Transcript Willow Bark - Learnblock

Herbal Medicines in Pain
Professor Basil D Roufogalis
Herbal Medicines Research Group
Pharm 3823
Faculty of Pharmacy 2011
Outline of this Presentation
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Use of complementary medicines in pain
Modes of Action
Levels of evidence
Some Herbal Products
 Devils’s Claw
 Willow Bark
 Rosehip
 Capsaicin
 Supplements
Utilization of Complementary
Medicine Among Rheumatology
Patients
– 63% reported using CAM for their condition (along
with conventional therapy)(232 responses (54%) to
questionnaire)
–
–
–
–
More often in severe pain (60% vs 40%)
Av 2.6 modalities used to control pain (1-11)
No association with satisfaction of care
Education predictor of utilisation of CAM
Rao et al. (1999) Ann Int Med 131, 409-16
Popularity of Herbal Medicines in
Pain of Osteoarthritis
Germany: Devil’s claw, Willow Bark and Nettle herb widely
used; capsaicin ointments
France: Avocado-soy bean fraction and Devil’s claw powder
Scandinavia: Rose Hip and Seed powder
Austria: Cat’s claw standardised on pentacyclic oxindol
Australia: Glucosamine, capsaicin, liprinol (NZ muscle), emu
oil
Less popular in Europe are: ginger preparations, salai
guggal (Boswellia serrata), gamma-linolenic acid (GLA)
containing seed oils from evening primrose, borage or
blackcurrant
Chrubasik, JE et al. Phytotherapy Research 2007
Evidence for Herbal Medicines
for Pain and Inflammation
• A 2001 systematic review found promising
evidence for effectiveness of some herbal
preparations in reducing pain and disability in
osteoarthritis
– while improving mobility and function
(Long et al, Rheumatology 2001)
• A Cochrane review identified five trials of
sufficient methodological quality with positive
findings for (avocado/soybean unsaponifiables),
willow bark preparation) (Reumalex) and topical
capsaicin (0.025%) (RA & OA)
Evidence for Herbal Medicines for
Low Back Pain
Cochrane Review (2006) (included ten RCT trials)
• Strong evidence: Harpagophytum procumbens (Devil’s claw)
standardised to 50 mg or 100 mg harpagoside – better than
placebo for short term improvements in pain and rescue
medication (2 trials)
• Moderate (but conflicting) evidence: Salix alba (White Willow
Bark) standardised to 120 mg or 240 mg salicin – better than
placebo for short term improvements in pain and rescue
medication (two trials)
• Moderate effects from low quality trials: Topical Capsicum
frutescens (Cayenne) – better than placebo (3 trials)
Gagnier et al. Herbal medicine for low back pain. The Cochrane Database of Systematic Reviews 2006,
Issue 2, Art No.: CD004504.pub3
Evidence for Herbal Medicines for
Low Back Pain
Adverse effects: primarily confined to mild, transient GI
complaints
Author’s Conclusion
Harpagophytum procumbens, Salix alba and Capsicum frutescens
seem to reduce pain more than placebo.
Additional trials against standard treatments are needed. Most trials
were moderate or high quality, but of short duration.
“No evidence yet that any of these substances are safe and useful for
long term use”
Gagnier et al. Herbal medicine for low back pain. The Cochrane Database of Systematic
Reviews 2006, Issue 2, Art No.: CD004504.pub3
Systematic Reviews of Herbal Medicines for
Painful Osteoarthritis and Low Back Pain
Fifteen Systematic Reviews Identified
Strong
– Avocado soybean unsaponifiable fraction, 300 mg (3 confirmatory studies, relevant clinical
effect size)
– Harphagophytum procumbens (Devil’s claw) containing more than 50 mg harpagoside in
daily dosage (2 confirmatory studies, small effect size; 2 exploratory studies of high quality.
Moderate :
– rose hip and seed powder from the subspecies lito (2 exploratory studies of high quality)
– ginger preparations (2 confirmatory studies (small effect size); 1 exploratory study of high
quality)
Insufficient :
– Boswellia serrata gum resin (1 exploratory study of low quality
– herbal mixtures and nettle herb mentioned in global systematic reviews
Conflicting (inconsistent findings):
– Willow bark due to a recent confirmatory study with a negative result
Chrubasik, JE et al. Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of
painful osteoarthritis and chronic low back pain. Phytotherapy Research (2007)
Clinical Efficacy of Herbal
Analgesics
• Analgesia may be slower to develop with
herbal products
• when the effect is less than expected with
pharmaceuticals for severe cases,
administration with low dose of NSAIDs
– may further alleviate pain
– may reduce the need of patient for NSAIDs
– may be cost effective
Quality of Herbal Medicinal
Products
• Herbal products are mixtures of numerous
compounds from plant sources
• Only some of the active ingredients are known;
require standardisation
• Active and some co-active ingredient contents
should be stated on the label
• herbal product should at least comply with
British Herbal Pharmacopeia or ESCOP
monographs or equivalent handbooks
• Results from clinical studies on one product
cannot be automatically transferred to another
plant product
The Need for Alternatives to
NSAID’s
• Recent recalls of COX-2 inhibitors (cardiovascular
problems)
• Significant adverse effects of COX-1 inhibitors on
the GI tract (bleeding and ulcer perforation)
– At least 7600 deaths each year in US
– 76,000 hospitalisations
• Renal damage in subgroups (< 1% gen pop)
• Particularly in high risk patients (aged, prednisone
concurrent use, GI side effect history, GI
hospitalisation, need for high doses)
Standardisation of Common Herbal
Anti-inflammatory Agents
Herb
Active
Principles
Standardized Daily Dosage
on
Willow Bark
Salicin, flavonoids
Salicin
120-240 mg (S)
Devil’s claw
Iridoid glycosides
Harpagoside
50-100 mg (H)
Stinging Nettle
Flavonoids, amines
Not yet defined
Rose hips
Galactolipid (?)
Vitamin C (500
mg/100 g powder)
2.5-5 g/day
Blackcurrant seed
Blackcurrent leaf
Gammalinolenic acid
Flavonoids, phenylcarbonic acids
GLA
Rutin
0.5 – 2 g (GLA)
Goldenrod herb +
aspen bark +ash
bark
Salicin, flavonoids
Salicin + salicylic
3.6-5.4 mg (S),
.12-.18 (R), .24 .35 (F)
Ginger
Gingerols, essential
alcohol + Rutin (R)
flavonoids (TF) + fraxin
(F)
Not defined
1-2 g fresh or dry
Mechanism of Action of Herbal
Anti-inflammatory Agents
Herb
Willow
Bark
Devil’s
claw
Stinging
nettle
Ginger
Rose hips
Cyclooxy Lipoxyg
genase
enase
+
+
Cytokine AntiRelease oxidant
+
+
+
+
+
?
+
+
+
?
+
+
+
+
+
+
+
Willow Bark
• Latin Name: Salicis cortex
• Part: Dried bark of some Salix species
Willow Bark
• Indications: Feverish conditions, symptomatic
treatment of mild rheumatic complaints; relief of
pain (including mild headache)
• Dose: 240 mg salicin per day (ESCOP)
• Key constituents: Flavonoids, salicin (prodrug of
various salicylates)
• Pharmacology: inhibition of COX-2-mediated
PGE2 release, lipoxygenase inhibition, cytokine
release, antioxidant action
Willow Bark –Clinical Evidence
Painful arthrosis of hip or knee
• Hydroethanolic Willow bark extract
• RDB : 240 mg salicin/day or placebo (78 patients)
• WOMAC pain score significantly improved after
two weeks
Willow Bark –Clinical Evidence
Chronic low back pain- acute exacerbations
• RDB: 786 mg or 1572 mg/day vs placebo (210 patients)
• After 4 weeks patients pain free for at least 5 days
within last treatment week (without consumption of
rescue medication)
– 39% high dose
– 21% lower dose
– 6% placebo
• Improvement in Arhus Low Back Pain Index
Willow Bark –vs Rofecoxib
Chronic low back pain- acute exacerbations
• AssalixR (1572 mg/day) vs Rofecoxib (VioxxR12.5 mg) (Open controlled, randomised study, 228 patients)
• No significant difference after 4 weeks (Patients pain
free, Arhus LBPI, its component pain, Global Pain Index)
• Lower GI incidence; less expensive
Chrubasik, S et al. (2001) Rheumatology 40, 1388-1393
Willow Bark –Systematic Review
OA and Chronic low back pain
Two trials showed moderate evidence of effectiveness
in low back pain at 120 mg or 240 mg salicin (std)
(Gagnier et al. 2006, Cochrane Group)
Conflicting results: due to negative recent trial of
a 70% ethanolic extract with 240 mg
salicin/day
Biegert et al (2004). Efficacy and safety of willow bark extract in the treatment
of osteoarthritis and rheumatoid arthritis: results of 2 randomized doubleblind controlled trials. J Rheumatol 31, 2121-2130
Willow Bark –Safety
• Safety: Regarded as safe (occasional allergy)
• Special warnings: Avoid in persons allergic to
aspirin (salicylates); preclinical safety data for
pregnancy and lactation not yet available
• Herb-Drug Interactions: minor effect on blood
clotting (monitor patients on anticoagulant
therapy); caution at high doses for patients
susceptible to GI bleeding
Willow Bark
Conclusions
• Preparations standardised on salicin may be
recommended for the treatment of pain
• Salicin is not the main active ingredient
• AssalixR clinically effective for osteoarthritic pain
• Lower adverse effect profile of AssalixR or
equivalent preparations may have advantages over
NSAID treatment
• Evidence of bioequivalence of Willow bark
products required
Devil’s Claw
• Latin Name: Harpagophytum procumbens
• Part: roots
Devil’s Claw
• Indication: Painful arthrosis or tendinitis
• Dose: up to 9 g crude decoction material or
equivalent aqueous or hydroalcoholic extracts
3 times per day, over 2-3 months (ESCOP)
• Key constituents: Iridoid glycosides (standardised
on harpagoside); flavonoids
• Pharmacology: inhibition of cyclooxygenasemediated prostaglandin release, inhibition of
lipoxygenase and cytokine release
Devil’s Claw – Clinical Evidence
Osteoarthritic Pain
• Four DB studies
• Harpagophytum preparations of 50 – 100 mg
harpagoside /day
Outcomes:
• Superior to placebo in chronic low back pain in two
studies
– 15% patients pain free after 4 weeks with 100 mg (cf 4%
placebo)
– 9% pain free with 50 mg
• No dose dependent effect on Arhus Pain Index measure
Devil’s Claw – Clinical Evidence
Osteoarthritis of knee or hip
• At least 60% of patients with aqueous extract
DoloteffinR benefited to various extents (Chrubasik et al 2002)
• Those who responded had a mean pain decrease of 80%
after 2-3 months, which was maintained over a year of
consumption (Chrubasik et al 2005)
Low back pain
• Equivalence of extract and rofecoxib (VioxxR)
• Number of pain free patients increased from week 1 to
week 6
• No difference between groups for Arhus and Total Pain
Index (Chrubasik et al 2003)
Positive Cochrane Review in Low back pain (Gagnier et al
2006)
Devil’s Claw – Osteoarthrits Pain
Systematic review on safety and effectiveness for pain
of OA
• Fourteen studies identified (4 of which were RDBCT)
• Data from higher quality trials shwed it to be effective in the main
clinical symptom of pain
• Minor safety risk compared to NSAIDs- longer trials needed
Brien, S, Lewith, GT, McGregor, G. J Alternative and Complementary Medicine 12 (10), 981-993, 2006
Devil’s Claw - Safety
Recent systematic review on safety for OA and low back
pain
• reviewed 28 clinical trials
• Minor adverse events in 3% of patients (allergy; gastric complaints
in iridoid glycoside sensitive individuals) – no higher than placebo
• No reports on chronic toxicity
Special warnings:
• contraindicated in gastric and duodenal ulcers
• possible interactions with antiarrhythmic drugs; monitor
anticoagulant therapy with warfarin
• minimum 3 months duration of treatment (ESCOP)
• No data in pregnancy
Vlachojannis, Roufogalis and Chrubasik (2008) Phytotherapy Research 22, 149-152
Pain Free Patients –Willow Bark
vs. Devil’s Claw
25
20
15
Devil's Claw
Willow Bark
10
5
0
Placebo
Low Dose
High Dose
Topical Capsaicin
• Latin Name: Capsicum annum and
frutescens
• Part: fruits
Topical Capsaicin
• Indication: recommended for specific pain
syndromes: osteoarthritis, rheumatoid
arthritis, diabetic neuropathy, postherpetic
pain; pain due to polyneuropathy or
neuralgia (all arising from altered nerve
function)
Topical Capsaicin
• Key constituents: capsaicin
• Pharmacology: selective action on
unmyelinated C fibre afferent neurons
– By activation/desensitization of TRPV-1
(vanilloid subtype-1) receptors
• A polymodal receptor sensitive to heat and
acidity
– Ca2+ dependent depletion of substance P
Mechanism in the Pain Pathway?
desensitization
Y511
Dorsal root ganglia
To brain
Spinal cord
capsaicin
TRPV1
activation
Peripheral terminal
Caterina et al., Nature, 1997;
Jordt et al., Cell 2002
TOPICAL CAPSAICIN FOR OROFACIAL
NEUROPATHIC PAIN
• Capsaicin has been used successfully to control pain in
– dental traumatic neuropathy
– trigeminal neuralgia
– postherpetineuralgia
– diabetic neuropathy
– postsurgical sensory disturbance involving the trigeminal nerve
– and other conditions of neuropathic pain
• such as pain from oral mucositis after chemotherapy or radiation.
• Capsaicin (0.025 % and 0.075 %) is available in an over-the-counter form
and can be mixed with agelatin, pectin, methylcellulose and benzocaine
cream (Orabase-B, Bristol-Myers Squibb) for intraoral use to improve its
consistency and to incorporate the local anesthetic effect of benzocaine.
PADILLA, M,GLENN T. CLARK, G T,. MERRILL, R L. TOPICAL MEDICATIONS FOR OROFACIAL NEUROPATHIC PAIN: A
REVIEW J
Am Dent Assoc 2000;131;184-195
Topical Capsaicin – Clinical
Evidence
Two meta analyses (MA)
– Superior to placebo after 12 weeks treatment in
osteoarthritis, diabetic neuropathy and psoriasis
– Trend towards efficacy in postherpetic pain
• As effective as amitriptyline in 8-week doubleblind study (235 patients) with painful diabetic
neuropathy (0.075%);
– significantly lower adverse effects
– effective in patients unresponsive or intolerant to
conventional therapy
Topical Capsaicin – Clinical
Evidence
Patients suffering from arthritis pain:
Indications for Zostrix
--- for the symptomatic relief of pain
• cream for topical application
• relief begins within 1-2 weeks (cf to 2-4 weeks
for neuralgia and 4-6 weeks for head and neck
neuralgia)
• builds gradually over 2-4 weeks treatment
Topical Capsaicin - Safety
Special warnings
• No data for use in pregnancy and children
below 2
• Not for use with broken or irritated skin
Contraindications
• Sensitivity to capsicum fruits or capsaicin
• Heat, humidity, wrappings, bathing, sweating
may intensify sensation of burning or warmth
• Inhalation may cause coughing
Capsaicin: Case Studies in trigeminal
neuralgia
Daily
dosage
Outcome
reported
in each study
Capsaicin 3 g
6/12 complete,
for 21 -- 28 days 4/12 partial
4/12 relapses
1/5 partial, 4/5
nil or little
Side effects/
withdrawals
(no of side effects
in reports)
Comments
Reference
Burning sensation
(NS)
Rub on the skin, Fusco et al.
temporary relief 1992
in majority,
avoid
contact on eyes Epstein et
al. 1994
Capsaicin: RCT in Burning Mouth Syndrome
Daily
dosage
Outcome
reported
in each study
Side effects/
withdrawals
(no of side effects
in reports)
Comments
Reference
Capsaicin
Systemic
0.25% capsule
3 times daily
for 1 month
Positive RCT
NNT 1-2
Gastric pain in
32% increase
over time
Poor-quality
From
trial, side
Zakrzewska
effects limit its J M
use
Expert
Opin.
Pharmacoth
er. (2010)
11(8)
RECENT CLINICAL TRIAL
Effectiveness and Safety of Topical Capsaicin
Cream in the Treatment of Chronic Soft
Tissue Pain
• Topical capsaicin is an established treatment option for various pain
conditions.
• In a randomized double-blind multi-centre study, 281 patients suffering
from chronic soft tissue pain were treated either with a cream containing
capsaicin 0.05% (‘Finalgon® CPDWärmecreme’, n = 140) or placebo (n =
141).
• The primary outcome measure was a positive treatment response,
defined as a pain sum score reduction of 30% or more.
• After 3 weeks of treatment, the median pain sum score had decreased by
49% (capsicum group) and 23%(placebo group
• Improvements in the secondary efficacy measures confirmed the results
S. Chrubasik, T. Weiser, B. Beime Phytother. Res. 24: 1877–1885 (2010)
Median relative pain sum score improvement (%) in
the patients suffering from chronic soft tissue pain
(ITT analysis). *** p < 0.001
Safety of Topical Capsaicin
(Continued)
• All patients were included in the safety assessments.
• More adverse events occurred in the capsicum group (n =
13) than in the placebo group (n = 6).
• The capsaicin cream was generally well tolerated.
Conclusions
• The results indicate that capsaicin cream is useful in
patients with chronic soft tissue pain
Rose Hips (Rosa canina)
Indications: Osteoarthritis
Nature: pseudofruit of the rose plant; rose hip is the ripe,
fresh or dried seed receptacle, freed of the seed and
attached trichomes); also used a rose hip ands seed
powder from the subspecies lito
Traditional use: 2-5 g of plant material used to prepare an
aqueous extract (eg tea taken 3-4 times a day). For
prevention and treatment of common colds; influenza-like
infections, fever, vitamin C deficiency, various gastric
conditions, general exhaustion, urinary tract conditions,
diuretic and laxative, gall bladder discomfort, gout,
arthritis, sciatica, diabetes, inadequate peripheral
circulation, astringent, eye rinse
Rose Hips (Rosa canina)
Constituents:
• Vitamin C, carotenoids, b-sitosterol, folic acid, Mg,
Zn, copper, flavonoids, proanthocyanidins,
tannins, volatile oils, vanillin
Pharmacology:
• inhibits chemotaxis of human peripheral blood
neutrophils
• inhibits production of reactive oxygen species
• antiinflammatory activities
Rose Hips (Rosa canina)
Clinical Evidence
Systematic Review
Identified four randomized controlled clinical trials using Rosa canina powder (5g daily)
over 3-4 months with LitozanR in OA
•
Evidence of effectiveness is moderate for OA (two exploratory studies of good quality
(Chrubasik et al, 2006)
•
Evidence poor for rheumatoid arthritis (one exploratory study)
Conclusions
Overall significant reductions in pain, stiffness and disability of the hand, knee, hip and
various joints.
Studies that objectify the effect sizes are urgently needed to assure clinical significance
Chrubasik, Roufogalis, Muller-Ladner and Chrubasik (2008) Phytotherapy Research 22, 725-733
Nutraceutical Supplements
Weight of
evidence
Effect
Comparator
Avocado-soybean
unsaponifiables
++
+
Placebo
Glucosamine
++
++
+
+
+
?+
Placebo, NSAIDs
+++
+
(+)
+
Placebo, NSAIDs
Osteoarthritis
Chondroitin
Greenlipped mussel
Placebo, NSAIDs
Rheumatoid arthritis
Fish oil
Selenium
Placebo
Macedo, T, New Zealand Pharmacy, June 29-36, 2003.
Acknowledgements
•
•
•
Professor Sigrun Chrubasik
Cathryn Rich
Staff of HMREC
www/pharm.usyd.edu.au/hmrec