Table 1.
Summary of clinical trials on neutraceuticals and evidence of their safety and efficacy.
| References | Product | Dose and comparator | Design and duration | Study population | Other outcome reported | Side effects |
|---|---|---|---|---|---|---|
| Uncaria tomentosa and Uncaria guianensis (cat’s claw) | ||||||
| [Piscoya et al. 2001] | Aqueous extract of cat’s claw bark (U. guianensis) | Treatment group (1 capsule 100 mg/ day). Placebo group 100 mg excipients without cat’s claw | Multicenter randomized double-blind placebo-controlled trial, 4 weeks | Men with OA aged 45–75 with grade II–III of Kellgren/Lawrence classification (n = 45; placebo group n = 15, treatment group n = 30) | Effective in knee OA (improvement in pain, disease indices) | No change in safety parameters and frequency of side effects (vomiting, dizziness and headache) were no different between groups |
| [Mehta et al. 2007] | Reparagen, a blend of two natural products – Vincaria (300 mg; U. guianensis) and RNI 249 (1500 mg; Lepidium meyenii) | Treatment 1800 mg as two capsules twice a day. Glucosamine sulfate (1500 mg; comparator) | Multicenter randomized double-blind trial with positive control, 8 weeks | Patients with OA (n = 95) men and women, Indian population >20 years of age, grade II–III of Kellgren/Lawrence classification and a baseline functional assessment of overall pain of at ≥40 mm and ≤80 mm on a 100 mm VAS score | Glucosamine (89%) and Reparagen (94%) showed substantial reduction in pain and significant benefits in WOMAC and VAS (45–62% reduction). Rescue medication use was significantly lower in the Reparagen group at each assessment period | Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Serum IGF-1 levels were unaltered by treatments |
| [Miller et al. 2005] | Sierrasil, a natural mineral product with or without Vincaria (containing U. guianensis extract) | High-dose Sierrasil (3 g/day), low-dose Sierrasil (2 g/day), low-dose Sierrasil (2 g/day) + Vincaria (100 mg/day) and placebo | Multicenter randomized double-blind placebo-controlled trial, 8 weeks | Patients with OA (n = 107), men and women, Indian population >20 years of age, grade II–III of Kellgren/Lawrence classification and a baseline functional assessment of overall pain of at ≥50 mm on a 100 mm VAS score | Combination of Sierrasil and Vincaria was effective in relief of OA symptoms (improved physical activity, VAS pain score) and 28% reduction in rescue medication (paracetamol) was observed | Tolerability was good for all groups, no serious adverse events were noted and safety parameters remained unchanged |
| Zingiber officinale (ginger) | ||||||
| [Bliddal et al. 2000] | EV.ext-33 ginger extract | Ginger extract (170 mg). Iboprofen (400 mg; comparator) as placebo, two capsules twice a day. Rescue medication acetaminophen 3 g/day throughout study | Randomized double-blind double-dummy placebo-controlled crossover study with a wash-out period of 1 week followed by 3 treatment periods in a randomized sequence, each of 3 weeks | Hip OA (n = 20) and knee OA (n = 36), aged 24–87 years, men and women (15:41) | Ranking of efficacy of three treatment periods for VAS and the Lequesne Functional Index was Ibuprofen>ginger extract>placebo Statistically significant effect of ginger extract was only demonstrated by explorative statistical methods in the first period of treatment before crossover, while a significant difference was not observed in the study as a whole | No serious adverse events reported during the periods with active medications |
| [Altman and Marcussen, 2001] | EV.EXT 77 highly concentrated extract of 2 ginger species, Z. officinale and Alpinia galanga | Ginger extract (each capsule contained 255 mg of EV.EXT 77, extracted from 2,500–4,000 mg of dried ginger rhizomes and 500–1,500 mg of dried galanga rhizomes) versus placebo daily | Randomized double-blind placebo-controlled multicenter parallel-group trial, 6 weeks | Knee OA (n = 247), moderate to severe pain, aged 45–72 years, men and women. Patients had to show OA grade II–IV of Kellgren/Lawrence classification | In 247 evaluated patients there was a reduction in knee pain on standing in ginger extract group compared with placebo (63% versus 50%). Secondary efficacy variables also showed reduction in knee pain on standing (24.5 versus 16.4 mm), reduction in knee pain after walking 50 ft (15.1 versus 8.7 mm), and reduction in the WOMAC OA index (12.9 versus 9.0 mm. Reduction in intake of rescue medication (acetaminophen) in the ginger extract group. | Good safety profile, with mostly mild GI adverse events in the ginger extract group compared with placebo group (59 patients versus 21 patients). |
| Boswellia serrata (Indian olibaum) | ||||||
| [Kulkarni et al. 1991] | Articulin-F, herbomineral formulation containing roots of Wifhania somnifera (450 mg), the stem of B. serrata (100 mg), rhizomes of Curcuma longa (50 mg) and a zinc complex(50 mg) | Articulin-F, two capsules every 8 h | Randomized double-blind placebo-controlled crossover study, 3 months. After a 15-day wash-out period the patients were transferred to the other treatment for a further period of 3 months | Patients with OA (n = 42) aged 48–50 years, men and women (10:32) | Treatment with the herbomineral formulation significantly altered only the severity of pain and disability score. Other parameters, including morning stiffness, Ritchie Articular Index, grip strength and joint score, showed favorable changes but were not statistically significant. Out of 42 patients, 39 preferred the herbomineral preparation, two the placebo and one was equivocal | Safety parameters were unchanged. Two patients complained of nausea, three with dermatitis and three with pain in the abdomen |
| [Kimmatkar et al. 2003] | B. serrata extract (333 mg) containing 65% organic acids or minimum 40% total boswellic acids | Boswellia serrata extract (300 mg/capsule). Placebo group starch powder (333 mg) three times a day | Randomized double-blind placebo-controlled crossover study, 8 weeks | Patients with knee OA (n = 30), aged 45–72 years, men and women (12:18) | Reduced joint pain and swelling and improved the loss of function in terms of increased knee flexion, stair climbing and walking distance. No change was observed radiologically | Boswellia serrata was well tolerated except for minor GI complaints, including loose motions in one patient, epigastric pain and nausea in one patient. |
| [Sengupta et al. 2008] | 5-Loxin, a novel B. serrata extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid | 100 mg (n = 25) or 250 mg (n = 25) of 5-Loxin or a placebo (n = 25) daily | Randomized double-blind placebo-controlled trial, 90 days | Patients with knee OA (n = 75) aged 45–72 years, men and women. Severity was measured using VAS, WOMAC pain score and the Lequesne Functional Index | Both doses of 5-Loxin conferred significant improvements in pain and physical function scores, significant reduction in synovial fluid matrix metalloproteinase-3 | Safety parameters were almost unchanged in the treatment groups compared with placebo |
| [Sengupta et al. 2010] | BE-30 (5-Loxin; 30% 3-O-acetyl-11-keto-β-boswellic acid) and Aflapin novel synergistic composition of O-acetyl-11-keto-β-boswellic acid and B. serrata, nonvolatile oil | 100 mg (n = 20) of 5-Loxin or 100 mg (n = 20) of Aflapin or a placebo (n = 20) daily for 90 days | Randomized double-blind placebo-controlled trial, 90 days | Patients with moderate to mild knee OA (n = 60) aged 40–80 years, both men and women. Severity was measured using VAS, WOMAC pain score and the Lequesne Functional Index | 5-Loxin and Aflapin conferred clinically and statistically significant improvements in pain scores and physical function scores. Significant improvements in functional ability after 7 days with 100 mg Aflapin. Aflapin exhibited better efficacy compared with 5-Loxin | Safety parameters were unchanged compared with placebo group |
| Curcuma longa (turmeric) | ||||||
| [Kulkarni et al. 1991] | Articulin-F, a herbomineral formulation containing roots of W. somnifera (450 mg), the stem of B. serrata (100 mg), rhizomesof C. longa (50 mg) and a zinc complex (50 mg) | Articulin-F, two capsules every 8 h | Randomized double-blind placebo-controlled crossover study, 3 months. After a 15-day wash-out period the patients were transferred to the other treatment for a further period of 3 months | Patients with OA (n = 42), aged 48–50, men and women (10:32) | Treatment with the herbomineral formulation significantly altered only the severity of pain and disability score. Other parameters, including morning stiffness, Ritchie Articular Index, grip strength and joint score, showed favorable changes but were not statistically significant. Out of 42 patients, 39 preferred the herbomineral preparation, two the placebo and one was equivocal. | Safety parameters were unchanged. Two patients complained of nausea, three had dermatitis and three had pain in the abdomen |
| Harpagophytum procumbens (devil’s claw) | ||||||
| [Bélaiche, 1982] | Harpagophytum extract (3000 mg) | Harpagophytum extract 3000 mg and 9000 mg/day containing herpagoside concentration of 90–270 mg/day | Observational 12–24 week study | Primary and secondary OA of knee, hip, finger and spine, men and women (n = 630) | Dependent on the condition and dosage. Improvement seen 14.9–56.2% in patients at 3000 mg/day dose; and 13.9–39.08% at 9000 mg/day dose | Mild GI disturbances reported |
| [Lecomte and Costa, 1992] | Harpagophytum extract (2010 mg) | Harpagophytum extract (2010 mg) versus placebo group containing herpagoside concentration of 60 mg/day | Randomized double blind placebo-controlled trial, 8 weeks | Patients with OA (n = 89) | Significant decrease in VAS pain score compared with placebo group after day 30 and 60. Significant improvement in mobility | No adverse effect reported. Safety profile normal |
| [Schmelz et al. 1997] | Harpagophytum extract (2500 mg) | Harpagophytum extract (2500 mg containing herpagoside concentration of 30 mg/day) versus placebo group | Randomized double blind placebo-controlled trial, 30 days | Patients with OA with chronic back pain and myalgia (n = 100). Severity was measured using a Likert scale | Harpagophytum extract showed better results than placebo group. Out of all treated patients six showed strong pain and one mild pain compared with placebo, for which 32 had strong pain and nine medium pain | Safety parameters were unchanged compared with placebo group |
| [Rutten and Schafer, 2000] | Harpagophytum extract (960 mg) | Harpagophytum extract (960 mg/day) plus twice weekly injection | Observational 6-week study | Patients (n = 99) with acute and chronic spinal disorder (n = 23) and OA of knee (n = 76) | 68% of patients were pain free with significant reduction in symptoms | Good tolerability |
| [Leblan et al. 2000] | H. procumbens extract (2610 mg) | Harpagophytum extract (2610 mg/day containing herpagoside concentration of 57 mg/day). Diacerhein (100–150 mg/day; comparator) | Multicenter randomized double-blind parallel-group study, 16 weeks | OA of hip and knee (n = 122). Severity was measured using VAS pain score | Harpagophytum extract was equally effective as diacerhein | Significantly lower adverse effects in Harpagophytum extract treated group compared to Diacerhein. Most common adverse complications were diarrhea and flatulence. |
| [Chantre et al. 2000] | Harpadol containing cryoground powder H. procumbens (435 mg) | Harpadol group (6 capsules/day). Diacerhein (100 mg/day; comparator) | Randomized double-blind multicenter study, 4 months | Patients with OA of knee or hip (n = 122), aged 30–79 years, had to show grade I–III on the Kellgren/Lawrence classification, a baseline functional assessment of overall pain of ≥50 mm on a 100 mm VAS and a score of at least 4 on the Lequesne Functional Index | Spontaneous pain showed a significant improvement and reduction in the Lequesne Functional Index in both groups. No significant difference in efficacy between the two groups. Harpadol group used significantly less NSAIDs and antalgic drugs | The adverse effect reported was diarrhea, which was low in the Harpadol group (8.1%) compared with the diacerhein group (26.7%) |
| [Frerick et al. 2001] | Harpagophytum extract (960 mg) | Harpagophytum extract (960 mg/day containing herpagoside concentration of 30 mg/day) versus placebo group | Randomized double-blind placebo-controlled trial, 20 weeks | OA of hip (n = 46). Severity was measured using WOMAC pain intensity | Significant improvement in WOMAC and stiffness scores in treatment group compared with placebo | An adverse reaction of one patient in treatment group, epigastric discomfort with suspected cholelithiasis |
| [Chrubasik et al. 2002] | Doloteffin a proprietary Harpagophytum extract (60 mg tablets) | Doloteffin (60 mg) two tablets three times a day. Back group with nonspecific pain, knee OA pain group and hip OA pain group. Patients were allowed to continue with their concomitant treatments and to supplement medication with other analgesics | Observational 8-week study (post-market surveillance of the effectiveness and safety) | Total patients (n = 250) with nonspecific low back pain (n = 104) or OA pain in the knee (n = 85) or hip (n = 61). Men (30%) and women (70%). Severity was measured using Arhus Low Back Pain Index, WOMAC index | Multivariate analysis confirmed that in all groups, the generic and disease-specific outcome measures improved by week 4 and further by week 8. Hip group tended to improve more than the back group. Improvement in the knee group was less than the back group. Back patients who required NSAIDs during the 8 weeks used significantly more per patient than other two groups | About 10% of the patients suffered from minor adverse events that could possibly have been attributable to Doloteffin. Between 50% and 70% of the patients benefited from Doloteffin with few adverse effects |
| [Warnock et al. 2007] | Harpagophytum extract tablets (480 mg) | Harpagophytum extract tablets twice daily | Single group open study, 8 weeks | Mild to moderate rheumatic disorder having pain (rated 2–7 on 10-point scale) including patients with OA (n = 222), men (n = 82) and women (n = 140), aged 18–75 years. Effectiveness was assessed by numeric rating scales, WOMAC Index and the Algofunctional Hand Osteoarthritis Index and quality of life was measured by SF-12 | Improvements in patient assessment of global pain, stiffness, function and quality of life. Reductions in mean pain scores for hand, wrist, elbow, shoulder, hip, knee and back pain. 60% of patients either reduced or stopped concomitant pain medication | No serious adverse events were reported and all were moderate GI complaints |
| Ananas comosus | ||||||
| [Tilwe et al. 2001] | Phlogenzyme (contains the proteolytic enzymes bromelain, trypsin and rutin) | Bromelain (1890 mg/day). Diclofenac (100–150 mg/day; comparator) | Prospective randomized controlled single-blind study with positive control, 7 weeks | Patients with knee OA (n = 50) aged 40–75 years | Equivalence not tested. Reduction in pain, tenderness and swelling in both groups | Well tolerated, no specific adverse events reported |
| [Klein and Kullich, 2000] | Phlogenzyme | Bromelain (540 mg/day). Diclofenac (100–150 mg/day; comparator) | Randomized double-blind trial with positive control, 4 weeks | Patients with knee OA (n = 73) | Reduction in pain indices by 80% at 4 weeks post treatment | No serious adverse events reported |
| [Singer et al. 2001] | Phlogenzym | Bromelain (540 mg/day). Diclofenac (100–150 mg/day; comparator) | Randomized double-blind controlled trial with positive control, 4 weeks | Patients with knee OA | Bromelain group showed reduction in pain score compared with diclofenac | No serious adverse events reported |
| [Brien et al. 2006] | Bromelain | Bromelain (800 mg/day) or placebo group | Randomized double-blind placebo-controlled trial, 12 weeks | Patients with moderate to severe knee OA (n = 47). Severity was measured using WOMAC and SF-36 questionnaires | No statistically significant differences were observed between groups for the primary outcome nor the WOMAC subscales or SF-36 | Adverse events were generally mild in nature |
GI, gastrointestinal; IGF-1, insulin-like growth factor 1; NSAID, nonsteroidal anti-inflammatory drug; OA, Osteoarthritis; SF-36, 36-item Short Form Health Survey; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Arthritis Index.