Nowadays, the world as we know it has been progressing and aging, rapidly becoming a society of elderly people. The number of people 65 years of age or older was projected to increase from an estimated of 524 million in 2010 to 1.5 billion in 2050 [
Thai traditional medicine (TTM) is the use of alternative treatments for knee osteoarthritis which include Thai traditional massage, herbal hot compression, topical herbal medicines, and oral herbal medicines. The Sahastara (SHT) remedy has long been used as anti-inflammatory drug to relieve muscle and joint pain including the pain of OA of the knee in hospital of Thailand for more fifty years [
Medicinal plants in Sahastara remedy formulations (for 1,000 g. of powder drug).
Thai name | Scientific name | Voucher specimen | Part of use | Weight (g) | Collected from |
---|---|---|---|---|---|
Prik-Thai |
|
SKP146161401 | Fruit | 240 | Chanthaburi, |
Jet-Ta-Mul-Plerng-Dang |
|
SKP148160901 | Root | 224 | Laos |
Sa-Mhor-Thai |
|
SKP049200301 | Fruit | 104 | Sa Kaeo, |
Dee-Plee |
|
SKP146160301 | Fruit | 96 | Chanthaburi, |
Tong-Tank |
|
SKP121021301 | Root | 80 | Kanchanaburi, |
Wan-Nam |
|
SKP015010301 | Rhizome | 88 | Nonthaburi, |
Has-Sa-Khun-Tade |
|
SKP183110801 | Root | 48 | Kanchanaburi, |
Ka-Ra-Boon |
|
SKP096030301 | — | 14 | China |
Dok-Chan |
|
SKP121130601 | Aril of seed | 13 | China |
Luk-Chan |
|
SKP121130601 | Seed | 12 | China |
Tien-Dang |
|
SKP057121901 | Seed | 11 | India |
Tien-Ta-Tuk-Ka-Tan |
|
SKP199010701 | Fruit | 10 | India |
Ma-Ha-Hing |
|
SKP199060101 | Resin | 10 | India |
Tien-Sut-Ta-But |
|
SKP199160101 | Fruit | 9 | China |
Tien-Khao |
|
SKP199030301 | Fruit | 8 | India |
Jing-Jor |
|
SKP054132201 | Root | 8 | Kanchanaburi, |
Tien-Dum |
|
SKP160141901 | Seed | 7 | China |
Kote-Kag-Kra |
|
SKP051011601 | Root | 6 | China |
Kote-Ka-Mao |
|
SKP051011201 | Rhizome | 5 | China |
Kote-Kan-Prao |
|
SKP177161101 | Root | 4 | India |
Kote-Pung-Pla |
|
SKP019200301 | Gall | 3 | India |
As taken from an
This study was a randomized, double-blind, and controlled trial (phase 2) designed to study the clinical efficacy and safety of the Sahastara remedy in comparison to diclofenac for the treatment of knee osteoarthritis at Thammasat University Hospital, Pathumthani Province, Thailand. This study was approved by the Medical Ethics Committee of the Faculty of Medicine, Thammasat University who accepted from FDA from Thai Government (registry number MTU-EC-TM-6-093/55).
The sixty-six outpatients from Department of Orthopedics, Thammasat University Hospital, between 45 and 80 years of age, who were diagnosed with primary osteoarthritis of the knee as based on the American College of Rheumatology’s clinical and radiological criteria, with no knee arthroplasty plan in 3 months and minimum pain symptom severity was ensured by visual analogue scale (VAS) score at least 20 mm. from 100 mm., were included in this study [
The Sahastara (SHT) remedy was prepared according to 2011 NLEM [
Informed consent was obtained from the patients who were eligible for the study. The patients were divided randomly into 2 groups of treatment, using a computer generated program by individual who did not contact all investigators involved in trial. The patients received randomized number sequentially from secret random list. Treatment assignment was also concealed to all investigator involved in trial. Each of patients received same appearance of treatment that contains treatment code, which was opened only in medical emergency condition. The masking was successfully achieved until open after data analysis.
In trial, demographic data, clinical signs and symptoms, laboratory tests (complete blood count, fasting blood sugar, lipid profile, liver functions test, renal functions test, and urine analysis), Visual Analogue Scale (VAS) for pain, 100-meter walk times, and the Western Ontario and McMaster Universities (WOMAC) index scores were collected on first visit for baseline data and after receiving treatment on day 14 and on day 28.
The eligible patients were divided randomly into 2 groups of treatment. The patients in group 1 received the SHT remedy at 3,000 mg/day (2 capsules of SHT three times a day before meals and 1 capsule of a placebo three times daily after meals). This is minimum dose of SHT remedy that was indicated in NLEM. The patients in group 2 received diclofenac sodium at 75 mg/day (2 capsules of placebo three times daily before meals and 1 capsule with 25 mg diclofenac sodium three times a day after meals). In addition, 20 mg of omeprazole was given twice daily to both groups for the prevention of adverse GI effects.
The treatment period was completed in 28 days with the clinical and laboratory investigation follow-up assessments at the 14th and 28th days. The global assessment was executed by the patients themselves at the last visit.
The clinical efficacy for the overall treatment was evaluated at the last follow-up by assessing the VAS pain score, the 100-meter walk times, the WOMAC index scores (ranging from 0 to 96) at day 0, day 14, and day 28, and the global assessment on a 0–4 likert scale (0: none, 4: excellent). The safety outcomes were evaluated by clinical examinations and laboratory investigations.
The toxicity of drug was considered for excluding patients following by guidance for industry in toxicity grading scale of USFDA such as creatinine more than 1.7 mg/dL, BUN more than 26 mg/dL AST, and ALT more than 2.5x upper limit of normal (ULN) or ALP more than 2.0x ULN.
The “paired
From a total of sixty-nine patients, 3 patients were excluded from the study due to abnormal liver functions tests. The remaining 66 patients were randomized into 2 groups (33 patients in each group). There were no significant differences in their baseline characteristics data (Table
Baseline characteristics of patients.
Data | SHT remedy ( |
Diclofenac ( |
|
---|---|---|---|
Female, number (%) | 28 (90.3) | 27 (90) |
|
Age; yrs, mean (SD) | 60.38 (6.97) | 58.23 (7.99) |
|
Weight; kg., mean (SD) | 68.48 (10.64) | 65.27 (9.81) |
|
Height; cm., mean (SD) | 158.29 (6.38) | 157.13 (5.90) |
|
BMI; Kg/m2, mean (SD) | 27.27 (3.69) | 26.35 (3.02) |
|
Visual analogue scale (VAS); mm., mean (SD) | 44.1 (23.5) | 43.5 (19.3) |
|
100-meter walking time; sec., mean (SD) | 103.77 (47.51) | 103.19 (35.43) |
|
|
|||
WOMAC index score, mean (SD) | |||
Pain index | 8.52 (3.77) | 8.47 (2.39) |
|
Stiff index | 3.32 (1.92) | 3.53 (1.61) |
|
Physical function index | 30.64 (11.69) | 31.03 (10.77) |
|
Total score |
|
|
|
|
|||
Laboratory data, mean (SD) | |||
Blood pressure | |||
Systolic (mm.Hg.) | 123.55 (11.42) | 121.83 (13.03) |
|
Diastolic (mm.Hg.) | 82.90 (8.24) | 80.50 (8.13) |
|
Renal function tests | |||
BUN (mg/dL) | 13.74 (4.69) | 15.35 (4.55) |
|
Creatinine (mg/dL) | 0.84 (0.27) | 0.80 (0.20) |
|
Liver function tests | |||
AST (U/L) | 28 (19.49) | 22.33 (10.35) |
|
ALT (U/L) | 46.48 (23.94) | 40.90 (12.91) |
|
ALP (U/L) | 108.26 (25.95) | 98.27 (23.26) |
|
The radiographic grading at entry into the study.
Kellgren and Lawrence X-ray grade | SHT remedy ( |
Diclofenac ( |
|
---|---|---|---|
Grade 1 | 2 | 1 | 0.61 |
Grade 2 | 17 | 20 | |
Grade 3 | 12 | 9 |
From the 66 patients, 61 (92.24%) of the patients completed the study (31 in the SHT group and 30 in the diclofenac group). Five patients dropped out at the first follow-up (4 patients who failed to follow up, and 1 patient who suffered from a traumatic wrist injury that required surgery). The results were shown in Figure
Flow of patients.
At the conclusion of the study, both the SHT remedy and diclofenac had significantly reduced the VAS pain scores. The SHT remedy significantly reduced the mean VAS pain scores at days 14 and 28, while diclofenac significantly reduced the mean VAS pain scores at day 28. However, there were no significant differences between the two groups. Both groups reduced the 100-meter walk times with no statistically significant differences. The WOMAC index scores have shown decrease in both groups. Significant improvements in the physical function index and the total scores were found in the SHT group but no differences in the pain and stiffness indexes. All WOMAC index scores were significantly improved in the diclofenac group. However, there were no significant differences between the SHT and diclofenac groups in all outcomes except the stiffness index diclofenac showed better stiffness index value than SHT group significantly (Table
The efficacy outcome of Sahastara remedy and diclofenac.
Data |
Follow-up | Treatments |
|
|
---|---|---|---|---|
SHT remedy | Diclofenac | |||
Visual Analogue Scale (VAS) (mm.) | Day 0 | 44.1 (23.5) | 43.5 (19.3) | 0.59 |
Day 14 | 31.8 (22.8) |
36.3 (24.3) | ||
Day 28 | 27.4 (18.3) |
31.5 (23.5) |
||
|
||||
100-meter time walk (seconds) | Day 0 | 103.77 (47.51) | 103.19 (35.43) | 0.09 |
Day 14 | 98.55 (25.21) | 101.37 (24.39) | ||
Day 28 | 96.58 (24.09) | 95.92 (18.77) | ||
|
||||
WOMAC index score | ||||
Pain index | Day 0 | 8.52 (3.77) | 8.47 (2.39) | 0.54 |
Day 14 | 7.94 (3.05) | 7.43 (3.92) | ||
Day 28 | 7.06 (3.31) | 6.30 (3.70) |
||
|
||||
Stiff index | Day 0 | 3.32 (1.92) | 3.53 (1.61) | 0.00 |
Day 14 | 3.42 (1.86) | 2.40 (1.79) |
||
Day 28 | 2.90 (1.87) | 2.5 (1.78) |
||
|
||||
Physical functions index | Day 0 | 30.64 (11.69) | 31.03 (10.77) | 0.83 |
Day 14 | 30.61 (12.54) | 27.57 (12.26) |
||
Day 28 | 22.48 (12.17) |
23.50 (13.06) |
||
|
||||
Total score | Day 0 | 42.65 (15.70) | 43.13 (13.69) | 0.64 |
Day 14 | 41.32 (15.69) | 37.40 (16.55) |
||
Day 28 | 34.61 (16.21) |
33.00 (18.02) |
At the end of the study, the global assessment showed improvement of symptoms in both groups but had shown no significant differences between the groups. The majority of the patients in both groups have indicated scores of “moderately better” and “very much better” (Table
Overall assessment of treatment evaluated at day 28th.
Global assessment (point) | SHT ( |
Diclofenac ( |
|
---|---|---|---|
0: none | 2 (6.5) | 0 (0) | 0.57 |
1: mild better | 6 (19.4) | 4 (13.3) | |
2: moderate better | 13 (41.9) | 13 (43.3) | |
3: very much better | 9 (29.0) | 11 (36.7) | |
4: excellent | 1 (3.2) | 2 (6.7) |
The most common adverse effect found in both groups was abdominal discomfort; it was found in SHT and diclofenac groups as 41.9% and 30%, respectively. However, there is no significant difference in both groups (Table
Adverse events of Sahastara remedy and diclofenac.
Adverse events | SHT ( |
Diclofenac ( |
---|---|---|
Abdominal discomfort | 13 (41.9) | 9 (30) |
Constipation | 1 (3.22) | 1 (3.33) |
Dry lips and throat | 1 (3.22) | 1 (3.33) |
Sweating | 1 (3.22) | 2 (6.66) |
Dizziness | 1 (3.22) | 1 (3.33) |
Blood pressure, renal functions, and liver functions in safety issue.
Data |
Follow-up | Treatment |
|
|
---|---|---|---|---|
SHT | Diclofenac | |||
Blood pressure | ||||
Systolic blood pressure (normal ≤ 140 mm.Hg.) | Day 0 | 123.55 (11.42) | 121.83 (13.03) | 0.66 |
Day 14 | 126.77 (10.13) | 127.00 (14.42)† | ||
Day 28 | 123.54 (12.79) | 128.67 (17.95) | ||
|
||||
Diastolic blood pressure (normal ≤ 90 mm.Hg.) | Day 0 | 82.90 (8.24) | 80.50 (8.13) | 0.68 |
Day 14 | 84.03 (6.38) | 83.50 (7.08) | ||
Day 28 | 83.55 (7.09) | 84.67 (6.81)† | ||
|
||||
Renal functions | ||||
Blood urea nitrogen; BUN (mg/dL) (ref. range = 7.0–18.0) | Day 0 | 13.74 (4.69) | 15.35 (4.55) | 0.15 |
Day 14 | 13.98 (3.87) | 14.70 (4.67) | ||
Day 28 | 13.54 (3.89) | 14.96 (3.52) | ||
|
||||
Creatinine (mg/dL) (ref. range = 0.7–1.3) | Day 0 | 0.84 (0.27) | 0.80 (0.20) | 0.60 |
Day 14 | 0.82 (0.22) | 0.79 (0.23) | ||
Day 28 | 0.81 (0.24) | 0.80 (0.20) | ||
|
||||
Liver functions | ||||
AST (U/L) (ref. range = 15–37) | Day 0 | 28.00 (19.50) | 22.33 (10.35) | 0.45 |
Day 14 | 25.77 (12.54) | 30.50 (20.88) | ||
Day 28 | 21.61 (7.05) † | 29.00 (14.93) † | ||
|
||||
ALT (U/L) (ref. range = 30–65) | Day 0 | 46.48 (23.94) | 40.90 (12.92) | 0.00 |
Day 14 | 44.13 (23.95) | 55.70 (36.66)††† | ||
Day 28 | 41.03 (11.45) | 56.37 (32.33)††† | ||
|
||||
ALP (U/L) (ref. range = 50–136) | Day 0 | 108.26 (25.95) | 98.27 (23.26) | 0.19 |
Day 14 | 110.13 (46.30) | 98.23 (21.85) | ||
Day 28 | 113.84 (35.68) | 106.17 (30.68)†† |
Although the SHT remedy has been used in TTM for more than 50 years, there were few reports in the literature. In the previous report, SHT showed the higher inhibitory effect on nitric oxide (NO) release as proinflammatory mediator in activated murine macrophages cell line (RAW 264.7) than indomethacin (
However, the SHT has many spicy plant ingredients and is recommended to be taken before meals as it can cause a burning sensation and abdominal pain which was found to be 41%. Omeprazole may not prevent the adverse GI effects from the spicy substances. More studies regarding the appropriate timing and dosage of the SHT administration need to be done. Taking SHT immediately before meals or taking more water with the medicine would help to alleviate the symptoms.
Blood pressure increase is one precaution for the use of both SHT and diclofenac. As ascertained from this study, blood pressure has shown to slightly increase in the diclofenac group but the SHT group did not show significantly change on blood pressure. However, this is the first report for the effects of the SHT remedy on blood pressure. The previous study of piperine, which is the main ingredient of the SHT remedy, has found that it decreased the percentages of iNOS, elastin, and smooth muscle cells actin SMCA and has been shown to decrease blood pressure from the third week of treatment [
This study confirms the results of a previous study of 17,289 arthritis patients who took diclofenac for 18 months and showed elevation of the AST or ALT levels because diclofenac is associated with aminotransferase elevations, especially in the first 4–6 months of use [
However, this study had the limitation that it was a sex recruitment because this study design did not block random for patients to be female or male. The sex depend on the out patients who visited at orthopedics department in that time. However, it was related to incidence of OA knee patients. This report showed most of patients to be female (90% in both groups). In addition, this is a short-term study because the limitation of NSAIDs use has the cautions of long-term used. However, the chronic toxicity of SHT in animal model should be continuously studied because it will be a drug of choice of chronic OA patients.
This research is the first report which did clinical trial in OA patients and compared with diclofenac. This report could be supported using SHT in hospital of Thailand.
The SHT remedy showed an equally clinical efficacy in alleviating symptoms of OA knee when comparing it with diclofenac. The anti-inflammatory effects of SHT have also shown an improved quality of life in the OA patient and also no toxicity on liver or renal function. It should be a drug of choice of OA of the knee patients who had abnormal liver function and hypertension because it showed no effect on blood pressure and liver function tested values. The SHT remedy has been proven to be a good alternative medicine for the treatment of knee osteoarthritis.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The project was supported by National Research Universities Project, Office of the Higher Education Commissions and Center of Excellence in Applied Thai Traditional Medicine, and Faculty of Medicine, Thammasat University, Thailand.