Influence of a Specific Ginger Combination on Gastropathy Conditions in Patients with Osteoarthritis of the Knee or Hip

Abstract

Background:

Nonsteroid anti-inflammatory drugs represent an important osteoarthritis (OA) therapy component, but also a leading cause of gastropathy: one of the most frequent and serious OA therapy complications. The aim of the present study was to study the influence of GI health in an OA population receiving either ginger or diclofenac.

Methods:

Forty-three (43) patients with confirmed OA (knee and hip) were included in a randomized controlled study. A ginger group of 21 patients (17 women, 4 men) was given a specific ginger combination daily (340 mg EV.EXT 35 Zingiber officinalis extract) for 4 weeks. A diclofenac group (positive control) of 22 patients (18 women, 4 men) received 100 mg diclofenac daily for the same period. Both groups also received 1000 mg glucosamine daily. Gastrointestinal pain and dyspepsia were evaluated according to the severity of dyspepsia assessment (SODA) form. Patients also underwent esophagogastroduodenoscopy (EGDS) including biopsy before and after the treatment. Serum gastrin-17 levels, and stomach mucosa prostaglandins (PG) E1, E2, F2α, and 6-keto PGF1α (PGI2) levels were measured. Arthritic pain was evaluated using the visual analogue scale (VAS) on standing and moving.

Results:

The ginger group showed a slight but significantly lowered SODA pain and no change of SODA dyspepsia. EGDS showed significantly increased levels of PGE1, PGE2, and PGF2α in the stomach mucosa. This rise in gastric mucosa PG levels correlated with an increase in serum gastrin-17. On the other hand, the diclofenac group showed increased SODA pain and dyspepsia values with a corresponding significant decrease of stomach mucosa prostaglandins and general negative stomach mucosa degeneration. Both groups showed a relevant and significantly lowered VAS pain both on standing and moving.

Conclusions:

The ginger combination is as effective as diclofenac but safer in treating OA, being without effect on the stomach mucosa. The increased mucosal PGs synthesis in the ginger group supports an increased mucosa-protective potential.

VAS; visual analogue scale, 0-100 mm

Introduction

O steoarthritis (OA) continues to be a major health issue. OA radiographic evidence is found among the majority of people older than 65 years and approximately 80% of people older than 75 years. In Russian population studies, disease frequency and incidence increase 2–10 fold during the period from 30 to 65 years of age.¹

The main OA clinical symptoms are pain and deformation of joints, leading to their malfunction. Various treatment modalities are used for treating these symptoms such as (1) fast-action symptomatic medications (nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen, opioid analgesics, corticosteroids, etc.) mainly influencing the clinical symptoms of pain and inflammation; and (2) delayed action modifying medications (glucosamine, chondroitin, hyaluronic acid), whose effect is expressed more slowly than symptomatic medications, and also maintain an effect after administration has ceased. These agents have a potential chondromodifying action, preventing articular cartilage degradation.

NSAIDs represent an indisputable OA therapy component but also a leading cause of gastropathy—one of the most frequent and serious OA therapy complications.² Gastrointestinal (GI) complications from NSAID treatment can become manifest within a 1–3-month period [3]. These have also been verified in Russian populations.⁴ An integrated approach toward treating and preventing NSAID gastropathy has not yet been found. A wide range of medications is used for treating and preventing NSAID gastropathy, including antacids, bismuth drugs, prostaglandin (PG) analogues, and antisecretory agents (H2 blockers, proton pump inhibitors). The major cause of NSAID-induced gastropathy is considered to be a cyclooxygenase (COX)-1 blockade leading to impaired GI mucosa. This led to the development of more specific COX-2 inhibitors. However, accumulated data regarding these new selective NSAIDs suggest a lack of safety in terms of GI-tract complications or cardiovascular effects such as thrombosis.²

Challenges to produce new types of more natural medications featuring anti- inflammatory activity with minor impact on the GI tract have recently been undertaken. Marine products containing a number of new compounds targeting COX-1, COX-2, and PLA2 have been identified.^5,6 Studies with ginger extracts have demonstrated anti-inflammatory and analgesic effects attributed to inhibition of COX-2 as well as leukotrienes.⁷ These preparations seem in a clinical setting to have an analgesic effect similar to NSAIDs, but with limited negative GI effects.⁸

The present study was performed in a population of patients with OA of the knee and hip to evaluate primarily the GI effects and secondarily pain relief of a specific ginger combination for 28 days in comparison with standard diclofenac treatment.

Materials and Methods

This study included 43 patients with verified OA of the knee or hip. The average age was 55.1±3.1 years, 35 women and 8 men, with an average disease duration of 7.1±1.3 years. This study was approved by the Ethical and Scientific Review Board at the Central Gastroenterology Scientific Research Institute, Moscow, Russia. Verbal and signed consent was received from all patients participating in the study. Specific patient characteristics and referral conditions are described in Table 1. Any previous use of NSAID was withdrawn for a minimum of 1 month before the start of the trial.

Table 1.

Patients' Baseline Characteristics and Referral Conditions

	Ginger group	Diclofenac group
Index	(n=21)	(n=22)
Average age (years)	56.3±3.2	54±3.6
Men/women (number)	4/17	4/18
Average OA duration (years)	7.2±1.5	6.9±1.3
Mostly gonarthrosis/coxarthrosis	13 (62%)/8 (38%)	15 (68%)/7 (32%)
Peptic ulcer disease in anamnesis	2 (10%)	1 (5%)
NSAID-gastropathy in anamnesis	4 (19%)	3 (14%)
Helicobacter pylori AG pos.	4 (18%)	3 (14%)
Helicobacter pylori AG neg.	17 (82%)	19 (86%)
Smoking	6 (29%)	7 (32%)
Referral conditions
Chronic gastritis/gastroduodenitis	6 (29%)	16 (73%)
GERD	7 (33%)	5 (23%)
Chronic cholecystitis	9 (43%)	4 (18%)
Chronic pancreatitis	14 (67%)	4 (18%)

OA, osteoarthritis; NSAID, nonsteroidal anti-inflammatory drug; AG, antigen; GERD, gastroesophageal reflux disease.

The patients were randomized in two groups using the sealed-envelope method.⁹ The ginger group (n=21) received a ginger and glucosamine combination (Zinaxin Glucosamine; 170 mg EV.EXT 35 mixture and 500 mg glucosamine, as glucosamine sulphate, per capsule, Ferrosan AS, Denmark) two capsules daily. The 170-mg EV.EXT 35 mixture contained 100 mg standardized ginger extract corresponding to 2000 mg of dry rhizome from Zingiber officinalis Roscoe (20:1 extract) and 70 mg of a lipid carrier. The ginger–Z. officinalis Roscoe used in the present study has undergone numerous quality checks regarding amount of active compounds, pesticides, microorganisms, solvents, and heavy metals to secure a highly standardized and safe extract.

The diclofenac group (n=22) received a Diclofenac Retard (100 mg diclofenac as sodium diclofenac in a slow-release formulation) and glucosamine (1000 mg glucosamine as glucosamine sulphate) once daily. Both groups received the same amount of glucosamine, allowing a comparison to be made between ginger and diclofenac.

The primary part of the study was performed during 28 days of administration, but patients were offered respective treatment to continue for up to 6 months to assess pain relief and general clinical observations.

Inclusion and exclusion criteria are given in Table 2. OA patients with visual analogue scale, 0–100 mm (VAS) pain higher than 40 mm were included in the study.

Table 2.

Inclusion and Exclusion Criteria

Inclusion criteria	Exclusion criteria
Joint pain syndrome present during walking. VAS pain higher than 40 mm	Ulcer presence during EGDS and more than 5 stomach mucosa and/or duodenum erosions, and/or erosive esophagitis
NSAID-gastropathy or dyspepsia development from NSAID therapy in anamnesis	NSAID administration, aspirin in anti-aggregant doses, glucocorticosteroids
Informed patient consent to administer the preparation, and compliance with the listed research protocol	Various disease conditions such as: High risk of cardiologic complications, arterial hypertension, cardiac insufficiency >II degree, myocardial infarction or apoplectic attack in anamnesis during the previous 3 years, chronic kidney disease, liver insufficiency, bronchial asthma, subcompensated or decompensated diabetes mellitus, oncological diseases
	Pregnancy

VAS, visual analogue scale; EGDS, esophagogastroduodenoscopy; NSAID, nonsteroidal anti-inflammatory drug.

All the patients underwent clinical, instrumental, and laboratory assessments, as shown in Table 3. Clinical examination consisted of patient medical history, and overall external examination including Helicobacter pylori antigen typing. Severity of dyspepsia assessment (SODA) was performed according to a validated questioning model.¹⁰ The SODA questionnaire is a set of 17 questions to evaluate intensity of abdominal pain, dyspeptic symptoms (heartburn, eructation, vomiting, etc.) as well as a patient satisfaction index. The SODA questionnaire was used before trial in each case to define basic GI status. Patients with severe dyspepsia and abdominal pain according to SODA were not included in the study.

Table 3.

Description and Timing of Analytical Parameters

Parameter	Start	Day 7	Day 14	Day 28	6 Months
Clinical observations	X	X	X	X	X
VAS pain dynamics^a
Standing (patient)	X	X	X	X	X
Movement (patient)	X	X	X	X	X
VAS overall health condition^b
Patient evaluation	X			X
Doctor evaluation	X			X
SODA evaluation	X			X
EGDS with a biopsy	X			X
Blood clinical analyses	X			X
Urine clinical analyses	X			X
Serum gastrin-17	X			X
Stomach mucosa prostagladins	X			X

0–100 mm visual analogue scale (VAS). 0 is no pain and 100 is maximum pain.

0–100 mm VAS. 0 is very poor state of health and 100 is very healthy.

SODA, severity of dyspepsia assessment; EGDS, esophagogastroduodenoscopy.

Esophagogastroduodenoscopy with a biopsy (EGDS), abdominal cavity organs and kidney ultrasonic evaluation (USR), urine clinical analyses, blood clinical chemistry analyses (protein, glucose, cholesterol, urea, creatinine, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase) were performed according to standard hospital procedures. Levels of prostaglandins (PGE1, PGE2, PGF2α, 6-keto PGF1α [PGI2]) were measured in mucosa biopsies from the antral stomach compartment.

The use of gastroscopy and biopsy allowed evaluation of adverse effects during treatment. This was considered important since one of the arms included a NSAID (diclofenac) with a known risk profile.

Prostaglandins were determined in stomach contents from mucosa biopsies of the pyloric stomach compartment. The biopsies were dried on salt-free paper, weighed, and dispersed by sonication in 2 mL of distilled water. The PG concentration was determined using commercial chemical reagents kits (BCM Diagnostics), on an automatic immune-enzyme analyzer (ChemWell EIA, Awareness Technology Inc., USA). The prostaglandin content was expressed as per gram of tissue.

Gastrin serum level was measured using a commercial reagent kit (Cat. no. 60105, Biohit) on an automatic immune-enzyme analyzer (ChemWell EIA, Awareness Technology Inc., USA).

All values are given as mean values±standard error of the mean. The nonparametric Wilcoxon test was used for statistical evaluation.

Results

Upper GI tract dyspepsia and mucosa endoscopic changes

The ginger group showed a slight, but significantly decreased upper SODA pain intensity index by the 28th day of treatment from 15.6±0.9 down to 14.2±0.6 (p=0.05). SODA dyspepsia did not change significantly during the treatment, and the dyspepsia index remained unchanged: Before the therapy it was 13.2±1.5, and at the end of the treatment it was 12.6±1.4 (p=0.6). Two (2) patients reported symptoms associated with esophageal reflux (epigastric burning, and regurgitation) by the 28th day of the preparation administration. This ceased 2–3 days after the therapy ended. The SODA satisfaction index (patient evaluation) significantly improved from 13.2±0.4 to 15.8±0.5 (p=0.05), at the end of treatment. None of the patients reported upper GI tract compartments erosive-canker signs during administration of the preparation.

In the diclofenac group, upper GI tract pain symptoms increased, and by the end of treatment the SODA pain intensity index increased significantly from 14.3±0.9 up to 16.4±1.0 (p=0.03). SODA dyspepsia symptoms also increased from 12.3±1 up to 13.3±1.5, however, not significantly (p=0.8). The SODA satisfaction index was not significantly changed. Before the treatment it was 16.3±0.6, and at the end of treatment it was 16±0.6 (p=0.8). Epigastric pain syndrome and dyspepsia required unplanned EGDS in 4 (20%) patients during the 7th–10th days of diclofenac+glucosamine (DG)–administration. In 2 cases, endoscopic signs of aggravated chronic gastritis were reported, in 2 cases erosive gastritis signs with prior severe erosions localization were reported in the antral stomach compartment, and 1 patient reported duodenum ulcer. In total, 5 (23%) patients in the DG group reported undesirable effects, and 1 patient was denied further diclofenac treatment due to ulcer development.

Influence on prostaglandin levels in the stomach mucosa

Stomach mucosa PG levels are presented in Table 4. The zinaxin glucosamine (ZG) group showed significant increases for PGE1, PGE2, PGF2α, and PGI2. On the contrary, the DG group showed significant decreases of PGE1, PGE2, and PGF2α. PGI2 showed a nonsignificant increase.

Table 4.

Prostaglandin Levels in Stomach Mucosa of the Patients with Osteoarthritis Before and After Various Therapies (Mean Values±Standard Deviation)

	Ginger group (n=21)			Diclofenac group (n=22)
Prostaglandin (ng/g tissue)	Before	After	Wilcoxon	Before	After	Wilcoxon
PGE1	244±53	486±88+99%	p<0.02	325±86	187±40−43%	p<0.05
PGE2	633±69	981±115+109%	p<0.02	756±178	363±211−52%	p<0.05
PGF2α	469±127	750±153+60%	p<0.02	520±147	215±103−59%	p<0.05
PGI2	599±117	865±181+44%	p<0.05	524±187	688±201+32%	ns

PG, prostaglandin; ns, not significant.

Pain dynamics

VAS pain on standing before the treatment was 47±3.7 mm for the ZG group and 46.8±3.3 mm for the DG group. VAS pain on standing significantly (p<0.05) decreased for both groups during the therapy as shown in Figure 1. Also, VAS pain on movement improved significantly during treatment in both groups as shown in Figure 2. Both pain on standing and pain on movement were maintained in both groups up to 6 months.

FIG. 1.

Changes in visual analogue scale (VAS), 0–100 mm pain dynamics on standing during therapy for the Zinaxin (ginger and glucosamine combination) group versus the diclofenac group. Mean values±standard error of the mean.

FIG. 2.

Changes in visual analogue scale (VAS), 0–100 mm pain dynamics on movement during therapy for the Zinaxin (ginger and glucosamine combination) group versus the diclofenac group. Mean values±standard error of the mean.

Patient overall health condition

VAS patient overall condition improved during ZG administration from 55.4±5.2 to 84.3±3.8 mm (p<0.05) and during DG administration from 55.3±4.8 to 81.1±4.2 mm (p<0.05). VAS doctor overall condition improved in the ZG group from 61.3±6.3 to 87.2±4.8 mm (p<0.005) and for the DG group from 60.8±5.7 to 84.2±3.7 (p<0.005).

Serum gastrin-17 levels

The ZG group (ginger) showed a significant increase of serum gastrin-17 levels from 24.6±3.4 to 38±5.1 pmol/L (p<0.05) by the 4th week of intake. Conversely, the DG group showed during the same period a slight nonsignificant decrease in gastrin-17 levels from 24.8 to 22.6 pmol/L.

Other analyses

All other analyses (abdominal cavity organs and kidney ultrasonic evaluation, urine clinical analyses, and blood clinical chemistry analyses) showed minor change and no significant differences between the groups.

Discussion

To the authors' knowledge, this is the first study examining the potential beneficial influence of ginger on gastropathy conditions in an OA population as compared with diclofenac, an NSAID with known detrimental effects.

The level of OA pain relief and efficacy observed for the ginger group was comparable to the traditional therapy group: diclofenac. Both groups showed a relevant and significant decrease in pain indexes (60%–70%), which was maintained up to 6 months. Overall health improvement (doctor and patient evaluations) supports a similar efficacy of ginger and diclofenac in this study.

Administration of diclofenac significantly increased both the SODA pain index and dyspepsia index. This was accompanied by higher prevalence of NSAID-induced gastropathy in the diclofenac group. Contrary to the diclofenac treatment, patients taking the ginger preparation did not show any signs of gastropathy, and no cases of increased SODA stomach pain syndrome were reported during treatment. Two (2) patients reported gastroesophageal reflux symptoms, which were relieved after the preparation administration stopped. This effect could be due to the ability of ginger to stimulate gastric secretion and evoke some reflux.¹¹

Since the traditional NSAIDs perform their anti-inflammatory action via COX inhibition, as well as overall inhibition of PG synthesis, the influence of the natural ginger preparation on PG synthesis in the stomach mucosa was also investigated. Diclofenac showed the expected decrease of PG in the mucosa. In contrast, the ginger preparation significantly increased synthesis of PGE1, PGE2, PGF2α, and PGI2 in the stomach mucosa by the end of the study (day 28). This means an improved mucosa protective potential, which is especially important during treatment of OA patients with NSAIDs—a gastropathy development risk factor. Since glucosamine was given in both arms, the effect should be ascribed to the ginger extract.

The precise mechanism is not fully understood at the present time. Previous studies with ginger clearly support an anti-inflammatory and pain modulatory action. This takes place without total inhibition of COX enzymes or inflammatory cytokines, leaving room for constitutive effects.^7,11 In various animal models, it has been shown that ginger has a general beneficial health effect on the stomach, including ulceration.^12,13 A study by Minaiyan et al.¹⁴ indicates an anti-ulcerogenic effect of ginger equal to that of ranitidine. Studies with other natural products also indicate ulcer-healing properties. A nutmeg extract (Myristica malabarica) promoted PG synthesis, angiogenesis acceleration, and ulcer regeneration in an experimental rat ulcer model, induced by indomethacin.¹⁵ A novel synthetic flavonoid, DA-6034, has been shown to protect stomach mucosa and increase endogenous PGE2 synthesis in various gastric mucosal damage models. This flavonoid reliably decreased damage frequency caused by ethanol, aspirin, indomethacin, or specific stress.¹⁶

A known PG synthesis stimulator in the stomach mucosa is the hormone gastrin, produced by G-cells.¹⁷ In the present study, serum gastrin-17 was measured before and after the therapy in both groups. The ginger preparation led to a significant and relevant increase in gastrin production (+54%) by the 4th week of administration. Patients with higher levels of gastrin showed a clear increase of PG stomach mucosa levels. This was especially noticeable in patients receiving the Zinaxin product. A positive correlation between the gastrin level and PGE1 and PGI2 was noted (r=0.65, p=0.02 and r=0.7, p=0.001, respectively).

The present study is to the authors' knowledge the first in humans with clinical OA, verifying a beneficial effect of ginger on stomach mucosa biology, while at the same time yielding a relevant anti-inflammatory and pain relief response. It is postulated that this health-promoting gastric mucosa effect could be due to the general anti-inflammatory action not being total, combined with additive effects of ginger compounds showing antioxidant and gastroprotective effects.^18,19

Conclusions

This study shows that the specific ginger preparation, Zinaxin, has an important gastroprotective potential while maintaining relevant pain relief and efficacy similar to a frequently used NSAID in OA populations.

Footnotes

Acknowledgments

Dr. L. Lindmark, Kasima Medical Development, Sweden is acknowledged for help in finalizing the manuscript. Financial support for the study has in part been received from Ferrosan AS, Denmark.

Disclosure Statement

No competing financial interests exist.

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