Upload
scot-small
View
228
Download
3
Embed Size (px)
Citation preview
Herbal Medicines in Pain
Professor Basil D Roufogalis
Herbal Medicines Research Group
Pharm 3823
Faculty of Pharmacy 2011
Outline of this Presentation
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 powderScandinavia: Rose Hip and Seed powderAustria: Cat’s claw standardised on pentacyclic oxindolAustralia: Glucosamine, capsaicin, liprinol (NZ muscle), emu
oilLess 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 ConclusionHarpagophytum 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 IdentifiedStrong
– 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 on
Daily Dosage
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, phenyl-carbonic acids
GLA
Rutin
0.5 – 2 g (GLA)
Goldenrod herb + aspen bark +ash bark
Salicin, flavonoids Salicin + salicylic alcohol + Rutin (R) flavonoids (TF) + fraxin (F)
3.6-5.4 mg (S), .12-.18 (R), .24 - .35 (F)
Ginger Gingerols, essential oils
Not defined 1-2 g fresh or dry rhizome
Mechanism of Action of Herbal Anti-inflammatory Agents
Herb Cyclooxygenase
Lipoxyg
enase
Cytokine Release
Anti-oxidant
Willow Bark
+ + + +
Devil’s claw
+ + + ?
Stinging nettle
+ + + ?
Ginger
Rose hips
+
+
+
+
+ +
+
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 EvidenceChronic 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 RofecoxibChronic low back pain- acute exacerbations
• AssalixR (1572 mg/day) vs Rofecoxib (VioxxR-12.5 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 double-blind 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 BarkConclusions
• 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
• 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 cyclooxygenase-mediated prostaglandin release, inhibition of lipoxygenase and cytokine release
Devil’s Claw – Clinical EvidenceOsteoarthritic Pain
• Four DB studies• Harpagophytum preparations of 50 – 100 mg
harpagoside /dayOutcomes: • 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 EvidenceOsteoarthritis 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 pregnancyVlachojannis, Roufogalis and Chrubasik (2008) Phytotherapy Research 22, 149-152
Pain Free Patients –Willow Bark vs. Devil’s Claw
0
5
10
15
20
25
Placebo Low Dose High Dose
Devil's ClawWillow Bark
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
Y511
capsaicin
To brain
Spinal cordDorsal root ganglia
Peripheral terminal
TRPV1 activation
Mechanism in the Pain Pathway?Mechanism in the Pain Pathway?
Caterina et al., Nature, 1997; Jordt et al., Cell 2002
desensitization
TOPICAL CAPSAICIN FOR OROFACIALNEUROPATHIC 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 double-blind 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
Dailydosage
Outcome reportedin each study
Side effects/withdrawals(no of side effectsin reports)
Comments Reference
Capsaicin 3 gfor 21 -- 28 days
6/12 complete, 4/12 partial4/12 relapses
1/5 partial, 4/5 nil or little
Burning sensation (NS)
Rub on the skin,temporary reliefin majority, avoidcontact on eyes
Fusco et al. 1992
Epstein et al. 1994
Capsaicin: RCT in Burning Mouth Syndrome
Dailydosage
Outcome reportedin each study
Side effects/withdrawals(no of side effectsin reports)
Comments Reference
CapsaicinSystemic0.25% capsule3 times dailyfor 1 month
Positive RCTNNT 1-2
Gastric pain in32% increaseover time
Poor-quality trial, sideeffects limit its use
From Zakrzewska J MExpert Opin. Pharmacother. (2010) 11(8)
RECENT CLINICAL TRIALEffectiveness and Safety of Topical CapsaicinCream in the Treatment of Chronic SoftTissue 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 (%) inthe 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, -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
Placebo++Selenium
Placebo, NSAIDs(+)+++Fish oil
Rheumatoid arthritis
?++Greenlipped mussel
Placebo, NSAIDs+++Chondroitin
Placebo, NSAIDs+++Glucosamine
Placebo+++Avocado-soybean unsaponifiables
Osteoarthritis
ComparatorEffectWeight of evidence
Macedo, T, New Zealand Pharmacy, June 29-36, 2003.
Acknowledgements
• Professor Sigrun Chrubasik
• Cathryn Rich
• Staff of HMREC
www/pharm.usyd.edu.au/hmrec