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

• 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 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

• 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 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

• 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

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