Re: Oral Administration of a Processed Form of Black Cumin Has Limited Benefit for Reducing Symptoms of Knee Osteoarthritis and Analgesic Use

Black Cumin (Nigella sativa, Ranunculaceae) Knee Osteoarthritis Date: 01-15-2018 HC# 061735-584 Salimzadeh A, Ghourchian A, Choopani R, Hajimehdipoor H, Kamalinejad M, Abolhasani M. Effect of an orally formulated processed black cumin, from Iranian traditional medicine pharmacopoeia, in relieving symptoms of knee osteoarthritis: a prospective, randomized, double-blind and placebo-controlled clinical trial. Int J Rheum Dis. June 2017;20(6):691-701. Osteoarthritis (OA) is among the most frequent causes of pain, loss of function, and disability in adults. OA pain is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs); however, those drugs can cause gastrointestinal, cardiovascular, and renal adverse effects. The seeds and oil of black cumin (Nigella sativa, Ranunculaceae) have been used traditionally in Iran to treat painful joints (the seeds orally and the oil topically) because of their anti-inflammatory and analgesic properties. The authors previously observed (unpublished data) that black cumin seeds and oil may induce adverse respiratory effects, so decided to evaluate its processed form using the method described in Iranian traditional medicine (ITM) pharmacopeia, which is therein specified for the purpose of reducing adverse effects. They conducted a prospective, randomized, double-blind, placebo-controlled study of a formulated form of processed black cumin and its effects on the symptoms of knee OA. The study was conducted at the Rheumatology Clinic of Sina Hospital at Tehran University of Medical Sciences, Iran, from February 2014 to March 2015. Black cumin seeds purchased from a market in Karaj, Iran, were powdered and processed by soaking in 5% grape (Vitis vinifera, Vitaceae) vinegar (Varda Company; Tehran, Iran). They were dried and then powdered again, sieved, and encapsulated. The placebo was corn (Zea mays, Poaceae) starch powder. Black cumin and placebo capsules were packaged in identical plastic containers. Enrolled in the study were 110 patients aged 40 to 79 years who had clinical evidence of primary knee OA based on diagnostic criteria of the American College of Rheumatology and a minimum level of pain of 40 mm on a 100-mm visual analog scale (VAS). Exclusion criteria included poor general health, other diseases affecting the lower extremities, abnormal values on laboratory tests, drug or alcohol abuse, recent (< 6 months) surgical or intra-articular pharmaceutical treatment, and recent (< 3 months) corticosteroid treatment. At baseline, the patients underwent a physical examination, a knee radiograph, routine safety laboratory tests, and assessment of knee OA severity. After 1 week, during which they took no analgesic drugs, the patients returned to the clinic and were randomly assigned to the black cumin (n=55) or placebo (n=55) group. Both groups were instructed to take two 500-mg capsules 20 minutes before breakfast, 1 capsule 20 minutes before lunch, and 1 capsule 20 minutes before dinner, for a total daily dose of 2 g, for 12 weeks. Both groups were also recommended to follow general recommendations and practice quadriceps-strengthening exercises. Acetaminophen was available as needed for pain. Study outcomes were measured by using the KOOS (Knee Injury and Osteoarthritis Outcome Score)-Persian version and a VAS for global satisfaction assessment. The KOOS includes 42 items on the following 5 subscales: Pain, Other Symptoms, Activities of Daily Living (ADL), Function in Sport and Recreation (Sport/Rec), and Knee-related Quality of Life (QoL); possible scores for each range from 0 (no problem) to 4 (extreme problems). All patients visited the clinic in weeks 2, 4, 8, and 12 after the first medication. At those visits, the patients completed the KOOS and underwent a physical examination of the knee, recorded global satisfaction by using a VAS, and reported any adverse effects and use of acetaminophen. Of the 110 patients who began the study, 15 in the placebo group did not complete it for the following reasons: severe earache (1), severe constipation (2), severe coughing (1), severe hypertension (1), drowsiness (1), dyspnea (1), lost to follow-up (3), lack of treatment success (4), and hospitalization for a reason unrelated to the study (1). Eighteen patients in the black cumin group did not complete the study for the following reasons: drowsiness (1), dyspepsia (1), severe itching (1), stomachache (1), nausea (1), lost to follow-up (6), lack of treatment success (6), and hospitalization for a reason unrelated to the study (1). The authors report that both groups showed an overall improvement in most KOOS categories. Compared with baseline, significant improvement was seen on the ADL and Sport/Rec subscales in the black cumin group at all timepoints (P<0.05 for all), whereas the only significant improvement from baseline on these subscales in the placebo group was the ADL scale at week 4 (P<0.05). Compared with baseline, significant improvement was seen on the QoL subscale in the placebo group at week 8; on the Other Symptoms subscale in the placebo group at week 12; and on the Pain subscale in both groups at week 12 (P<0.05 for all). Between-group differences were not significant. Although both patient and physician satisfaction increased more in the black cumin group than in the placebo group, the between-group differences were not statistically significant (P=0.31 and P=0.97, respectively). Patients in the black cumin group used fewer rescue medications compared with the placebo group (mean of 11.40 vs. 24.25 doses over 12 weeks); however, the between-group difference was not quite significant (P=0.06). Adverse effects were minimal and easily controlled. No patient experienced symptoms of hepatic or renal dysfunction. The authors note that the placebo group improved considerably at the latest timepoints, and speculate that there was a placebo effect substantial enough to obscure any benefit of the active treatment. They also point out that the percentage of thymoquinone, which is known to be an active constituent of black cumin and partly responsible for its medical properties, was 0% in the processed form of black cumin versus 1.7% in the crude form. The traditional processing may convert thymoquinone into another compound that, though less inclined to induce side effects, might also be less active. The main limitation of this study is that patients were selected according to conventional medical criteria and not according to ITM practices. According to ITM, say the authors, black cumin may not be useful in all patients with OA. Other limitations include the small sample size, short-term follow-up, the use of a single study center, and the absence of objective outcome measures, such as radiographic changes and quadriceps strength, that may be less responsive to placebo effects. "Although the mean changes of KOOS subscale scores from baseline did not show any statistically significant differences between active and placebo groups, the promising results of within-group differences of the active group treatment in comparison to the placebo treatment group, made us feel a glimmer of hope for future programmed studies," the authors conclude. ―Shari Henson