3-Soltanian

JRHS 2009; 9(2): 19-24

Copyright © Journal of Research in Health Sciences

Assessment of Marhame-Mafasel Pomade Effect on Knee Osteoarthritis with Non-Compliance

Soltanian AR (MSc)a, Faghihzadeh S (PhD)a, Mehdibarzi D (MD)b, Gerami A (PhD)c, Nasery M (MD)d, Cheng J (PhD)e

a Department of Biostatistics, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran

b Department of Orthopedics, Faculty of Medical Sciences, Shahed University, Tehran, Iran

c Department of Mathematical Statistics, School of Mathematics, Statistics and Computer Sciences, Tehran Uni­versity, Iran

d Department of Pharmacology, Faculty of Medical Sciences, Shahed University, Tehran, Iran

e Department of Biostatistics &Epidemiology, University of Florida, Gainesville, U.S.A

*Corresponding author: Dr Soghrat Faghihzadeh, E-mail: faghihzadehs@yahoo.com.

Received: 2 Septamber 2009; Accepted: 23 November 2009

Abstract

Background: Osteoarthritis is the most prevalent chronic non-infective joint arthritis. In the present study, the effect of new herbal pomade (Marhame-Mafasel) on knee osteoarthritis was investigated in a randomized trial. The objective of this study was to assess efficacy of Marhame- Mafasel pomade, which was consisted of several medic herbs like Arnebia euchroma and Martricaria chamomilla in pri¬mary osteoarthritis of the knee with non-compliance.

Methods: The 22 crossover trial enrolled 42 osteoarthritis patients (Marhame-Mafasel versus pla¬cebo) in 2006. The instrument of data collection was Western Ontario and McMaster Universities (WOMAC) LK3.1 standard questionnaires. We used conditional estimation to adjust non-compliance ef¬fect.

Results: The participants in each group were 21 patients. About 30 (71.4%) were female. The partici¬pants were between 40-76 years old. Positive analgesic effect of herbal pomade “Marhame-Mafasel” on knee osteoarthritis severity was considerable (P< 0.01). After adjusting results to compliance level, the estimators were sharper than crude results.

Conclusion: Herbal joint pomade "Marhame-Mafasel" has significant positive analgesic effect on pri¬mary knee osteoarthritis.

Keywords: Osteoarthritis, Herbal medicine, Compliance, Randomized trials

Introduction

Osteoarthritis was known as degenerative joint disease occurs when the cushiony carti­lage be­tween two bones becomes worn down, and the bones begin to rub against each other in the knee joint (the area where two bones come to­gether) (1). Osteoarthritis of the knee often leads to pain, swelling, limi­tation in range of motion, stiffness, or the formation of bone spurs (tiny growths of new bone) (1). Osteo­arthri­tis is the most prevalent chronic non-in­fec­tive joint ar­thri­tis. Approximately 25% of people at age 55 yr or above have daily knee pain in (2). There is a significant positive cor­relation be­tween age and osteoarthritis of the knee (3). The preva­lence of this disease in women is greater than men (4). Prevalence of osteo­arthri­tis of the knee in Ame­r­ica is ap­proximately 0.9% (1.2% in women and 0.4% in men) (5). Osteoarthritis of the knee is one of the main leading causes of impaired mo­bil­ity in the elderly people (6). Many pa­tients with knee pain have limitations in their physi­cal func­tions, which prevented them from en­gag­ing in their usual daily activities.

Drugs more frequently used in osteoarthritis are analgesics, supporter of cartilage, steroid, and non-steroidal anti-inflammation drugs (NSAD). In addition, there are many pharma­cological, supportive, and surgical in­terventions, which de­pend on the disease se­verity. The disease is chronic; hence, drugs used locally are pre­ferred due to less complica­tion. As steroid and non-steroidal anti-inflammation drugs have sys­temic side ef­fects like digestive and renal impair­ment, they should be used carefully (7, 8). Local drugs like pomade, cream, gel, etc. are sim­ply used. Thus, preparing pomade to reduce pain and dis­ability of patients is very impor­tant. Despite the long history of herbal medi­cine in Iran, a few studies were carried out to investigate the ef­fect of herbal medication on osteoarthritis.

In order to reduce pain in patients suffering from osteoarthritis, the effect of new herbal po­made on osteoarthritis of the knee was in­ves­ti­gated in a double-blinded crossover trial.

Methods

Double-blinded crossover randomized trial on efficacy of herbal joint pomade (EHJP)

The EHJP study(9) conducted a double blinded placebo controlled randomized cross­over trial in­volving 42 osteoarthritis pa­tients aged 40 to 80 yr who had explicit symptoms of arthritis dis­ease to investigate the effect of herbal joint pomade “Marhame-Mafasel” (EHJP) on knee os-­teoarthritis, which participants drown from pa­tients attend­ing the Clinic of Mostafa- Khomeini Hospital in 2006. Pomade "Marhame-Mafasel" (MM) consisted of several medic herbs (like Arnebia euchroma and Martri­caria chamomilla) and was made by Pharma­cology Division of Shahed University, Iran. MM pomade and pla­cebo were inserted in the similar tubs. Pa­tients with acute knee ar­thritis or secondary os­teo­arthritis were ex­cluded from the study. The pro­to­col was ap­proved by the Research Ethics Committee at Shahed University, Tehran. Be­fore starting of the study, participants signed the in­formed consent forms according to Hel­sinki Declaration rule. Then a computer ran­dom number generator was used to allocate par­tici­pant to either placebo or treatment groups. Pa­tients used locally either MM po­made or pla­cebo 3 times a day for 3 wk. After 3 wk, sub­jects were as­sessed using checklist. Subjects were evalu­ated based on three characteristics including: a) pain score ranged from 0 (no pain) to 100 (extreme pain); b) physical function score ranged from 0 (no difficulty) to 100 (ex­treme dif­ficulty); and c) stiffness score ranged 0 (no stiffness) to 100 (extreme stiff­ness) at the end of both periods. These charac­teristics were meas­ured using Western Ontario and McMaster uni­ver­sities (WOMAC) checklist. After 1 wk wash out period, participants received alter­na­tive in­ter­vention in period II. In this study, we had two sequences: AB (MM pomade fol­lowed by pla­cebo) and BA (placebo fol­lowed by MM). The participants were known as com­pli­ance if they had consumed 50% or more of the as­signed po­made, other­wise they were known as non-com­pli­ance. In this study, the non-com­pliance and com­pli­ance distribution was showed in Ta­ble 1.

Table 1: The Distribution of Compliance status (two levels) in two periods of two sequences



Period I

Period II

Total

Sequences

Compliance Level

Frequency

Proportion of

Compliance

Frequency

Proportion of

Compliance

Frequency

Proportion

of

Compliance

AB*

Noncompliance

5

0.76

5

0.76

10

0.76

Compliance

16

16

32

BA

Noncompliance

9

0.57

6

0.71

15

0.64


Compliance

12


15


27










* In AB sequence MM pomade, A, followed by placebo, B; and in BA sequence placebo followed by MM pomade.

Statistical model and analysis

We used principle component analysis and con­sidered a new outcome that was a linear com­pound of three characteristics including pain, physical function, and stiffness scores. The new outcome was named osteoarthritis in­tensity score ranged 0(no intension) to 100(extreme inten­sity). In the EHJP study, the observed com­pliance status of each sub­ject was classified to a binary variable (1 or 0) based on the amount of pomade in tubes taken by the subject. One subject was consid­ered to comply with the as­signed treat­ment (compliance= 1) if more than 50% of the pomade in the tubes was taken. Other­wise, the subject's observed compli­ance to the assigned treatment was classified as 0. Un­der complete data assumption (9), poten­tial outcome (Yijk) for individual k in period j (j= 1, 2) of sequence i (i=1, 2) may be mod­eled as a function of treatment effect (τd[I,j], is treat­ment effect in period j of sequence i), pe­riod effect (Πj , is jth period effect), effect of sub­ject k in sequence i (Sik), carryover ef­fect (λ) and error term (εijk). When there is no carry-over effect and all subjects comply with their as­signed treatment, the widely used model is (10):

Yijk = μ + τd[I,j] + Πj + Sik + εijk

(i=1,2 ;   j=1,2 ;  k=1,2,…,n),                    [1]

The equation (1), standard model is appro­pri­ate to estimate of treatment effects without non-compliance. Since there is non-compli­ance we suggest equation 2 (adjusted model) that outcome was modeled by treat­ment effect (τd[I,j]), period effect (Πj), ef­fect of subject k in sequence i (Sik) and error term (εijk).

       [2]

where, R=r (r=A, B) to denote the assigned treatment and is indicator of patient at period j of sequence i. We use D(R) to denote the observed treat­ment received of the subject in Jth period of ith sequence with assigned treatment r. D(r)= r (r= A, B) if the subject k took more than 50% of the assigned dose of R=r and D(r)=0 otherwise. We let  Yijk(R,D(R)) to denote the po­ten­tial outcome of the kth subject in the Jth period of the ith sequence with as­signed treatment R and treatment received D(R), which has a normal distribution.  is an indicator for ob­served treatment received for subject k in the period j of the sequence i; Sik is the random ef­fect of the kth subject in the ith sequence, which has a normal dis­tri­bution with mean 0 and variance σ2s; εijk is the random error term, which has a normal dis­tri­bution with mean 0 variance σ2e. In this study, Chi-square or Student's t-Test tests were used to analysis of baseline demographic and scores. Statistical analysis was performed by SAS In­stitute Inc. Version 9.1 (2002). All sta­tisti­cal tests were two-sided and were performed at the 0.05 significance level.

Results

Forty two patients participated in the present study. Thirty (71.4%) were female (Table 2). One third of participants had family history of joint arthritis. Based on clinical symptoms and results of radiography, 6 patients (14%) had low arthritis, 15 patients (36%) had moder­ate ar­thri­tis and 21 patients (50%) had severe ar­thritis. However, the difference was not sta­tis­tically significant in both treatment groups (P>0.05). We did not evaluate the side effect of the new treatment (MM po­made). There was not a sta­tistical significant difference at baseline scores between herbal joint pomade and placebo (Table 2) for pain, physical function, stiffness, and os­teoarthri­tis intensity. There was not carry over ef­fect.

Compliance to assigned drug dosage be­tween participants was divided into two catego­ries (com­pliance= 1, noncompli­ance= 0; Table 1). Table 3 shows mean of out­comes (osteoarthri­tis intension scores) in two periods having two sequences correspond­ing to complete com­pli­ance (stan­dard model) and non-compliance (adjusted model) assumption. The results in­dicated that MM pomade in comparison with pla­cebo had more positive effects on de­creasing the knee pain and symptoms of arthritis dis­ease where the patients did not have a com­plete com­pliance to the treatment (Table 3). In addi­tion, Table 3 showed that t-test statis­tics cor­responding to equation [1] and [2] was 1.96 and 2.01, respectively. Effect size based on standard model (equation 1) and ad­justed model (equation 2) was 0.62 and 0.64, respectively (see Table 3).

Table 2: Baseline demographic and characteristics of patient in both treatment groups


Placebo (n=21)

MM pomade (n=21)

P-value

Age (yr)a

58.48±10.25

58.56±10.67

0.979

Weight (kg)a

75.81±17.58

69.56±10.97

0.138

Height (cm)a

158.1±8.9

164.44±9.53

0.023

Children (number) a

4.57±1.91

3.85±2.1

0.229

BMI (kg/m2) a

30.26±6.18

25.77±3.89

0.004

Education (illiterate)b

75.81

69.55

0.074

Sex (Female) b

81

55.6

0.04

Pain score a

50±21.6

41.63±25.4

0.236

Physical function score a

40±26.48

53.9±40.1

0.61

Stiffness score a

71.77±26.48

63.95±40.1

0.085

Osteoarthritis intension score*a

48.8±13.94

41.3±21.16

0.16

a Data are presented as mean ±SD; b Data are presented as percent.

* Osteoarthritis intension score was a compound of pain, physical function and stiffness scores by principle compo­nent analysis, ranged 0 (no osteoarthritis) to 100 (extreme osteoarthritis)

Table 3: Summary statistics of parameters, without pretreatment variables, under the model (1), based on com­pletely compliance assumption; and model (2), based on non-compliance assumption (Standard deviation in paren­theses)


Period I

Period II

Based on model (1)

Based on model (2)

Mean (SD)

Mean (SD)

Standard Model

(i1)

Adjusted Model

Standard Model

(i2)

Adjusted Model






i1(R,R)


i1(R,0)


i2(R,R)


i2(R,0)

τD

Effect size

τD

Effect size

Sequence BA

38.45

(16.27)

37.92

(12.05)

39.17

(21.47)

31.61

(16.17)

26.94

(11.31)

43.26

(21.45)


3.94*

(2.01)


0.62


- 1.97*

(0.98)


0.64

Sequence AB

33.73

(22.41)

27.67

(23.29)

35.62

(20.39)

37.93

(19.94)

35.82

(17.40)

44.67

(27.88)





* P< 0.01;

SD= Standard deviation; Standard model is a model based on complete compliance assumption or equation (1); Adjusted model is a model based on non-compliance assumption or equation (2); B to denote placebo and A to denote Marhame-Mafasel pomade

Discussion

Osteoarthritis is the most prevalent chronic non-infective joint arthritis and it does not have an absolute remedy (1). The oral and in­jec­tion forms of existing treatments have sys­temic side effects and are not recom­mended for a long time. MM pomade does not have sys­temic side effects. MM pomade like Piroxicam gel, Diclofenac ointment, and comfrey root ex­tract ointment (11-20) has suit­able anti-inflam­mation effect. Cap­saeicine ointment (chili ex­tract) has cutane­ous and mucoid side effects, while MM po­made is a suitable pomade with no side ef­fects (like itch, bleb) (21, 22). The palliative ef­fects of MM pomade on painful os­teoarthri­tis of the knee was more than Cop­per-Salicylate gel ointment, because previ­ous studies indicated that efficacy of Cop­per-Sali­cylate gel ointment was similar to placebo ef­fects; and, occasionally it had se­vere side effect (19). This study like other randomized trials may be marred by devia­tions from protocol, notably some patients failing to comply with the prescribed treat­ment. Therefore, we adjusted the treatment ef­fects (τD) corresponding to com­pliance lev­els.

In this study, we estimated conditional aver­ages and variances in two periods including two sequences (based on equation 2 or ad­justed model) rather than unconditional sum­mary sta­tistics (based on equation 1 or stan­dard model).

In conclusion, herbal joint pomade "Mar­hame-Mafasel" in comparison with placebo has more positive analgesic effects on pri­mary knee os­teoarthritis. In addition, accord­ing to these find­ings, treatment effect should be adjusted for non-compliance in random­ized trials.

Acknowledgments

The EHJP study was supported by Shahed Uni­versity. Pomade "MM" was made by Phar­macology Division of Shahed Univer­sity, Iran; which its formula exists at Pharma­cology Di­vision of Shahed Univer­sity. We thank all trial site investigators for their dedication on data collected, registry and patients follow up.  The authors declare that they have no conflicts of in­terest.

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