stress
in
the
ae&ology
of
diabe&c
neuropathy

•  “When
you
consider
I
could
barely
walk
ten
 •  In
hyperglycaemia:‐

paces
without
having
to
lean
on
something...”

 –  Mul&ple
metabolic
pathways
are
impaired

–  Advanced
glyca&on
end
products
are
produced
including

•  “I
admit
to
being
a
liale
scep&cal
at
first...”
 glycated
proteins
with
decreased
func&on,
affec&ng

energy
produc&on,
cell
signalling,
nutrient
transport
etc

•  “…I
am
finding
that
even
ac&vi&es
such
as
 •  These
factors
converge
in
a
vicious
cycle
to
enhance

ten‐pin
bowling
are
possible.”
 oxida&ve
stress
resul&ng
in
diabe&c
neuropathy


Vincent AM, et al Endocr Rev. 2004; 25: 612

Alpha‐lipoic
acid
(LA)


Personal
details:


 Treatment/advice:

• 42
yr
old
woman,
diagnosed
with
type
1
 Diet:

5‐a‐day
fruit&veg

diabetes
at
18
yrs.


 3
por&ons
of
oily
fish/wk

•  A
water‐
and
fat‐soluble
sulfur‐containing
faay
acid/
• BMI
28.


 Wholegrains
 metabolite
which
can
cross
the
blood‐brain
barrier



• Diet
:

Low
fruit
and
veg,
low
dairy,
admits
to
 Avoid
seed
oils,
use
olive
oil

14
units
alcohol/wk
 Supplements:

MVM,
Cr,
Ca+Mg,
vitC

•  Found
in
all
cells
–
a
cofactor
for
mitochondrial
enzymes

• Blood
lipids
normal

 1000mg,
vitE
1000
iu,
500
mg
omega‐3.


 with
a
key
role
in
energy
produc&on

• Bp
normal
 α‐lipoic
acid
(ALA)
600
mg
bid
 •  Acts
by
mul&ple
mechanisms:‐


• HbA1c
7%
 Herbs:

Various,
an&‐inflammatory

Drugs:

Insulin
injec&ons
 –  An&oxidant


Aug
2003
Main
Presenta2on
:

 Outcome
Dec
2003
 –  Chelates
transi&on
metal
ions

‘Fli~ng’
neuropathy

pain:‐


 Neuropathy
pain
gone
completely.

(This
 –  Mi&gates
heavy
metal
toxicity

• severe
shoo&ng
(“electric”)
pains
in
legs

 only
happened
ader
including
ALA
–Px
 –  Helps
regenerate
other
‘spent’
an&oxidants



• Occ
‘sparks’
in
heels.


 had
been
on
a
similar
regime

since
Nov

• Occ
‘burning’
sensa&on
L&R
calf
 2002
without
ALA)
 –  May
subs&tute
for
other
an&oxidants
when
the
body
is

• Palms
of
hands:

‘fizzing’
sensa&on
 deficient
in
them


Singh U & Jialal, I, Nutr Rev. 2008 ; 66: 646

6
 3/24/10

α‐lipoic
acid
&
diabe&c
peripheral

Alpha‐lipoic
acid
 neuropathy:

the
evidence

•  A
healthy
body
makes
enough
lipoic
acid
to
supply
its
 •  Evidence
convincing
for
intravenous
lipoic
acid,
but


requirements;

external
sources
are
not
necessary

 contradictory
for
oral
supplementa&on

•  In
a
RCT
of
500
people
intravenous
lipoic
acid
reduced
symptoms

•  Low
levels
have
been
found
in
diabetes,
liver
 over
a
3‐week
period,
but
oral
supplementa&on
did
not
prove

cirrhosis,
and
atherosclerosis
 effec&ve

•  Liver
and
yeast
contain
some
lipoic
acid
but
 •  Ziegler
D
et
al.
Diabetes
Care.
1999;
22:
1296

supplements
are
necessary
to
obtain
therapeu&c
 •  On
the
other
hand
a
RCT
in
published
in
of
181
people
given

either
placebo
or
600,
1,200
or
1,800
mg
lipoic
acid
daily
for
five

dosages
 weeks
showed
benefits
in
all
treatment
groups
compared
with

•  The
typical
dosage
for
diabe&c
neuropathy
is
at
least
 placebo

100
to
200
mg
3
&mes
daily



 •  Ziegler
D,
et
al.
Diabetes
Care.
2006;
29:
2365

•  Other
posi&ve
evidence
for
oral
lipoic
acid
comes
from
small‐
•  Several
weeks
are
necessary
for
full
effects
to
 scale
RCTs



develop
 •  E.g.
3‐week
interven&on:

Ruhnau
KJ
et
al.
Diabet
Med.
1999;
16:
1040



Safety
Issues
 Other
applica&ons
of
LA

•  Cardiac
autonomic
neuropathy:

•  Lipoic
acid
appears
to
have
no
significant
side
 –  A
German
study
of
73
people
with
diabetes
and
symptoms

of
nerve
damage
to
the
heart:


800
mg
daily
of
oral
LA

effects
at
dosages
up
to
1,800
mg
daily
 showed
improvement
compared
to
placebo

–  Ziegler
D
&
Gries
FA.
Diabetes.
1997;46
(suppl
2):S62


•  Ziegler
D,
et
al.
Diabetes
Care.
1999;22:1296

•  Burning
mouth
syndrome:


•  Safety
for
young
children,
women
who
are
 –  In
a
2‐month
RCT
of
60
people,
LA
reduced
symptoms

compared
to
placebo


pregnant
or
nursing,
or
those
with
severe
liver
 –  Femiano
F
&
Scully
C.
J
Oral
Pathol
Med.
2002;
31:267

or
kidney
disease
has
not
been
established
 –  However,
3
small
RCTs
showed
no
benefit

•  Glucose
control:

–  Preliminary
evidence
suggests
that
LA
may
improve
blood

sugar
control
through
improving
insulin
sensi&vity

•  E.g.

Jacob
S
et
al.
Free
Radic
Biol
Med.
1999;27:309


Healthy
diet
to
reduce
pain/ Nutrient
supplements
for
in/
inflamma&on
 inflamma&on

•  Five
por&ons
or
more
of
fruit
&
vegetables/ •  A
mul&‐vitamin
&
mineral
supplement

day
 containing
all
vitamins
&
essen&al

•  A
balance
of
essen&al
faay
acids:‐
 minerals,
including
selenium,
manganese

–  Replace
omega‐6
seeds
oils
with
olive
oil
 and
zinc


–  Eat
oily
fish
at
least
twice
a
week
 •  Vitamin
C:

500
‐1000
mg

•  Eat
wholegrain
cereals,
nuts,
seeds,
beans
 •  Vitamin
E:

500
–
1000
mg


•  Fish
oil
(giving
2
g
of
DHA+EPA)

•  Vitamin
D:


50
mcg


7
 3/24/10

Conclusions

•  Inflamma&on
is
a
fundamental
aspect
of
pain

•  Mild
symptoms
can
indicate
a
pro‐inflammatory
body

status

•  Inflammatory
tendency
can
be
reduced
by
balancing
the

omega‐3:6
ra&o
of
diet
and
enhancing
an&oxidant
intake

•  Vitamin
D
supplementa&on
should
also
be
considered
for

all
pa&ents
with
pain

•  Essen&al
and
non‐essen&al
nutrients,
including
herbal

medicine,
can
work
together
to
provide
an
an&oxidant

environment
adequate
to
counter
inflamma&on/pain