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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Objective

To evaluate the efficacy and safety of a standardized and highly concentrated extract of 2 ginger species, Zingiber officinale and Alpinia galanga (EV.EXT 77), in patients with osteoarthritis (OA) of the knee.

Methods

Two hundred sixty-one patients with OA of the knee and moderate-to-severe pain were enrolled in a randomized, double-blind, placebo-controlled, multicenter, parallel-group, 6-week study. After washout, patients received ginger extract or placebo twice daily, with acetaminophen allowed as rescue medication. The primary efficacy variable was the proportion of responders experiencing a reduction in “knee pain on standing,” using an intent-to-treat analysis. A responder was defined by a reduction in pain of ≥15 mm on a visual analog scale.

Results

In the 247 evaluable patients, the percentage of responders experiencing a reduction in knee pain on standing was superior in the ginger extract group compared with the control group (63% versus 50%; P = 0.048). Analysis of the secondary efficacy variables revealed a consistently greater response in the ginger extract group compared with the control group, when analyzing mean values: reduction in knee pain on standing (24.5 mm versus 16.4 mm; P = 0.005), reduction in knee pain after walking 50 feet (15.1 mm versus 8.7 mm; P = 0.016), and reduction in the Western Ontario and McMaster Universities osteoarthritis composite index (12.9 mm versus 9.0 mm; P = 0.087). Change in global status and reduction in intake of rescue medication were numerically greater in the ginger extract group. Change in quality of life was equal in the 2 groups. Patients receiving ginger extract experienced more gastrointestinal (GI) adverse events than did the placebo group (59 patients versus 21 patients). GI adverse events were mostly mild.

Conclusion

A highly purified and standardized ginger extract had a statistically significant effect on reducing symptoms of OA of the knee. This effect was moderate. There was a good safety profile, with mostly mild GI adverse events in the ginger extract group.

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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Study design

The study was a 6-week, double-blind, placebo-controlled, parallel-group trial performed at 10 clinical centers in the US. It was designed according to guidelines on conduct of clinical trials as reported by the Osteoarthritis Research Society International (22) and as outlined in the International Conference on Harmonisation clinical practice guidelines (23). The protocol followed the 1975 Declaration of Helsinki as revised in 1983, with institutional review board approval, and all patients provided their oral and written informed consent. Patients were centrally randomized to receive treatment by a computer-generated allocation schedule, balanced by center, and both the investigators and the patients were blinded to treatment assignment.

Patients

Patients had OA of the knee by the American College of Rheumatology classification criteria using the decision tree format that includes radiographs (24). The radiographic changes had to include at least osteophytes and correspond to OA grades 2, 3, or 4 by the Kellgren and Lawrence criteria (25).

Admission criteria included the presence of knee pain on standing that had to be between 40 mm and 90 mm on a 100-mm visual analog scale (VAS) during the preceding 24 hours. This was assessed after a 1-week washout period. Both men and women ≥18 years old were included. Pain had to be of a degree so that it could be tolerated with alleviation using acetaminophen as an escape medication for 6 weeks. Prior treatment for OA was not a requirement. Patients with any of the following were excluded: rheumatoid arthritis, fibromyalgia, gout, recurrent or active pseudogout, cancer or other serious disease, signs or history of liver or kidney failure, asthma requiring treatment with steroids, treatment with oral corticosteroids within the prior 4 weeks, intraarticular knee depo-corticosteroids within the previous 3 months, intraarticular hyaluronate within the previous 6 months, prior treatment with immunosuppressive drugs such as gold or penicillamine, arthroscopy of the target joint within the previous year, significant injury to the target joint within the previous 6 months, other investigational drugs within the previous 1 month, fever >38°C at screening, and allergy to acetaminophen or ginger.

After screening, patients entered a 1-week “washout” for antiinflammatory and analgesic medications, during which they were allowed to take acetaminophen as needed up to 4 gm/day. Aspirin for anticoagulation up to 325 mg daily was allowed throughout the study.

If patients were determined to be eligible for the study, a baseline assessment of pain was performed after washout of medications that would affect the arthritis and prior to randomization. Each center was block-randomized with 130 patients receiving ginger extract and 131 patients receiving placebo.

Treatment

During the 6-week treatment period, patients ingested 1 capsule twice daily, morning and evening. 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 and produced according to good manufacturing practice (Eurovita Holding, Karlslunde, Denmark). Matching placebo capsules contained coconut oil. To minimize a possible pungent sensation, patients were instructed to swallow the whole (intact) capsule with a glassful of water at the time of a meal.

Acetaminophen was permitted as a rescue medication. Patients were instructed to take the rescue medication only when needed, to a maximum dosage of 2 tablets 4 times daily, i.e., 4 gm/day.

Drug accountability was calculated by pill count for both the study treatment and the rescue medication.

Assessments

The OA knee deemed to be more symptomatic was defined as the target joint by the investigator, and the knee-specific pain was assessed for this joint. The primary efficacy parameter was the proportion of responders experiencing at least a 15-mm reduction in pain between baseline and the final visit for knee pain on standing during the preceding 12 hours, as measured by a 100-mm VAS. Pain on standing is a validated measure of pain and coincides with question 5 of the Western Ontario and McMaster Universities (WOMAC) OA composite index (26). At the time of the design of this study, the full WOMAC index was not generally accepted as a primary efficacy variable in clinical trials of OA of the knee.

Secondary efficacy measures that were used to compare the 2 study groups were as follows: 1) average improvement in pain on standing, as measured by a 100-mm VAS; 2) consumption of rescue medication; 3) WOMAC index as measured by VAS, with one end of the scale being “no pain/stiffness/difficulty” and the other end, “extreme pain/stiffness/difficulty” (the total score was calculated as the mean response); 4) patient assessment of global status, in which the question, “Given all the ways your osteoarthritis affects you, how have you been doing the last 24 hours?” was evaluated on a 5-point Likert scale (1 = very poor, 2 = poor, 3 = average, 4 = good, 5 = very good); 5) quality of life assessment using the Short Form 12 (SF-12), which asks questions regarding the patient's condition during the preceding 4 weeks (27); and 6) pain in the knee after walking 50 feet, recorded immediately after walking and measured by a 100-mm VAS.

Efficacy and safety assessments were performed at baseline and after 2 and 6 weeks of treatment. The SF-12 was administered at screening and after 6 weeks of treatment only. Safety was assessed via open-ended questions concerning changes in the patients' health at each visit, supported by patients' responses on diary cards. For all adverse events, the onset, duration, and intensity (mild, moderate, or severe) of the event, as well as the action taken and outcome, were recorded. The relationship between an adverse event and the study medication was assessed, by the investigator, as none, remote, possible, probable, or definite. Adverse events were coded according to World Health Organization adverse reaction terminology (28). The adverse events were analyzed by preferred terms and by system organ classes.

Statistical analysis

Blinding was maintained until the final database was cleaned and locked. However, there was an interim analysis of 116 patients that was performed at a significance level of 0.01% by an independent statistician. The results were disclosed to the sponsor only. Neither the investigators nor the clinical research organization monitoring the study were aware of the results.

Sample-size calculation was based on results of an unpublished clinical trial using a ginger extract. Statistical evaluation was performed using SAS (SAS Institute, Cary, NC). The statistical analysis was performed using analysis of covariance for analysis of means, with baseline scores, center, sex, treatment-by-center interaction, and age as the covariates. Chi-square tests were used for analysis of responders, Student's t-test to analyze intake of rescue medication, and Fisher's exact test for comparing incidence of adverse events between groups. Except for the analysis of intake of rescue medication, the ITT last observation carried forward method was used. All analyses were performed 2-sided, with a minimum significance level of 5%.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

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*
VariableRandomized (n = 261)Per protocol (n = 194)Intent-to-treat
Ginger extract (n = 124)Placebo (n = 123)
  • *

    OA = osteoarthritis.

  • By the Kellgren and Lawrence criteria (25).

Age, mean ± SD years65.2 ± 11.465.3 ± 11.364.0 ± 11.566.3 ± 11.6
Sex, %
 Men37.536.140.336.6
 Women62.563.959.763.4
Race, %
 White93.593.394.493.5
 Nonwhite6.56.75.66.5
Body mass index, mean ± SD kg/m230.4 ± 6.630.3 ± 6.630.6 ± 6.830.1 ± 6.6
Diagnosed OA, mean ± SD years7.3 ± 8.07.2 ± 7.57.0 ± 7.17.0 ± 7.5
Radiographic classification of knee OA, %
 Stage 240.240.237.943.1
 Stage 354.054.654.852.0
 Stage 45.45.27.34.1

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 terminationGinger extract (n = 130)Placebo (n = 131)
  • *

    Values are the number of patients.

  • P = 0.025 versus placebo.

Adverse event176
Withdrew consent21
Perceived lack of efficacy97
Noncompliance12
Lost to followup65
Intercurrent illness00
Death00
Other10
Total3621

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).

thumbnail image

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 pointPlacebo (n = 123)*Ginger extract (n = 124)*Between-group differenceP
MeanSDChangeMeanSDChange
  • *

    Numbers of patients vary between 121 and 124 at the single visits, and for quality of life (QOL), between 111 and 114.

  • Western Ontario and McMaster Universities osteoarthritis index (WOMAC) consists of 24 questions, assessed on 100-mm visual analog scale, analyzed in 3 subscales as the average score for 5 questions on pain, 2 questions on stiffness, and 17 questions on function. The total score is calculated as the mean score for all 24 questions.

  • The Short Form 12 (SF-12) consists of 12 questions that are combined into 8 scales, which are summarized in the physical and mental component summaries shown here.

Pain after walking 50 feet
 Baseline53.125.149.924.3
 Visit 444.228.3−8.734.629.5−15.16.40.016
WOMAC
 Pain
  Baseline49.919.149.619.4
  Visit 440.824.4−9.136.126.2−13.54.40.112
 Stiffness
  Baseline60.423.459.221.6
  Visit 449.126.3−11.640.828.1−18.46.80.018
 Function
  Baseline52.119.449.520.4
  Visit 443.423.7−8.837.725.3−11.83.00.134
 Total
  Baseline52.318.450.219.0
  Visit 443.523.3−9.037.325.1−12.93.90.087
Global status
 Baseline2.80.83.00.8
 Visit 43.20.90.43.51.00.50.10.100
QOL (SF-12)
 Physical summary
  Baseline32.07.432.98.9
  Visit 435.39.53.436.99.74.10.70.300
 Mental summary
  Baseline53.110.952.610.8
  Visit 453.010.50.053.410.90.50.50.700
thumbnail image

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.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

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.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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