The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis

Abstract The study aimed to evaluate the effect of Zingiber officinale and Echinacea angustifolia extract supplementation (25 mg of ginger and 5 mg of Echinacea) for 30 days on inflammation and chronic pain in knee osteoarthritis (OA). Consecutive nonsteroidal anti-inflammatory-drugs (NSAIDs) poor responders with chronic inflammation and pain due to knee arthrosis were assessed (15 subjects, age: 67.2 ± 7.9, body mass index: 30.6 ± 7.1, men/women:2/13). The primary endpoint was to determine pain improvement from baseline to Day 30 by Tegner Lysholm Knee Scoring. The secondary endpoints were the assessment of Visual Analog Scale for Pain, health-related quality of life, by the ShortForm36 (SF-36), anthropometric parameters, hydration. After supplementation, a significant improvement of 12.27 points was observed for Lysholm scale score (p < 0.05), SF-36 (p < 0.05), and a decrease in −0.52 cm in knee circumference (left) (p < 0.01). This pilot study provides feasibility and safety data for the use of highly standardised ginger and Echinacea extract supplementation in people with knee OA. Graphical Abstract


Introduction
Osteoarthritis (OA) of the knee is an active disease process involving cartilage destruction, subchondral bone thickening and new bone formation (Peat et al. 2001). The major complaint by individuals who have arthritis is joint pain. In 2014, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee OA (Bruyère et al. 2016). Starting from these guidelines, today, therapeutic approach of OA is based principally on acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Recently, new classes of natural products raised a great interest for their potential effectiveness in the modulation of pain. Alkylamides from Echinacea angustifolia roots (isobutylamides and 2-methylbtylamides) could be used in order to alleviate symptoms of knee pain. They can interact functionally as agonists on CB 2 , and furthermore, they inhibit fatty acid amide hydrolase. Due to the CB 2 receptor interaction, they modulate the expression of inflammatory chemokines ). In addition, they act on oxygenase, COX and LOX, showing a complementary direct contribution of anti-inflammatory activity (Hinz et al. 2007). In this context, highly standardised plant extracts enriched in alkylamimides could be used in relief of chronic peripheral pain by reducing inflammation and modulating pain receptors. Also gingerols and shogaols of Zingiber officinale are agonists of transient receptor potential cation channel subfamily V member 1 (TRPV 1 ) receptors (Dedov et al. 2002) and they exhibit inhibitory activity on arachidonic acid (prostaglandins, thromboxanes) metabolism via the COX 2 (Vriens et al. 2008;Semwal et al. 2015). Therefore, this study planned to evaluate the effect of ginger (Z. officinale) and Echinacea (E. angustifolia) roots extract supplementation on inflammation and chronic pain in knee OA.

Results
Out of 25 patients invited to participate, 6 were excluded from the initial screening. During the supplementation, there were two dropouts shortly after inclusion due to diarrhoea.
Fifteen patients (13 women and 2 men) completed the study and their data were analysed. The mean age was 67.2 years, the mean of the body mass index was 30.64 ± 7.15 kg/m 2 .
As regards the body composition assessment, no significant variations in waist to hip ratio, arm muscle area, arm fat area, wrist, arm, calf, waist and hips circumference were recorded. As regards the swelling assessment, the knee circumference (left) decreased −0.52 cm in a significant manner (p < 0.01). No significant variations in bioimpedance analysis were found. Suggestive but not significant was the decrease in intracellular water of 0.40 L. The mean change in measures of pain showed a statistic significant variation in increase in 12.27 points of Lysholm scale score (p < 0.05) (Table S1). Suggestive but not significant was the decrease in VAS scale (both left and right pain in knees). Concerning health-related quality of life, treatment effects were seen for PCS (p < 0.05), while no treatment effect was seen for MCS, mental component summary. It is evident a median pain decrease of over 1.5 points in both knees from baseline to Day 15 supported a fast improvement in pain relief. In the remaining two weeks, there is a median increase in VAS score, but no more than 1 point.

Discussion
In this pilot study carried out on NSAIDs poor responders with knee OA, we observed for the first time in literature that the four-week supplementation with highly standardised ginger and Echinacea extract supplementation is associated with a significant amelioration in values of Tegner Lysholm Knee Scoring, thus fulfilling the primary end-point of the study. As far as the secondary end-points of the study are concerned, after supplementation, a significant improvement was observed for SF-36 physical component summary and knee circumference (left). To date, only a study on the pharmacokinetics and immunomodulatory effect of lipophilic Echinacea was performed in healthy subjects (Dall'Acqua et al. 2015). The results of our study appear to be of relevant clinical interest due to the fact that OA is a leading cause of musculoskeletal pain worldwide and the knee is one of the most commonly affected joints. As there is currently no cure for OA, treatment has focused on symptomatic relief with the aim of reducing pain and disability and maintaining or improving joint mobility (Harvey & Hunter 2009). Drug treatments such as simple analgesics and NSAIDs are associated with adverse events (Bjordal et al. 2004;Zhang et al. 2008). The potential use of a highly standardised ginger and Echinacea extract supplementation as a treatment of OA could represent an interesting alternative to the use of NSAIDs avoiding the risk of unwanted symptoms and complications. Furthermore, it could be also an alternative option in subjects of NSAIDs non-responders. As a matter of fact, the intervention with this dietary supplement appears to be safe: no relevant side effects were observed in the intervention group. Among the biologically active constituents of E. angustifolia roots, the lipophilic alkylamides are reported to play a pivotal role in the management of pain. Alkylamides are thought to reduce inflammation through three mechanisms: modulation of the expression of pro-inflammatory chemokines via the cannabinoid CB2 receptor, inhibition of leukotriene synthesis and inhibition of prostaglandine E2 synthesis. As regards selective CB2 receptor activation, which does not imply a central effect, it is nowadays considered one of the new relevant strategies for treating pathological pain states (Guindon & Hohmann 2008). The binding affinity of alkylamides isolated from E. angustifolia roots for the cannabinoid CB1 and CB2 receptors and the effects on cytokine mediated inflammatory pathway have been determined in vitro studies (Woelkart et al. 2005;Raduner et al. 2006). Recently, the lypophilic Echinacea extract has been administered in volunteers with interesting results in terms of bioavailability and reduction of pro-inflammatory cytokines (Dall'Acqua et al. 2015). It has been demonstrated in two separated in vitro studies (Müller-Jakic et al. 1994;Merali et al. 2003) that E. angustifolia extracts inhibited 5-lipoxygenase (5-LOX). Leukotrienes are synthesised from arachidonic acid via 5-LOX, so by inhibiting 5-LOX activity, an inflammatory response mediated by leukotrienes is disrupted. Moreover, it has been demonstrated that alkylamides determined inhibition of prostaglandin E2 synthesis (Birt et al. 2008). Finally, E. angustifolia has a potent activity as a transient receptor potential channel (TRPV1) agonist, an integrator of inflammatory pain and hyperalgesia (Aimbire et al. 2007). The use of ginger in pain relief is based on anti-inflammatory and analgesic properties. In fact, several studies demonstrated that gingerols and shagaols from fresh ginger root possesses inhibitory activity on arachidonic acid metabolism via the COX-2 (prostaglandins, thromboxanes) (Sang et al. 2009) and lipoxygenases (leukotrienes) pathways (Young et al. 2005). However, a direct inhibitory action on genes encoding for pro-inflammatory substances (e.g. cytokines) may also play a role (Fouda & Berika 2009). Furthermore, preliminary studies support the analgesic effect (Ojewole 2006) for both 6-shoagaol and 6 gingerol (Young et al. 2005). Another important study demonstrated the therapeutic effects of ginger peel in colorectal carcinoma: hydroalcoholic extract of ginger peel extract was more potent against colon cancer cells than ginger pulp hydroalcoholic extract using MTT assay, while ginger pulp hydroalcoholic extract showed higher anti-inflammatory and antioxidant activities (Marrelli et al. 2015). It is important in the research of diabetes and nutritional cares: kaempferol and kaempferol-3-O-methylether are potent inhibitors of α-glucosidase enzyme, aldose reductase enzyme and glycation reaction, the three main targets of drugs for the treatment of diabetes and its complications (Ajish et al. 2015). Gingerols are potent vanilloid receptor (VR1) agonists which may in part explain ginger's analgesic effects (Dedov et al. 2002). Z. anamalayanum rhizome oil showed significant antiproliferative and antioxidant activities (Salim et al. 2015). There are some limitations of our study. Firstly, as mentioned, the small sample size of this pilot trial reduces statistical power, and the relatively short follow-up period. Future clinical trials with larger sample sizes and longer follow-up periods should be planned to support the observed preliminary good evidences in symptoms and functions improvement.

Conclusion
This pilot study provides feasibility and safety data for the use of highly standardised ginger (Z. officinale) and Echinacea (E. angustifolia) extract supplementation in subjects with inflammation and chronic pain due to knee OA. Future clinical trials with larger sample sizes and longer follow-up periods should be planned to support the observed preliminary good evidences that showed improvement of the symptoms and functions following the ginger (Z. officinale) and Echinacea (E. angustifolia) supplementation.

Disclosure statement
No potential conflict of interest was reported by the authors.