Singhal S, Hasan N, Nirmal K, et al. Bioavailable turmeric extract for knee osteoarthritis: a randomized, non-inferiority trial versus paracetamol. Trials. 2021;22(1):105.
To explore the safety and effectiveness of bioavailable turmeric extract in comparison to paracetamol (also known as acetaminophen) in the improvement of pain for patients suffering with knee osteoarthritis
A randomized, noninferiority, controlled, prospective study at a single institution
Investigators screened a total of 210 individuals for the study and selected 193 participants. They randomized participants into 2 groups and also blinded them to treatment allocation.
Of those participants, investigators assigned 97 to the bioavailable-turmeric-extract group and 96 to the paracetamol group. However, only 144 participants completed the study, with 73 in the turmeric group and 71 in the paracetamol group, respectively.
Participants included both males and females, aged 40–80 years. The symptoms for each individual had to fit the measures to be scaled using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, distinction of those with unilateral pain from those with bilateral knee pain, and those advised for knee replacement.
Inclusion criteria for this study involved several factors: Participants had to have a diagnosis of knee osteoarthritis (OA) according to the American College of Rheumatology (ACR) criteria, no usage of analgesic medication or nonsteroidal anti-inflammatory drugs (NSAIDs) within 24 hours, chronic knee pain with active flare-ups at least every other day during the month, knee arthritis diagnosed by radiological imaging with Kellgren-Lawrence grades between 2 to 4, and ability to fully comprehend the study instructions provided.
Investigators initially excluded a total of 17 participants from the study for not being meeting the criteria. Additionally, they removed from the study 24 participants from the turmeric group and 25 from the paracetamol group due to failure to follow up.
Exclusion criteria included individuals with OA attributed to metabolic arthropathy; those with history of trauma of less than 1 month as the causative factor for knee pain; those who had received knee steroid injections 1 month before the start of this study; those with a history of serious comorbidities; women who were pregnant or lactating; and those with allergies to paracetamol, ibuprofen, or turmeric.
Six weeks of treatment with bioavailable turmeric extract (BCM-95, 500-mg capsule 2 times daily) in comparison to paracetamol (650-mg tablet 3 times daily) in knee OA patients.
Study Parameters Assessed
An orthopedic surgeon evaluated the knee symptoms of the participants at the start of the trial and after 6 weeks based on the WOMAC scale.
The WOMAC scale consists of 24 items divided into 3 subcategories: stiffness, physical function, and pain. Investigators scored test questions on a scale rating of 0 to 4, with 0=none, 1=mild, 2=moderate, 3=severe, and 4=extreme. The score for each subcategory is summed up with score ranges of 0 to 8 for stiffness, 0 to 68 for physical function, and 0 to 20 for pain; all 3 scores summed provides the value of the total WOMAC score.
Investigators collected blood samples at the start of the study (day 0) and during week 6 (day 42) for evaluation of tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP). Patients reported adverse reactions, and investigators compared them between the 2 groups.
Investigators used sample t tests for noninferiority to calculate the sample size to determine WOMAC scores and achieve the P value for testing equivalency. They assessed WOMAC pain scores between the turmeric extract and paracetamol for noninferiority using 2 one-sided tests (TOST).
Investigators analyzed the subcategories of WOMAC in response to treatment for reduction in pain alone and also pain with physical function and stiffness, which were scored at 3 different levels (≥20%, ≥50%, and ≥70%) of response for each patient for the duration of the 6 weeks.
Primary Outcome Measures
Investigators assessed a comparison of WOMAC scores for pain in addition to the total WOMAC score, WOMAC function and stiffness scores, and inflammatory markers after 6 weeks of treatment between the turmeric extract and paracetamol groups. For the turmeric-extract group after 6 weeks of treatment, the WOMAC total score and the pain, stiffness, and function scores improved 23.59%, 32.09%, 28.5%, and 20.25% respectively.
A noninferiority margin of 2.2 with a standardized effect size of 0.5 and significance level of 0.05 showed that WOMAC scores were equal for turmeric-extract and paracetamol groups (P<0.05). However, the values of CRP and TNF-α were not equivalent in both groups, with a statistically significant difference in TNF-α (P=0.0529) and a nonstatistically significant difference in CRP (P=0.2589). The turmeric-extract group had a reduction of TNF-α (74.81%) and CRP (37.21%) over the 6-week intervention period.
Investigators compared the effectiveness and efficacy parameters after 6 weeks of treatment between both groups after baseline covariate adjustment. There were no changes from baseline between the paracetamol and turmeric-extract groups for the WOMAC scores and CRP values (P>0.05) for the mean change after covariate adjustment.
Changes from baseline for TNF-α showed a significant reduction for the turmeric-extract group when compared to the paracetamol group (P=0.0095).
Patients in both groups had a similar response of reduction in WOMAC pain score at ≥20% reduction at values of 80% for paracetamol and 77% for turmeric. With the WOMAC pain and function/stiffness, the scores for paracetamol and turmeric extract were 61% vs 58% at ≥20% reduction respectively. “In the turmeric extract group, 18% of patients got more than 50% improvement and 3% of patients got more than 70% improvement in WOMAC pain and function/stiffness score and none of the patients in the paracetamol group met the criteria.”
There were no serious adverse effects reported from either group; however, there were some adverse effects experienced by patients in both groups that were mild and self-limiting in nature. Some of the adverse effects that individuals in the paracetamol group reported include restlessness (1.41%), abdominal pain (5.63%), tingling sensation (1.41%), melena (1.41%), and dry mouth (2.81%). Of those symptoms, 5.48% of patients in the turmeric group reported similar adverse effects of both tingling sensation (1.37%) and restlessness (4.11%).
The bioavailable turmeric extract was better at reducing WOMAC scores for pain, function, and stiffness than paracetamol while providing more safety and efficacy in reducing CRP and TNF-α in knee OA patients. CRP and TNF-α were significantly reduced when comparing baseline values to the 6-week treatment value for both groups. Turmeric was associated with minimal side effects as compared to paracetamol. When considering the WOMAC scores for pain with stiffness/function, patients in the paracetamol group did not respond to the treatment, while the patients in the turmeric group had significant improvement with a better response to treatment. Noninferiority was equal for both groups, allowing corresponding WOMAC scores to have equivalency in all the domains. This study shows that drugs used to treat OA may not be as effective if they do not relieve the pain and discomfort caused by OA, further contributing to the progression of the disease. When considering treatment, adverse effects have to be taken into consideration as this can add to patient discomfort and aggravation of symptoms.
Chronic pain from OA can be debilitating and cause physical and emotional stress. The importance of assessing both the biological and psychosocial factors of OA is becoming increasingly evident, as shown by a recent study on OA-related pain and psychological status.1 Persistent pain from OA can be associated with other health conditions such as depression, resulting in a decline in overall quality of life.2 OA also has economic, psychological, and social impacts on those who suffer from this disease.2 To date, the economic burden of OA has exceeded $60 billion per year in the United States.3 These are just some of the reasons why treatment for OA needs to be evaluated for long-term effectiveness to help reduce the burdens this disease creates, as prognosis for this condition is poor.
Treatment of OA should focus on alleviating pain, sustaining functional capacities, and improving quality of life for patients to help lessen the long-term effects this disorder will have on those who suffer from it.3 Due to inadequate treatment options and no current effective interventions to reduce the progression of OA except for joint replacement surgery, other alternative treatments show great benefit for the management of OA.3
OA is an irreversible degenerative disease that occurs through the progressive breakdown of joints, cartilage, and ligaments.4 An estimated 10% to 15% of the adult population aged 60 years and over have some level of OA, with women being more affected than men.4 Knee OA impairs quality of life for those who suffer from the condition, and eventually deterioration of bony structures decreases physical function.4 The mechanisms involved in the pathogenesis of OA are not completely understood.3 However, low-grade chronic inflammation and oxidative stress are 2 factors that contribute to the pathogenesis of OA.4 The most commonly affected areas of the body are the joints of the knees, hips, hands, and spine, with the main indicators being pain, stiffness, and local inflammation.4
Prevalence of OA increases with age and obesity.4 Obesity is 1 of the strongest risk factors for OA.5 Based on data from the Third National Health and Nutrition Examination Survey (NHANES III), there is a 5.26-fold increased risk of OA in individuals with metabolic syndrome at the age of 43.8 years, the mean age of the study population.5 According to the authors, OA’s association with metabolic syndrome implicates possible pathogenic mechanisms linking metabolic abnormalities and systemic inflammation.5
Other inflammation markers involved in OA are TNF-α and CRP.4 CRP is a nonspecific, predictive indicator for the development and progression of OA as it increases, with further injury of tissue and structural breakdown in the joint.6 Evidence suggests that therapeutically reducing inflammation can potentially help to decrease several pathologic components of OA, resulting in slowing the progression of the disease.6 Reduction in the levels of CRP and interleukin-6 can result from associated weight loss in individuals with OA, thus lessening existing OA symptoms or preventing the onset of symptoms altogether.6
OA is treated by a number of pharmacological therapies, with paracetamol, commonly known as acetaminophen, being a first-line drug for treatment, according to the American College of Rheumatology.4 Several studies have been done testing the safety and efficacy of paracetamol for its use in patients with arthritis pain in the knees, hips, and hands.4 The mechanism of action for paracetamol is officially deemed “unknown” and has some central-nervous-system effects on pain perception. Paracetamol also suppresses prostaglandin activity by inhibiting cyclooxygenase-2; however, it is not considered an anti-inflammatory drug.7
The combination of turmerones and curcuminoids has powerful benefits for prevention of inflammation, due to the curcuminoid–essential oil complex allowing increased bioavailability with more free curcumin circulating in the blood.
Paracetamol is generally well tolerated at moderate doses, but there have been cases of paracetamol causing liver toxicity when taking it in large doses of > 4 g/day, leading to potential acute liver failure.7 It is considered generally safer than NSAIDs, so it is more commonly preferred by practitioners.8 However, new evidence available suggests that paracetamol is linked to increasing risk for cardiovascular, gastrointestinal, and renal diseases, similarly to NSAIDs, necessitating caution with its use.8 Other concerns raised with using paracetamol long term are the potential effects it can have on the offspring of pregnant women who have used this drug.9 Additionally, in a study comparing paracetamol with placebo, it was found that paracetamol had a relatively small benefit in reducing pain in OA patients, making efficacy of paracetamol poor overall.10
In the study currently under review, paracetamol effectively reduced pain associated with OA and improved function at ≥ 20% reduction as shown in this study; however, paracetamol does not stop the destruction of tissue or prevent the onset of OA.4 The WOMAC scores for pain and function/stiffness were limited to this mild effect, with the paracetamol group having no reduction in symptomology in the “≥ 50%” and “≥ 70%” levels, making it less effective in reducing pain when compared to turmeric.4
Several herbal extracts and supplements have been examined for their potential benefit in the maintenance and treatment of OA, with particular attention on Curcuma longa (turmeric).4 The constituents of turmeric extracts, often called “curcumin” on the label, actually include 3 curcuminoids: curcumin, dimethoxy-curcumin, and bis-demethoxy-curcumin, all of which contain anti-inflammatory, antioxidant, and antimicrobial properties.4 The particular extract used in the trial under review here (BCM-95) is unique in that it contains standardized dosing of curcuminoids and turmeric essential oil as well.
One of the earliest therapeutic uses of curcumin appears to be in Ayurvedic medicine in treatment of inflammatory conditions.11 Its historic use combined with modern testing of curcumin in human clinical trials has established the safety, nontoxicity, and tolerability of turmeric, even at high doses.12 For example, curcumin taken at 8 g/day in combination with the chemotherapy gemcitabine was well-tolerated and safe in patients with pancreatic cancer.12 Turmeric has possible therapeutic effects for an array of conditions such as cancer, liver disease, cardiovascular disease, and musculoskeletal disorders.12
The anti-inflammatory properties of curcumin have great benefits for OA. Specifically, pro-inflammatory signals from prostaglandins and leukotrienes to various cytokines and mediators like TNF-α, interleukin-1, and interleukin-8 are all suppressed.4
Curcumin’s anti-inflammatory effects are reflected in its ability to lower CRP.12 As shown from the results in this study, TNF-α was reduced significantly in the turmeric extract group as compared to the paracetamol group.4 Curcumin suppression of nuclear factor kappa B activity effectively downregulates hundreds of genes; among them are those for the enzymes cyclooxygenase-2 and inducible nitric oxide synthase. This disrupts the inflammatory process, hence its benefit in treating OA.11 In this study, turmeric also caused fewer adverse effects than paracetamol, though none of the patients experienced severe adverse events and most of the effects were self-limiting.4
Although it shows some effectiveness in treating OA, curcumin still has some limiting biological characteristics that make it less bioavailable, like poor absorption and rapid metabolism.4 However, bioavailability can be increased by using adjuvants such as the black-pepper constituent piperine. However, this still poses a risk as piperine can influence the pharmacokinetics of other drugs by potentially decreasing liver metabolism.4
The bioavailable turmeric extract used in this study is BCM-95; this formulation contains curcuminoids and an essential oil comprised of turmerones.4 The combination of turmerones and curcuminoids has powerful benefits for prevention of inflammation, due to the curcuminoid–essential oil complex allowing increased bioavailability with more free curcumin circulating in the blood.4 This complex proved to be significantly beneficial in rheumatoid arthritis patients during a pilot study using diclofenac sodium in comparison for pain reduction.4 Having alternative treatment options for OA will help patients who may be intolerant of NSAIDs and are interested in using natural supplements for management of their symptoms due to less harmful side effects.4
The conventional standard of care for OA is acetaminophen, and if that fails, the next in line is NSAIDs, followed by corticosteroid injections for pain relief.4 For patients who do not experience relief from pain, the second line of therapy is opioids.4 Opioids can provide palliative care for pain relief; however, they can potentially cause serious side effects and also lead to physical dependence.13 The increased usage of opioids has significantly impacted the death rate, and overdoses are reducing life expectancy in America.14 Concerns about the use of pharmacotherapy are growing due to its partial effectiveness and its association with adverse effects.15 These concerns are causing the public to pursue other means of care for OA, with increased interest in therapies they deem to be safer.15 Other medical interventions for OA include massage therapy and acupuncture, which have benefits for reducing pain with minimal side effects.15,16 It was found that subjects who received massage saw improvements in pain, physical function, and stiffness over 8 weeks, making it a great short-term treatment for knee OA by enhancing quality of life.15 Both electroacupuncture and laser acupuncture can be used to reduce pain in knee OA.16 Understanding the OA pathogenesis can create breakthroughs and lead to the development of new and targeted therapeutic strategies to treat the disease.17
- Pereira D, Ramos E, Branco J. Osteoarthritis. Acta Med Port. 2015;28(1):99-106.
- Chronic pain and mental health. Mental Health America. https://www.mhanational.org/chronic-pain-and-mental-health. Accessed April 3, 2021.
- Xia B, Di Chen, Zhang J, Hu S, Jin H, Tong P. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int. 2014;95(6):495-505.
- Singhal S, Hasan N, Nirmal K, et al. Bioavailable turmeric extract for knee osteoarthritis: a randomized, noninferiority trial versus paracetamol. Trials. 2021;22(1):105.
- Litwic A, Edwards MH, Dennison EM, Cooper C. Epidemiology and burden of osteoarthritis. Br Med Bull. 2013;105:185-199.
- Robinson WH, Lepus CM, Wang Q, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580-592.
- Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014;71(1):11-23.
- Leopoldino AO, Machado GC, Ferreira PH, et al. Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019;2(2):CD013273.
- McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ. Long-term adverse effects of paracetamol - a review. Br J Clin Pharmacol. 2018;84(10):2218-2230.
- Machado G, Maher C, Ferreira P, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350:h1225.
- Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research [published correction appears in Altern Med Rev. 2009 Sep;14(3):277]. Altern Med Rev. 2009;14(2):141-153.
- Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15(1):195-218.
- Salsitz EA. Chronic pain, chronic opioid addiction: a complex nexus. J Med Toxicol. 2016;12(1):54-57.
- Opioid medications. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-drug-class/opioid-medications. Published 2021. Accessed April 3, 2021.
- Perlman A, Fogerite SG, Glass O, et al. Efficacy and safety of massage for osteoarthritis of the knee: a randomized clinical trial. J Gen Intern Med. 2019;34(3):379-386.
- Wu SY, Lin CH, Chang NJ, et al. Combined effect of laser acupuncture and electroacupuncture in knee osteoarthritis patients: a protocol for a randomized controlled trial. Medicine (Baltimore). 2020;99(12):e19541.
- Maruotti N, Corrado A, Cantatore FP. Osteoblast role in osteoarthritis pathogenesis. J Cell Physiol. 2017;232(11):2957-2963.