The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis

      Abstract

      Objective: Evaluation of the effect of a ginger extract (Zintona EC) on patients suffering from gonarthritis.
      Material and methods: Twenty-nine patients (6 men and 23 women) with symptomatic gonarthritis (ACR criteria), in the age range 42–85 years, were included after randomization in a double blind, placebo controlled, crossover study of 6 months' duration. The treatment group was given a ginger extract (250 mg of Zingiberis Rhizoma per capsule, qid), while the placebo group received the same number of identical looking capsules per day. The crossover occurred after 3 months of therapy. Results were evaluated by a 100 mm visual analog scale (VAS) of pain on movement and of handicap.
      Results: Eight patients dropped out because of inefficacy, three from group 1 (ginger extract first) and five from group 2 (placebo first). One patient from group 1 and one from group 2 dropped out because of heartburn (while they were on ginger extract). Twenty patients completed the study period of 24 weeks and 19 that of 48 weeks follow-up. By the end of 24 weeks there was a highly statistically significant difference between the VAS of pain and handicap of the two groups (P<0.001). However, at crossover both groups showed a statistically significant decrease in VAS of pain on movement and of handicap, but the differences between the groups did not reach statistical significance.
      Conclusions: Zintona EC was as effective as placebo during the first 3 months of the study, but at the end of 6 months, 3 months after crossover, the ginger extract group showed a significant superiority over the placebo group.

      Keywords

      Introduction

      Osteoarthritis (OA) is the most common rheumatic disease, the prevalence of which increases with advancing age
      • Lawrence R.C.
      • Helmick C.G.
      • Arnett F.C.
      • Deyo R.A.
      • Felson D.T.
      • Gianini E.H.
      • et al.
      Estimates of the prevalence of arthritis and selected musculoskeletal disorder in the United States.
      • Van Saas J.L.C.M.
      • Van Romunde L.K.J.
      • Cats A.
      • Vandenbroucke J.P.
      • Valkebnurg H.A.
      Epidemiology of osteoarthritis. Zoeerterneer survey. Comparison of radiologic osteoarthritis in a Dutch population with that in 10 other populations.
      . The 1995 American College of Rheumatology (ACR) recommendations for the management of OA of the hip and knee outlined both the use of nonpharmacological modalities as well as that of pharmacological agents
      • Hochberg M.C.
      • Altman R.D.
      • Brandt K.D.
      • Clark B.M.
      • Dieppe P.A.
      • Griffin M.R.
      • et al.
      Guidelines for the medical management of osteoarthritis.
      . The 2000 ACR update of these recommendations
      American College of Rheumatology Subcommittee on Osteoarthritis Guidelines
      Recommendations for the medical management of osteoarthritis of the hip and knee. 2000 update.
      • Schnitzer T.J.
      American College of Rheumatology Update of ACR guidelines for osteoarthritis: role of the coxibs.
      includes a discussion of the place of acetaminophen, COX-2 inhibitors and nonselective NSAIDs, tramadol, opioids, intra-articular glucocorticoids and hyaluronan, topical capsaicin and methylsalicylate in OA management. Agents under investigation, such as glucosamine, chondroitin sulfate and others, are also discussed. Altman and Marcussen
      • Altman R.D.
      • Marcussen K.C.
      Effects of a ginger extract on knee pain in patients with osteoarthritis.
      recently reported a statistically significant effect of a ginger extract on reduction of knee pain in patients with OA. Their study was a 6-week double blind placebo controlled parallel-group study.
      We report here the effects of a ginger extract on symptomatic OA of the knee in a double blind placebo controlled, crossover study of 6 months' duration.

      Patients and methods

       Study design

      Twenty-nine patients (six men and 23 women) aged 42–85 years were included in the study after they signed an informed consent according to the Ethics Committeerequirement.

       Inclusion criteria

      Patients aged 40–85 years of both genders, with a diagnosis of OA of the knee according to the ACR criteria
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee.
      (showing at least one osteophyte on X-ray) and corresponding to OA grades 2, 3 or 4 by the Kellgren and Lawrence criteria
      • Kellgren J.H.
      • Lawrence J.S.
      Radiological assessment of osteoarthritis.
      , were considered for inclusion. They had to report pain on knee movement on a 100 mm visual analog scale (VAS) of at least 35 mm (Math Eq) after a 4 day washout period of any previous medication. Patients were excluded from the trial if pregnant or lactating or not using acceptable contraception, if they had participated in any other drug trial during the preceding 3 months, if they had intra-articular injections of corticosteroids or hyaluronan within the preceding 3 months, if they were on glucosamine/chondroitin preparations or diacerein less than a month before the trial onset, if they were on anticoagulants except for mini-aspirin (75–325 mg/day), if they had, besides OA, a concomitant rheumatic disease or secondary OA, or recent surgical orthopedic intervention in the lower limbs (within 6 months prior to trial onset). They were also excluded if mentally incapable of understanding or complying with the study protocol or for failing to sign the informed consent.
      No active physiotherapy or balneotherapy for the knees was allowed during the trial period.
      After randomization by computer-generated allocation schedule they were divided into two groups: group 1 (14 patients, who received the ginger extract first) and group 2 (15 patients who received placebo first). Both patients and investigators were blinded to treatment assignment. After 12 weeks, group 1 was switched to placebo and group 2 was given ginger extract for an additional 12 weeks. By the end of the double blind trial at week 24 the code was broken and interested study participants continued on ginger extract and were followed for an additional 24 weeks.
      Demographic characteristics of patients included in the study and radiographic classification of the target knee are described in Table I.
      Table IDemographic characteristics of patients and radiographic classification of knee OA
      Group 1 (ginger first)Group 2 (placebo first)
      Age: mean (range, years)64.7 (47–85)59.3 (42–81)
      Sex: male/female ratio1/135/10
      Disease (OA) duration: mean years±SD8±4.85.9±3.4
      Radiographic classification of knee OA
       Stage 232
       Stage 3710
       Stage 443

       Treatment

      Following discontinuation of any NSAID treatment for 4 days (washout period) patients were allocated to either Zintona EC (enteric coated) or placebo which were administered qid in identical opaque capsules. Paracetamol, up to four tablets per day, was allowed throughout the study except for a 12 h period before every point of clinical evaluation (weeks 4, 12, 16, 24, 32, 40 and 48) and their consumption recorded. The preparation Zintona EC (enteric coated ginger extract) was produced by Dalidar Pharma (Beer Sheva). It is a preparation (250 mg per enteric coated capsule) based on an extract of the plant ginger (Zingiber officinale). The plant root was subjected to extraction by liquid carbon dioxide under supercritical conditions. The liquid extract was absorbed on maltodextrin and microencapsulated to form an enteric coated product. The potency of the preparation was followed by analysis with HPLC on the active molecule gingerol. The dissolution of the preparation was done in a USP type 2 dissolution apparatus in gastric fluid (0.1 M HCl) for 1 h and the pH was rapidly increased to that of intestinal fluid (phosphate buffer pH=7.4). The release of gingerol was followed at several time points by HPLC analysis. The preparation was designed to release 20% under acidic gastric conditions in 2 h and the rest of the active material under intestinal conditions. Each capsule was filled to contain 10 mg gingerol. Placebo capsules contained maltodextrin only.

       Assessments and statistical analysis

      VAS of pain and handicap were determined by the Hebrew validated version of WOMAC
      • Wigler I.
      • Neumann L.
      • Yaron M.
      Validation study of a Hebrew version of WOMAC in patients with osteoarthritis of the knee.
      . Knee circumference was measured by tape at the level of the patellar center. Means of VAS of pain on movement, handicap and target knee circumference were calculated at each visit while stratifying for treatment group. The means of each of these visits were compared to the baseline mean (the second visit, after 4 days of washout). Statistical significance of these comparisons was calculated by the paired t-test. At each visit the differences from baseline of the means of VAS of pain on movement, handicap and target knee circumference were compared between the treatment groups. The statistical significance of these comparisons was calculated by independent sample t-test.
      Data concerning pain on movement, handicap and knee circumference reduction were analyzed by intention to treat. Since we could not compare means because the results concerning those who were lost to follow-up were not available, the intention to treat analysis was done for success versus failure, while referring to those who were lost to follow-up as treatment failures. Patients who reported more than 30% reduction in pain and handicap or presented more than 5% reduction in knee circumference were regarded as treatment success. The proportion of treatment success was calculated at each visit, while those who were lost to follow-up were regarded as treatment failure. These proportions were compared between treatment groups. Statistical significance was calculated by Fisher's exact test.

      Results

      The means of VAS of pain on movement and handicap at each visit, according to treatment group, are presented in Fig. 1, Fig. 2and Table II. During the first 12 weeks of the trial (phase one), VAS of pain on movement and VAS of handicap were reduced in both treatment groups. By the 12th week, in those treated with Zintona EC, the mean VAS of pain on movement was reduced from 76.14 (95% CI: 67.69–84.60) at baseline to 41.00 (95% CI: 22.50–59.49)(P=0.001) and that of handicap was reduced from 75.86 (95% CI: 68.00–83.72) at baseline to 39.72 (95% CI: 22.24–57.22) (P=0.001). In those who were treated with placebo, the mean VAS of pain on movement decreased from 76.87 (95% CI: 71.64–82.09) at baseline to 50.00 (95% CI: 33.46–66.53) (P=0.001) and that of handicap decreased from 73.47 (95% CI: 66.66–80.28) to 46.08 (95% CI: 29.75–62.40) (P=0.002). The differences between groups were not statistically significant. At phase two (after crossover) VAS of pain on movement and of handicap continued to decrease in the group that switched from placebo to Zintona EC, with means of 9.30 (95% CI: 3.29–15.31) and 10.00 (95% CI: 3.84–16.16), respectively, at the 24th week. In the groups that switched from Zintona EC to placebo, these means started rising, with the mean VAS of pain on movement and of handicap reaching 82.10 (95% CI: 69.81–94.39) and 80.80 (95% CI: 68.47–93.12), respectively, at the 24th week. The differences at this time were found to be statistically significant (P<0.001 for both comparisons). At phase three, when patients from both groups received Zintona EC, VAS of pain on movement and of handicap remained low in the group that continued Zintona EC from phase two, and decreased again in the group that received placebo at phase two. Both groups reached a low mean, which was statistically different from the baseline mean. No statistically significant difference was observed between the groups at this phase.
      Figure thumbnail gr1
      Fig. 1Comparison of mean VAS of pain on movement in the two treatment groups.
      Figure thumbnail gr2
      Fig. 2Comparison of mean VAS of handicap in the two treatment groups.
      Table IIMean VAS of pain on movement and handicap at each visit, according to treatment group
      TimeNMean VAS of pain on movementMean VAS of handicap
      Group 1
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      Group 2
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      Group 1
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      Group 2
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      Group 1
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      Group 2
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      MeanP-value
      P-values for the difference between each visit and the baseline within the same group (paired t-test).
      MeanP-value
      P-values for the difference between each visit and the baseline within the same group (paired t-test).
      P-value
      P-values for the difference between each group mean at the same visit (independent t-test).
      MeanP-value
      P-values for the difference between each visit and the baseline within the same group (paired t-test).
      MeanP-value
      P-values for the difference between each visit and the baseline within the same group (paired t-test).
      P-value
      P-values for the difference between each group mean at the same visit (independent t-test).
      −4 days141570.4376.000.23370.2172.130.691
      0 (baseline)141576.1476.870.87575.8673.470.623
      2 weeks131563.230.01764.270.0380.89561.150.01062.530.0870.862
      4 weeks121547.17<0.00154.330.0050.41147.58<0.00154.600.0330.438
      8 weeks121546.470.00552.670.0130.55941.33<0.00147.930.0080.568
      12 weeks (crossover)111341.000.00150.000.0010.43239.720.00146.080.0020.566
      14 weeks111337.550.00141.77<0.0010.73437.450.00139.62<0.0010.858
      16 weeks111253.550.00943.580.0050.49653.090.01140.420.0020.377
      20 weeks111155.450.06134.450.0020.13353.550.05732.09<0.0010.113
      24 weeks (opening)101082.100.9309.30<0.001<0.00180.801.00010.00<0.001<0.001
      32 weeks10834.100.00420.880.0010.41332.330.00320.880.0010.468
      40 weeks9812.22<0.00116.38<0.0010.62711.44<0.00111.38<0.0010.992
      48 weeks989.00<0.00115.63<0.0010.4918.78<0.00115.00<0.0010.515
      Group 1: treatment first (until week 12), then placebo (until week 24). Group 2: placebo first (until week 12), then treatment (until week 24). Both groups received treatment from week 25 through week 48.
      P-values for the difference between each visit and the baseline within the same group (paired t-test).
      P-values for the difference between each group mean at the same visit (independent t-test).
      At phase one, knee circumference was reduced in both treatment groups (Fig. 3). In those who were treated with Zintona EC, the mean target knee circumference decreased from 43.25 cm (95% CI: 40.37–46.13) at baseline to 39.36 cm (95% CI: 36.77–41.95) at the 12th week (P=0.003), while in those who were treated with placebo, it decreased from 41.27 cm (95% CI: 39.52–43.01) to 38.58 cm (95% CI: 36.71–40.45) at the 12th week (P<0.001). However, reduction of knee circumference in the group treated with Zintona EC was greater, though the difference was not statistically significant (P=0.15). At phase two (after crossover), the target knee circumference stopped decreasing and even increased in the group that moved from Zintona EC to placebo, while it continued to decrease in the group that moved from placebo to Zintona EC. At phase three, when both groups received Zintona EC, the mean target knee circumference continued to decrease in both groups. Groups 1 and 2 reached a low mean of 38.78 cm (95% CI: 34.84–42.72) and 36.38 cm (95% CI: 32.94–39.81), respectively, which was statistically different from the baseline mean (P=0.008 and P<0.001, respectively). No statistically significant differences were observed between the groups at this phase (P=0.971).
      Figure thumbnail gr3
      Fig. 3Comparison of target knee circumference in the two treatment groups.

       Intention to treat analysis

      The proportion of patients who reported more than 30% reduction in pain on movement and handicap was compared between treatment groups. The only statistically significant difference between the groups was found at the 24th week. Ten of the 15 patients in the group which started with placebo and finished with Zintona EC reported treatment success for both parameters as defined above. Only one patient in the other group reported treatment success at the end of the second phase (P=0.001).
      When comparing the proportion of patients with more than 5% reduction in target knee circumference, no statistically significant difference was observed between thegroups.

       Adverse events

      The only adverse effect was heartburn experienced by two patients: one patient from group 1 who dropped out after 1 week of treatment with Zintona EC and one from group 2 who dropped out in week 48 while on Zintona EC.

       Inefficacy and dropout

      In the first phase, three Zintona EC patients and two placebo patients dropped out. In the second phase, three Zintona patients and one placebo patient dropped out. Altogether six Zintona patients and three placebo patients dropped out before breaking the code. After code breaking, three more patients dropped out of the study.

      Discussion

      Our data show that Zintona EC as used in the present study was effective in reducing pain on movement, handicap and knee circumference in patients with gonarthritis.
      During the first 12 week phase of the study this effect was not statistically different from that of placebo. However, after crossover the difference between the group switched from Zintona EC to placebo and the group switched from placebo to Zintona EC became highly statistically significant at 24 weeks in both VAS of pain on movement and of handicap. The target knee circumference, though significantly lower at 24 weeks in the group switched from placebo to Zintona EC (as compared to baseline), was not significantly different from the group switched from Zintona EC to placebo. During the additional 24 week open study the patients switched from placebo to Zintona EC again showed statistically significant improvement (from baseline) at week 48.
      The fact that a statistically significant difference between groups was reached only at week 24 could be explained as follows: In the first phase, no significant difference was observed because of the remarkable placebo effect of different remedies used in OA
      • Moseley J.B.
      • O'Malley K.
      • Petersen N.J.
      • Menke T.J.
      • Brody B.A.
      • Kuykendall D.H.
      • et al.
      A controlled trial of arthroscopic surgery for osteoarthritis of the knee.
      . In the second phase (after crossover) the groups reached a statistically significant difference only at week 24 because of a delayed effect of Zintona EC and lack of a washout period. In the third phase (after opening), when both groups received Zintona EC, similar results were observed in both groups, as expected.
      The higher dropout rate while on Zintona EC could be related to possible side effects. In fact, two of the patients (one in each phase) dropped out due to heartburn. It could be that the other patients who were lost to follow-up suffered from heartburn or other side effects.
      Routine laboratory evaluations, including blood counts, liver tests and creatinine performed on day 0 andweeks 4, 12, 16, 24, 32, 40 and 48, remained within normal limits.
      Our observations are in accord with those of Altman and Marcussen
      • Altman R.D.
      • Marcussen K.C.
      Effects of a ginger extract on knee pain in patients with osteoarthritis.
      and Bliddal et al.
      • Bliddal H.
      • Rosetzky P.
      • Schlichting M.S.
      • Weider L.A.
      • Andersen L.A.
      • Ibfelt H.H.
      • et al.
      A randomized, placebo-controlled, crossover study of ginger extracts and ibuprofen in osteoarthritis.
      and support the need for studies of longer duration than those previously published
      • Altman R.D.
      • Marcussen K.C.
      Effects of a ginger extract on knee pain in patients with osteoarthritis.
      • Bliddal H.
      • Rosetzky P.
      • Schlichting M.S.
      • Weider L.A.
      • Andersen L.A.
      • Ibfelt H.H.
      • et al.
      A randomized, placebo-controlled, crossover study of ginger extracts and ibuprofen in osteoarthritis.
      . In addition, data provided suggest lack of toxicity of prolonged ginger extract therapy (48 weeks) as evaluated by routine blood counts, liver and renal function tests. However, a sound comparison between results of different studies of ginger extracts is difficult because we do not know the exact nature and dose of the active material in this plant extract. Previous studies have attributed an anti-prostaglandin and anti-inflammatory effect
      • Kiuchi F.
      • Iwakami S.
      • Shibuya M.
      • Hanaoka F.
      • Sandawa U.
      Inhibition of prostaglandin and leukotriene biosynthesis by gingeroles and diarylheptanoids.
      • Jana U.
      • Chattopadhayay R.N.
      • Shaw B.P.
      Preliminary studies on anti-inflammatory activity of Zingiber officinale Rosc., Vitex negundo Linn and Tinospora cordifolia (Willid) in albino rats.
      as well as an anti-TNFα effect
      • Frandoza C.G.
      • Frazier C.
      • Polotsky A.
      • Lahiji K.
      • Hungerfold D.S.
      • Weidner M.S.
      Inhibition of chondrocyte and synoviocyte TNFα expression by hydroxy-alkoxy-phenyl compounds (HAPS).
      to ginger preparations. The reduction of target knee circumference observed in our study may suggest an anti-inflammatory effect of Zintona EC.
      Our study has several limitations. The first is the absence of a washout period at crossover. However, in the group that started with placebo, a washout period is not needed, since these patients did not receive any active medication during the first phase. As for the second group, with the absence of a washout period the effect of the drug (Zintona EC) could continue after moving to placebo. This could explain the fact that the patients in this group continued to improve 2 weeks after starting on placebo and the onset of deterioration was noticed only after 4 weeks (week 16 of the study). We believe that this observation indicates a positive effect of Zintona EC. Since two patients who were on Zintona EC complained of heartburn one can speculate that some after taste or other sensation would result in unblinding. However, the patients who complained of heartburn were removed from the study and the researchers remained blinded to the end of the controlled study at week 24. We believe that all other patients did not identify the drug they received in each phase. Measuring of knee circumference using a tape may not be valid. However, since the investigators were blinded to the treatment module, this measurement method could lead to a nondifferential bias. In that case, the size of the difference between the study's arms should be less than the real difference. This could explain the nonsignificant difference between the study groups observed for this parameter. Finally, a higher dropout rate was observed in the patients who were on Zintona EC, as compared to placebo. Six Zintona EC patients and three placebo patients dropped out before opening at week 24. Since we could not compare means because the results concerning those who were lost to follow-up were not available, we performed an intention to treat analysis for success versus failure, referring to those lost to follow-up as treatment failures. This assumption could lead to bias. If some of the patients who were lost to follow-up in the placebo group had treatment success, it could be that the difference between the groups was smaller. On the other hand, if patients in the Zintona EC group (in which most of the dropouts occurred) who were lost to follow-up had treatment success, the difference between groups could be larger.
      Herbal medicinals are widely used in the United States and elsewhere
      • Johnston B.A.
      One third of nation's adults use herbal remedies.
      • Eisenberg D.M.
      • Kessler R.C.
      • Foster C.
      • Norlock F.E.
      • Calkins D.R.
      • Delbanco T.L.
      Unconventional medicine in the United States: prevalence, costs and patterns of use.
      . Ginger is considered one of the commonly used herbal medicinals
      • Miller L.G.
      Herbal medicinals.
      . It has been used for vertigo
      • Grontved A.
      • Hentzer E.
      Vertigo-reducing effect of ginger root.
      , motion sickness
      • Mowrey D.B.
      • Clayson D.E.
      Motion sickness, ginger and psychophysics.
      and as an antiemetic
      • Bone M.E.
      • Wilkinson D.J.
      • Young J.R.
      • McMeil J.
      • Charlton S.
      Ginger root: a new antiemetic: the effect of ginger root on postoperative nausea and vomiting after major gynecological surgery.
      . Evidence is now provided suggesting that it may have a place in the management of OA of the knee. Official recommendations for the management of knee OA are periodically revised
      • Hochberg M.C.
      • Altman R.D.
      • Brandt K.D.
      • Clark B.M.
      • Dieppe P.A.
      • Griffin M.R.
      • et al.
      Guidelines for the medical management of osteoarthritis.
      American College of Rheumatology Subcommittee on Osteoarthritis Guidelines
      Recommendations for the medical management of osteoarthritis of the hip and knee. 2000 update.
      • Schnitzer T.J.
      American College of Rheumatology Update of ACR guidelines for osteoarthritis: role of the coxibs.
      . Coated ginger extract may be considered for this purpose in the future.

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