The Role of Herbsin Pain Management

Kerry BoneAdjunct Associate Professor, University of New EnglandCo-Founder and Director R & D, MediHerb 1

Topics Covered

• Osteoarthritis

• Low back pain

• Dysmenorrhoea

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Osteoarthritis

• Defining osteoarthritis (OA)• Pathophysiology and pain in OA• Rational OA therapy versus

NSAIDs• Evidence for Boswellia, willow

bark and other herbs• Case history

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Defining Osteoarthritis

• Osteoarthritis (OA) has been defined as the failed repair of damage caused by excessive mechanical stress on joint tissues1

• All joint structures are affected,but the major hallmarks are thedestruction of articular cartilageand changes in the subchondralbone

• Historically OA was called “osteoathrosis”, a term implying the absence of inflammation

1 Van Weeren PR, de Grauw JC. Pain in osteoarthritis. Vet Clin North Am Equine Pract 2010; 26(3): 619-642 4

Defining Osteoarthritis• However, high-sensitive assays (such as for C-

reactive protein, CRP) demonstrates that low-grade inflammation is present andthat synovial tissue is alsoinvolved in the pathology1

• A recent review highlightedthat while the OA process(attempted healing) maycause joint pain, it is oftensuccessful in leading to a stable, painless joint2

1 Heinegård D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol 2011; 7(1): 50-56

2 Brandt KD, Dieppe P, Radin E. Etiopathogenesis of osteoarthritis. Med Clin N Am 2009; 93(1): 1-24 5

Pathophysiology of OA: Cartilage

• The precise mechanisms behind cartilage degradation are still unclear. Early on there is an increase of water and a decrease of proteoglycans (aggrecans) and type II collagen

• The predominant enzymes responsible for cartilage matrix degradation in OA are the matrix metalloproteinases (MMPs) and aggrecanases

• Later cartilage mineralisation (predominantly calcium pyrophosphate and phosphate) occurs and could accelerate inflammation

Umlauf D, Frank S, Pap T et al. Cartilage biology, pathology, and repair. Cell Mol Life Sci 2010; 67(24): 4197-4211 6

Pathophysiology of OA: Synovium

• Synovial inflammation (synovitis) occurs in early OA but can be subclinical. It is possibly induced by cartilage matrix degradation

• It becomes more extensive as OA progresses, with synovial hypertrophy and hyperplasia occurring

• There are increased numbers of immune cells, such as activated B cells and T lymphocytes

• In turn, the synovitis may contribute to the progression of cartilage degradationMartel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues? Eklem Hastalik Cerrahisi 2010; 21(1): 2-14Attur M, Samuels J, Krasnokutsky S et al. Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence? Best Pract Res Clin Rheumatol 2010; 24(1):71-79

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Pathophysiology of OA: Subchondral Bone

• The degeneration and erosion of cartilage has recently been challenged as the primary pathological event in OA

• Subchondral bone is suggested to play a key role: after all the disease was originally called osteoarthritis because of the prominence of the bone reaction

• The subchondral bone plate is in direct contact with the cartilage and could influence its degradation

• Evidence from humans and animal models has shown that subchondral bone alterations may precede cartilage degeneration 8

Pathophysiology of OA: Subchondral Bone

• There is also increasing evidence that bone marrow lesions (BMLs) and bone cysts have an important role in the pathogenesis of knee OA

• BMLs are strongly associated with radiological progression of knee OA and BML enlargement predicts increased cartilage loss, and the reverse

Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues? Eklem Hastalik Cerrahisi 2010; 21(1): 2-14Kwan TS, Lajeunesse D, Pelletier JP et al. Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Pract Res Clin Rheumatol 2010; 24(1): 51-70

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Pathophysiology of OA

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Attur M, Samuels J, Krasnokutsky S et al. Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence? Best Pract Res Clin Rheumatol 2010; 24(1): 71-79

Inflammation in OA• The common observation that chronic OA

patients can experience flare-ups speaks to it being an inflammatory disease

• Inflammation seems to be a very early event in OA, perhaps elicited by the initial traumatic injury

• Elevated levels of CRP can be observed well before clinical disease

• Inflammation and its triggers directly affect synovial cells (fibroblasts and macrophages), as well as cartilage chondrocytes, causing them to produce cytokines, particularly interleukin (IL)-1 and later tumor necrosis factor (TNF)-. (The macrophage is a key inflammatory cell in OA)

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Inflammation in OA

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Inflammation in OA

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Pain in OA• Cartilage is aneural, hence cannot be the tissue

that directly generates pain• In contrast subchondral bone, synovium,

marginal periosteum, ligaments and the joint capsule are all richly innervated

• But rarely can the precise tissue origin of pain be identified in the individual patient and many people with severe radiographic changes are asymptomatic

• Imaging studies at the knee joint have shown a correlation between pain and both synovitis and subchondral bone changes

Brandt KD, Dieppe P, Radin E. Etiopathogenesis of osteoarthritis. Med Clin N Am 2009; 93(1): 1-24 14

OA and Insulin Resistance• Insulin resistance (IR) predisposes to an increased

incidence of AGEs (advanced glycation end products)

• Current information suggests that OA shares a similar biochemical and inflammatory profile to metabolic syndrome1

• Analysis of the National Health and Nutrition Examination Survey III data (7714 people) revealed that OA is associated with an increased prevalence of metabolic syndrome, particularly in younger people2

1 Katz JD, Agrawal S, Velasquez M. Getting to the heart of the matter: osteoarthritis takes its place as part of the metabolic syndrome. Curr Opin Rheumatol 2010; 22(5): 512-519

2 Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data. Postgrad Med 2009; 121(6): 9-20 15

OA, Circulation andSubchondral Bone

• One recent review suggested there is mounting evidence that a microvascular pathology plays a key role in the initiation and/or progression of OA

• Disruption of microvascular blood flow in subchondral bone may reduce nutrient diffusion to articular cartilage in OA

• Ischaemia in subchondral bone due to microthrombi may produce osteocyte death, bone resorption and articular damage in OA

Findlay DM. Vascular pathology and osteoarthritis. Rheumatology 2007; 46(12): 1763-1768 16

Rational OA Therapy• OA is not simply mechanical wear and tear• Neither is it a solely PGE2-mediated inflammatory

disease and the source of pain can be enigmatic• OA is instead an active and complex biological

process of matrix degradation mediated by cells within and adjacent to the joint involving a range of inflammatory factors and pathological processes

• Insulin resistance and compromised circulation (especially microvascular) predispose to the condition

• Rational therapy for OA should target the underlying processes driving matrix degradation and the true sources of pain and inflammation 17

The NSAID Dilemma• In the often-cited NEJM study it was estimated

that the number of hospitalisations inthe United States for seriousgastrointestinal complicationsfrom NSAIDs was at least103,000 patients per year

• It was also estimated in the same study that 16,500 NSAID-related deaths occurred every year in the United States. This figure was similar to the number of deaths per year from AIDS

Wolfe M, Lichtenstein D, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. NEJM 1999; 340: 1888

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The NSAID Dilemma• Not surprisingly physicians were enthusiastic

when the selective COX inhibitors were released on the market. Yes they were expensive, but they were seen as lifesavers

• Unfortunately this relief was short-lived. In 2004 rofecoxib (Vioxx) was withdrawn from the US market, shortly followed by valdecoxib (Bextra) in 2005

• This was because both drugs were linked to unacceptably high risks of heart attacks and strokes. But we now know that this problem is not just confined to selective NSAIDs

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The NSAID Dilemma• One systematic review and meta-analysis

included 23 observational studies of the impact of NSAID use on heart attack rates

• Apart from rofecoxib (RR 1.33) the other NSAIDs with a significantly increased risk were diclofenac (RR 1.40) and indomethacin (RR 1.30)

• There was no protective effectobserved from any of the NSAIDsstudied

1 McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296(13): 1633-1644 20

The NSAID DilemmaDo They Work Long-term?• NSAIDs have also been questioned in terms of

their long-term clinical efficacy• A meta-analysis and systematic review of 23

clinical trials including more than 10,000 patients found that NSAIDs as a whole (includingselective COX-2 inhibitors) wereineffective for long-term painrelief in osteoarthritis of the knee1

1 Bjordal JM, Ljunggren AE, Klovning A et al. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ 2004; 329: 1317-1322

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What are the Options?Saving Lives!• Clearly the message from all the research

is that NSAIDs should not be the firstoption for the treatment of arthritic pain

• Many medical authorities now share this view and are, for example, recommending paracetamol instead1

• If you can advise your patients about the use of alternatives to NSAIDs, you could be saving their lives (especially if they are over 60)

• “For decades, evidence-based data and reported experience have warned that the common chronic oral NSAID therapy for OA in elderly patients is ultimately dangerous.”2

1 Day RO, Graham GG. Paracetamol should be first-line therapy in osteoarthritis. MJA 2005; 182(4): 198-199

2 Roth SH, Anderson S. The NSAID dilemma: managing osteoarthritis in high-risk patients. Phys Sportsmed 2011; 39(3): 62-74 22

Boswellia: A RationalTherapy for OA

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Boswellic Acids

CH3

HOOC CH3

HO

CH3 CH3

CH3

CH3

H3C

-Boswellic Acid

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Boswellia: A RationalTherapy for OA

• A 2010 review noted the following anti-inflammatory effects of Boswellia or boswellic acids from in vitro and in vivo experiments: Inhibition of 5-LOX, but only minor activity on

PGE production Downregulation of TNF- by inhibition of NF-B Inhibition of IL-1 production Inhibition of C3-convertase of the complement

system• Particularly active are 11-keto--boswellic acid

(KBA) and acetyl-11-keto--boswellic acid (AKBA)

Ammon HP. Modulation of the immune system by Boswellia serrata extracts andboswellic acids. Phytomedicine 2010; 17(11): 862-867

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Boswellia: The Clinical Evidence

• The clinical evidence for Boswellia in OA is good

• In particular, there are suggestions from some trials that Boswellia treatment might be disease- modifying, rather than just providing symptom control

• This disease-modifying effect should be no surprise given the range of its anti-inflammatory effects that are relevant to OA

• There are 5 published randomised, controlled clinical trials. Some of the results are striking and informative 26

Boswellia: The Clinical Evidence

• A placebo-controlled, crossover trial in 30 patients with knee OA found that 8 weeks of Boswellia extract (1000 mg/day, 40% boswellic acids) significantly (p<0.001) reduced the pain index from 2.7 to 0.26 and the swelling index from 1.1 to zero1

• Another trial in 66 patients with knee OA found that Boswellia extract (1000 mg/day, 40% boswellic acids) was as effective as valdecoxib (10 mg/day) over 6 months2

1 Kimmatkar N, Thawani V, Hingorani L et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial. Phytomedicine 2003; 10(1): 3-7

2 Sontakke S, Thawani V, Pimpalkhute S et al. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of the knee. Indian J Pharmacology 2007; 39(1): 27-29 27

Boswellia: The Clinical Evidence

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From: Sontakke S, Thawani V, Pimpalkhute S et al. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of the knee.Indian J Pharmacology 2007; 39(1): 27-29

Boswellia: The Clinical Evidence

• However, while Boswellia had a slower onset of action (about 1 month), its effect persisted after discontinuation of therapy (unlike valdecoxib)

• This suggests it could be disease modifying• In a 2008 trial, 75 patients with

knee OA received either twodoses of a specialised Boswelliaextract (100 or 280 mg/day ofa AKBA-enriched extract) ora placebo for 90 days1

1 Sengupta K, Alluri KV, Satish AR et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther 2008; 10: R85 29

Boswellia: The Clinical Evidence

• Symptom alleviation was faster in the higher dose group (as early as 7 days) and significantly better than placebo and MMP-3 in synovial fluid was significantly and substantially reduced in both Boswellia groups

• A 2010 trial compared the specialised extract above at 100 mg/day with 100 mg/day of a similar extract (but with enhanced bioavailability) and a placebo over 90 days in 60 patients with knee OA1

• Clinical results were remarkable, the WOMAC pain subscale fell from 45.0 to 13.9 in patients taking the enhanced extract (p<0.0001)

1 Sengupta K, Krishnaraju AV, Vishal AA et al. Comparative efficacy and tolerability of 5-Loxin and AflapinAgainst osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci 2010; 7(6): 366-377 30

BoswelliaOptimising Pharmacokinetics

• In a randomised, open, single-dose,two-way crossover study, 12 healthy male volunteers received 786 mg ofBoswellia extract either with orwithout a standard high-fat meal1

• Plasma concentrations of boswellicacids were measured up to 60 hoursafter the oral dosing

1 Sterk V, Buchele B, Simmet T. Effect of food intake on the bioavailability of boswellic acids from a herbal preparation in healthy volunteers. Planta Med, 2004; 70(12): 1155-1160

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Boswellia

Optimising Pharmacokinetics

• Administration in conjunction with a high-fat meal led to a substantial improvement in the bioavailability of the boswellic acids

• For example, the maximum concentration for AKBA was 6.0 ng/mL for the fasted conditions versus28.8 ng/mL with food

• This means that Boswellia is best taken with meals, especially those containing some animal or vegetable fat

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Willow BarkWhat is It?• Many willow bark species are used

therapeutically especially Salix alba, S. daphnoides and S. purpurea

• They all contain derivatives of salicylic acid, mainly salicin

• Clinical trials have found that a high potency willow bark extract standardised for salicin has significant analgesic activity, but with fewer side effects than conventional NSAIDs

• In fact it acts quite differently to NSAIDs: willow bark is NOT a herbal aspirin

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Willow Bark: Not an Herbal Aspirin

• While the idea for aspirin (acetylsalicylic acid) came from the salicin found in willow bark, aspirin is a synthetic drug

• It is the synthetic part of aspirin – the acetyl group – which gives it its ability to inhibit COX

• Aspirin therefore has potent analgesic and anti-inflammatory activities (COX-2) but also can cause gastric damage and inhibits platelet function(COX-1)

• How willow bark works is still a mystery of nature, but it is likely that many of its components work together to provide pain relief

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Willow BarkA Large-Scale Study• A large-scale study found that willow bark when

tested in a clinical setting had a superior safety and efficacy profile compared to NSAIDs

• This was presented at a Berlin conference inearly 2004 and involved922 physicians and4,731 patients inGermany1

1 Werner G, Scheithe K. Willow bark extract (Assalix®) for chronic back pain and arthralgia, a post-authorization surveillance study. Congress Phytopharmaka and Phytotherapy. Berlin,February 26-28, 2004

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Willow Bark

A Large-Scale Study• Over 6 to 8 weeks, patients with arthritis or

back pain took various doses of willow bark extract (an average of around 3 tablets per day) and rated their pain intensity from 1 to 10 (with 10 representing pain of the highest intensity)

• Most of the patients had previously been taking NSAIDs, but had generally discontinued these because of either a lack of efficacy or side effects

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Willow Bark: Clinical Trials

A Large-Scale Study• During the observation period, only 15.5%

needed supplementary antirheumatic drugs in addition to their willow bark

• Average pain intensity reduced from 6.4 to 3.7 points in the first 4 weeks of treatment and had fallen further to 2.7 after 8 weeks, with 97% of patients reporting a reduction in pain and 18% reporting no pain at all

• Side effects were judged as minor and occurred in only 1.3% of patients. These were mainly abdominal pain or an allergic skin rash

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Willow Bark: Clinical Trials• In a randomised, double-blind, parallel group

trial the efficacy of willow bark extract was compared with diclofenac sodium in 79 patients with knee or hip OA1

• The patients were allocated randomly to one of three groups, receiving either 150 mg/day of diclofenac sodium or willow bark extract in two different doses (corresponding to 90 or 180 mg/day salicin respectively)

• Pain intensity (VAS) was reduced by 48.0% for the NSAID and by 39.5% and 31.3% for the two willow bark groups

1 Lardos A, Schmidlin CB, Fischer M et al. Efficacy and tolerance of an aqueous willow bark dry extract in patients with knee or hip arthrosis. Zeitschrift fur Phytotherapie, 2004; 25:275-281

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Willow Bark: Clinical Trials

• Functional capacity was significantly (p<0.05) improved in all groups (after NSAID treatment 100% of patients were grouped in the lowest ratings of 1 or 2 compared to 90% for the higher dose of willow bark)

• The percentage of symptom-free patients (with various daily activities) increased by similar amounts for all groups

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OPCs and OA• A double blind, placebo-controlled trial involving

38 knee OA sufferers found 150 mg/day Pine Bark OPCs (PBO) for 3 months reduced pain and stiffness and improved physical function.1 Differences were quite significant clinically, with a 49% reduction in the WOMAC score and a significant drop in conventional painkiller use

• A similar design trial, but with 156 patients and PBO at 100 mg/day again showed a 50% reduction in the WOMAC score and a significant drop in oedema2

1 Farid R, Mirfeizi Z, Mirheidari M et al. Pycnogenol supplementation reduces pain and stiffness and improves physical function in adults with knee osteoarthritis. Nutr Res 2007; 27(11): 692-697

2 Belcaro G, Cesarone MR, Errichi S et al. Treatment of osteoarthritis with Pycnogenol. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects. Phytother Res 2008; 22(4): 518-523

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OPCs and OA

• A follow-up study of this trial found CRP was lowered by PBO by 71% and fibrinogen by 37%1

• Another similar trial in 100 patients receiving 150 mg/day foundreduced stiffness anduse of other painkillers2

1 Belcaro G, Cesarone MR, Errichi S et al. Variations in C-reactive protein, plasma free radicals and fibrinogen values in patients with osteoarthritis treated with Pycnogenol. Redox Rep 2008; 13(6): 271-276

2 Cisár P, Jány R, Waczulíková I et al. Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis. Phytother Res 2008; 22(8): 1087-1092

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Devil’s Claw:Systematic Review

• The effectiveness of devil’s claw (Harpagophytum procumbens) was evaluated by a systematic review

• 12 trials were included with 5 investigating osteoarthritis, 4 low back pain and 3 mixed-pain conditions

• There was moderate evidence of efficacy for devil’s claw powder equivalent to 60 mg harpagoside per day for OA of the spine, hip and knee (about 2-3 g of root per day)

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Devil’s Claw:Systematic Review

• Strong evidence exists for the use of an aqueous extract of devil’s claw equivalent to 50 mg harpagoside per day foracute exacerbations ofnon-specific low back pain

Gagnier JJ, Chrubasik S, Manheimer E. Harpgophytum procumbens for osteoarthritis and low back pain: a systematic review BMC Complement Altern Med 2004; 4: 13 43

Case History

• A female patient aged 67 presented with severe OA in both knees and degenerative changes in her lumbar spine

• Her left knee was swollen and tests revealed a Baker’s cyst, osteophytes and cartilage loss

• She was recommended for knee replacement (both knees)

• Her current supplements included fish oil andglucosamine and she had been taking these for some time

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Case History

• A tablet containing Boswellia, celery, turmeric and ginger was prescribed at 3 per day for her OA, together with the same dose of a tablet containing gotu kola, Ginkgo and grape seed to promote healing and improve microvascular health

• In the first few months there was moderate improvement in her knee signs and symptoms

• At 18 months the patient was largely free of these and is no longer contemplating surgery45

OA Conclusions• OA is not necessarily a one-way degenerative

process: joints can heal• Rational therapy for OA requires attention to

downregulating a range of inflammatory factors, not just PGE2, and facilitating healing

• As part of this, attention should be paid to blood quality, microvascular health and glycaemic control

• A strong case can be argued that modern phytotherapy (informed by both traditional knowledge and scientific discovery) exemplifies a rational approach for managing OA 46

Chronic Low Back Pain• The prevalence of chronic low back pain is

reported as around 23%, with 11-12% of the population being disabled by this (European data)1

• Degenerative disk disease is a strong aetiological risk factor, but other causes include muscular injury and OA2

• In terms of conventional treatments, Cochrane reviews support opioids versus placebo and equivalence of NSAIDs versus opioids, but do not support antidepressants3

• From the herbal perspective, trials support high-dose devil’s claw (see previous) and willow bark

1 Balagué F, Mannion AF, Pellisé F et al. Non-specific low back pain. Lancet 2012; 379(9814): 482-491

2 Karppinen J, Shen FH, Luk KD et al. Management of degenerative disk disease andchronic low back pain. Orthop Clin North Am 2011; 42(4): 513-528

3 White AP, Arnold PM, Norvell DC et al. Pharmacologic management of chronic low back pain: synthesis of the evidence. Spine (Phila Pa 1976) 2011; 36(21 Suppl): S131-143 47

Willow BarkChronic Low Back Pain• This was a landmark study completed

by 191 patients (there were anadditional 19 dropouts, mostly in theplacebo group)

• Clinical endpoint was alleviation of acute exacerbation of chronic low back pain

• Under double-blind conditions two doses of willow bark extract (containing 120 or 240 mg of salicin per day) were compared against a placebo

Schaffner W. In Chrubasik S, Wink M (eds). Rheumatherapie mit Phytopharmaka. Stuttgart, Hippokrates Verlag, 1997, pp 125-127

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Willow Bark

Chronic Low Back Pain

• Tramadol was the rescue medication

• After 4 weeks the number of pain-free patients was 39% for the higher dose group and 21% for the lower dose group, versus only 6% for placebo

• A significant response in the higher dose group was evident after only one week of treatment

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Willow Bark and Low Back Pain

12

34

0

10

20

30

40

50

Placebo 2 Willow Bark tablets per day 4 Willow Bark tablets per day

Percentage of Painfree Patients

weeks

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Willow Bark - Match the Trial Doses

• In all the trials a high potency willow bark extract was used

• The amount of extract was around 400 mg per tablet, standardised to 15% salicin

• 2 to 4 tablets per day were prescribed (containing 120 to 240 mg/day salicin)

• 400 mg of extract containing 15% salicin corresponds to 6 to 8 g of willow bark, depending on the species used

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Dysmenorrhoea

• Most herbal clinicians rely on traditional use for selecting herbs to alleviate dysmenorrhoea

• Treatments are either just to manage the pain or in more severe cases herbs to improve hormonal balance are prescribed throughout the cycle

• Key traditional herbs include wild yam, cramp bark, black haw, raspberry leaf, ginger and fennel

• There is supportive evidence from clinical trials for fennel oil (open-label) and ginger

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Ginger and Dysmenorrhoea• In a double blind, comparative trial conducted in

Iran, 150 female students (mean age of about 21 years) with primary dysmenorrhoea were assigned to one of three groups: ginger, mefenamic acid or ibuprofen1

• Students in the ginger group took 250 mg capsules of ginger rhizome powder 4 times a day for 3 days from the start of their menstrual period

• The other groups received 250 mg mefenamic acid or 400 mg ibuprofen capsules under the same protocol

1 Ozgoli G, Goli M, Moattar F. Comparison of effects of ginger, mefenamic acid, and ibuprofen on pain in women with primary dysmenorrhea. J Altern Complement Med 2009; 15(2): 129-132

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Ginger and Dysmenorrhoea• The incidence of severe dysmenorrhoea

decreased from 28% to 8% in the ginger group, 32% to 6% in the mefenamic acid group and 38% to 18% in the ibuprofen group

• The change in pain severity was similar in all three groups, for example, 36% were considerably relieved in the gingergroup, with 30% and36% considerablyrelieved in the mefenamic acid and ibuprofen groups,respectively

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