Present-day therapy for osteoarthritis (OA) of the knee is directed at symptoms, since there is no established disease-modifying therapy. Treatment programs involve a combination of nonpharmacologic and pharmacologic measures, utilizing a combination of analgesia, antiinflammatory, and intraarticular programs (1–3). If these are unsuccessful, a variety of surgical interventions are appropriate. Since none of the medicinal programs consistently provides adequate relief of pain, yet has attendant risk, the search continues for agents that might provide improvement in symptoms with minimal risk. While scientists have turned to the investigation of newly discovered pharmaceuticals, many patients have turned to herbal and other remedies that have not been adequately studied.
The purpose of the present study was to test an extract of Zingiber officinale Roscoe and Alpinia galanga Linnaeus Willdenow (both are of the Zingiberaceae family, commonly called “gingers”). The Zingiberaceae family consists of 49 genera and 1,300 species, of which there are 80–90 species of Zingiber and 250 species of Alpinia (4). The subspecies used in the tested extract were selected after analysis and testing of >100 varieties (species and subspecies) of Zingiberaceae for antiinflammatory effects, by in vivo assays and using animal models. The species selected by this process were grown and harvested under controlled conditions.
Ginger is a very popular spice and the world production is estimated at 100,000 tons annually, of which 80% is grown in China (5). Ginger also has a long tradition of medicinal use and has been used as an antiinflammatory agent for musculoskeletal diseases, including rheumatism, in Ayurvedic and Chinese medicine for more than 2,500 years (6, 7). The German Commission E Monographs contains reviews of drugs, including herbal drugs, for quality, safety, and effectiveness. As a result of this review of more than 300 herbs by an expert committee under the German Federal Institute for Drugs and Medical Devices, many herbs have been excluded from sales in Germany. The Monographs lists ginger for use in dyspepsia and prevention of motion sickness (8). In the standard German text, Hager's Handbuch der Pharmazeutischen Praxis, ginger is listed as being used against nervousness, chronic inflammation of the intestine, coughing, conditions of the urinary tract and lower abdomen, rheumatism, and a sore throat (9).
Pharmacologically, ginger, similar to other plants, is a very complex mixture of compounds. Zingiber officinale contains several hundred known constituents (10), among them gingeroles, beta-carotene, capsaicin, caffeic acid, and curcumin. In addition, salicylate has been found in ginger in amounts of 4.5 mg/100 gm fresh root (11). This would correspond to <1 mg salicylate in 1 capsule of the presently tested ginger extract. The actions and especially the interactions of these ingredients have not been (and probably can not be easily) evaluated. Various powders, formulations, and extracts have, however, been commercially used and tested, both in vitro and in vivo, in animal models. In these models, ginger has been shown to act as a dual inhibitor of both cyclooxygenase (COX) and lipooxygenase (12), to inhibit leukotriene synthesis (13), and to reduce caregeenan-induced rat-paw edema (14, 15), an animal model of inflammation.
Another related plant, galanga, commonly called greater galanga, is also widely used as a spice in the East and as a remedy for various ailments. It has an antiinflammatory action through inhibition of prostaglandin synthesis (16), and has traditionally been used for rheumatic conditions in South East Asian medicine (17). The volatile oil of Alpinia galanga L., which can be obtained by steam distillation of the rhizome, is a complex mixture containing 1,8-cineol and 1′-acetoxychavicol acetate which has antifungal (18) and antitumor (19) activity. The German Commission E Monographs lists the use of Alpinia officinarum, which is closely related to Alpinia galanga, for dyspepsia and loss of appetite. The US Food and Drug Administration lists ginger and Alpinia officinarum as “generally regarded as safe” (20). New research based on the traditional use of the gingers has led to the development of a patented ginger extract (EV.EXT 77). In vitro experiments have shown that the combined extract also inhibits the production of tumor necrosis factor α (TNFα) through inhibition of gene expression in human OA synoviocytes and chondrocytes (21).
In this study, we have evaluated the safety and efficacy of the extract in a double-blind, placebo-controlled study with intent-to-treat (ITT) analysis.
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- PATIENTS AND METHODS
Patients. There was no clinically relevant difference in the demographics between the 2 treatment groups (Table 1). The patients were predominantly women and predominantly white. Patients in both study groups were generally overweight, since the average body mass index was >30 kg/m2 (range 18–65 kg/m2).
Table 1. Demographic characteristics of study population*
|Variable||Randomized (n = 261)||Per protocol (n = 194)||Intent-to-treat|
|Ginger extract (n = 124)||Placebo (n = 123)|
|Age, mean ± SD years||65.2 ± 11.4||65.3 ± 11.3||64.0 ± 11.5||66.3 ± 11.6|
|Body mass index, mean ± SD kg/m2||30.4 ± 6.6||30.3 ± 6.6||30.6 ± 6.8||30.1 ± 6.6|
|Diagnosed OA, mean ± SD years||7.3 ± 8.0||7.2 ± 7.5||7.0 ± 7.1||7.0 ± 7.5|
|Radiographic classification of knee OA, %†|
| Stage 2||40.2||40.2||37.9||43.1|
| Stage 3||54.0||54.6||54.8||52.0|
| Stage 4||5.4||5.2||7.3||4.1|
All patients with at least 1 visit after the baseline evaluation were included in the ITT analysis. Fourteen patients, 8 receiving placebo and 6 receiving ginger extract, discontinued the trial before completing any evaluation of efficacy. Among the patients in the placebo group who discontinued, 3 dropped out due to adverse events, 4 were lost to followup, and 1 withdrew consent. Among the patients receiving ginger extract who discontinued, 3 dropped out due to adverse events and 3 were lost to followup. Thus, the modified ITT analysis included the 247 patients (95% of the total enrolled) who completed any postbaseline efficacy evaluation. A total of 194 patients (74%) completed the study without protocol violations. Fifty-seven patients discontinued prematurely (22% of the randomized population) (Table 2). The overall withdrawal rate was 28% in the ginger extract group and 16% among those receiving placebo. The withdrawal rate due to adverse events was 13% in the ginger extract group and 5% in the placebo group. There were no followup data available for the patients who withdrew from the study prematurely.
Table 2. Discontinuations among the randomized population*
|Primary reason for early termination||Ginger extract (n = 130)||Placebo (n = 131)|
|Perceived lack of efficacy||9||7|
|Lost to followup||6||5|
Compliance. Compliance was calculated from the amount of study medication (number of capsules) returned and the number of empty slots in the blister cards. Compliance was 98 ± 12% (mean ± SD) for the ginger extract group and 98 ± 18% for the placebo group.
Primary efficacy variable: pain on standing. Pain on standing after 6 weeks of treatment showed improvement in both treatment groups. However, as the primary efficacy parameter, there was a higher percentage of responders (improvement ≥15 mm on the VAS pain scale) in the ginger extract group (n = 78 [63%]) than in the placebo group (n = 62 [50%]; P = 0.048). An ITT analysis of all patients enrolled, regardless of whether they underwent any postbaseline efficacy evaluation, also showed a higher rate of responders in the ginger extract group (78 of 130, or 60%) than in the placebo group (62 of 131, or 47%) (P = 0.040). The analysis of means for pain on standing showed that the ginger extract group improved an average 8.1 mm more than did the placebo group (P = 0.005) (Figure 1).
Figure 1. Knee pain on standing as measured by 100-mm visual analog scale after 2 and 6 weeks in patients with osteoarthritis receiving placebo (n = 123) or ginger extract (n = 124), in the intent-to-treat analysis. Bars show the mean pain rating (in mm) and 95% confidence intervals.
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A subset analysis was performed for increased responder levels. For ≥20-mm improvement in pain on standing, the ginger extract group showed a response superior to that of the placebo group (n = 73 [59%] versus n = 56 [46%]; P = 0.036). For a ≥25-mm improvement, the ginger extract group again displayed a superior response compared with that of the placebo group (n = 65 [52%] versus n = 48 [39%]; P = 0.035).
In an analysis of the patients who completed the study per protocol and experienced ≥15-mm improvement in pain on standing, results were similar to those of the ITT analysis, although the difference between the 2 treatment groups was smaller. The ginger extract group showed a response that was numerically superior (60 of 92, or 65%) to that of the placebo group (54 of 102, or 53%) (P = 0.083). In other parameters, significant improvements comparable with those in the ITT analysis were seen.
Secondary efficacy variables. The results of the secondary parameters were consistent with the findings with the primary parameter (Table 3). Pain after walking also demonstrated a significant improvement in the ginger extract group compared with the placebo group. The change in total WOMAC score was numerically superior in the ginger extract group versus the placebo group, with the greatest improvement seen in stiffness. Figure 2 shows the response on the individual questions of the WOMAC questionnaire, with responses to questions 6, 7, 11, 14, and 15 showing a significant improvement among patients receiving the ginger extract. Improvement in patient global status was numerically better in the ginger extract group and was statistically superior in a per protocol analysis (P = 0.042). There was no difference in the SF-12 score, since there was little change from baseline in either group. Acetaminophen use was equal in the 2 study groups (mean ± SD number of tablets daily 2.0 ± 1.9 in the ginger extract group and 2.2 ± 2.0 in the placebo group).
Table 3. Results of secondary parameters in the intent-to-treat analysis
|Parameter, time point||Placebo (n = 123)*||Ginger extract (n = 124)*||Between-group difference||P|
|Pain after walking 50 feet|
| Visit 4||44.2||28.3||−8.7||34.6||29.5||−15.1||6.4||0.016|
| Visit 4||40.8||24.4||−9.1||36.1||26.2||−13.5||4.4||0.112|
| Visit 4||49.1||26.3||−11.6||40.8||28.1||−18.4||6.8||0.018|
| Visit 4||43.4||23.7||−8.8||37.7||25.3||−11.8||3.0||0.134|
| Visit 4||43.5||23.3||−9.0||37.3||25.1||−12.9||3.9||0.087|
| Visit 4||3.2||0.9||0.4||3.5||1.0||0.5||0.1||0.100|
| Physical summary|
| Visit 4||35.3||9.5||3.4||36.9||9.7||4.1||0.7||0.300|
| Mental summary|
| Visit 4||53.0||10.5||0.0||53.4||10.9||0.5||0.5||0.700|
Figure 2. Mean change from baseline to the fourth visit in each functional measure of the Western Ontario and McMaster Universities osteoarthritis index for the 2 treatment groups, in the intent-to-treat analysis. Bars show the mean and standard error.
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Analysis of individual variables showed no effect of age (>65 years versus <65 years), sex, center, or treatment-per-center interaction on the efficacy parameters. This analysis did show a difference in the baseline scores, especially in global status, with the placebo group having the worse scores. This difference cannot be explained, but it was adjusted for through the analysis of covariance.
Adverse events. There were 314 adverse events reported on diary cards and by questioning. Seventy-six patients (59%) receiving ginger extract experienced 202 adverse events. Forty-nine patients (37%) receiving placebo experienced 112 adverse events. Only 1 group of adverse events showed a significant difference between the treatment groups: gastrointestinal (GI) adverse events were more common in the ginger extract group (116 events in 59 patients [45%]) compared with the placebo group (28 events in 21 patients [16%]).
None of the GI adverse events were considered serious by the investigators; 70% were reported as mild, 24% moderate, and 6% severe. When analyzing the events by preferred terms, the only events seen significantly more often in the ginger extract group were eructation, dyspepsia, and nausea. Words used by the patients included burping, belching, bad taste in the mouth, stomach upset, heartburn, and a burning sensation in the stomach. To examine whether preexisting conditions had any influence on this response, the patients' medical history was related to the adverse events. Thirty-six patients in each treatment group had a previous diagnosis of reflux disease, dyspepsia, ulcer, heartburn, gastritis, or hiatus hernia. Of these, 4 patients (11%) in the placebo group and 10 (28%) receiving ginger extract had at least 1 of the adverse events, including dyspepsia, eructation, or nausea; it was concluded that there was no connection to previous conditions.
There was no statistically significant difference between the number of severe adverse events in the 2 treatment groups. One serious adverse event occurred in the study, a myocardial infarction in a patient receiving placebo.
There was concern that the adverse events might affect the blinding of treatment status. Therefore, we examined the percentage of responders for pain on standing in the ginger extract group in the presence or absence of GI adverse events. There were 65% responders in the presence of dyspepsia, eructation, or nausea, and 62% responders in the absence of these adverse GI events (P = 0.85). Through this analysis, the adverse events were not found to significantly affect the outcome of the study.
Patients were informed about the possible pungency upon entering the study. Experience of the pungent taste was captured as adverse events to an extent, which may explain the incidence of these events. Still, the possibility exists that some subjects were not truly blinded due to the pungency of the ginger extract.
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In a 1999 Gallup questionnaire among Americans with arthritis, 28% thought that herbals have a role in the treatment of arthritis, and 17% believed that herbals have a preventative role (29). In a 1997 US survey among 2,055 people, 27% of those with arthritis had used an alternative treatment for the disease within the last year (30). Herbal remedies and other nutraceuticals or botanicals are thus increasingly used by both the healthy and the sick. Unfortunately, few of the remedies have been tested for efficacy and safety in well-designed clinical trials.
In order to address this issue, in a 6-week, randomized clinical trial using ITT analysis in patients with OA of the knee, treatment with a ginger and galanga extract (EV.EXT 77) demonstrated a reduction in knee pain on standing when compared with patients receiving placebo. Additional analyses of the primary efficacy variable as well as changes in the WOMAC index and global status were consistent with the results of the primary efficacy variable. In this short-term study, there was no essential difference in the ginger and placebo groups for quality of life (measured by the SF-12) or consumption of rescue analgesia (acetaminophen). The treatment group also had an increase in GI adverse events.
The benefits found in this trial are consistent with the results described in the few existing reports in the literature. Three published studies on the use of ginger in arthritis have been identified. Two were collections of anecdotal reports (31, 32). In the larger cohort, involving 56 patients with rheumatic disorders, more than 75% experienced relief of pain and swelling after an average dosage of 3 gm raw ginger per day for periods varying between 3 months and 2 years (32). A randomized clinical trial included 67 patients, of whom 56 were able to be evaluated (33). This was a 3-way, crossover study comparing ibuprofen, ginger extract, and placebo. The ranking of efficacy was ibuprofen > ginger extract > placebo for VAS scores on pain and the Lequesne index, but no significant difference was seen when comparing ginger extract and placebo directly. Exploratory testing of the first period of treatment (before crossover) was performed and this showed a better effect of both ibuprofen and ginger extract compared with that of placebo (P < 0.05 by chi-square test).
In the WOMAC subgroups in the present study, the greatest improvement was seen in stiffness. The WOMAC index is described as being more sensitive to change in pain, followed by stiffness and function (34). Further investigation into the effects of ginger on stiffness appears warranted, since this may indicate a different mechanism of action than most other OA remedies.
This was a short-term study. At 6 weeks, the placebo effect appeared to fade, whereas the group treated with ginger extract continued to improve. Longer-term studies are needed.
Although the COX-2–specific inhibitors have less GI adverse effects than do nonselective nonsteroidal antiinflammatory drugs (NSAIDs), their overall safety versus placebo is not entirely known, and there are no studies comparing COX-2–specific inhibitors with the ginger extract. Both nonselective NSAIDs and COX-2–specific inhibitors have potential renal adverse effects (35) not described with the ginger extracts.
Some of the patients reported mild GI side effects in the form of dyspepsia, eructation, and nausea. These may be caused by the pungent taste of the ginger extract. Adverse events for NSAIDs can be classified into 3 categories (36): 1) “nuisance” symptoms, such as heartburn, nausea, dyspepsia, and abdominal pain; 2) mucosal lesions; and 3) serious GI complications, such as bleeding and perforation. On average, 10–12% of patients will experience dyspepsia while taking a nonselective NSAID, sometimes leading to death (36, 37). Because ginger inhibits prostaglandin synthesis, there is the potential for GI ulceration. However, the effect of NSAIDs on the inflammatory process is mainly caused by inhibition of prostaglandin synthesis. Contrary to this, the ginger extract is a complex mixture that reduces inflammation through inhibition of prostaglandin synthesis, inhibition of lipooxygenase (13), and reduced production of TNFα (21).
We could find no data indicating mucosal lesions or bleeding after intake of ginger despite widespread use of ginger throughout the world. Surprisingly, both ginger (38) and galanga (39) have been shown to protect against ulcers in animal studies. The lack of severe GI adverse events seen in this study is consistent with the observations in the above-mentioned studies as well as in studies on other uses of ginger: seasickness (40), postoperative antiemetic (41, 42), and vertigo (43).
A warning has been reported on the possible effect of ginger on bleeding time (44). In vitro studies have shown that ginger inhibits thromboxane synthesis and thereby platelet aggregation (45). In humans, an ex vivo study tested a single dose of 2 gm dried ginger (46). Another 3-way crossover study compared the oral intake of 15 gm raw ginger/day, 40 gm cooked stem ginger/day, and placebo for 2 weeks in 18 healthy volunteers (47). None of the tested ginger preparations produced any significant change in thromboxane synthesis. We could find no published data on adverse events connected with coagulation with ginger.
The average body mass index for this study population was high. Patients were enrolled without weight restrictions and may constitute a typical OA population in the US. The dosing of the ginger extract given was empirically based on the 1–2 capsules per day that is typically consumed in Europe. In retrospect, there may be concern that the US patients may have been underdosed. Without a dose-finding study, it is uncertain if a higher dose would have a better effect.
In conclusion, this study showed that a highly purified ginger extract has demonstrated a statistical effect of reducing pain in patients with OA of the knee. There was a good safety profile with mostly mild GI side effects. Long-term effects bear further investigation.
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We thank Dr. Fong Wang Clow for preparing the statistical plan and Rebecca Hoagland for performing the statistical analysis. In addition to Dr. Altman, contributing investigators were as follows: Neal Birnbaum, MD, Pacific Rheumatology Associates, San Francisco, California; Lon Blaser, MD, Marshfield Clinic, Marshfield, Wisconsin; Jacque Caldwell, MD, Halifax Clinical Research Institute, Daytona Beach, Florida; Guy Fiocco, MD, Gundersen Lutheran Clinic, La Crosse, Wisconsin; Elie Gertner, MD, Regions Hospital, St. Paul, Minnesota; Larry Gilderman, MD, University Clinical Research, Pembroke Pines, Florida; Robert Leff, MD, Duluth Clinic, Duluth, Minnesota; Howard Offenberg, MD, Halifax Clinical Research Institute, New Smyrna Beach, Florida; and Albert Razetti, MD, University Clinical Research, Deland, Florida.