INTRODUCTION

Worldwide, musculo-skeletal conditions are the most common cause of

severe long-term pain and physical disability.1 Osteoarthritis is one such

form of chronic degenerative joint disease.2 The etiological factor

includes articular cartilage degeneration that presents clinically in the

form of gradual development of joint pain, swelling, instability, stiffness

and loss of movement.3

Approximately 50 million population has real joint disease and

among them osteoarthritis is the commonest disease that is emerging as a

major health and economical burden on the society.4 Its prevalence has

increased in the past 2 to 3 decades because of increased life expectancy

due to better living conditions and health facilities in India. The reported

prevalence of osteoarthritis in India is 22% to 39 % that accounts for 30%

of all rheumatological problems.5 There is a strong correlation between

the prevalence of osteoarthritis and age. Radiological evidence of OA

occurs in the majority of people by 65 years of age and in about 80% of

those aged over 75 years. Osteoarthritis is more common in women than

men but the prevalence increases dramatically with age as a consequence

of menopausal changes (primarily as a loss of estrogen) in women.

Above 65 years of age, 45% women have clinical symptoms where as

1
radiological evidence of OA has been found in 70% of women.6 In

comparison to western population, the Indians have a high incidence of

OA of knee joint while involvement of hip joint is less common in India.7

In our society, high involvement of knee joint is because of social habits

of using Indian toilet seats, squatting and sitting cross-legged. Many

factors like age of the patient, co-morbidities, clinical severity of

osteoarthritis, cost factors, individual doctors or patient preference play a

vital role in treatment

The main objectives for management of osteoarthritis are

the reduction of pain with improvement in the functional status of the

joint and to limit the progression of pathological changes to either delay

or minimize the risk of arthroplasty.8 The management of OA includes

non-pharmacological measures, pharmacological therapy and

rehabilitational therapy and surgical procedures.

Non-pharmacological non-surgical therapy for osteoarthritis is

in the form of patient education, weight loss, physical therapy,

occupational therapy, reorientation of living style and has been tried with

some success.

Currently symptomatic relief is provided by the use of

nonsteroidal anti-inflammatory drugs (NSAIDs) but they do not reverse

and may accelerate the basic pathology of disease like degeneration of

2
cartilage, inhibit chondroitin synthesis and suppress proteoglycans

synthesis by the chondrocyte.9,10

Attempts have been made in combining NSAIDs with other groups of

drugs having analgesic activity. Opioid analgesic agents have been

combined with NSAIDs in order to achieve an effective degree of

analgesia but the undesirable part of this combination is addictive

properties of opioids and their usefulness is only for a short span of

time.11

Combining paracetamol with traditional nonsteroidal anti-

inflammatory drugs (NSAIDs) for short courses is useful in OA without

an increase in side effects but over long term, increased risk of upper GIT

bleed has been observed than that conferred by NSAID alone.12,13,14

The above said combinations, though provide symptomatic relief,

yet are unable to prevent or limit further progression or worsening of the

disease. Thus there is an urgent need to find a drug which can modify the

disease process in addition to its analgesic activity.

The drugs that modify the disease progression are classified as

symptomatic slow acting drugs in osteoarthritis (SYSDOA). They have a

slow onset of efficacy with a long carry over effect after the treatment is

withdrawn.15 Glucosamine, chondriotin sulphate and Diacerein8 are the

available options that can be combined with NSAIDs as add on therapy

3
so that both disease symptomatology as well as progression can be

controlled.

Glucosamine-chondriotin sulphate combination has been found to

increase glucose levels by causing insulin resistance in diabetic

osteoarthritic patients.16,17 As almost half of the osteoarthritic patients are

diabetic18, giving glucosamine-chondriotin sulphate combination as add

on therapy to NSAIDs still needs more evaluation. Moreover a recent

trial GAIT has shown that glucosamine hydrochloride and chondriotin

sulfate alone or in combination did not reduce pain effectively in

comparison to celecoxib or placebo in the overall group of patients with

OA of the knee.19

Research shows that IL-1β plays a fundamental role in osteoarthritis

pathophysiology and cartilage destruction.20 Diacerein, a purified

compound with anthraquinonic structure, has been shown to inhibit, in

vitro21 and in vivo22, the production and activity of IL-1 and the secretion

of metalloproteases, without affecting the synthesis of prostaglandins.

Hence, by inhibiting IL-1 diacerein retards all pathological prepossess

initiated in OA. Also, Diacerein has proven analgesic efficacy

comparable to that of diclofenac in patients of osteoarthritis knee.23 So,

diacerein is one drug that can stop the disease progression as well as

contribute to improve symptomatology in patients of osteoarthritis knee.

4
 Because of these factors, the present study has been planned

to evaluate the clinical effectiveness of diacerein as add on therapy to

diclofenac sodium in patients of osteoarthritis knee.

5
 AIMS AND OBJECTIVES

Osteoarthritis, a degenerative joint disorder, is the most common

rheumatologic problem in India. Its prevalence has increased in the past

2 to 3 decades because of increased life expectancy due to better living

conditions and health facilities in India. Currently symptomatic relief is

provided by the use of nonsteroidal anti-inflammatory drugs (NSAIDs)

but they do not reverse and may accelerate the basic pathology of disease.

Thus there is an urgent need to find a drug which can be combined with

NSAIDs so that both disease symtomatology as well as progression can

be targeted. Recently, diacerein has been reported to have action that

prevents cartilage degeneration.

Considering these factors the present research work has been

planned to evaluate the clinical efficacy and safety of diclofenac sodium

with diacerein and alone in patients of osteoarthritis knee.

6
 REVIEW OF LITERATURE

Osteoarthritis (OA) or osteoarthrosis or degenerative arthritis is a chronic

debilitating disorder which is the most common disease to affect synovial

joints. OA is currently defined by the American College of

Rheumatology as a heterogeneous group of conditions that leads to

articular cartilage degeneration, in addition to related changes in the

underlying bone at the joint margins.2

Osteoarthritis is classified in two groups24:

1. Primary/Idiopathic/Age related

a. Localized

b. Generalized

2. Secondary

a. Post-traumatic

• Acute: Road traffic accident, etc.

• Chronic: Occupational, sports, etc.

b. Due to structural abnormalities: Congenital and

developmental defects

c. Due to Metabolic, Endocrine and Calcium deposition

diseases

7
 d. Neuropathic joints: Charcoat joints

e. Any other known intra-articular pathology

Risk factors/etiology25:

The cause of primary osteoarthritis is unknown26, but the

predisposing risk factors are:

• Age: It is the most important risk factor. There is a strong

correlation between the prevalence and incidence of

osteoarthritis and age. Radiographic evidence of OA occurs in

the majority of people by 65 years of age and in about 80% of

those aged over 75 years.27

• Female gender: 45% of women over the age of 65 have

symptoms while radiological evidence is found in 70% of those

over 65.28

• Race: African Americans had slightly higher prevalence of

knee symptoms, radiographic knee OA, and symptomatic knee

OA, but significantly higher prevalence of severe radiographic

knee OA compared to Caucasians.29

• Obesity: OA is twice more common in obese and mainly affect

weight bearing joints.30

• Quadriceps weakness31

8
 • Genetic factors: epidemiologic study suggests osteoarthritis is

an articular expression of a generalized condition resulting from

inherited metabolic abnormality.32

• Prior inflammatory joint disorders: crystals accumulate in

articular cartilage making it susceptible to destruction.33,34

Physiology:

Hyaline cartilage is the pearly gristle, which covers the bone ends

in every diarthrodial joint. It has a gel like matrix consisting of a

proteoglycan ground substance in which is embedded architecturally

structured collagen network and a relatively sparse scattering of

specialized cells, the chondrocytes, which are responsible for producing

all the structural components of the tissue.35 It has high water contents

(60-80%). The proteoglycans exist mainly in the form of aggregan, a

large aggregating molecule with a protein core along which are arranged

upto 100 chondroitin sulphate and keratin sulphate glycosaminoglycans,

like the bristles on a bottlebrush. Hundreds of aggregan molecules are

linked in turn, to a long, unbranched hyaluronate chain, to form an even

larger molecule with a molecular weight of over 100 million Daltons.

These negatively charged macromolecules are responsible for the

stiffness and springiness of articular cartilage. Antibodies of cathepsin D

are capable of preventing autolysis of cartilage. The fibrillar component

9
of articular cartilage is mainly type II collagen. Proteoglycans have a

strong affinity for water, resulting in the collagen network being

subjected to considerable tensile stresses. With loading, the cartilage

deforms and water is slowly squeezed on to surface where it helps to

form a lubricating film. When loading ceases, the surface fluid seeps back

into the cartilage up to the joint where the swelling pressure in the

cartilage is balanced by the tensile force of the collagen network. As long

as the network holds and proteoglycans remain intact, cartilage retains

intact its compressibility and elasticity. If the collagen network is

disrupted, the matrix becomes waterlogged and soft; loss of

proteoglycans, cellular damage and splitting of the articular cartilage, in

turn, follows.36

Pathogenesis37:

The pathological changes occur in articular cartilage, adjacent

bones and synovium. Articular cartilage transmits load and provides

bearing surface for joint motion. Deformable articular cartilage is able to

absorb some of the energy of impact. Because of the thinness, cartilage

transmits most of the loads to the subchondral plate.38

Articular cartilage has an important role in distributing and

dissipating the forces associated with joint loading. When joint load is

beyond the tolerance of the tissue, there is concomitant reduction in

10
 viscoelasticity and stiffness of articular cartilage.39 When it loses its

integrity these forces are increasingly concentrated to subchondral bone

and repetitive impulse loading of cartilage results in subchondral plate

stiffness associated with the loss of matrix proteoglycan.40 This results in

focal trabecular degeneration and cyst formation, as well as increased

vascularity and relative sclerosis in zone of maximal loading.41

Remaining cartilage is still capable of regeneration, repair and

remodeling.

The chemicals and debris abraded from the joint pass from

cartilage to synovial fluid and synovial membrane that lead to low grade

chronic synovitis and villous hypertrophy which eventually leads to

formation of spurs and bone cysts.42

The exposed subchondral bone is now under stress and undergoes

intensive activity and increased vascularity. Its growth continues and by

the traction of capsular attachment leads to formation of osseous

outgrowths called osteophytes which so clearly distinguish osteoarthritis

from ‘atrophic’ disorders such as rheumatoid disease.43

Cardinal features are:

• Progressive cartilage destruction.

• Sub-articular cyst formation.

• Sclerosis of the surrounding bone.

11
• Osteophyte formation.

• Capsular fibrosis.

Stages of osteoarthritis(Ultrastructural)44:

• Early: minute surface irregularities, loss of the fine fibrillar surface

covering, decrease in electron density of the interfiber matrix, cellular

changes (enlargement of cells in the superficial and middle zone), increase

in the amount of golgi apparatus, rough endoplasmic reticulum and in the

number of centrioles.

• Moderate: superficial layer infoldings deepen and extend toward

the deeper zones. The collagen fibers become arranged parallel to the

surface of these clefts in the superficial zone and perpendicular to the joint

surface in the middle and deep zones. In these zones, the viable

chondrocytes are hypertrophied and have increased number of intracellular

organelles having to do with synthesis. The number of degenerating

chondrocytes increases with the severity of the disease, and these cells

often contain large numbers of intracellular filaments and lysosome like

structure.

• Advanced: all cells appear degenerated and there are numerous

micro scars.

Complications of osteoarthritis of knee joint45:

12
• Capsular herniation.

• Loose bodies.

• Deformities (varus\valgus).

• Degeneration of menisci.

• Flexion contracture.

• Limitation of knee joint movements.

• Locking.

Differential diagnosis of osteoarthritis

• Rheumatoid arthritis.

• Pseudogout.

• Gout.

• Psoriatic arthritis.

• Collagen vascular disorders.

• Osteochondritis in adults.

Clinical features:

Pain46:

The pain associated with osteoarthritis is the single most important

cause of disability and handicap from the disease. The degree of pain

13
experienced may not necessarily reflect the severity of the condition as

determined by radiographic examination. The onset of pain is usually

gradual, initially only occurring after exertion. As the disease progresses,

pain becomes more frequent, and discomfort may be experienced at rest or

during the night, causing sleep disturbance.

Joint stiffness:

Joint stiffness whilst often severe, is usually transient. It normally

arises as a result of prolonged period of inactivity such as following a

night’s sleep (morning stiffness), and usually resolves with 30 minutes. A

grating sensation in the joint, ‘crepitus’ may also present in later stages47.

Loss of function:

Disability among the elderly may be more attributable to

osteoarthritis than to any other single condition. Whilst pain may be

primarily responsible for restricting activities; swelling, joint deformity

and restrictions in the range of motion of the joint also contribute to the

overall loss of function.48

Joint swelling:

Swollen joints in osteoarthritis tend to be hard due to the presence of

osteophytes, abnormal bony growths which are readily distinguishable on

X-ray. Some more malleable swelling may be attributable to effusion

14
and/or inflammation that is more frequent during an acute exacerbation of

the disease.49

Deformity:

Results from capsular contracture, joint instability or postural

abnormalaity.

Crepitus:

Crepitus on movements of joint is usually soft in the initial stages

but gets coarser and louder when cartilage is damaged and subchondral

bone is exposed.

Joint instability:

In late stages of disease joint instability occurs because of loss of

cartilage and bone, asymmetrical capsular contracture and muscle

weakness.50

Causes of pain in Osteoarthritis51:

Pain is the main symptom for which patients seek medical advice. In

osteoarthritis it is most common and frequent symptom due to occurrence

of pathological changes in various tissues of joint.

Tissue Pathological change
Subchondral bone Microfractures
Osteophytes Stretching of periosteum and rupture
Ligaments Inflammation and stretching
Enthesitis Inflammation of tendon-bone junctions
Joint capsule Inflammation, fibrosis and stretching
Periarticular muscle Spasm and fatigue
15
Synovium Inflammation
Micro and Macro debris Chemical and mechanical irritation
Radiological features:

1. Osteophyte

2. Joint space narrowing

3. Subchondral sclerosis

4. Subchondral cysts

Grading of osteoarthritis knee52:

Kellgren and Lawrence graded osteoarthritis of knee joint in to 5

grades based on radiological findings.

Grade 0: Normal

Grade 1: Questionable presence of osteophytes/questionable presence

of joint space narrowing/both.

Grade 2: Definite presence of osteophytes with possible joint space

narrowing or definite mild joint space narrowing

Grade 3: Definite moderate joint space narrowing (at least 50%)

Osteophytes usually present, Cysts/sclerosis may be present

Grade 4: Severe joint space narrowing

Grading the joint pain

Visual Analogue Scale (VAS)53

16
 In VAS a 100 mm line free of marking is commonly used, and the

patient is asked to mark the amount of pain at each visit.

Other scales include: WOMAC [Westren Ontario and McMaster’s

Universities] pain subscale54, HAQ[Health Assessment Questionnaire]55,

KGMC index.56

Management of osteoarthritis of the knee is based on both non-

pharmacological57 as well as pharmacological measures58 in addition to

surgical ones. Non-pharmacological measures are in the form of patient

education to reduce overweight, physical therapy, occupational therapy

and has been tried with some success.

Medical treatment consists of following modalities59

1. Symptom modifying drugs

• Acetaminophen

• NSAIDs

• Corticosteroids

• Opioids

2. Structure modifying drugs

• Glucosamine

• Chondroitin Sulphate

• Diacerein(60)

17
 • Viscosupplementation (Hyaluronic acid)61

3. Surgical Techniques

• Knee lavage

• Knee replacement

Current medical management is mostly palliative with NSAIDs

being the mainstay of therapy.62 They function as anti-inflammatory and

analgesic agents by inhibiting cyclooxygeanse enzyme (COX-1 & COX-

2) and thus decreasing synthesis of prostaglandins. Commonly used

NSAIDs include diclofenac potassium, naproxen, ibuprofen, celecoxib,

valdecoxib, rofecoxib.63 Onset of analgesia occurs rapidly usually within

one hour with all NSAIDs. Anti-inflammatory activity often requires a

week or more to become established.64

Non- selective NSAIDs cause a variety of side effects including

nausea, diarrhea, constipation, dizziness, headache, confusion, edema,

rash, and pruritis.65 They can also cause more serious toxicities such as

gastrointestinal (GI) ulceration/bleeding, hematologic disturbances,

bronchospasm, angioedema, renal dysfunction, and hepatotoxicity.66

Many of these are related to NSAID induced inhibition of COX –1

enzyme. COX-2 inhibitors67 can be considered for use because of better

gastrointestinal tolerability.68 Celecoxib, etoricoxib in the dose of 60

18
mg/day and valdecoxib as 10mg/day are as efficacious as non-selective

NSAIDs in pain relief.69 However recent studies are challenging the

cardiovascular safety of COX-2 inhibitors.70

Results from in vitro studies indicate that NSAIDs affect

proteoglycan metabolism of articular cartilage.71 Data from in vivo

studies suggest that salicylate administration may accelerate articular

cartilage damage in several animal models of osteoarthritis.72 Several

NSAIDs suppress proteoglycan synthesis by the chondrocyte at in vitro

concentrations comparable to those that are achieved in the synovial fluid

of patients treated with the drug.73 These NSAID-related effects on

chondrocyte metabolism appear unrelated to inhibition of prostaglandin

synthetase. These effects are much more profound in osteoarthritic

cartilage than in normal cartilage due to enhanced uptake of NSAIDs by

the osteoarthritic cartilage. Depletion of matrix proteoglycans appears to

be a major factor in the increased vulnerability of chondrocytes in

degenerating cartilage to effects of the symptomatic improvement

provided by NSAIDs. 67,74,75

Paracetamol (acetaminophen) has negligible anti-

inflammatory activity and acts by inhibition of cyclooxygenase

predominantly in the central nervous system.12 Acetaminophen is often

effective in osteoarthritis and associated with fewer adverse reactions

than NSAIDs. It is recommended as initial therapy for osteoarthritis in

19
addition to non-pharmacological interventions. Salicylates and traditional

NSAIDs are considered only for patients who do not obtain adequate pain

relief with Paracetamol.76

Combining nonsteroidal anti-inflammatory drugs (NSAIDs) and

acetaminophen for short courses provides more relief of pain in

osteoarthritis without an increase in side effects. Combining

acetaminophen at 4 g/d with an NSAID can also decrease the daily dose

of NSAID required for pain relief, thus reducing the potential risk from

higher-dose NSAID therapy.77

However over the long term this combination may increase the risk of

upper gastrointestinal bleeding more than that conferred by the NSAID

alone. If combination therapy is necessary, limiting the dose of

acetaminophen to < 2 g/d minimizes gastrointestinal toxicity.78

Several small-randomized controlled trials comparing the individual

efficacy of NSAIDs and acetaminophen in osteoarthritis have found that

both provide more pain relief than placebo. In the initial treatment period

NSAIDs provide more pain relief compared with acetaminophen.79 One

randomized controlled trial comparing 750 mg/d naproxen with 2600

mg/d acetaminophen for 2 years found similar pain relief for both

medications and a dropout rate of 65% in both groups. Similar numbers

of persons taking acetaminophen or naproxen dropped out because of

20
adverse effects (20%) or lack of efficacy (19%). No difference was seen

in functional improvement between the 2 groups.80

A 6-week randomized double-blind crossover trial of 227

patients compared 75 mg diclofenac and 200 mg misoprostol with

acetaminophen 4 g/d. Diclofenac-misoprostol combination provided

more pain control than acetaminophen alone. Adverse events were

slightly more common in the diclofenac group (54% vs 46%; P=.046).81

The COX-2 inhibitors rofecoxib and celecoxib have been shown

to provide equal pain relief compared with naproxen for patients with

osteoarthritis.82 In a randomized trial rofecoxib was found superior to

both celecoxib and acetaminophen in treatment of osteoarthritis pain.

There was no difference in the incidence of side effects among the 3

medications. Thirty percent of patients taking 4 g/d acetaminophen

discontinued the study because of lack of efficacy, compared with 20% of

those taking either celecoxib or rofecoxib.83

Few studies have evaluated the safety or efficacy of the

combination of NSAIDs and acetaminophen in osteoarthritis. One

double-blind, double-dummy crossover trial of 18 patients with

osteoarthritis of the hip compared naproxen at doses of 500 mg and 1000

mg, with and without 4 g/d of acetaminophen, and 1500 mg/d of

21
naproxen alone over 5 one-week trial periods. Adding acetaminophen

improved patient-reported pain scores compared with naproxen alone.

Higher doses of naproxen alone provided less pain relief than a lower

dose of naproxen combined with acetaminophen. GI side effects

increased with the increase in naproxen dose, but were unaffected by the

addition of acetaminophen. Functional ability was not affected during this

short study.84 No studies have evaluated the efficacy or safety of

acetaminophen combined with rofecoxib or celecoxib.

A meta-analysis of randomized controlled trials found a higher incidence

of serious thrombotic cardiovascular events among patients taking COX-

2 inhibitors compared with naproxen.85

The American College of Rheumatology (ACR) recommends

acetaminophen up to 4 g/d as a first-line pharmacologic treatment for

osteoarthritis of the hip and knee, and advises NSAIDs be used at the

lowest effective dose if they are necessary for pain control.86 The ACR

does not specifically comment on combining NSAID and acetaminophen

use. The American Academy of Orthopaedic Surgeons recommends

initial use of an NSAID or acetaminophen but does not comment on the

combination of NSAIDs and acetaminophen.

22
 NSAIDs although, particularly useful in controlling the

symptoms of acute phase of osteoarthritis, do not affect the underlying

pathogenesis of the disease. With these only pain is relieved, arthritis is

still free to progress and worsen. So, there is need for combining the

drugs targeting the underlying disease pathogenic mechanisms87 along

with NSAIDs, so that both the disease symptomatology as well as disease

progression can be targeted.

The drugs that modify the disease progression are classified as

symptomatic slow acting drugs in osteoarthritis (SYSDOA).88 These

include Glucosamine-chondriotin sulphate combination, Diacerein89 and

Hyaluronic acid.90 These drugs have a slow onset of efficacy and long

carry over effect once treatment is interrupted.59

Glucosamine is a precursor for glycosaminoglycans and help to

rebuild cartilage in osteoarthritis. Its use as a therapy for osteoarthritis

appears safe but there is conflicting evidence as to its effectiveness.

Multiple clinical trials in the 1980s and 1990 demonstrated a benefit for

glucosamine. However, these studies were of poor quality due to

shortcomings in their methods, including small size, short duration, poor

analysis of drop-outs, and unclear procedures for blinding.91,92 Two large

three-year-long, placebo-controlled clinical trials demonstrated a clear

benefit for glucosamine treatment.93,94 There was not only an

improvement in symptoms but also an improvement in joint space

23
narrowing on radiographs. This suggested that glucosamine, unlike pain

relievers such as NSAIDs, can actually help prevent the destruction of

cartilage that is the hallmark of osteoarthritis. A review by Bruyere et al.

about glucosamine and chondroitin sulfate for the treatment of knee and

hip osteoarthritis concludes that both products act as valuable

symptomatic therapies for osteoarthritis disease with some potential

structure-modifying effects.95 The National Institutes of Health-sponsored

GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) compared

placebo, glucosamine hydrochloride, chondroitin sulfate, a combination

of glucosamine and chondroitin sulfate and celecoxib in a parallel,

blinded 6-month multicentre study of patients with knee OA. This trial

showed that glucosamine hydrochloride and chondroitin sulfate alone or

in combination did not reduce pain effectively in the overall group of

patients with OA of the knee. However, exploratory analyses suggest that

the combination of glucosamine hydrochloride and chondroitin sulfate

may be effective in the subgroup of patients with moderate-to-severe

knee pain.19

A review conducted by Anderson et al in 2005 summarizes the

effects of glucosamine on glucose metabolism in in vitro studies, the

effects of oral administration of large doses of glucosamine in animals

and the effects of glucosamine supplementation with normal

recommended dosages in humans, concluding that glucosamine does not

24
cause glucose intolerance and has no documented effects on glucose

metabolism. Other studies conducted in lean or obese subjects concluded

that oral glucosamine at standard doses does not cause or significantly

worsen insulin resistance or endothelial dysfunction.96,97 A recent trial

studied insulin resistance in patients of OA taking oral glucosamine.

Study result showed that patients with underlying poorer insulin

sensitivity are at risk for worsening insulin resistance and vascular

function with the use of glucosamine in doses used to treat

osteoarthritis.98

A study was done to compare the chondroprotective effect of diacerein

and glucosamine regarding degenerative changes and articular stiffness in

an experimental model of arthritis. Comparison of the two drugs showed

that the degree of articular stiffness was significantly lower with

diacerein, although degenerative changes were similar.99

Much of the attention is focused on identifying the agents

responsible for the initial occurrence of matrix degradation.100 Current

knowledge clearly indicates the involvement of matrix

metalloproteases.101 Research over the last two decades has shown that

the cytokine interleukin-1-beta (IL-1b) plays a key role not only in

cartilage degradation102 but also in subchondral bone remodelling103,

chondrocyte apoptosis and joint inflammation.104 IL-1 plays a

25
fundamental role in osteoarthritis pathophysiology and cartilage

destruction as shown in figure 1. IL-1 also promotes expression of

inducible nitric oxide synthase, increase release of prostaglandin E2, IL-

6, IL-8 in human osteoarthritis chondrocytes, which promote joint

degradation.105,106 Diacerein, a purified compound with anthraquinonic

structure, has been shown to inhibit, in vitro107 and in vivo108, the

production and activity of IL-1 and the secretion of metalloproteases,

without affecting the synthesis of prostaglandins.109 Hence, by inhibiting

IL-1(110) diacerein retards all pathological prepossess initiated in OA

(Figure 1). Diacerein also inhibits IL-1 induced expression of cartilage

degrading enzymes.111 It also enhances expression of TGF BETA-1 and

TGF BETA-2 thus favoring matrix synthesis and turnover in articular

chondrocytes112, thereby accounting for disease modifying property of

diacerein(figure1). It also inhibits superoxide production, chemotaxis and

phagocytic activity of neutrophils110,113 in addition to effect on

macrophage migration and phagocytosis.114

DIACEREIN
IL-1

Activates
Monocytes/ Induces
Activates Activates
Macrophages fibroblast
chondrocytes osteoclasts
proliferation

26
 Inflammati Synovial Bone
Cartilage
on Pannus resorption
Breakdown
Formation

Figure 1

Diacerein inhibits IL-1 production and prevents cartilage degradation115

Diacerein116

Name:Diacerein,Diacetylrhein

Systematic name:

• 2-Anthracenecarboxylic acid, 4,5-bis(acetyloxy)-9,10-dihydro-

9,10-dioxo- (9CI)

• 2-Anthroic acid, 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-,

diacetate

• 9,10-Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthroic acid, diacetate

Formula:C19-H12-O8

Synonyms:

• 1,8-Diacetoxyanthraquinone-3-carboxylic acid

27
 • 4,5-Diacetylrhein

• 9,10-Dihydro-4,5-diacetoxy-9,10-2 anthracenecarboxylic acid

• 9,10-Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthroic acid diacetate

Chemical Structure of Diacerein:

Metabolism:117

Diacerein is entirely converted into rhein before reaching the systemic

circulation. Rhein itself is either eliminated by the renal route (20%) or

conjugated in the liver to rhein glucuronide (60%) and rhein sulfate

(20%); these metabolites are mainly eliminated by the kidney. The

pharmacokinetics characteristics of diacerein are about the same in young

healthy volunteers and elderly people with normal renal function, both

after a single dose (50 mg) or repeated doses (25 to 75 mg twice daily).

Rhein kinetics after single oral doses of diacerein are linear in the range

50 to 200 mg. However, rhein kinetics are time-dependent, since the

nonrenal clearance decreases with repeated doses. This results in a

28
moderate increase in maximum plasma concentration, area under the

plasma concentration-time curve and elimination half-life. Nevertheless,

the steady-state is reached by the third administration and the mean

elimination half-life is then around 7 to 8 hours. Taking diacerein with a

standard meal delays systemic absorption, but is associated with a 25%

increase in the amount absorbed. Mild-to-severe (Child Pugh's grade B to

C) liver cirrhosis does not change the kinetics of diacerein, whereas mild-

to-severe renal insufficiency (creatinine clearance < 2.4 L/h) is followed

by accumulation of rhein which justifies a 50% reduction of the standard

daily dosage. Rhein is highly bound to plasma proteins (about 99%), but

this binding is not saturable so that no drug interactions are likely to

occur, in contrast to those widely reported with nonsteroidal anti-

inflammatory drugs. The optimal daily dose which relief symptoms in

osteoarthritis knee calculated from effect on VAS assessment criteria of

pain on movement was found to be 100mg/day. Diacerein is well

tolerated, the predominant adverse effect include transient change in

bowel habits. It seems neither responsible for gastrointestinal bleeding

nor for renal, liver nor hematological toxicities. Non significant

discoloration of urine occurs during treatment because of urinary

elimination of metabolites of diacerein. No allergic cutaneous reaction

were reported in knee osteoarthritis trial. In 3 year hip osteoarthritis trial,

29
rash or pruritis was noted in 3% patients on placebo and in 7% patients

on diacerein 100mg daily.

In a study conducted in 1989, Diacerein was given to 40

patients whose age ranged from 45 to 87 years. Diacerein 50 mg twice a

day was given for 4 weeks. The results were classified good in 78% of

the patients. Improvement was manifested after 2 weeks of starting

treatment. Diarrhoea was the only adverse effect in 15% of the cases. In

conclusion, Diacerein was shown to have positive effects on

osteoarthrosis.118

Another study evaluating the in vitro effects of

diacerhein and its active metabolite, rhein, on interleukin 1beta (IL-1beta)

and tumor necrosis factor-alpha (TNF-alpha) synthesis in human OA

synovial membrane was conducted in 1998. Levels of IL-1beta and TNF-

alpha were determined using specific ELISA in culture medium of human

synovial membrane explants incubated in the presence of 1 microg/ml of

lipopolysaccharide with or without therapeutic concentrations of

diacerhein and rhein. IL-1beta synthesis was significantly inhibited by

diacerhein and rhein (p < 0.02) at the cartilage level.21

A 16-week, randomized, double-blind, placebo-controlled,

parallel study with 3 diacerein dosages of 50 mg/day, 100 mg/day, and

150 mg/day (administered twice daily) was done to evaluate the efficacy

and safety of Diacerein. A total of 484 patients fulfilling the American

30
College of Rheumatology criteria for knee OA were enrolled in the study.

In the intent-to-treat population

• 100 mg/day diacerein (50 mg twice daily) was significantly

superior (P < 0.05) to placebo using the primary criterion (visual

analog scale [VAS] assessment of pain on movement).

• Significant improvement (P < 0.05) was also observed for the

secondary criteria, which included the Western Ontario and

McMaster Universities OA Index (WOMAC), the WOMAC

subscores and the VAS assessment of handicap.

• Mild-to-moderate transient changes in bowel habits were the most

frequent AEs, increasing with the dosage.

The study concluded that Diacerein can be an effective treatment for

symptoms in patients with knee OA at 50 mg twice daily dose.119

In another study Diacerein was investigated in

animal models of carrageenin-, zymosan-, or dextran-induced paw edema

and adjuvant-induced arthritis and in ovariectomized rats.

• In acute inflammatory models, unlike classical nonsteroidal anti-

inflammatory drugs such as naproxen and ibuprofen, diacerein

inhibited the rat paw edema induced by various agents.

• In the adjuvant-induced arthritic rats, diacerein at 100 mg/kg/day

significantly suppressed the paw edema and the increase in serum

31
 mucoprotein. Addition of 3 mg/kg/day naproxen to each diacerein

(3, 10, 30 mg/kg/day) dose resulted in significantly greater anti-

inflammatory activity than with naproxen alone.

These findings indicate that diacerein is a

novel anti-inflammatory drug with pharmacological properties different

from those of classical nonsteroidal anti-inflammatory drugs and support

the clinical investigation of the use of combination therapy with diacerein

and nonsteroidal anti-inflammatory drugs in patients with osteoarthritis.22

A systematic meta-analysis on randomized controlled

trials with diacerein was performed to provide an evidence-based

assessment of its symptomatic efficacy in the treatment of osteoarthritis.

Electronic databases were searched for randomized controlled trials with

diacerein. A manual review of the literature, abstracts, and posters was

also conducted. A total of 23 studies were identified, 19 of which were

included. Findings of meta-analysis showed

• Diacerein was significantly superior to placebo during the active

treatment phase (Glass score, 1.50 [95% confidence interval, 0.80-

2.20]).

• Both diacerein and nonsteroidal anti-inflammatory drugs

(NSAIDs) were similarly efficacious during the treatment period.

• Diacerein but not NSAIDs, showed a carryover effect, persisting

up to 3 months after treatment, with a significant analgesic-sparing

32
 effect during the follow-up period (Glass score, 2.06 [95%

confidence interval, 0.66-3.46]).

• Tolerability assessment revealed no differences between diacerein

and NSAIDs, although the latter showed more severe events.

This systematic meta-analysis provides evidence for the symptomatic

efficacy of diacerein in the treatment of knee and hip osteoarthritis, with

reasonable tolerability.120

A 17-week, randomized, double-dummy, diclofenac

sodium-controlled trial, with diacerein dosage of 100 mg/d and

diclofenac sodium of 75mg/d was done to evaluate the efficacy and safety

of diacerein in patients with knee osteoarthritis. A total of 223 patients

satisfying the American College of Rheumatology criteria for knee OA

were chosen. Totally 106 patients in the diacerein group and 107 patients

in the diclofenac group were considered qualified for the evaluation.

After 12 weeks of treatment, the total effective rates of

patients/physicians' overall assessment in diacerein and diclofenac groups

were 65.4%/61.6% and 61.2%/61.2%, respectively (P > 0.05). The

primary efficacy parameter [visual analog scale (VAS) assessment of

pain on 20 metres walking] and the secondary efficacy parameters

[tenderness on palpation, Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC), and 36-item Short-Form (SF-36) Health

33
Survey] significantly improved compared with baseline in both groups (P

< 0.05). In the follow-up period

• There were no obvious changes in above parameters in diacerein

group. However, in diclofenac group, pain on 20 metres walking,

tenderness on palpation, and WOMAC became aggravated after

withdrawing the drug for 4 weeks (P < 0.05).

• Moreover, the consumption of paracetamol was significantly

lower in diacerein group than in diclofenac group during follow-up

(P < 0. 001).

• The incidences of related adverse events were 35.7% in diacerein

and 45.1% in diclofenac group, respectively. Mild-to-moderate

gastrointestinal disorders were the most frequent adverse events.

The study concluded that Diacerein is as effective as

diclofenac sodium in treating patients with knee OA.121

A double blind randomised piroxicam-controlled, parallel-group

study was done to evaluate the efficacy, safety and carry-over effect of

diacerein, in comparison to piroxicam, in the treatment of Thai

patients with symptomatic knee osteoarthritis. A 7-day non-steroidal

anti-inflammatory drug washout period was followed by a 16-week

treatment period with either diacerein 100mg/day or piroxicam

20mg/day, and an 8-week treatment-free observation period. The

primary efficacy criterion was pain on Western Ontario and McMaster

34
 University Osteoarthritis (WOMAC) A. The secondary criteria

included WOMAC B, C and total WOMAC, paracetamol intake,

Short Form-36 questionnaire and global judgements on efficacy and

tolerability by patients and investigators. Of 171 randomised patients,

150 completed the study and 161 were analysed in the intent-to-treat

population (diacerein: 82, piroxicam: 79).

• Pain (WOMAC A) decreased to a similar extent in both groups at

Week 16 (diacerein: -69.7%+/-31.5%; piroxicam: -74.1+/-26.2%;

P=n.s.).

• On treatment discontinuation, pain increased in the piroxicam

group at Weeks 20 (-47%+/-47.8%) and 24 (-26.8%+/-60.6%)

while improvements persisted in the diacerein group at Weeks 20

(-66.9%+/-35.9%) and 24 (-69.5%+/-33.7%), with a significant

difference in favour of diacerein at Weeks 20 and 24,

demonstrating the carry-over effects of the drug.

• The incidence of adverse events was similar in both groups but

more patients from the piroxicam group dropped out of the study

due to these events.

• Diacerein was as effective as piroxicam in reducing pain and

improving function and has a better safety profile.122

Diclofenac sodium123

35
 Diclofenac sodium is an established therapy in

treatment of Osteoarthritis knee. It is an aryl–acetic acid derivative

NSAID.

Chemical name: [2-(2,6-Dichloroanilino)phenyl]acetic acid

Molecular formula: C14H10Cl2NNaO2 =318.

Chemical structure:

It is a non-selective inhibitor of prostaglandin synthesis. It is available in

various dosage forms for different routes of drug administration.

Diclofenac is efficiently absorbed from the gastrointestinal tract; peak

plasma concentrations occur 1.5 to 2.0 hours after ingestion in fasting

subjects. Even though diclofenac has a relatively short elimination half-

life in plasma (1.5 hours), it persists in synovial fluid. The drug is

metabolized in the liver and is eliminated by urinary and biliary

excretion. In clinical trials, diclofenac was as effective as aspirin,

diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, and naproxen

in improving function and reducing pain in patients with rheumatoid

arthritis. For treatment of osteoarthritis, diclofenac was equivalent in

36
efficacy to aspirin, indomethacin, sulindac, ibuprofen, ketoprofen,

naproxen, flurbiprofen, mefenamic acid, and piroxicam Bioavailability of

diclofenac is 30-70% due to first pass metabolism. It accumulates in

synovial fliud with good tissue penetration. Gastrointestinal adverse

effects are more common in form of epigastric pain, nausea, gastric

ulceration and GIT bleeding. Diclofenac is eliminated following

biotransformation to glucoroconjugated and sulphate metabolites which

are excreted in urine, very little drug is eliminated unchanged.

MATERIAL AND METHODS

The approval for the protocol of study was sought from the

institutional thesis committee and the institutional ethics committee.

After obtaining approval from the concerned authorities, the study was

initiated and sixty subjects were recruited in accordance with the

established protocol.

Drugs investigated were:

1. Capsule Diacerein 50 mg once daily

2. Tablet Diclofenac sodium 75 mg sustained release once

daily

37
A total of 60 patients of symptomatic osteoarthritis visiting the

OPD/Wards of the Department of Orthopaedics, Guru Teg Bahadur

Hospital attached to the Government Medical College, Amritsar were

recruited in the present study after the inclusion criterion was fulfilled.

Inclusion criteria:

Patients who fulfill American College of Rheumatology criterion for the

diagnosis of osteoarthritis and were found fit in baseline examination

were included in the present study as per given below:

1. With symptomatic osteoarthritis of age 35 to 60 years

2. New or old patients of OA on NSAIDS or other analgesic

medications after their discontinuation with a wash out period of

one week.

Exclusion criteria:

Patients were excluded in the present study who:

1. Were of age less than 35 years or more than 60 years.

2. Present with active concomitant gastroduodenal disorders, hepatic

and renal impairment within last 30 days prior to receiving the

study drug.

3. Were having active cardiac lesion or hypertension.

4. Were pregnant females and those who were planning their

pregnancy during the study.

38
 5. Have received oral, intramuscular, intraarticular or soft tissue

injections of corticosteroids within last four weeks before

receiving the first dose of the study medication.

6. Were diagnosed to have any inflammatory arthritis, gout or acute

trauma of the knee, hip or spine.

7. Were having a known hypersensitivity to NSAIDS.

8. Were having any known contraindication of the said drugs.

9. Were female patients on oral contraceptive pills.

• Informed consent was sought from all the patients included in

the present study.

Experimental methods:

It was a prospective, single blind, placebo-controlled and

intention to treat study, conducted in accordance with the principles of

good clinical practice and the Declaration of Helsinki.

Sixty patients were randomly divided into two groups as A & B,

consisting of 30 patients each. Patients were recruited in these groups on

the basis of random number assigned to them. The duration of the study

was three months. Patients were examined and evaluated at week zero,

third, sixth and twelfth for clinical efficacy and safety of study drug. The

study drug was withdrawn at the end of third month and the patients were

39
examined and evaluated for carry over effect of drug under investigation

at the end of fourth month.

The patients were advised to bring the empty blister packs of the

medications at every visit to ensure compliance with medication.

Experimental groups:

Group A

Patients in this group received Tab. Diclofenac sodium 75 mg

sustained release once daily for three months and placebo as

capsule once daily for first month and twice daily for second and

third month.

Group B

Patients in this group received Tab. Diclofenac sodium 75 mg

sustained release once daily for three months and capsule Diacerein 50

mg once daily for first month and twice daily for second and third month.

Parameters:

Screening or baseline clinical assessment of osteoarthritis: -

Screening or baseline clinical assessment of osteoarthritis

included patient’s assessment of arthritic pain on a Visual Analogue

Scale (VAS), Western Ontario and McMaster Universities (WOMAC)

osteoarthritis index, patients and physician’s global assessment of

osteoarthritis.

40
Visual Analogue Scale (VAS)53

A visual analogue scale which is a 100mm long vertical line with the

extremes marked as ‘no pain’ on one end while the extremely unbearable

pain on the other end, was used for this study. The subject was asked to

put a mark on this scale that correlates best with his perception of pain

and accordingly patients pain score was recorded.

VAS was utilized at the level of screening of the patient to

100
determine the initial pain score and was also used for efficacy assessment

at the intervals at which the patients were subsequently examined.

0 100
No Pain VAS Scale Unbearable Pain

WOMAC Osteoarthritis Index54

The WOMAC Osteoarthritis index score and the osteoarthritis severity

index score was calculated on a scale based upon the Western Ontario

and McMaster Universities (WOMAC) osteoarthritis index. The

WOMAC measures three separate dimensions, five regarding pain, two

regarding joint stiffness and seventeen concerning physical function.

DAY O 3WEEKS 6WEEKS 12WEEKS

PAIN ASSESSMENT ON V.A.S.
SEVERITY
(A) PAIN
1. Walking on a flat surface
2. Going up or down stairs
3. At night while in bed
4. Sitting or lying
5. Standing upright
(B) STIFFNESS
1. Severity of stiffness after first waking in

41
the morning
2. Severity of stiffness after sitting/lying

or resting later in

the day.
(C) FUNCTION: DEGREE OF DIFFICULTY

WHILE
1. Descending stairs
2. Ascending stairs
3. Rising from sitting
4. Standing
5. Bending to floor
6. Walking on a flat surface
7. Getting in/out of car or any other vehicle
8. Going shopping
9. Putting on socks/stockings/shoes
10. Rising from bed
11. Taking off socks/stockings/shoes
12. Lying in bed
13. Letting in/out of bath
14. Sitting
15. Getting on/off toilet
16. Heavy domestic duties
17. Light domestic duties
PATIENT’S GLOBAL ASSESSMENT
(1) Very Good
(2) Good
(3) Fair
(4) Poor
(5) Very Poor
PHYSICIAN’S GLOBAL ASSESSMENT
(1) Very Good
(2) Good
(3) Fair
(4) Poor
(5) Very Poor

Each item will be rated on a 5- point scale

0 = None,

1 = Mild,

2 = Moderate,

3 = Severe,

4 = Extreme,

Yielding maximum possible subscale scores of 20, 8 and 68 for pain,

stiffness and physical functioning respectively. WOMAC composite

42
scores (possible range 0-96) was calculated by addition to individual item

scores.

• WOMAC user aggrement was obtained before using the

WOMAC scale(Appendix-3)

Patient’s Global Assessment:

Patient’s global assessment was utilized to know the patients overall

perception of his/her condition. Accordingly the patients were put in

various categories in relation to their condition. This was labeled as very

good, good, fair, poor and very poor. This was first done to assess the

patient’s condition at the time of screening and then as a prognostic

criteria post treatment for ascertaining any improvement or deterioration

in the patient’s condition.

Physician’s global assessment:

Physician’s global assessment was used to know the physician’s

assessment of the patient’s condition. Accordingly the physician

categorized the patient’s condition as very good, good, fair, poor and very

poor. Physician’s global assessment was done at the time of screening

and then as a prognostic criterion post treatment for assessing any

improvement or deterioration in patient’s condition.

Baseline Laboratory Investigations:

43
 The investigation carried out at zero day and twelve week

were:

• X-ray of both the knees AP view and lateral view were taken to

corroborate the diagnosis of osteoarthritis.

• Hemoglobin estimation.

• Urine examination.

The results of the study were tabulated in the form of mean ± standard

deviation (SD) and analyzed using unpaired ‘t’ test. The level of

significance was determined as its p value with p < 0.05 taken as

statistically significant.

OBSERVATIONS

Out of total 84 patients screened, 74 have been found eligible to be

included in the study and were randomized to either group A or group B.

N=84 44
Patients screened
 30 patients in each group completed the treatment period of 3months to

form the per-protocol population.

N=10
Screening failure reason:
Did not met selection criteria(9)
Patient’s decision(1)

N=74 patients randomised

N=74 patients receiving single

blind medication

N=37 N=37
Diclofenac + Diacerein Diclofenac + Placebo

N=30 N=7 patients N=7 patients N=30

patients completed discontinued discontinued patients completed
study: per-protocol Adverse event(5) Adverse event(5) study: per-protocol
population Lost due to follow up(2) Lack of efficacy(1) population
Lost due to follow up(1)

Fig 2. Disposition of patients

Table 1. Baseline Characteristics

Parameter Group A Group B

30 30
Total No.
52.167±6.608 53.133±4.725
Age, years
80.56±14.57 81.66±13.55
Weight, Kg

45
 161.45±8.45 160.33±8.11
Height, cm
BMI, Kg/m2 31.01±5.31 31.55±5.76

Body
Sex(F:M)* VAS 22:08
Scores 20:10
weight
(BMI)Duration (year) Group A
Disease 5.62±5.98 Group B 6.1±5.64
< 60 61-80 81-100 < 60 61-80 81-100
Normal
Diabetic* 2 2 1 14 0 1 15 0
(18.5-24.9)
Hypertensive* 4 5
Overweight 0 9 2 0 4 6
VAS**
(25-29.9) 78.333±11.769 80.667± 10.400

WOMAC PAIN** 16.633±1.497 16.767± 1.406

Obese 0 5 9 2 9 8
(>30)
WOMAC STIFFNESS** 7.367±0.5561 7.30± 0.6513

WOMAC FUNCTION** 49.067±2.900 48.733±2.490

Hb > 10(mg/dl)* 19 22

Hb <10(mg/dl)* 11 8

*Number of patients
**Score

Table 2. Relationship between Body mass index (BMI) & VAS scores
at Day Zero
(n= number of patients)

Table 3. Relationship between Body mass index (BMI) & VAS scores
at Day Zero
(n= percentage of patients)

46
 Body
weight WOMAC Scores
(BMI) Group A Group B
61-70 71-80 >80 61-70 71-80 >80
Normal 1 3 0 0 1 0
(18.5-24.9)

Overweight 2 8 1 2 8 0
(25-29.9)

Obese 6 9 0 4 15 0
(>30)

Table 4. Relationship between Body mass index (BMI) & WOMAC

scores at Day Zero
(n= number of patients)

Body weight (BMI) VAS Scores

61-80 81-100
Overweight 13(21.66%) 8(13.33%)
(25-29.9)

Obese 14(23.33%) 17(28.33%)

(>30)

Combined Overweight 27(45%) 25(41.7%)

and Obese

Table 5. Relationship between BMI & WOMAC scores at Day Zero

47
 (n= percentage of patients)

Body weight WOMAC scores

(BMI)
61-70 71-80 >81

Overweight 4(6%) 16(26.6%) 1(1.6%)

(25-29.9)

Obese 10(16.66%) 24(40%) 0

(>30)

Combined 14(23.33%) 40(66.66%) 1(1.6%)

Overweight
and Obese

Table 6. Distribution of patients according to BMI in Group A &

Group B
(n= number of patients)

Body weight (BMI) Group A Group B

Normal 4 1
(18.5-24.9)

Overweight 11 10
(25-29.9)

Obese 5 19
(>30)

Table 7. Involvement of Knee in Group A & Group B

(n= number of patients)

48
Involvement of Knee Group A Group B

Unilateral 9 7
Group A Group B P value

Week 0
Bilateral 78.33± 11.7621 80.66 ±10.4 0.41
23

3rd week 52.5 ±10.8 52.66 ±10.2 0.95

6th week 26.5 ±6.45 33 ±8.8 0.0019*

3rd month 15.3± 5.07 22.83± 6.90 0.0017*

4th month 14.83 ±5.167 33± 7.724 0.0012*

Table 8. VAS scores in Group A & Group B

*Significant p value<0.05

49
 Table 9. WOMAC scores in Group A & Group B

Group A Group B P value

Week 0 72.66± 4.02 72.96 ±2.82 0.7392

3rd week 61.73± 3.413 61.97± 2.77 0.7724

6th week 32.4 ±3.047 47.66 ±3.29 0.0011*

3rd month 15.9 ±2.44 36.8 ± 2.92 0.0019*

4th month 16± 2.56 48.26± 3.5 0.0008*

*Significant p value<0.05

Table 10 A. Patient’s Global Assessment 3rd week

3rd week Very Good Fair Poor Very P value
good poor
Group A 6(10%) 11(18.33% 4 5 4 >0.05
)
Group B 5(8.33%) 9(15%) 4 6 6

Table 10 B. Patient’s Global Assessment 6th week

6th week Very good Good Fair Poor Very P value

poor
Group A 13(21.66% 9(15%) 4 2 2 <0.05
)
Group B 5(8.33%) 9(15%) 5 4 7

Table 10 C. Patient’s Global Assessment 3rd month

50
3rd month Very good Good Fair Poor Very P value
poor
Group A 16(26.66% 11(18.33% 2 1 0 <0.05
) )
Group B 7(11.66%) 7(11.66%) 8 6 2

Table 10 D. Patient’s Global Assessment 4th month

4th month Very good Good Fair Poor Very P value

poor
Group A 12(20%) 6(10%) 9 2 1 <0.05
Group B 4(6.66%) 5(8.33%) 15 3 3

Table 11 A. Physician’s Global Assessment 3rd week

3rd week Very Good Fair Poor Very P value
good poor
Group A 8(13.33%) 9(15%) 5 4 4 >0.05
Group B 4(6.66%) 5(8.33%) 9 6 6

Table 11 B. Physician’s Global Assessment 6th week

6th week Very good Good Fair Poor Very P value

poor
Group A 12(20%) 10(16.66% 4 2 2 <0.05
)
Group B 5(8.33%) 7(11.66%) 9 4 5

Table 11 C. Physician’s Global Assessment 3rd month

51
3rd month Very good Good Fair Poor Very P value
poor
Group A 15(25%) 10(16.66% 3 1 1 <0.05
)
Group B 7(11.66%) 7(11.66%) 12 2 2

Table 10 D. Physician’s Global Assessment 4th month

3rd month Very good Good Fair Poor Very P value

poor
Group A 14(23.33% 9(15%) 4 2 1 <0.05
)
Group B 6(10%) 6(10%) 13 2 3

Table 12. Commonly observed treatment-emergent Adverse Events

Group A Group B

Urine discoloration 10 1

Diarrhea 11 4

Dyspepsia 12 14

Abdominal pain 6 5

Bowel motility disorder 4 3

Constipation 1 1

Nausea 1 2

52
 Hypertension 2 1

Myalgia 1 1

Oedema 2 2

Dizziness 1 1

Figure 3A. Comparison of Group A & Group B for VAS Scores

53
Figure 3B. Comparison of Group A & Group B for VAS Scores

54
Figure 4A. Comparison of Group A & Group B for WOMAC Scores

55
Figure 4B. Comparison of Group A & Group B for WOMAC Scores

56
Figure 5A. Comparison of Group A & Group B for Physician’s
global judgement

57
Figure 5B. Comparison of Group A & Group B for Physician’s
global judgement

58
Figure 5C. Comparison of Group A & Group B for Physician’s
global judgement

59
Figure 5D. Comparison of Group A & Group B for Physician’s
global judgement

60
Figure 6A. Comparison of Group A & Group B for Patient’s global
judgement

61
Figure 6B. Comparison of Group A & Group B for Patient’s global
judgement

62
Figure 6C. Comparison of Group A & Group B for Patient’s global
judgement

63
Figure 6D. Comparison of Group A & Group B for Patient’s global
judgement

64
Figure 7. Comparison of paracetamol consumption between Group A
& Group B

65
 DISCUSSION

The main focus of research in osteoarthritis is to find a new

drug or adjuvant that can prevent or retard the progression of

degeneration of articular cartilage and that is why symptomatic slow

acting drug in osteoarthritis (SYSDOA) are receiving increasing attention

of researchers. These include glucosamine-chondriotin sulphate

combination, diacerein and hyaluronic acid. They have a slow onset of

efficacy with a long carry over effect once treatment is interrupted.

Diacerein has been reported to prevent cartilage degeneration.

This prompts the conduction of present study for evaluation of the

clinical effectiveness of Diacerein as add on therapy to Diclofenac

sodium in patients of osteoarthritis knee.

The baseline characteristics of the two groups were comparable

(Table 1). In the present study female preponderance (70%) was observed

which was in conformity with other studies conducted in China (83%)

and Thailand (93%). Average age was found 52 years in our study as

compared to other controlled trials where the reported age was 58 years

66
(China)121 and 54 years(Thailand)122. This showed that in Indian patients

osteoarthritis occurred in younger age group.

The present study has shown that involvement of Knee was

bilateral in 74 % of the patients (Table 7) whereas Louthrenoo W

reported bilateral involvement of knee in 84% of the patients.122

In present study out of 35 % (21) patients that fall in category

of overweight (BMI 25-29.9), 21.66% (13) have VAS score in range of

61-80 and 13.33%(8) in range of 81-100. In BMI category of obese

(BMI>30), out of total 61% (31) patients, 23.33% (14) have VAS score in

range of 61-80 and 28.33% (17) in range of 81-100. (Table 2, 3)

In present study out of 32.6% (20) patients that fall in

category of overweight(BMI 25-29.9), 6%(4) have WOMAC score in

range of 61-70 and 26.6%(16) in range of 71-80. In category of obese

(BMI>30), out of total 56.66%(34) patients, 16.66%(10) have WOMAC

score in range of 61-70 and 40%(24) in range of 71-80. (Table 4, 5)

This shows a positive correlation between BMI and VAS and

WOMAC scores that as BMI increases, VAS and WOMAC scores also

increases. This depicts that as BMI increases, severity of osteoarthritis

also increases with more deterioration in quality of life. This association

had also been reported by Tukker A which concludes a strong association

between overweight/obesity and osteoarthritis knee.124

67
 Baseline score for VAS(78.3±11.769) and WOMAC(72.667

± 4.020) in group A was comparable with score of VAS (80.667±10.40)

and WOMAC(72.967± 2.82) in group B with no significant difference(p

value >0.05)(Table 1).

At 3rd week, as compared to baseline, mean reduction in VAS of

25.83(32.97%) and WOMAC of 10.93(15.04%) in group A and a mean

reduction in VAS of 28(34.71%) and in WOMAC of 10.99(15%) in

group B( p value>0.05) has been observed. (Table 8,9)(Fig 3A, 4A)

At 6 th week, group A showed a mean reduction in VAS of

51.83(66%) and WOMAC of 40.26(55.4%) whereas in group B mean

reduction in VAS of 47.66(59%) and WOMAC of 25.3(34.6%) was

observed as compared to baseline, with a p value >0.05. (Table 8, 9)(Fig

3A, 4A).

At 3 rd month, reduction in mean VAS of 63 (80.4%) and

WOMAC of 56.76 (78.11%) in group A and reduction in mean VAS of

57.83(71.69%) and WOMAC of 36.16 (49.56%) in group B was

observed as compared to baseline (p value<0.05)(Table 8, 9). Our study

confirmed the results found by Pelletier in a controlled trial of

diacerein.119

Analyzed at 3rd week, difference between two groups for scores of

VAS and WOMAC was non-significant, p value >0.05. At 6th week,

68
group A showed a significant difference over group B for mean scores of

VAS by 6.5(19.1%) and WOMAC by 15.26(32%) (p value<0.05)(Fig 3B,

4B). This confirmed the observation of Provvedini125 that diacerein takes

4-6 weeks to show its effect in contrary to observation made by Mazzar118

where favourable effects of diacerein were observed after 2 weeks of

starting the treatment. At 3rd month, significant difference among two

groups for VAS of 7.53(32.98%) and WOMAC of 20.9(56.79%) was

observed (p value <0.05) with group A being superior to group B. During

the follow up period rise in scores of VAS 10.17(30.81%) and WOMAC

11.46(23.74%) in group B was significant (p value<0.05) whereas rise in

scores of VAS and WOMAC in group A was non significant (p

value>0.05) (Fig 3B, 4B). This demonstrates the carry over effect of

diacerein in patients of group A that has also been reported in a double-

blind, randomised, piroxicam-controlled study.122

In physician’s global efficacy judgement, after 3 weeks of

treatment, physician assessed 9(15%) patients in group A and 5(8.33%)

patients in group B as good and 8(13.33%) patients in group A and

4(6.66%) patients in group B as very good with no significant difference

between two groups (p value >0.05). (Fig 5A)(Table 11A). At 6 th week,

greater proportion of patients in group A (12(20%)) were assessed as very

good as compared to group B (5(8.33%)) and 10(16.66%) patients in

group A and 7(11.66%) in group B were assessed as good with

69
significant difference among two groups(p value <0.05) (Fig 5B)(Table

11B). At 3rd month, physician’s judgements were again in favour of group

A with 15(25%) patients being assessed as very good as compared to

7(11.66%) patients in group B whereas 10(16.66%) patients in group A

and 7(11.66%) patients in group B were assessed as good (p value <0.05)

(Fig 5C)(Table 11C). At 4th month, physician assessed

14(23.33%)patients in group A, 6(10%) patients in group B as very good

and 9(15%) patients in group A, 6(10%) patients in group B as good (p

value <0.05) (Fig 5D)(Table 11D).

In Patient’s Global efficacy judgement, after 3 weeks of treatment,

11(18.33%) patients in group A and 9(15%) patients in group B assessed

the treatment as good and 6(10%) patients in group A and 5(8.33%)

patients in group B assessed the treatment as very good with no

significant difference (p value >0.05) (Fig 6A)(Table 10 A). At 6 th week,

greater proportion of patients in group A (13(21.66%)) assessed the

treatment as very good as compared to group B (5(8.33%)) and 9(15%)

patients each in group A and group B assessed the treatment as good (p

value <0.05) (Fig 6B) (Table 10 B). At 3rd month, judgements were again

in favour of group A with 16(26.66%) patients assessing the treatment as

very good as compared to 7(11.66%) patients in group B whereas

11(18.33%) patients in group A and 7(11.66%) patients in group B

assessed the treatment as good (p value <0.05) (Fig 6C)(Table 10 C). At

70
4th month, 12(20%) patients in group A and 4(6.66%) patients in group B

assessed the treatment as very good and 6(10%) patients in group A and

5(8.33%) patients in group B assessed the treatment as good (p value

<0.05) (Fig 6D)(Table 10 D). Similar results of global efficacy

judgements of patient and physician were found in various other

controlled trials of Diacerein.116,126,127

Observations showed that the mean number of paracetamol

consumption during the follow up period was significantly lower in group

A(6) as compared to group B(12), p value <0.05(Fig 7). This further

supports the fact that diacerein has a carry over effect after stopping the

treatment that is in conformity with results reported in a 17-week,

randomized, double-dummy, diclofenac sodium-controlled trial where

paracetamol consumption was lower in diacerein group(5.83±16.6) as

compared to diclofenac group(21±31.12), p value<0.05.116

Adverse effect profile was similar with regard to upper GIT side

effects with equal number of patients suffered from flatulence, dyspepsia

and nausea in both the groups. Diarrhoea occurred in 11 patients in

group A as compared to 4 patients in group B, p value <0.05(Table 12).

Although the incidence of diarrhoea was higher in diacerein group, it was

self-limiting. In our study diarrhoea was observed with diacerein in 36%

of the patients whereas in other clinical trials incidence of 20-40% was

reported with diacerein.23,126

71
 Yellowish discoloration of urine was observed in 10 (33.33%)

patients in group A. On urine analysis, no red blood cell was found in any

of the case. Non significant discoloration of urine occurred during

treatment because of urinary elimination of metabolites of diacerein.

Similar results of urine discoloration were found in a study on diacerein

in which 50% of the patients were having urine discoloration.127

No hepatic function abnormality was recorded in our study

whereas in one study in china121, two cases of increase in hepatic enzymes

were observed that returned to normal after discontinuation of therapy. In

the present study, no serious adverse event was recorded in any of the

groups.

The present work has demonstrated that use of diacerein in combination

with diclofenac sodium caused improvements in pain and functional

indices of VAS and WOMAC significantly better than diclofenac alone.

Also, the overall patient and physician global assessment is better with

the combination therapy.

The better improvement of symptomatology in group A on

combination therapy is probably due to the fact that diacerein is having

reported analgesic, anti-inflammatory and chondroprotective activity.

Diacerein inhibits production of cytokine interleukin-1-beta (IL-1b) that

plays a key role not only in cartilage degradation but also in subchondral

bone remodelling, chondrocyte apoptosis and joint inflammation.120

72
 Hence, by inhibiting IL-1 diacerein retards all pathological processes

initiated in OA (Fig 1). Diacerein had also been reported to inhibit IL-1

induced expression of cartilage degrading enzymes and to enhance

expression of TGF BETA-1 and TGF BETA 2 thus favoring matrix

synthesis and turnover in articular chondrocytes, thereby accounting for

disease modifying property of diacerein as shown in fig-1. It also inhibits

superoxide production, chemotaxis and phagocytic activity of neutrophils

in addition to effect on macrophage migration and phagocytosis.23,128,129

Diarrhoea is possibly due to the fact that derivatives of diacerein

have a laxative effect. Another hypothetical explanation is that because

diacerein has been shown to be capable of inducing prostaglandins

synthesis, a local increase in PGs may lead to an increase in gut motility

and thus causes diarrhea.116

Present research work has demonstrated that diacerein

as adjuvant to diclofenac sodium is useful in patients of osteoarthritis

knee, provided its effect is confirmed in larger multicentric trials of

longer duration.

73
 SUMMARY AND CONCLUSION

Present study was undertaken to evaluate the clinical effectiveness of

Diacerein as add on therapy to Diclofenac in patients of osteoarthritis

knee. 60 patients who met American College of Rheumatology criteria

for OA were randomly divided in two groups of 30 patients each.

Diclofenac sodium 75mg sustained release tablet once daily was given to

both groups for 3 months. Capsule diacerein 50mg in study group and

matched placebo in control group were given once daily for first month

and twice daily for next two months. After 3 months, drug therapy was

withdrawn and patients were observed for one more month, using

paracetamol as rescue therapy.

Treatment efficacy was assessed by Visual Analogue Scale(VAS)

and Western Ontario and McMaster University(WOMAC) Osteoarthritis

Index and global patient and physician assessment at week 3, 6 and at 3rd

and 4th months.

Present study demonstrated the following:

1. Average age of the patients was found to be 52.45 ± 4.82 years

2. Female preponderance was seen with female: male ratio of 21:9

74
3. Number of patients in BMI category of normal, overweight and

obese was 6(10%), 21(35%) and 33(55%) respectively.

4. In BMI category of overweight 21(35%) have VAS above 60

whereas in obese 31(61%) patients have VAS above 60. This

depicts that as BMI increases, severity of osteoarthritis also

increases with more deterioration in quality of life.

5. A non significant difference between two groups at 3rd week for

scores of VAS(0.16) and WOMAC (O.24)

6. A significant difference between two groups at 6th week for

scores of VAS 6.5(19.1%) and WOMAC 15.26(32%) showed

has taken 6 weeks to show its effect.

7. A significant difference between two groups at 3rd month for

scores of VAS 7.53(32.98%) and WOMAC 20.9(56.79%)

8. A significant rise in scores of VAS 10.17(30.81%) and

WOMAC 11.46(23.74%) during the follow up period in group

B that received diclofenac alone

9. Non- significant rise in scores of VAS and WOMAC during the

follow up period in group A that received diclofenac along with

diacerein.

10. A significant difference in number of paracetamol consumption

in group A(6) as compared to group B(12)

75
 11. Diarrhoea (36%) and yellowish discoloration of urine (33%) as

the most common adverse effects with diacerein. Diarrhoea was

self limiting in nature and yellowish discoloration of urine was

of no clinical relevance.

12. Dyspepsia occurred in 12(20%) patients in group A and

14(23.33%) patients in group B.

From the observations made in the present study it can be concluded

that

• Combination therapy improves patient symptomatology

as well as quality of life better than diclofenac sodium

alone.

• Diacerein has a carry over effect.

• Diacerein as adjuvant to diclofenac sodium is well

tolerated.

Presently therapy focuses on treating osteoarthritic pain only with

NSAIDs. Diacerein could be useful adjuvant to NSAIDs in patients of

osteoarthritis knee provided, these results are confirmed in larger

multicentric trials of longer duration.

76
 BIBLIOGRAPHY

(1) Woolf AD, Pfleger B. Burden of major musculoskeletal conditions.

Bull World Health Organ 2003; 81(9):646-656.

(2) Rubin BR. Osteoarthritis. J Am Osteopath Assoc 2001; 101(4

Suppl Pt 2):S2-S5.

(3) Brandt KD. Osteoarthritis. Clin Geriatr Med 1988; 4(2):279-293.

(4) Spector TD. Epidemiology of the rheumatic diseases. Curr Opin

Rheumatol 1993; 5(2):132-137.

(5) Chopra A, Patil J, Billempelly V, Relwani J, Tandle HS.

Prevalence of rheumatic diseases in a rural population in western

India: a WHO-ILAR COPCORD Study. J Assoc Physicians India

2001; 49:240-246.

(6) Global Burden of Disease 2000. World Health Organization . 8-15-

2006. Ref Type: Electronic Citation

77
 (7) Ndongo S, Ka MM, Leye A, Diallo S, Niang EH, Sy MH et al.

[Epidemiological and clinical features of the knee osteoarthritis].

Dakar Med 2003; 48(3):171-175.

(8) Sarzi-Puttini P, Cimmino MA, Scarpa R, Caporali R, Parazzini F,

Zaninelli A et al. Osteoarthritis: an overview of the disease and its

treatment strategies. Semin Arthritis Rheum 2005; 35(1 Suppl 1):1-

10.

(9) Singh G. Treatment options for osteoarthritis. Surg Technol Int

2003; 11:287-292.

(10) Dingle JT. Cartilage maintenance in osteoarthritis: interaction of

cytokines, NSAID and prostaglandins in articular cartilage damage

and repair. J Rheumatol Suppl 1991; 28:30-37.

(11) Goodwin JL, Kraemer JJ, Bajwa ZH. The use of opioids in the

treatment of osteoarthritis: when, why, and how? Curr Pain

Headache Rep 2005; 9(6):390-398.

(12) Brandt K. [Paracetamol in the treatment of osteoarthritis pain].

Drugs 2003; 63 Spec No 2:23-41.

(13) Emkey R, Rosenthal N, Wu SC, Jordan D, Kamin M. Efficacy and

safety of tramadol/acetaminophen tablets (Ultracet) as add-on

78
 therapy for osteoarthritis pain in subjects receiving a COX-2

nonsteroidal antiinflammatory drug: a multicenter, randomized,

double-blind, placebo-controlled trial. J Rheumatol 2004;

31(1):150-156.

(14) Buescher JS, Meadows S, Saseen J. Clinical inquiries. Does

acetaminophen and NSAID combined relieve osteoarthritis pain

better than either alone? J Fam Pract 2004; 53(6):501-503.

(15) Goldberg SH, Von Feldt JM, Lonner JH. Pharmacologic therapy

for osteoarthritis. Am J Orthop 2002; 31(12):673-680.

(16) Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral

glucosamine in doses used to treat osteoarthritis worsens insulin

resistance. Am J Med Sci 2007; 333(6):333-339.

(17) Dahmer S, Schiller RM. Glucosamine. Am Fam Physician 2008;

78(4):471-476.

(18) Del Rosso A, Cerinic MM, De Giorgio F, Minari C, Rotella CM,

Seghier G. Rheumatological manifestations in diabetes mellitus.

Curr Diabetes Rev 2006; 2(4):455-466.

(19) Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO, III,

Harris CL et al. The effect of glucosamine and/or chondroitin

79
 sulfate on the progression of knee osteoarthritis: a report from the

glucosamine/chondroitin arthritis intervention trial. Arthritis

Rheum 2008; 58(10):3183-3191.

(20) Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J.

Diacerhein and rhein reduce the interleukin 1beta stimulated

inducible nitric oxide synthesis level and activity while stimulating

cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes.

J Rheumatol 1998; 25(12):2417-2424.

(21) Martel-Pelletier J, Mineau F, Jolicoeur FC, Cloutier JM, Pelletier

JP. In vitro effects of diacerhein and rhein on interleukin 1 and

tumor necrosis factor-alpha systems in human osteoarthritic

synovium and chondrocytes. J Rheumatol 1998; 25(4):753-762.

(22) Tamura T, Shirai T, Kosaka N, Ohmori K, Takafumi N.

Pharmacological studies of diacerein in animal models of

inflammation, arthritis and bone resorption. Eur J Pharmacol 2002;

448(1):81-87.

(23) Hunter DJ, Wise B. Review: diacerein is more effective than

placebo and is as effective as NSAIDs for knee and hip

osteoarthritis. Evid Based Med 2007; 12(3):74.

80
(24) Altman RD. The classification of osteoarthritis. J Rheumatol Suppl

1995; 43:42-43.

(25) Cimmino MA, Parodi M. Risk factors for osteoarthritis. Semin

Arthritis Rheum 2005; 34(6 Suppl 2):29-34.

(26) Krasnokutsky S, Samuels J, Abramson SB. Osteoarthritis in 2007.

Bull NYU Hosp Jt Dis 2007; 65(3):222-228.

(27) Buckwalter JA, Martin JA. Osteoarthritis. Adv Drug Deliv Rev

2006; 58(2):150-167.

(28) O'Connor MI. Osteoarthritis of the hip and knee: sex and gender

differences. Orthop Clin North Am 2006; 37(4):559-568.

(29) Jordan JM, Helmick CG, Renner JB, Luta G, Dragomir AD,

Woodard J et al. Prevalence of knee symptoms and radiographic

and symptomatic knee osteoarthritis in African Americans and

Caucasians: the Johnston County Osteoarthritis Project. J

Rheumatol 2007; 34(1):172-180.

(30) Eaton CB. Obesity as a risk factor for osteoarthritis: mechanical

versus metabolic. Med Health R I 2004; 87(7):201-204.

(31) Baker KR, Xu L, Zhang Y, Nevitt M, Niu J, Aliabadi P et al.

Quadriceps weakness and its relationship to tibiofemoral and

81
 patellofemoral knee osteoarthritis in Chinese: the Beijing

osteoarthritis study. Arthritis Rheum 2004; 50(6):1815-1821.

(32) Neame RL, Muir K, Doherty S, Doherty M. Genetic risk of knee

osteoarthritis: a sibling study. Ann Rheum Dis 2004; 63(9):1022-

1027.

(33) Whelan LC, Morgan MP, McCarthy GM. Basic calcium phosphate

crystals as a unique therapeutic target in osteoarthritis. Front Biosci

2005; 10:530-541.

(34) O'Shea FD, McCarthy GM. Basic calcium phosphate deposition in

the joint: a potential therapeutic target in osteoarthritis. Curr Opin

Rheumatol 2004; 16(3):273-278.

(35) Hyc A, Osiecka-Iwan A, Jozwiak J, Moskalewski S. The

morphology and selected biological properties of articular

cartilage. Ortop Traumatol Rehabil 2001; 3(2):151-162.

(36) Benedek TG. A history of the understanding of cartilage.

Osteoarthritis Cartilage 2006; 14(3):203-209.

(37) Brandt KD, Dieppe P, Radin EL. Etiopathogenesis of

osteoarthritis. Rheum Dis Clin North Am 2008; 34(3):531-559.

82
(38) Burr DB, Radin EL. Microfractures and microcracks in

subchondral bone: are they relevant to osteoarthrosis? Rheum Dis

Clin North Am 2003; 29(4):675-685.

(39) Muehleman C, Arsenis CH. Articular cartilage. Part II. The

osteoarthritic joint. J Am Podiatr Med Assoc 1995; 85(5):282-286.

(40) Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular

cartilage defects in 1,000 knee arthroscopies. Arthroscopy 2002;

18(7):730-734.

(41) Yuan GH, Tanaka M, Masuko-Hongo K, Shibakawa A, Kato T,

Nishioka K et al. Characterization of cells from pannus-like tissue

over articular cartilage of advanced osteoarthritis. Osteoarthritis

Cartilage 2004; 12(1):38-45.

(42) Gelse K, Soder S, Eger W, Diemtar T, Aigner T. Osteophyte

development--molecular characterization of differentiation stages.

Osteoarthritis Cartilage 2003; 11(2):141-148.

(43) Gelse K, Soder S, Eger W, Diemtar T, Aigner T. Osteophyte

development--molecular characterization of differentiation stages.

Osteoarthritis Cartilage 2003; 11(2):141-148.

83
(44) Brandt KD. Osteoarthritis. Preface. Rheum Dis Clin North Am

2003; 29(4):ix-xiii.

(45) Haq I, Murphy E, Dacre J. Osteoarthritis. Postgrad Med J 2003;

79(933):377-383.

(46) Miranda H, Viikari-Juntura E, Martikainen R, Riihimaki H. A

prospective study on knee pain and its risk factors. Osteoarthritis

Cartilage 2002; 10(8):623-630.

(47) Sowers M. Epidemiology of risk factors for osteoarthritis: systemic

factors. Curr Opin Rheumatol 2001; 13(5):447-451.

(48) Sharma L. Local factors in osteoarthritis. Curr Opin Rheumatol

2001; 13(5):441-446.

(49) Doherty M. Risk factors for progression of knee osteoarthritis.

Lancet 2001; 358(9284):775-776.

(50) Sangha O. Epidemiology of rheumatic diseases. Rheumatology

(Oxford) 2000; 39 Suppl 2:3-12.

(51) Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG,

Jordan JM et al. Osteoarthritis: new insights. Part 1: the disease and

its risk factors. Ann Intern Med 2000; 133(8):635-646.

84
(52) Schiphof D, Boers M, Bierma-Zeinstra SM. Differences in

descriptions of Kellgren and Lawrence grades of knee

osteoarthritis. Ann Rheum Dis 2008; 67(7):1034-1036.

(53) Myles PS, Troedel S, Boquest M, Reeves M. The pain visual

analog scale: is it linear or nonlinear? Anesth Analg 1999;

89(6):1517-1520.

(54) Bellamy N. WOMAC: a 20-year experiential review of a patient-

centered self-reported health status questionnaire. J Rheumatol

2002; 29(12):2473-2476.

(55) Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of

patient outcome in arthritis. Arthritis Rheum 1980; 23(2):137-145.

(56) Das SK, Ramakrishnan S, Mishra K, Srivastava R, Agarwal GG,

Singh R et al. A randomized controlled trial to evaluate the slow-

acting symptom-modifying effects of colchicine in osteoarthritis of

the knee: a preliminary report. Arthritis Rheum 2002; 47(3):280-

284.

(57) Breedveld FC. Osteoarthritis--the impact of a serious disease.

Rheumatology (Oxford) 2004; 43 Suppl 1:i4-i8.

85
(58) Akyuz G, Bulak E. [Osteoarthritis and pain]. Agri 2007; 19(1):31-

35.

(59) Huskisson EC. Pharmacologic and non-drug therapies for

osteoarthritis. Scand J Rheumatol Suppl 1988; 77:34-36.

(60) Juni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approach

to treating the individual. Best Pract Res Clin Rheumatol 2006;

20(4):721-740.

(61) Rosier RN, O'Keefe RJ. Hyaluronic acid therapy. Instr Course Lect

2000; 49:495-502.

(62) Fawaz-Estrup F. The osteoarthritis initiative: an overview. Med

Health R I 2004; 87(6):169-171.

(63) Tacconelli S, Capone ML, Patrignani P. Clinical pharmacology of

novel selective COX-2 inhibitors. Curr Pharm Des 2004;

10(6):589-601.

(64) Rehman Q, Lane NE. Getting control of osteoarthritis pain. An

update on treatment options. Postgrad Med 1999; 106(4):127-134.

(65) Brabant T, Stichtenoth D. [Pharmacological treatment of

osteoarthritis in the elderly]. Z Rheumatol 2005; 64(7):467-472.

86
(66) Brandt KD. The role of analgesics in the management of

osteoarthritis pain. Am J Ther 2000; 7(2):75-90.

(67) Urban MK. COX-2 specific inhibitors offer improved advantages

over traditional NSAIDs. Orthopedics 2000; 23(7 Suppl):S761-

S764.

(68) Kneitz C, Tony HP, Kruger K. [NSAIDs and COX-2-inhibitors:

current status]. Internist (Berl) 2006; 47(5):533-8, 540.

(69) Hinz B, Brune K. New insights into physiological and

pathophysiological functions of cyclo-oxygenase-2. Curr Opin

Anaesthesiol 2000; 13(5):585-590.

(70) Watson DJ, Yu Q, Bolognese JA, Reicin AS, Simon TJ. The upper

gastrointestinal safety of rofecoxib vs. NSAIDs: an updated

combined analysis. Curr Med Res Opin 2004; 20(10):1539-1548.

(71) Rainsford KD, Skerry TM, Chindemi P, Delaney K. Effects of the

NSAIDs meloxicam and indomethacin on cartilage proteoglycan

synthesis and joint responses to calcium pyrophosphate crystals in

dogs. Vet Res Commun 1999; 23(2):101-113.

(72) Gilroy DW, Tomlinson A, Greenslade K, Seed MP, Willoughby

DA. The effects of cyclooxygenase 2 inhibitors on cartilage

87
 erosion and bone loss in a model of Mycobacterium tuberculosis-

induced monoarticular arthritis in the rat. Inflammation 1998;

22(5):509-519.

(73) van den Berg WB. Impact of NSAID and steroids on cartilage

destruction in murine antigen induced arthritis. J Rheumatol Suppl

1991; 27:122-123.

(74) Hungin AP, Kean WF. Nonsteroidal anti-inflammatory drugs:

overused or underused in osteoarthritis? Am J Med 2001;

110(1A):8S-11S.

(75) Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on

chondrocyte metabolism in vitro and in vivo. Am J Med 1987;

83(5A):29-34.

(76) Ellman MH, Curran J. Trial of tramadol/acetaminophen tablets for

osteoarthritis pain in subjects receiving a COX-2 nonsteroidal

antiinflammatory drug. J Rheumatol 2005; 32(3):568-569.

(77) Bertin P, Keddad K, Jolivet-Landreau I. Acetaminophen as

symptomatic treatment of pain from osteoarthritis. Joint Bone

Spine 2004; 71(4):266-274.

88
(78) Buescher JS, Meadows S, Saseen J. Clinical inquiries. Does

acetaminophen and NSAID combined relieve osteoarthritis pain

better than either alone? J Fam Pract 2004; 53(6):501-503.

(79) Shamoon M, Hochberg MC. Treatment of osteoarthritis with

acetaminophen: efficacy, safety, and comparison with nonsteroidal

anti-inflammatory drugs. Curr Rheumatol Rep 2000; 2(6):454-458.

(80) Williams HJ, Ward JR, Egger MJ, Neuner R, Brooks RH, Clegg

DO et al. Comparison of naproxen and acetaminophen in a two-

year study of treatment of osteoarthritis of the knee. Arthritis

Rheum 1993; 36(9):1196-1206.

(81) Pincus T, Koch GG, Sokka T, Lefkowith J, Wolfe F, Jordan JM et

al. A randomized, double-blind, crossover clinical trial of

diclofenac plus misoprostol versus acetaminophen in patients with

osteoarthritis of the hip or knee. Arthritis Rheum 2001;

44(7):1587-1598.

(82) Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper

gastrointestinal safety of celecoxib for treatment of osteoarthritis

and rheumatoid arthritis: systematic review of randomised

controlled trials. BMJ 2002; 325(7365):619.

89
(83) Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ.

Efficacy of rofecoxib, celecoxib, and acetaminophen in

osteoarthritis of the knee: a randomized trial. JAMA 2002;

287(1):64-71.

(84) Seideman P, Samuelson P, Neander G. Naproxen and paracetamol

compared with naproxen only in coxarthrosis. Increased effect of

the combination in 18 patients. Acta Orthop Scand 1993;

64(3):285-288.

(85) Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events

associated with selective COX-2 inhibitors. JAMA 2001;

286(8):954-959.

(86) Recommendations for the medical management of osteoarthritis of

the hip and knee: 2000 update. American College of Rheumatology

Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;

43(9):1905-1915.

(87) Setnikar I. Antireactive properties of "chondroprotective" drugs.

Int J Tissue React 1992; 14(5):253-261.

(88) Wildy KS, Wasko MC. Current concepts regarding pharmacologic

treatment of rheumatoid and osteoarthritis. Hand Clin 2001;

17(2):321-38, xi.

90
(89) Taccoen A, Berdah L. [Diacetylrhein, a new therapeutic approach

of osteoarthritis]. Rev Rhum Ed Fr 1993; 60(6 Pt 2):83S-86S.

(90) Geier KA, Keeperman JB, Sproul RC, Roth K, Reynolds HM.

Viscosupplementation: a new treatment option for osteoarthritis.

Orthop Nurs 2002; 21(5):25-32.

(91) Adams ME. Hype about glucosamine. Lancet 1999;

354(9176):353-354.

(92) McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine

and chondroitin for treatment of osteoarthritis: a systematic quality

assessment and meta-analysis. JAMA 2000; 283(11):1469-1475.

(93) Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere

O et al. Long-term effects of glucosamine sulphate on osteoarthritis

progression: a randomised, placebo-controlled clinical trial. Lancet

2001; 357(9252):251-256.

(94) Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G,

Rovati LC. Glucosamine sulfate use and delay of progression of

knee osteoarthritis: a 3-year, randomized, placebo-controlled,

double-blind study. Arch Intern Med 2002; 162(18):2113-2123.

91
(95) Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as

therapeutic agents for knee and hip osteoarthritis. Drugs Aging

2007; 24(7):573-580.

(96) Muniyappa R, Karne RJ, Hall G, Crandon SK, Bronstein JA, Ver

MR et al. Oral glucosamine for 6 weeks at standard doses does not

cause or worsen insulin resistance or endothelial dysfunction in

lean or obese subjects. Diabetes 2006; 55(11):3142-3150.

(97) Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann

Pharmacother 2006; 40(4):694-698.

(98) Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral

glucosamine in doses used to treat osteoarthritis worsens insulin

resistance. Am J Med Sci 2007; 333(6):333-339.

(99) Rezende MU, Gurgel HM, Vilaca Junior PR, Kuroba RK, Lopes

AS, Phillipi RZ et al. Diacerhein versus glucosamine in a rat model

of osteoarthritis. Clinics 2006; 61(5):461-466.

(100) [Functional manifestations of osteoarthritis: key points to the

clinical efficacy of diacerhein]. Presse Med 1998; 27(25):1302-

1304.

92
(101) Kay AG, Griffiths LG, Volans GN, Grahame R. Preliminary

experience with diacetylrhein in the treatment of osteoarthritis.

Curr Med Res Opin 1980; 6(8):548-551.

(102) Adami S, Bortolotti R, Guarrera G, Marini G, Rosini S, Zampieri

A et al. [Diacetylrhein in the treatment of degenerative

arthropathies]. Clin Ter 1985; 112(5):439-443.

(103) Cruz TF, Tang J, Pronost S, Pujol JP. [Molecular mechanisms

implicated in the inhibition of collagenase expression by

diacerheine]. Rev Prat 1996; 46(6 Spec No):S15-S19.

(104) Mian M, Trombi L, Rosini S, Benetti D, Caracciolo F, Carulli G et

al. Experimental studies on diacerhein: effects on the phagocytosis

of neutrophil cells from subcutaneous carrageenan-induced

exudate. Drugs Exp Clin Res 1987; 13(11):695-698.

(105) Moldovan F, Pelletier JP, Jolicoeur FC, Cloutier JM, Martel-

Pelletier J. Diacerhein and rhein reduce the ICE-induced IL-1beta

and IL-18 activation in human osteoarthritic cartilage.

Osteoarthritis Cartilage 2000; 8(3):186-196.

(106) Carrabba M, Mele G, Chevallard M, Angelini M. [Diacereine: an

original approach in the treatment of degenerative and/or extra-

articular rheumatism]. Minerva Med 1987; 78(3):179-185.

93
(107) de Isla NG, Stoltz JF. In vitro inhibition of IL-1beta catabolic

effects on cartilage: a mechanism involved on diacerein anti-OA

properties. Biorheology 2008; 45(3-4):433-438.

(108) de Isla NG, Yang JW, Huselstein C, Muller S, Stoltz JF. IL-1beta

synthesis by chondrocyte analyzed by 3D microscopy and flow

cytometry: effect of Rhein. Biorheology 2006; 43(3-4):595-601.

(109) Beccerica E, Ferretti G, Curatola G, Cervini C. Diacetylrhein and

rhein: in vivo and in vitro effect on lymphocyte membrane fluidity.

Pharmacol Res 1990; 22(3):277-285.

(110) Yaron M, Shirazi I, Yaron I. [Anti-interleukin-1 effects of

diacerhein in vitro]. Rev Prat 1997; 47(17 Suppl):S20-S23.

(111) Spencer CM, Wilde MI. Diacerein. Drugs 1997; 53(1):98-106.

(112) Del Rosso M, Fibbi G, Magnelli L, Pucci M, Dini G, Grappone C

et al. Modulation of urokinase receptors on human synovial cells

and osteoarthritic chondrocytes by diacetylrhein. Int J Tissue React

1990; 12(2):91-100.

(113) Brandt KD, Smith G, Kang SY, Myers S, O'Connor B, Albrecht M.

[Effects of diacerhein on canine model with accelerated

osteoarthritis]. Rev Prat 1997; 47(17 Suppl):S27-S30.

94
(114) Alvarez-Soria MA, Herrero-Beaumont G, Sanchez-Pernaute O,

Bellido M, Largo R. Diacerein has a weak effect on the catabolic

pathway of human osteoarthritis synovial fibroblast--comparison to

its effects on osteoarthritic chondrocytes. Rheumatology (Oxford)

2008; 47(5):627-633.

(115) Uebelhart D. Clinical review of chondroitin sulfate in

osteoarthritis. Osteoarthritis Cartilage 2008; 16 Suppl 3:S19-S21.

(116) Fidelix TS, Soares BG, Trevisani VF. Diacerein for osteoarthritis.

Cochrane Database Syst Rev 2006;(1):CD005117.

(117) Nicolas P, Tod M, Padoin C, Petitjean O. Clinical

pharmacokinetics of diacerein. Clin Pharmacokinet 1998;

35(5):347-359.

(118) Mazzaro C, Bocchieri E, Tesolin GF, Ventre L, Romagnoli A.

[Clinical evaluation of diacerein in the treatment of osteoarthrosis].

Minerva Med 1989; 80(9):1025-1027.

(119) Pelletier JP, Yaron M, Haraoui B, Cohen P, Nahir MA, Choquette

D et al. Efficacy and safety of diacerein in osteoarthritis of the

knee: a double-blind, placebo-controlled trial. The Diacerein Study

Group. Arthritis Rheum 2000; 43(10):2339-2348.

95
(120) Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled

clinical studies with diacerein in the treatment of osteoarthritis.

Arch Intern Med 2006; 166(17):1899-1906.

(121) Zheng WJ, Tang FL, Li J, Zhang FC, Li ZG, Su Y et al. Evaluation

of efficacy and safety of diacerein in knee osteoarthritis in Chinese

patients. Chin Med Sci J 2006; 21(2):75-80.

(122) Louthrenoo W, Nilganuwong S, Aksaranugraha S, Asavatanabodee

P, Saengnipanthkul S, Thai Study Group. The efficacy, safety and

carry-over effect of diacerein in the treatment of painful knee

osteoarthritis: a randomised, double-blind, NSAID-controlled

study. Osteoarthritis Cartilage 2007; 15(6):605-614.

(123) Small RE. Diclofenac sodium. Clin Pharm 1989; 8(8):545-558.

(124) Tukker A, Visscher T, Picavet H. Overweight and health problems

of the lower extremities: osteoarthritis, pain and disability. Public

Health Nutr 2008;1-10.

(125) Provvedini D, Cohen P. [Efficacy of diacerein on the symptoms

and radiographic progression of osteoarthritis]. Presse Med 2002;

31(39 Pt 2):4S13-4S15.

96
(126) Sharma A, Rathod R, Baliga VP. An open prospective study on

postmarketing evaluation of the efficacy and tolerability of

diacerein in osteo-arthritis of the knee (DOK). J Indian Med Assoc

2008; 106(1):54-6, 58.

(127) Pavelka K, Trc T, Karpas K, Vitek P, Sedlackova M, Vlasakova V

et al. The efficacy and safety of diacerein in the treatment of

painful osteoarthritis of the knee: a randomized, multicenter,

double-blind, placebo-controlled study with primary end points at

two months after the end of a three-month treatment period.

Arthritis Rheum 2007; 56(12):4055-4064.

(128) Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD,

Arden N et al. OARSI recommendations for the management of

hip and knee osteoarthritis, Part II: OARSI evidence-based, expert

consensus guidelines. Osteoarthritis Cartilage 2008; 16(2):137-162.

(129) Brandt KD. Studies in animal models of osteoarthritis as predictors

of a structure-modifying effect of diacerhein in humans with

osteoarthritis. Biorheology 2006; 43(3-4):589-594.

97