Safety and efficacy of Curcumin versus Diclofenac in Knee Osteoarthritis: a randomized open label parallel arm study

doi:10.21203/rs.1.2/v2

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Safety and efficacy of Curcumin versus Diclofenac in Knee Osteoarthritis: a randomized open label parallel arm study

https://doi.org/10.21203/rs.1.2/v2

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published 11 Apr, 2019

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Background: To compare the efficacy and safety of curcumin with diclofenac in the treatment of knee osteoarthritis (OA). Methods: In this randomized, open label, parallel, active controlled clinical study, 139 patients of knee OA were randomized to receive either Curcumin 500 mg (Curcugreen®) capsule thrice daily or diclofenac 50 mg tablet twice daily for 28 days. Patients underwent assessment at baseline, day 7, day 14 and day 28. Primary efficacy measures were severity of pain (Visual Analogue Scale) and the Knee injury and osteoarthritis outcome score (KOOS) subscale at day 14 and day 28. Anti-flatulent effect (at day 7), anti-ulcer effect, weight lowering effect, patient and physician’s global assessment of therapy at day 28 were included as secondary endpoints. Safety after treatment was evaluated by recording adverse events and laboratory investigation. Results: Both treatment groups showed similar improvement in primary endpoints at day 14 and day 28. Patients receiving curcumin showed similar improvement in severity of pain and KOOS scale when compared to diclofenac, and the difference was not statistically significant (p>0.05). On day 7, the patients treated with curcumin experienced significantly greater reduction in number of episodes of flatulence compared with diclofenac (p<0.0001). Similar trend was observed at day 28 for weight lowering effect of curcumin (p<0.0001) and anti-ulcer effect. None of the patients required H2 Blockers in curcumin group and 19 patients required H2 blockers in diclofenac group (0% Vs 28%, respectively; p<0.00001). Adverse effects were significantly less in curcumin group (13% vs. 38% in diclofenac group; p=0.0015). Patient’s and physician’s global assessment of therapy was similar towards both the treatment. Conclusion: Curcumin has similar efficacy, but better tolerated than diclofenac among patients with knee OA. Curcumin can be an alternative treatment option in the patients of knee OA who are intolerant to the side effects of NSAIDS. Trial Registration: ISRCTN, ISRCTN10074826, Registered 21 November 2017 - Retrospectively registered, http://www.isrctn.com/ISRCTN10074826 Keywords: Knee osteoarthritis; Pain; Curcumin; Diclofenac; Anti-flatulent; Weight lowering; Anti-ulcer

General Medicine

Knee Osteoarthritis (OA) is one of the most common and fourth leading cause of disability [1]. Symptoms of knee OA normally begin after the age of 40 years, but they can affect younger people after a traumatic injury. It is highly prevalent among obese patients, with the estimated incidence of 10% to 15% in population aged above 60 years [1, 2]. Due to increasing prevalence of obesity and aging population, the prevalence of knee OA is expected to increase [3, 4]. Activity restriction and functional limitations among elderly obese patient with knee OA gradually reduce physical, psychological, and social well-being of patients leading to worsening of their quality of life, [5,6] also it significantly enhances financial burden on patients and their family as well as health care systems. A study conducted by Dominick et al. (2004) among more than 4000 OA patients showed worst quality of life, in most patients especially for item related to poor general health, pain and activity limitation [7].

Pain is one of the key symptoms that drive individuals to seek medical attention, and contributes to functional limitations and reduced quality of life [8-11]. Current recommendations for managing OA focus on relieving pain, improving physical functions and to slow the progress of the underlying disease as important goals of therapy. Usual first line pharmacologic therapy for knee OA is non-steroidal anti-inflammatory drugs (NSAIDs) which provides effective relief of symptoms in most patients [12, 13]. Pharmacological therapy with NSAIDs offer temporary relief in symptoms but is associated with serious risk after long-term use. Chronic administrations of NSAIDs cause gastroduodenal mucosal erosions in approximately 35–60% of patients, gastric or duodenal ulceration in 10–25% of patients [14]. These events are consequence of non-selective mechanism of action of traditional NSAIDs [13]. Additionally, elderly patients are at greater risk for gastrointestinal (GI) bleeding secondary to use of NSAIDs [15]. Long-term use of non-opioid analgesics such as acetaminophen and NSAIDs, including cyclo-oxygenase (COX)-2 inhibitors have been found to be associated with enhanced risk for gastrointestinal bleeding, hypertension, congestive heart failure and renal insufficiency [16]. There is need of an effective and safer alternative treatment for patients with knee OA.

Curcumin, a polyphenolic compound derived from dietary spice turmeric (Curcuma longa), possesses diverse pharmacologic and biological properties. Curcumin has been used for centuries in traditional Chinese and Ayurvedic medicine for its anti-inflammatory properties [17]. Efficacy of curcumin is shown to be similar to that of ibuprofen for the treatment of knee OA [18]. Study done with curcumin on patients with rheumatoid arthritis demonstrated a significant improvement in the duration of walking time and joint swelling which was almost comparable with phenylbutazone [19]. Pre-clinical studies conducted on ratssuggested thatcurcumin is a gastroprotective agent and acts as a potent antiulcer compound, protecting against gastric mucosal injury [20, 21]. A study has shown that curcumin acts as a potent antiulcer compound to protect indomethacin (NSAID)-induced gastric ulcer [22]. It inhibits increased acid secretion to prevent ulcer aggravation. Clinical evidences confirmed that curcumin is safe for human use [23-24]. Anti-flatulent and body weight lowering effect was also reported with the use of curcumin in pre-clinical studies [25-26].

However, poor oral bioavailability of curcumin hampers its therapeutic efficacy which is a major concern. Bioavailability of curcumin can be increased by combining curcuminoids with essential oil of turmeric [27-28]. Availability of curcumin in blood plasma was seven folds higher after consuming curcuminoids and essential oil of turmericthan normal curcumin and retained significant levels of curcumin even at 8 hours post administration and found to be non-toxic and safe [29-31]. Studies has been conducted on curcuminoid–essential oil complex showing therapeutic efficacy in numerous diseases like major depressive disorders, alzhiemer’s disease, rheumatoid arthritis and has potential for widespread application and radioprotective effect in different kinds of cancer [32-38].

Diclofenac is a well-known NSAID with anti-inflammatory, analgesic and antipyretic properties, comparable or superior to other NSAIDs [39]. Curcumin has been extensively used in traditional medicine in India, particularly as an anti-inflammatory agent [40]. The objective of this study was to compare efficacy and safety of curcumin versus diclofenac in patient with knee OA. We also investigated the anti-flatulent and weight lowering effect of curcumin among patients with knee OA and compared it with diclofenac.

Ethics & participant confidentiality:

This study was conducted according to the Declaration of Helsinki, the ICH-GCP E6 (R1, R2), and ICMR-National Ethical Guidelines for Biomedical and Health Research 2006. The Ethics committee approval was obtained from Krishna Institute of medical sciences, Karad, Maharashtra, India before initiating study (Reference No: kimsu/PhD/11/2010). Prior to any study-related screening procedures, written informed consent was obtained by the principal investigator from each patient before enrolling in the study. The study was registered with the ISRCTN registry (ISRCTN10074826). The participant was only identified by the participant study number and all documents in the study carried only the initials and participant study number. The patient identification information was handled only by a delegated staff and stored in locked cabinets accessible only to that staff.

Trial Design & Participant selection

This trial was designed as a prospective, randomized, open label, active controlled parallel group study. The randomization sequence was generated by an independent statistician using the Graphpad software with an allocation ratio 1:1. Then, the allocation was concealed using sequentially numbered identical boxes. . Patients fulfilling the eligibility criteria were enrolled and randomized to receive either the intervention or the comparator. The pharmacist designated by the investigator dispensed the investigational products.

This study was conducted at City Care Accident Hospital, Parli Vaijnath, Maharashtra, India. All patients (aged 38-65 years) suffering from symptomatic knee OA for at least 3 months with no joint deformities and requiring treatment with anti- inflammatory drugs were screened for eligibility after taking written informed consent. Patient meeting the American College of Rheumatology (ACR) criteria for knee OA (confirmed by X-ray) and having moderate pain (Visual analogue scale score 4 or greater) in the knee joint were included in the study. Patients taking analgesics were given a washout period of at least 3-7 days (or longer depending on the pharmacokinetic of drug) before starting the study intervention. The dietary intake of curcumin was restricted. The patients were advised not to change their routine dietary habits and physical activity which can lead to weight gain/loss. Patients with flatulence episodes ranging from 5 to 20 per day were enrolled to evaluate anti-flatulent effect.

Patients who received corticosteroid injection within last 4 week; history of active peptic ulcer, gastric ulceration, stomach pain or GI bleeding or bleeding disorders; had secondary osteoarthritis due to syphilis, metabolic bone disorder, acute trauma; patients who required prescription anticoagulants, hydantoin, lithium, steroids, methotrexate and colchicines or concurrent pain relieving medication such as tranquilizers, hypnotics, excessive alcohol or any other drug affecting the evaluation of analgesic action, or patient having known hypersensitivity to diclofenac sodium and turmeric were excluded from the study. Patients with medical history of significant impairment of hepatic or renal functions, cardiac insufficiency, and bronchitis were also excluded. Pregnant and lactating women and women of child bearing age not practising or not willing to use contraceptive were not included.

Interventions & Dosage

The intervention used in this clinical trial was Curcumin 500 mg zero size hard gelatin capsule (Curcugreen® from Arjuna Natural Ltd, India). Each capsule contained curcuminoids and essential oil of turmeric complex (Curcumin, demethoxycurcumin, bisdemethoxycurcumin and Volatile oils from Turmeric Rhizome) total not less than 95%, curcuminoids not less than 88% and curcumin not less than 68%.

The comparator used was diclofenac 50 mg uncoated tablet (Diclofenac) manufactured by Lupin Pharmaceuticals)

The dosage was Curcumin 500 mg thrice daily or diclofenac 50 mg twice daily for 28 days. Patients were also provided with rescue medications paracetamol 500 mg tablet (Calpol - Manufactured by GlaxoSmithKline Pharmaceuticals Ltd) and ranitidine 150 mg tab (Rantac - Manufactured by J B Chemicals & Pharma Ltd).

Assessments

Patients were evaluated at baseline (day 0), week 2 (day 14) and week 4 (day 28). Primary endpoints were improvement in the pain intensity on visual analogue scale (VAS) and Knee injury and osteoarthritis outcome score (KOOS) subscale assessment at each evaluation visits. The visual analog scale system was shown to be valid and comparable to other methods. It brought greater sensitivity and greater statistical power to data collection and analysis by allowing a broader range of responses. It removed bias that was introduced by examiner questioning, and it allowed graphic temporal comparisons [41]. The KOOS is a valid, reliable and responsive self-administered instrument that can be used for short term and long-term follow-up of several types of knee injury including osteoarthritis [42]. Secondary endpoints were: anti-flatulent effect, weight lowering effect, patient’s global assessment for over all symptom relief and physician’s global evaluation of treatment and anti-ulcer effect. The patients were asked to record the number of episodes of flatulence over past 24 hours before administering medication and on day 7. The anti-flatulent effect was assessed by comparing the mean fall in number of episodes of flatulence. The weight lowering effect was assessed by comparing the mean fall in weight on day 28 with baseline weight. Anti-ulcer effect was assessed by recording the number of patients consumed H2 Blocker tablets during study period. Requirement of rescue medication throughout the study period was recorded in case report form. Compliance to study medications was checked in each visit. Adverse events (AE) reported/observed during study period were recorded in case report form at each study visit.

Statistical Analysis:

Sample size calculation was performed using software PS Power and Sample Size Calculations (version no.3). Based on a power of 80% and a Type I error rate of alpha= 0.05 (2-tailed), a sample size of 65 participants per group was required to detect an estimated difference of 1.24 in the mean pain scores between the treatment arms with standard deviation (SD) of 2.5. Assuming dropout rate of 5%, a total sample size of 69 participants per treatment group was considered sufficient in this study. All statistical analyses were performed on intention-to-treat basis with last observation carried forward method. Normality was tested for the data using Shapiro-wilk test. Paired t-test or / unpaired t-test, was used for normally distributed data and Wilcoxon-signed rank test or Mann Whitney test was used for the non-normally distributed data to compare the continuous data within groups and between groups respectively and Chi-square or Fishers exact test was used to compare the categorical data of study groups. For comparing VAS score between the groups independent t-test was used as the scores were not on one of the extremes. A comparison of two treatments (curcumin & diclofenac) with the perfect analgesic was also done and the correlation coefficient was determined. P-value of less than 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS version 24.

Patient disposition and characteristics:

160 patients were screened and 149 patients were enrolled in the study. A total of 139 patients (curcumin: 70; diclofenac: 69) completed the study and were subjected to statistical analysis. Drop-outs included four patients from curcumin group and six from diclofenac group [Figure 1]. Both treatment groups were comparable in terms of demographic characteristics i.e. age, weight, height and gender. Clinical assessment of pain on VAS and KOOS subscale at the start of the trial (baseline) was similar between both treatment groups. Overall, demography and baseline characteristics between both the treatment group was similar before the start of study treatment [Table 1].

Table 1: Demography and baseline characteristics in patients with knee OA

Patient characteristic	Curcumin (N=70)	Diclofenac (N=69)
Age (years)	53.09 4.17	52.14 ± 3.76
Gender (M/F)	M = 45; F = 25	M = 48; F = 21
Weight (Kg)	61.37 5.46	63.51 ± 5.19
Duration of knee osteoarthritis (months)	7.40 ± 3.53	7.45 ± 3.15
Baseline pain intensity on Visual analogue scale (VAS)	7.84 ± 0.63	7.81 ± 0.73
Values are expressed in Mean ± SD except for gender variable (presented as number of patients in each category). Visual analogue scale (0 to 10 where 0 indicates “No pain” and 10 indicates “Worst possible pain”

Efficacy results:

Both treatment groups showed significant reduction in VAS scores on Day 28 from their base lines (p<0.0001). However, there was no significant difference in reduction in pain intensity between the groups (p>0.05). The number of patients having more than 50% improvement in VAS score were 66 and 67 in curcumin and diclofenac group respectively and the difference when compared were not statistically significant (p=0.681) [Table 2].

Table 2: Comparison of pain as determined by VAS in patients with knee OA

Visit	Curcumin (N=70)	Diclofenac (N=69)	p value
Baseline	7.84 ± 0.63	7.81 ± 0.73	0.7876t
Day 14	4.69 ± 0.79	4.58 ± 0.60	0.3755t
Day 28	2.20 ± 0.81	2.20 ± 0.61	0.98t
Change at Day 14	-3.16 ± 0.79	-3.23 ± 0.91	0.6061t
Change at Day 28	-5.93 ± 0.99	-5.61 ± 0.88	0.8229 t
p value	P<0.0001wc	P<0.0001wc
VAS Reduction % ≤ 50	N=4	N=2	p=0.681f
VAS Reduction % > 50	N=66	N=67
Values are expressed in Mean ± SD. wc= Wilcoxonsigned rank test, t= Independent T-test. f=Fisher Exact test, N= number of patients in each group. p< 0.05 considered as statistically significant difference. Visual analogue scale (0 to 10 where 0 indicates “No pain” and 10 indicates “Worst possible pain”). Change in mean score at day 14and day 28 is calculated from baseline VAS score.

In our study, pain relief for diclofenac and curcumin are well below the “perfect analgesic” (slope =1) and above “no treatment” (slope=0) graph and the contribution of slope change due to the initial pain score is practically nil and statistically not significant (p= 0.7876) [Figure 2].

Both treatment groups showed continuous improvement in scores in all 5 subscales of KOOS at each treatment visit from baseline and the difference at the end of the study was statistically significant (p<0.0001). The patients receiving curcumin showed similar improvement in KOOS score of all subscales as compared to diclofenacat the end of study, as difference was not statistically significant (p>0.05) [Table 3].

Table 3: Assessment of KOOS subscale in patients with knee OA

KOOS subscale*	Visit	Curcumin (N=70)	Diclofenac (N=69)	p valuem
Pain	Baseline	53.29 ± 5.70	53.15±4.24	0.887
	Day 14	72.70 ± 4.89	73.69 ± 3.97	0.5594
	Day 28	88.77 ± 5.62	90.38 ± 3.61	0.0703
	Change at Day 14	19.40 ± 2.89	20.55± 3.22	0.2494
	Change at Day 28	35.48± 4.07	37.23 ± 2.05	0.1466
	p valuewc	<0.0001	<0.0001
Symptoms	Baseline	55.77 ± 6.00	55.87 ± 5.97	0.6559
	Day 14	61.58 ± 5.65	61.93 ± 5.47	0.8789
	Day 28	67.95 ± 5.86	69.13± 5.50	0.8208
	Change at Day 14	5.82 ± 3.81	6.06± 3.36	0.8326
	Change at Day 28	12.19 ± 5.28	13.26 ± 4.44	0.9444
	p valuewc	<0.0001	<0.0001
Function in daily living	Baseline	58.45 ± 4.96	61.26 ± 5.24	0.2074
	Day 14	77.67 ± 5.90	80.54 ± 6.10	0.0484
	Day 28	94.58 ± 6.58	96.23 ± 2.71	0.4944
	Change at Day 14	19.22 ± 2.99	19.275 ± 2.38	0.5488
	Change at Day 28	36.13 ± 3.61	34.971 ± 5.05	0.3425
	p valuewc	<0.0001	<0.0001
Function in sport and recreation	Baseline	44.86 ± 8.47	48.55 ± 7.58	0.0080
	Day 14	68.43 ± 5.81	71.88 ± 5.01	0.0004
	Day 28	89.14 ± 6.43	91.88 ± 4.38	0.0066
	Change at Day 14	23.57 ± 4.27	23.33 ± 4.34	0.6340
	Change at Day 28	44.28± 6.44	43.33 ± 6.22	0.1457
	p valuewc	<0.0001	<0.0001
Quality of life	Baseline	42.95 ± 5.31	41.91 ± 6.88	0.0549
	Day 14	59.64 ± 6.08	59.15 ± 7.73	0.5815
	Day 28	73.57 ± 7.46	72.26 ± 8.61	0.6386
	Change at Day 14	16.70 ± 8.22	17.23± 8.44	0.6246
	Change at Day 28	30.63 ± 10.16	30.35 ± 10.02	0.6004
	p valuewc	<0.0001	<0.0001
*Higher score indicated better improvement. Values are expressed in Mean ± SD. wc=Wilcoxon signed rank test(within the group), m=Mann-Whitney test (between the group), N= number of patients in each group. P < 0.05 considered as statistical significant difference. KOOS scale (0 to 100 where 0 indicates “Extreme Problem” and 100 indicate “No Problem”). Change in mean score at day 14and day 28 is calculated from baseline KOOS score for each subscale.

The number of episodes of flatulence between both the treatment groups at baseline were comparable (p>0.05). The patients who were treated with curcumin experienced significantly greater reduction in number of episodes of flatulence from baseline compared to patient treated with diclofenac (p<0.0001) (Table 4). The patients who were treated with curcumin experienced significantly greater reduction in body weight from baseline (p<0.0001) compared to patient treated with diclofenac (p=0.2146). The difference in anti-flatulent effect and weight loss in patients between the groups were statistically significant (p<0.0001) [Table 4].

Table 4: Comparison of anti-flatulent and weight lowering activity

Visit	Curcumin (N=70)	Diclofenac (N=69)	p valuem
Anti-flatulent activity	N=25	N=25	-
At baseline	12.04 ± 2.17	11.32 ± 2.21	0.2927
Day 7	2.32 ± 1.11	10.8 ± 2.1	<0.0001
Weight lowering activity	N=70	N=69	-
At baseline	61.37 5.46	63.51 ± 5.19	0.0232
Day 28	60.36 ± 5.19	63.39 ± 5.21	0.0013
Change from baseline (at Day 28)	1.01 ± 0.81	0.12 ± 0.70	<0.0001
p-value of weight lowering activitywc	p<0.0001	p=0.2146
Values are expressed in Mean ± SD. Data were analyzed by wc=Wilcoxon signed rank test and m=Mann-Whitney test. N= number of patients in each group. p< 0.05 considered as statistical significant difference.

Global assessments of treatment by patient and physician based on overall efficacy and safety was similar towards both the treatment (curcumin and diclofenac) [Table 5]. The need for rescue medication (paracetamol) was numerically higher in curcumin group (15 patients; 21%) compared to diclofenac group (12 patients; 17%), however, the difference was not statistically significant (p=0.6689). None of the patients required H2 Blockers in curcumin group when compared to diclofenac group (0% vs. 28%, respectively; p<0.00001), this indicates anti-ulcer effect of curcumin.

Table 5: Global assessment by Physicians and Patients after study drug treatment

Global Assessment Rating	Physician’s global assessment	Patient’s global assessment
	Curcumin (N=70) n (%)	Diclofenac (N=69) n (%)	Curcumin (N=70) n (%)	Diclofenac (N=69) n (%)
Excellent	10 (14)	10 (14)	11 (16)	12 (17)
Good	56 (80)	54 (78)	54 (77)	52 (75)
Fair	1 (1)	1 (1)	2 (3)	1 (1)
Poor	3 (4)	4 (6)	3 (4)	4 (6)
p- value	>0.05	>0.05
Values are expressed as absolute number of patients (percentage) in each category. Data were analyzed by Chi-Square test. N = Total number of patients in each treatment group. p< 0.05 considered as statistical significant difference. n = number of patients in each category.

Safety variables

Overall, 13% of patients receiving curcumin and38 % of patients receiving diclofenac reported at least one adverse effect and this difference was statistically significant (p=0.0015). All reported adverse effects were mild and transient. The most common adverse effects were nausea, diarrhea, abdominal pain/acidity and flatulence. Incidence of each adverse effect was significantly lesserinthe curcumin group compared to the diclofenac group. Relative risk of all adverse events except nausea and diarrhea in curcumin group is reduced to less than 10% which is clinically significant. Relative risk of nausea and diarrhea is only reduced to 80% and 60% respectively. Relative risk is calculated on comparing the curcumin group and diclofenac group [Table 6]. Analysis of laboratory values did not reveal any significant adverse outcomes [Table 7].

Table 6: Summary of adverse reactions in each treatment group

Adverse reactions	Curcumina (N=70) n (%)	Diclofenacb (N=69) n (%)	RR	RRLB	RRUB	NNT
	n (%)	n (%)
Total number of patients experienced AEs*	9 (13%)	26 (38%)
Dyspepsia	0	6 (8.7%)	0.08**	0	1.3	12
Nausea	6 (9%)	7 (10.14%)	0.8	0.3	2.4	64
Vomiting	0	7(10.14%)	0.07**	0	1.1	10
Diarrhoea	5 (7%)	8 (11.6%)	0.6	0.2	1.8	23
Constipation	0	6 (8.7%)	0.08**	0	1.3	12
Abdominal pain /acidity	0	19 (27.53%)	0.03**	0	0.4***	4
Flatulence	0	9 (13.04%)	0.05**	0	0.9***	8
Upper respiratory Tract Infection	0	5 (7.25%)	0.09**	0	1.6	14
p= 0.0015 for Curcumin vs Diclofenac Values are expressed as absolute number of patients (percentage) in each category. N = Total number of patients in each treatment group. n = number of patients in each category. a= Treatment group, b = Control Group, RR: Relative Risk, RRLB : Relative risk Lower boundary, RRUB: Relative risk upper boundary, NNT: Number Needed to Treat Clinically Significant AE (RR<0.5), **Statistically significant AE (95% CI does not include1)

Table 7: Laboratory-based evaluations of safety

Laboratory Parameter	Curcumin (N=70)	Diclofenac (N=69)	p-value#
	Before treatment	After treatment	p-value*	Before treatment	After treatment	p-value*
Haemoglobin (gm/dl)	14.67±0.37	14.67±0.36	0.2882	14.67±0.35	14.74±0.37	0.0335	0.3739
R.B.C. Count (million/cu.mm)	5.01 ± 0.32	5.06±0.31	0.0644	5.06±0.34	5.12±0.36	0.0172	0.2864
Total WBC Count (/cmm)	7577.14 ± 1723.26	7841.43 ± 1512.60	0.1443	7633.33 ± 1841.09	7682.61 ± 1603.76	0.6980	0.5852
Red Cell Absolute Values
Packed Cell Volume %	44.79 ± 2.72	45.06 ± 2.51	0.5144	44.86 ± 2.88	45.38 ± 2.77	0.0098	0.4032
Mean Corpuscular Volume (cubic micron)	80.56 ± 3.13	80.91 ± 2.91	0.1419	81.20 ± 3.47	81.50 ± 3.45	0.0597	0.4558
Mean Corpuscular Hemoglobin (picogram)	29.02 ± 1.34	29.23 ± 1.23	0.0583	29.17 ± 1.52	29.29 ± 1.39	0.1673	0.8217
Mean corpuscular Hb Con.(g/dl)	33.62 ± 0.89	33.66 ± 0.82	0.6931	33.68 ± 0.97	33.74 ± 0.97	0.1510	0.4222
Differential Count
Neutrophils %	48.67 ± 4.84	49.08 ±4.72	0.5802	48.85 ± 4.45	49.81 ± 4.68	0.0283	0.4258
Lymphocytes %	28.58 ± 5.24	28.99 ± 5.09	0.4991	28.30 ± 4.74	29.19 ± 4.86	0.0570	0.8037
Eosinophil %	3.57 ± 0.58	3.39 ± 0.55	0.0990	3.61 ± 0.57	3.52 ± 0.58	0.4800	0.1504
Monocytes %	3.96±0.91	4.06±0.80	0.5016	4.03±0.74	4.09±0.80	0.7022	0.8111
Basophils %	0	0	-	0	0	-	-
Peripheral smear examination
Platelets ( /cmm)	269757.1 ± 55561.02	268514.3 ± 57049.62	0.7145	286942 ± 49707.34	279956.5 ± 60135.25	0.3658	0.2993
ESR ( /hr)	13.06 ± 2.90	12.86 ± 2.59	0.5911	12.88 ± 2.83	12.93 ± 2.82	0.7787	0.8191
Biochemistry
Serum Creatinine (mg/dl)	0.88 ± 0.27	0.91 ± 0.26	0.3582	0.93 ± 0.30	0.96 ± 0.30	0.0464	0.4101
SGPT IU/L	22.71 ± 5.26	23.6 ± 4.75	0.4227	25 ± 4.81	23.71 ± 5.45	0.1289	0.9815
SGOT IU/L	23.6 ± 4.17	23.79 ± 3.51	0.7620t	25.12 ± 4.19	24.15 ± 4.04	0.1161	0.7091
Data expressed as Mean ± SD. *p value (within the group) by Wilcoxon Signed Rank test #p value ( between the groups) (after treatment) by Mann Whitney test t=Paired t-test

This study demonstrated that curcumin also possess pain relief effect on patients with knee OA when compared to diclofenac. On the basis of KOOS subscales for symptoms, functions in daily living, functions in sports and recreation and knee related quality of life, curcumin showed similar improvement as compared to diclofenac, as the difference was not statistically significant. Overall, curcumin showed similar improvement in pain, stiffness, and symptoms, functions of daily living, sports /recreational activities and quality of life that have been attributed to its ability to inhibit COX-2, which results in the suppression of prostaglandin synthesis. Further, curcumin has been shown to suppress several pro-inflammatory cytokines and mediators of their release such as tumour necrosis factor (TNF-alpha), interleukin (IL)-1, IL-8 and nitric oxides synthase (NOS).

Poor bioavailability is amajor drawback of free curcumin. In the meta-analysis of data from clinical trials with curcumin supplementation, it was reported that reduction in pain severity did not reach statistical significance with respect to treatment duration. The results of subgroup analysis confirmed that bioavailable optimized preparations increased the analgesic effect of curcuminoids [43]. Beneficial results obtained in our study is possibly due to the combination of curcuminoids and essential oil of turmeric present in curcumin capsules which increased the bioavailability.

Permeability of curcumin is increased by turmerones which acts by inhibiting p-glycoprotein [44]. Combination of curcumin with turmerones prevented inflammation associated colon carcinogenesis reporting synergistic effect of the combination than curcumin or turmerones alone [45]. The superiority of curcuminoids with essential oil of turmeric with turmerones was reported in many research papers. Anti-inflammatory and synergic potential of curcuminoid essential oil of turmeric complex showed superior protection from dextran sodium sulfate (DSS)-induced colitis than curcumin alone [46]. A study done on same composition (previously BCM-95) with Boswellia serrata reduced pain-related symptoms in patients with osteoarthritisand was effective in treating knee osteoarthritis than celecoxib (NSAID) [47-48]. Research on the same composition showed significantly better results in active rheumatoid arthritis when compared to diclofenac sodium [35].

Weight loss can be considered beneficial in the treatment for knee OA, it has been reported that weight reduction of 10% results in improved function by 28% in patients with knee OA [49]. In the study, significant body weight reduction from baseline was shown in the patients treated with curcumin (1.65 % weight reduction in curcumin group and 0.19% weight reduction in diclofenac group). Similar effect from curcumin has been reported by Asma Ejaz et al [26]. Curcumin suppresses angiogenesis in adipose tissue together with its effect on lipid metabolism in adipocytes may contribute to lower body fat and body weight gain. Curcumin induces apoptosis by suppressing the differentiation of preadipocytes to adipocytes. Adipokine- induced angiogenesis of human endothelial cells is also inhibited by suppressing the expression of vascular endothelial growth factor-α. Curcumin increase the activation of AMP-activated protein kinase (AMPK) in adipocytes. Phosphorylation of the α-subunit of AMPK and suppressing the expression of aminocyclopropane carboxylic acid activates AMPK in adipocytes. Beneficial effect of curcumin in obesity is obtained by increasing the fatty acid oxidation in adipocytes and thus produce beneficial effects in obesity [50]. Hence, the weight reduction caused by curcumin can be beneficial in the treatment for knee osteoarthritis especially in obese patients.

In our study, the patients treated with curcumin experienced lesser GI related side effects than the patients treated with diclofenac. Lesser GI related side effects may be due to potent antiulcer action or protection against gastric mucosal injury by curcumin. The mechanism of antiulcer activity of curcumin has also been understood. Neutrophils, lymphocytes and monocytes/ macrophages at the inflammatory site in stomach is primarily activated by the local inflammatory cytokine IL6. This initiates different oxidative bursts toxic metabolites and lysosomal enzymes which is responsible for local tissue damage in peptic ulcer disease. The severity and duration of inflammation, particularly in its acute phase, can be predicted more precisely by the proinflammatory IL6 than TNFα. Curcumin exhibits its anti-ulcer activity by inhibiting IL6 secretion and also by affecting oxidative stress by its total antioxidant capacity [51]. According to another study, curcumin protects gastric damage by efficient removal of H2O2 and H2O2 -derived SOH by preventing peroxidase inactivation by NSAID [22]. Further, there is also an evidence for possible involvement of glutathione in the curcumin-mediated gastroprotection [21].

Patients treated with curcumin experienced significantly greater reduction in number of episodes of flatulence from baseline compared to patient treated with diclofenac. The effect of curcumin on intestinal gas formation has been demonstrated in vitro and in vivo experiments [52]. Thus, the reduction in number of episodes of flatulence may be associated with anti-flatulent effect of curcumin.

The visual analogue scale (VAS) is most commonly used to assess intensity of pain. It is reliable, valid, sensitive to change, and easy to administer for measurement of severity of pain [53]. In clinical trials measure of pain relief is more preferred over pain severity as it is not dependent on initial pain severity, equality of the change in different parts of scale and variation in the patient's expression. The effectiveness of any particular treatment can be accurately measured by the pain relief which is the change between pain score after treatment and initial pain score [54]. As long as all data points are in between the 'no treatment' and 'perfect analgesic", more steeper line is directly proportional to better treatment efficacy. The effect of the slope variation and its effect on the mis-interpretation of the results is already reported [55]. A significant difference in the initial pain score can misguide the interpretation of the result as the effect of treatment. In our study, there is no chance for mis-interpretation of the results. Pain relief for Diclofenac and Curcumin are well below the “perfect analgesic” (slope=1) and above “no treatment” (slope=0) graph. The contribution of slope change due to the initial pain score is practically nil and statistically not significant (p= 0.7876). The slope variation obtained in the study results purely indicates the treatment effect of both the groups.

In estimating pain relief, it may not be appropriate simply to compare only the scores before and after treatment, because the magnitude of this difference is limited by the placement of the initial mark [56]. Quantal method measures pain relief based on proportion of patients achieving defined degree of pain relief. Such a method is not suitable for testing drugs which produce moderate pain relief and a more sensitive method is required. Assessment of pain severity based on the percentage change from the initial level and a minimum cut off of 50% in pain relief greatly improves the sensitivity of pain measurement scales [55]. In our study, both curcumin and diclofenac group had almost equal proportion (n=66 and n=67respectively) of patients who had more than 50% of reduction in VAS score from baseline levels with p value 0.681.

Significantly less number of patients in curcumin group reported adverse events compared with diclofenac group. None of the patients in curcumin group required H2 blockers. The favorable safety profile in curcumin group was observed due to its gastro-protective and antiulcer effect, which may be an alternative to the GI side effect of NSAIDs. Overall assessment of efficacy and safety of treatment by patient and physician was similar for both the groups (Curcumin and Diclofenac), which reflects the better acceptability of curcumin and diclofenac among patients of knee OA.

Limitations of the study

Open label study design without a placebo controlled group was one of the limitations of the study. The treatment duration of 28 days may not be sufficient enough to assess long term efficacy and prevention of progression of disease as evidenced by structural damage in OA patients. Hence a long term study is warranted with curcumin in OA patients. Though validated scales were used, the efficacy of curcumin in treatment of OA was not based on objective measures but on subjective measurement of pain which is another limitation of the study.

Our findings suggest that the curcumin thrice daily has similar efficacy, but better safety profile to diclofenac two times daily among patients with knee OA. Our study results suggest that the curcumin with increased bioavailability (Curcugreen®) can be a better alternative treatment option in the patients of knee OA who are intolerant to the side effects of NSAIDS.

ACR American College of Rheumatology

AE Adverse events

AMPK AMP-activated protein kinase

COX Cyclo-oxygenase

GI Gastrointestinal

IL Interleukin

KOOS Knee injury and osteoarthritis outcome score

NOS Nitric oxides synthase

NSAIDs Non-steroidal anti-inflammatory drugs

OA Osteoarthritis

TNFα. Tumour necrosis factor-alpha

VAS Visual analog score

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and got approved by Institutional Ethics Committee, Krishna Institute of Medical sciences, Karad, Maharashtra, India before initiating study (Reference No: kimsu/PhD/11/2010). Prior to any study-related screening procedures, written informed consent was obtained by the principal investigator from each patient before enrolling in the study.

Consent for publication

Not Applicable

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

Not Applicable

Author’s contribution

DS made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data.

CK involved in drafting the manuscript, revising it critically for important intellectual content and gave final approval of the version to be published.

PG involved in drafting the manuscript, revising it critically for important intellectual content.

SK agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

All authors read and approved the final manuscript.

Acknowledgements

All authors would like to thank the subjects for their participation in this study, Dr. Rakesh Ojha for performing statistical analysis, Arjuna Natural Ltd, India, for providing the patented and trademark registered curcumin (Curcugreen®) capsules as study samples.

1. Fransen M, Bridgett L, March L, Hoy D, Penserga E, Brooks P.. The epidemiology of osteoarthritis in Asia. Int J Rheum Dis. 2011;14:113-21.

2. Osteoarthritis.http://www.who.int/medicines/areas/priority_medicines/Ch6_12Osteo.pdf.Accessed 06 June 2016.

3. Riyazi N, Rosendaal FR, Slagboom E, Kroon HM, Breedveld FC, Kloppenburg M. Risk factors in familial osteoarthritis: the GARP sibling study. Osteoarthr Cartil. 2008;16:654–9.

4. Gonzalez Sáenz de Tejada M, Escobar A, Herrera C, García L, Aizpuru F, Sarasqueta C. Patient expectations and health‐related quality of life outcomes following total joint replacement. Value in Health. 2010;13:447–54.

5. Focht BC. Move to improve: how knee osteoarthritis patients can use exercise to enhance quality of life. ACSMs Health Fit J. 2012;16:24–8.

6. Cook C, Pietrobon R, Hegedus E. Osteoarthritis and the impact on quality of life health indicators. Rheumatol Int. 2007;27:315–21.

7. Dominick KL, Ahern FM, Gold CH, Heller DA.. Health-related quality of life among elder adults with arthritis. Health Qual Life Outcomes. 2004;2:5.

8. Hadler NM. Knee pain is the malady-not osteoarthritis. Ann Intern Med. 1992;116:598–9.

9. Ayis S, Dieppe P. The natural history of disability and its determinants in adults with lower limb musculoskeletal pain. J Rheumatol. 2009;36:583–91.

10. Dominick KL, Ahern FM, Gold CH, Heller DA. Health-related quality of life and health service use among older adults with osteoarthritis. Arthritis Rheum. 2004;51:326–31.

11. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Determinants of disability in osteoarthritis of the knee. Ann Rheum Dis. 1993;52:258–62.

12. Sangdee C, Teekachunhatean S, Sananpanich K, Sugandhavesa N, Chiewchantanakit S, Pojchamarnwiputh S, Jayasvasti S.. Electroacupuncture versus Diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. BMC Complement Altern Med.2002;2:3.

13. Tannenbaum H, Berenbaum F, Reginster JY, Zacher J, Robinson J, Poor G, Bliddal H, Uebelhart D, Adami S, Navarro F, Lee A, Moore A, Gimona A. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib. Ann Rheum Dis. 2004;63:1419-26.

14. Devi RS, Narayan S, Vani G, Shyamala Devi CS. Gastroprotective effect of Terminalia arjuna bark on diclofenac sodium induced gastric ulcer. Chem Biol Interact. 2007;167:71-83.

15. Schnitzer TJ, Tesser JR, Cooper KM, Altman RD.A 4-week randomized study of acetaminophen extended-release vs rofecoxib in knee osteoarthritis. Osteoarthr Cartil. 2009;17:1-7.

16. Sengupta K, Alluri KV, Satish AR, Mishra S, Golakoti T, Sarma KV, Dey D, Raychaudhuri SP.. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10(4):R85.

17. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol. 2008;75(4):787-809.

18. Kuptniratsaikul V, Thanakhumtorn S, Chinswangwatanakul P, Wattanamongkonsil L, Thamlikitkul V. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med. 2009;15(8):891-7

19. Kohli K, Ali J, Ansari M J, Raheman Z. Curcumin: A natural anti-inflammatory agent. Indian J Pharmacol 2005;37:141-7

20. Mei X, Luo X, Xu S, Xu D, Zheng Y, Xu S, Lv J. Gastroprotective effects of a new zinc(II)-curcumin complex against pylorus-ligature-induced gastric ulcer in rats. Chem Biol Interact. 2009;181:316-21.

21. Sudjarwo SA. Gastroprotective effect of curcumone on ethanol-induced gastric mucosal lesions in rats. Folia Med Indones. 2005;41:2.

22. Chattopadhyay I, Bandyopadhyay U, Biswas K, Maity P, Banerjee RK. Indomethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen. Free Radic Biol Med. 2006;40(8):1397-408.

23. ChengAL HC, Lin JK, Hsu MM, HoYF ST, Ko JY, Lin JT, Lin BR, Wu MS, Yu HS, Jee SH, Chen GS. Phase I clinical trial of curcumin, a chemo preventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895-9000.

24. Baum L, Cheung SK, Mok VC, Lam LC, Leung VP, Hui E, Ng CC, Chow M, Ho PC, Lam S, Woo J.. Curcumin effects on blood lipid profile in a 6-month human study. Pharmacol Res. 2007;56(6):509-14.

25. Turmeric: The genus Curcuma. RavindranPN,NirmalBabu K, Kandaswamy Sivaraman, editors. p. 417

26. Asma Ejaz, Dayong Wu, Paul Kwan, Mohsen Meydani. Curcumin Inhibits Adipogenesis in 3T3-L1 Adipocytes and Angiogenesis and Obesity in C57/BL Mice. J Nutr. 2009;139(5):919-25.

27. Antony B, Benny M, Rao SB. Enhancing the Absorption of Curcuminoids, Spice India 2005;23-26

28. Maheshwari M. Comparative bioavailability of curcumin, turmeric and Biocurcumax™ in traditional vehicles using non-everted rat intestinal sac model. J Funct Foods. 2010;2(1):60–5

29. Benny M, Antony B. Bioavailability of BiocurcumaxTM(BCM-095TM), Spice India 2006 (Sept);11-15

30. Antony B, Merina B, Iyer VS, Judy N, Lennertz K, Joyal S. A Pilot Cross-Over Study to Evaluate Human Oral Bioavailability of BCM-95®CG (Biocurcumax™), A Novel Bioenhanced Preparation of Curcumin, Indian J Pharm Sci 2008;70(4):445-449

31. Aggarwal ML, Chacko KM, Kuruvilla BT. Systematic and comprehensive investigation of the toxicity of curcuminoid - essential oil complex: A bioavailable turmeric formulation. Mol Med Rep. 2016;13(1):592-604.

32. Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, Goel A, Tripathi CB. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014;28(4):579-85.

33. Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. J Affect Disord. 2014;167:368-75.

34. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008;28(1):110-3.

35. Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytother Res. 2012;26(11):1719-1725.

36. Siddappa G, Kulsum S, Ravindra DR, Kumar VV, Raju N, Raghavan N, Sudheendra HV, Sharma A, Sunny SP, Jacob T, Kuruvilla BT. Curcumin and metformin‐mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Mol Carcinog. 2017;56(11):2446-60.

37. Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Ehtejab G A Pilot Clinical Trial of Radioprotective Effects of Curcumin Supplementation in Patients with Prostate Cancer. J Cancer Sci Ther. 2013;5: 320-324. doi:10.4172/1948-5956.1000222

38. Kuriakose MA, Ramdas K, Dey B, Iyer SS, Rajan G, Elango KK, Suresh A, Ravindran D, Kumar R, Prathiba R, Ramachandran S. A randomized double-blind placebo-controlled phase IIB trial of curcumin in oral leukoplakia. Cancer Prevention Research. 2016;9(8):683-91

39. Chuasuwan B, Binjesoh V, Polli JE, Zhang H, Amidon GL, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM. Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium. J Pharm Sci. 2009;98(4):1206-19.

40. Liang G, Li X, Chen L, Yang S, Wu X, Studer E, Gurley E, Hylemon PB, Ye F, Li Y, Zhou H. Synthesis and anti-inflammatory activities of mono-carbonyl analogues of curcumin. Bioorg Med Chem Lett. 2008;18(4):1525-9.

41. Flandry F, Hunt JP, Terry GC, Hughston JC. Analysis of subjective knee complaints using visual analog scales. Am J Sports Med. 1991;19(2):112-8

42. Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes. 2003;1(1):64.

43. Sahebkar A, Henrotin Y. Analgesic efficacy and safety of curcuminoids in clinical practice: a systematic review and meta-analysis of randomized controlled trials. Pain Med. 2015;17(6):1192-1202.

44. Yue GG, Cheng SW, Yu H, et al. The role of turmerones on curcumin transportation and P-glycoprotein activities in intestinal Caco-2 cells. J Med Food. 2012;15(3):242-252.

45. Murakami A, Furukawa I, Miyamoto S, Tanaka T, Ohigashi H. Curcumin combined with turmerones, essential oil components of turmeric, abolishes inflammation‐associated mouse colon carcinogenesis. Biofactors. 2013;39(2):221-232.

46. Toden S, Theiss AL, Wang X, Goel A. Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. Sci Rep. 2017;7(1):814.

47. Haroyan A, Mukuchyan V, Mkrtchyan N, et al. Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study. BMC Complement Altern Med. 2018;18(1):7.

48. Kizhakkedath R. Clinical evaluation of a formulation containing Curcuma longa and Boswellia serrata extracts in the management of knee osteoarthritis. Mol Med Rep. 2013;8(5):1542-8.

49. Christensen R, Astrup A, Bliddal H. Weight loss: the treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthr Cartil.. 2005;13(1):20-7

50. Aggarwal BB. Targeting inflammation-induced obesity and metabolic diseases by curcumin and other nutraceuticals. Annu Review Nutr. 2010;30:173-99.

51. Tourkey M, Karolin K. Antiulcer Activity of Curcumin on Experimental Gastric Ulcer in Rats and Its Effect on Oxidative Stress /Antioxidant,IL6 and Enzyme Activities. Biomed Environ Sci. 2009;22(6):488-95.

52. Ammon HP, Wahl MA. Pharmacology of Curcuma longa. Planta medica. 1991;57(01):1-7.

53. Bendinger T, Plunkett N. Measurement in pain medicine. BJA Education. 2016;16(9):310-5.

54. Wilderman I, Berkovich R. Integral of Pain Relief as an Innovative Method of Pain Measurement. J Pain Relief. 2017;6(277):2167-0846.

55. Huskisson EC, Meaurement of pain. The Lancet. 1974;1127-1131.

56. Measuring Health- A Guide to Rating Scales and Questionnaires 3rd ed. Ian McDowell p.478

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Safety and efficacy of Curcumin versus Diclofenac in Knee Osteoarthritis: a randomized open label parallel arm study

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Abstract

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Background

Methods

Results

Efficacy results:

Table 2: Comparison of pain as determined by VAS in patients with knee OA

In our study, pain relief for diclofenac and curcumin are well below the “perfect analgesic” (slope =1) and above “no treatment” (slope=0) graph and the contribution of slope change due to the initial pain score is practically nil and statistically not significant (p= 0.7876) [Figure 2].

Discussion

Conclusion

List of abbreviations

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References

Supplementary Files

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