Table 2.
Summary of the findings of clinical trials (including a meta-analysis of six clinical trials) on the efficacy and safety of the oral enzyme combination of bromelain, trypsin, and rutin relative to the NSAID diclofenac
| References | Design | Country | Number of subjects | Duration | Clinical target | Clinical outcome |
|---|---|---|---|---|---|---|
| Ueberall et al. [13] | Meta-analysis of six comparator-controlled trials from 1998–2015 | Germany | 774 | 3–12 weeks | Joint health (knee) | As effective as diclofenac; significantly fewer adverse events and safety profile regarding liver and hematology significantly better than diclofenac |
| Boltena et al. 2015 [92] | Randomized, double-blind, placebo-controlled comparator trial | Germany | 150 | 12 weeks | Joint health (knee) | Placebo group integrated; as effective as diclofenac, with few side effects as placebo, and lower intake of rescue medication with the oral enzyme combination |
| Akhtara et al. [91] | Randomized, double-blind, parallel-group (comparator) | Germany | 103 | 6 weeks | Joint health (knee) | Non-inferior efficacy in OEC compared to diclofenac demonstrated |
| Singera et al. [96] | Randomized, double-blind, parallel-group (comparator) | Germany | 63 | 3 weeks, plus 4 weeks observation | Joint health (knee) | As effective as diclofenac, but longer-lasting effect even after end of treatment |
| Klein and Kullicha [94] | Randomized, double-blind, parallel-group (comparator) | Germany | 73 | 3 weeks | Joint health (knee) | As effective as diclofenac |
| Herreraa [93] | Randomized, double-blind, parallel-group (comparator) | Mexico | 59 | 3 weeks | Monoarticular gonarthritis (knee) | The LAFI scores and the sum score of the symptoms were equivalent in both treatment groups at the end of the study; however, the pre-calculated number of patients was too low for statistical proof of equivalence |
| Roth and Staudera [95] | Randomized, double-blind, parallel-group (comparator) | 268 | 6 weeks | Joint health (knee) | ||
| Tilwe et al. [98] | Randomized, single-blind, parallel-group (comparator) | Germany | 50 | 3 weeks, plus 4 weeks follow-up | Joint health (knee) | As effective as diclofenac overall; OEC significantly better than diclofenac in terms of joint tenderness |
| Klein et al. [99] | Randomized, double-blind, parallel-group (comparator) | Germany | 90 | 6 weeks | Joint health (hip) | Evidence of non-inferiority in OEC compared to diclofenac demonstrated with regard to the WOMAC dimensions of pain, stiffness and physical function, the LAFI score, the investigator and patients’ assessments of efficacy, and the responder rates based on pain and physical function |
| Jayachandran and Khobre [100] | Randomized comparator-controlled trial | India | 30 | 10 days | Temporomandibular joint OA | The OEC was as effective as diclofenac. A combination of OEC as an adjunctive treatment with diclofenac was demonstrated to significantly improve pain management (P < 0.05) compared to OEC or diclofenac alone |
LAFI Lequesne Algofunctional index, OA osteoarthritis, OEC oral enzyme combination therapy, WOMAC Western Ontario and McMaster Universities Arthritis Index
aClinical trials included in Ueberall meta-analysis [13]