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Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review

Wolfgang M Marx, Laisa Teleni, Alexandra L McCarthy, Luis Vitetta, Dan McKavanagh, Damien Thomson, Elisabeth Isenring
DOI: http://dx.doi.org/10.1111/nure.12016 245-254 First published online: 1 April 2013

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of cytotoxic treatment. It continues to affect a significant proportion of patients despite the widespread use of antiemetic medication. In traditional medicine, ginger (Zingiber officinale) has been used to prevent and treat nausea in many cultures for thousands of years. However, its use has not been confirmed in the chemotherapy context. To determine the potential use of ginger as a prophylactic or treatment for CINV, a systematic literature review was conducted. Reviewed studies comprised randomized controlled trials or crossover trials that investigated the anti-CINV effect of ginger as the sole independent variable in chemotherapy patients. Seven studies met the inclusion criteria. All studies were assessed on methodological quality and their limitations were identified. Studies were mixed in their support of ginger as an anti-CINV treatment in patients receiving chemotherapy, with three demonstrating a positive effect, two in favor but with caveats, and two showing no effect on measures of CINV. Future studies are required to address the limitations identified before clinical use can be recommended.

  • chemotherapy
  • CINV
  • ginger
  • nausea

Introduction

Chemotherapy is one of medicine's key interventions in the treatment of cancer. While cytotoxic interventions for cancer are efficacious, they are often accompanied by a variety of adverse effects. Chemotherapy-induced nausea and vomiting (CINV) is a relatively common side effect of this treatment. A combination of different classes of anti-emetic medications such as 5-HT3 antagonists, neurokinin 1 (NK1) receptor antagonists, corticosteroids, and anti-anxiolytics have been shown to have additive effects and are commonly prescribed for patients having chemotherapy. Incidence of vomiting has substantially reduced, but efforts to control nausea have been less successful, with nausea continuing to affect upward of 60% of patients.1 Persistent nausea is also considered one of the most distressing physical symptoms for patients in this setting.2,3 This is of particular concern as nausea and vomiting in oncology patients can adversely affect food intake, increasing the risk of malnutrition during treatment. Previous studies report one in two patients in this setting as malnourished.4 The cumulative effect of pretreatment and treatment-related malnutrition can be one of compromised immune function, decreased performance status, poor response to treatment, and sometimes treatment discontinuation.57

The use of integrative or complementary therapies has been steadily increasing in western countries,8 resulting in an increased interest in the investigation of these therapies as either stand-alone or adjuvant treatments for treating clinical conditions. Ginger (Zingiber officinale) has a long history in many cultures as a folk-remedy for nausea and gastrointestinal discomfort. Empirical research has demonstrated that ginger may be effective as an anti-nausea agent; in particular, it has been proposed as a possible candidate for anti-CINV therapy.

While the exact mechanism of action is unknown, multiple active constituents within ginger (i.e., gingerols, shogoals, zingiberene, zingerone, and paradol) have been identified as potentially exerting beneficial effects on multiple areas implicated in the pathophysiology of CINV. Cell culture and animal studies suggest that these constituents stimulate oral and gastric secretions, regulate gastrointestinal motility,9,10 interact with the 5-HT3 receptors implicated in the CINV reflex,11 and assist in rescuing intracellular redox.12,13 Furthermore, animal studies provide preliminary support for the role of ginger supplementation in the prevention of cisplatin-induced emesis.14,15

Few adverse effects from the ingestion of ginger are reported in the literature.16 Oral ginger is generally well tolerated, with mild gastrointestinal adverse effects including abdominal discomfort, heartburn, and diarrhea being the most commonly reported. Theoretically, ginger inhibits platelet aggregation, which could result in excessive bleeding, but the evidence for this is equivical.17 When added to conventional antiemetics used in the prophylaxis and treatment of CINV, ginger does not appear to increase adverse effects.18 Indeed, conventional antiemetics appear to have a more varied adverse effect profile (including more severe adverse effects) compared to ginger. For example, steroids such as dexamethasone used for short durations commonly cause gastrointestinal adverse effects such as dyspepsia and psychological effects such as insomnia, while 5-HT3 receptor antagonists, such as ondansetron, commonly cause constipation and headache.19,20

Whilst direct cost comparisons between ginger and standard antiemetic therapies are difficult to perform due to lack of dose equivalency, it is likely that ginger would compare well, given its low ingredient cost and high accessibility. Ginger is already readily available in several commercial nonprescription formulations, and requires little technical innovation in terms of cultivation and preparation.21

In the year 2000, Ernst and Pittler16 published a review on the effect of ginger on nausea and vomiting in a variety of settings, including only one paper that specifically investigated its effects on CINV. That review found that ginger was generally beneficial; however, firm conclusions could not be made due to the low number of studies in each setting. Multiple papers have since been published in this area. The aims of the present review were to detail the current published research from randomized controlled trials (RCTs) and crossover trials that evaluated the efficacy of ginger in the prevention of CINV, and to highlight areas for future investigation.

Method

A systematic search of the literature was conducted using PubMed, the Cochrane Library, and CINAHL, as well as bibliographies of past research on the subject (Figure 1). Search terms were not limited by timeframe; instead, all searches were from the date of each database's inception until April 2012. Articles were identified using the search terms “(‘Zingiber officinale’ OR ‘ginger’) AND (‘cancer’ or ‘chemotherapy’) AND (‘nausea’ OR ‘emesis’ OR ‘vomit’ OR ‘CINV’).” Inclusion criteria for this review were as follows: 1) RCT and/or crossover trials that used either placebo or current anti-CINV treatment as a control; 2) trial of human subjects undergoing chemotherapy; 3) ginger used as the main intervention and specific investigation of its effects on nausea and vomiting; and 4) trial results published in English.

Figure 1

Flow diagram of the literature search conducted for the present systematic review.

All studies included in this review were analyzed for common characteristics and methodologies, major findings, and potential limitations. Additionally, all studies were individually rated for evidence level using the National Health and Medical Research Council (NHMRC) Hierarchy of Evidence guidelines (IV-I, with I being the strongest level of evidence) as well as assessed in terms of quality (positive, neutral, negative) using the American Dietetic Association's quality criteria checklist.22,23

The overall body of evidence (based on a summary of the individual studies) evaluated within this review was assessed using a separate tool, the NHMRC's body of clinical evidence assessment matrix, which is an assessment tool that assigns a letter grade (A: strongest to D: weakest) based on the strength of the literature reviewed.22

Results

The search strategy identified seven studies (Table 1) that provided Level II evidence and all had a positive quality rating. Hence, all studies included in this review possessed attributes consistent with rigorous scientific methodology, such as randomized group allocation and clear inclusion and/or exclusion criteria. Of note, two additional studies did not meet the inclusion criteria as they were unpublished, and two further studies (Levine et al.,24 Meyer et al.25) were excluded as they utilized an ineligible study design.

View this table:
Table 1

Characteristics of the studies reviewed

ReferenceStudy designPopulationType of cancerChemotherapy protocolCountryLevel of evidenceQuality
Ryan et al. (2012)28Randomized, double-blind, placebo-controlled, dose-finding trial576 adult cancer patients.

Mean age: 53 years.

93% women
72% breast, 28% alimentary genitourinary, gynecologic, hematologic, lungNot specifiedUSAIIPositive
Panahi et al. (2012)29Randomized, open-label, pilot clinical trial78 women.

Mean age: 51.83 years
Advanced breast cancerPredominately, the TEC regimen (docetaxel, epirubicin, and cyclophosphamide)IranIIPositive
Pillai et al. (2011)30Prospective, double-blind, randomized controlled trial58 children, cancer patients.

Mean age: 15 years.

40 men, 20 women
Bone sarcomaCombination of cisplatin (40 mg/m2/day) and doxorubicin (25 mg/m2/day)IndiaIIPositive
Fahimi et al. (2010)31Randomized, crossover, double-blind, placebo-controlled trial36 adult cancer patients.

Mean age: 50.23 years.

10 women, 26 men
50% lung cancer, 50% unspecifiedCisplatin with at least one of the following agents: etoposide, docetaxel, gemcitabine, docetaxel, vinorelbine cyclophosphamide, paclitaxel, doxorubicin, 5-FU, pemetrexedIranIIPositive
Zick et al. (2009)18Randomized, double-blind, placebo-controlled trial129 adult cancer patients.

Mean age: 55.5–58 years.

Approximately 75% female
UnspecifiedMultiple regimens of varying emetogenicityUSAIIPositive
Manusirivithaya et al. (2004)27Randomized, double-blind crossover trial43 female cancer patients.

Mean age: 43 years
76% ovary, 23% cervixCisplatin with one of the following agents: cyclophosphamide, ifosfamide, etoposide & bleomycin, 5-fluorouracilThailandIIPositive
Sontakke et al. (2003)26Randomized, prospective, crossover, double-blind trial50 cancer patients.

Median age: 46 years.

39 female, 11 male
UnspecifiedCyclophosphamide (500–1,000 mg) with at least one of the following agents: vincristine, methotrexate, 5-fluorouracil, actinomycin DIndiaIIPositive

Study characteristics

All seven studies included in this review were RCTs, and three of them utilized a crossover design. Two of the crossover trials used current anti-CINV treatment as the control group rather than placebo.26,27 Five of the seven studies had relatively small sample sizes (approximately 30–70 participants in total). Zick et al.18 and Ryan et al.28 were the exceptions, with 129 and 576 participants completing each trial, respectively. The length and timeframe of symptom assessment varied among the studies, with assessment of CINV symptoms conducted from 3 days prior to chemotherapy treatment and up to 10 days post treatment. The outcomes measured in the majority of studies (5/7) were acute nausea and vomiting (24 h post chemotherapy) and delayed nausea and vomiting (between 2 and 10 days post chemotherapy); however, Ryan et al.28 did not measure vomiting symptoms and Sontakke et al.26 measured acute nausea and emetic events only.

Typical dosing regimens were 1–2 g of ginger, divided into 4–8 capsules and consumed over a period of 1–10 days. The majority of studies used encapsulated, powdered ginger preparations, while two studies used extracts that were standardized to either their gingerol content or to a combination of active compounds (shogoals, gingerols, and zingerone). Zick et al.18 independently verified the preparations using high-performance liquid chromatography to ensure the potency of the intervention and found their extract contained “5.38 mg (2.15%) 6-gingerol, 1.80 mg (0.72%) 8-gingerol, 4.19 mg (1.78%) 10-gingerol, and 0.92 mg (0.37%) 6-shogaol.” Ryan et al.28 reported that the ginger preparation used in their study contained 8.5 mg of active constituents per capsule; however, it was unclear whether this was determined through independent analysis or based on the manufacturers' analysis. None of the studies that used a powdered formulation reported an analysis of active constituents. The timing of doses did not vary greatly among studies, with the initial dose generally given ±1 h of the first chemotherapy session. Ryan et al.28 was the sole exception, providing ginger supplementation for the 3 days prior to chemotherapy.

Five of the seven studies used standard anti-CINV medication in conjunction with ginger. In the two studies that did not use ginger as an adjuvant to standard therapy, ginger was compared to ondansetron and metoclopramide as a stand-alone treatment in a crossover trial26 or combined with standard anti-CINV treatment in the acute phase, but compared as a stand-alone treatment in the delayed phase of the study.27 Participants in four of the seven studies were adults of mixed gender, with the exceptions of Panahi et al.29 and Manusirivithaya et al.,27 who studied females, and Pillai et al.,30 who studied children.

Study results

The results of the studies included in the review were mixed. Two of the seven studies reported no benefit,18,31 three determined some benefit on measures of CINV (measures of either acute nausea28,29 or both acute and delayed nausea and vomiting30), and two reported that ginger performed equally as well as metoclopramide (Table 2).26,27 Zick et al.18 found that higher doses (2 g) of ginger had a negative effect on delayed CINV in participants prescribed aprepitant (P = 0.01).16

View this table:
Table 2

Protocols and results of the studies reviewed

ReferenceGinger regimenDuration of interventionEndpoint measuredResults and adherenceComments
Ryan et al. (2012)28Placebo, 0.5 g ginger, 1 g ginger, or 1.5 g ginger (6 capsules, combination of ginger and placebo)Received regimen for 2 × 6-day periods. Measured for 3 × 4-day periodsPrimary: acute nausea.

Secondary: delayed nausea, anticipatory nausea, and quality of life
All doses reduced acute, but not delayed, nausea (P = 0.003) using an assessment tool developed by Burish et al.330.5 and 1 g doses were most effective in reducing acute CINV. Largest study to date
77.4% of participants completed the trial (n = 576/744); 83–93% adherence rate, depending on treatment arm
Panahi et al. (2012)291.5 g (3 × 500 mg)4 days post chemotherapyPrevalence, score, and severity of nausea, vomiting, and retchingReduction in nausea 6–24 h post chemotherapy (P = 0.04) using a simplified version of the Rhodes Index of Nausea, Vomiting, and Retching. All other measures were non-significantNonblinded.

Sample group relatively homogenous compared to other studies in this review
78% of participants completed the trial (n = 78/100); 18 participants were either withdrawn due to lack of adherence or were lost to follow-up
Pillai et al. (2011)301 g ginger (6 × 167 mg) or 2 g (5 × 400 mg) determined by participant's weight, or placeboReceived regimen for 3 days post chemotherapy; symptoms measured for 10 days post chemotherapyIncidence and severity of acute and delayed nausea and emetic eventsReduction in moderate and severe acute nausea and emesis (P = 0.003, P = 0.002, respectively) and reduction in moderate and severe delayed nausea and emesis (P < 0.001, P = 0.022, respectively), using Edmonton's Symptom Assessment Scale and National Cancer Institute guidelinesExperimental group contained a larger proportion of males, almost reaching statistical significance.

Gender may influence susceptibility to nausea and vomiting
95% of participants completed the trial (n = 57/60); 2 participants were withdrawn due to non-adherence with data collection protocol
Fahimi et al. (2010)311 g (4 × 250 mg) or placebo then crossed over2 × 3-day periods with a 3-week washout period in betweenPrevalence, severity, and duration of acute and delayed nausea and emetic eventsNo benefit in any measure of acute or delayed CINV, using MANE assessment tool.

Prevalence: day 1 (P = 0.14), day 2 (P = 0.31), day 3 (P = 0.73).
72% of participants completed the trial (n = 36/50); 13 participants were withdrawn due to non-adherence
Zick et al. (2009)181 g (4 × 250 mg, 4× placebo) or 2 g (8 × 250 mg) per day or placebo3 days post chemotherapyPrimary: severity and prevalence of delayed nausea and emetic events.

Secondary: severity and prevalence of acute nausea and emetic events as well as determining safety and blinding of study
No benefit in any measure of acute or delayed CINV, using MANE assessment tool.

Prevalence: acute: P = 0.86; delayed: 0.16.

Severity in non-appretiant group: acute: P = 0.47; delayed: P = 0.69
Delayed nausea was more severe in participants receiving 2 g ginger with aprepitant.

Blinding assessment found that participants were more likely to correctly determine the treatment group to which they were assigned
80% of participants completed the trial (n = 129/162).

79% of participants reported consuming 80% of all study medication
Manusirivithaya et al. (2004)271 g ginger (4 × 250 mg) or placebo then crossed over.2 × 5-day periods with 3–4-week washout period in-betweenAcute and delayed nausea and emetic eventsNo benefit in acute nausea. Reduction in delayed CINV equal to standard treatmentThe assessment tool used in this study was not reported
90% of participants completed the trial (n = 43/48). No data on adherence rate specifiedIn delayed phase, ginger was compared as a stand-alone treatment to metoclopramide, not placebo
Sontakke et al. (2003)262 g (4 × 500 mg) ginger, crossed over with two control groups3 × 24-h periods with 21 days between sessionsControl of acute nausea and emesisComplete control of vomiting was achieved in 68% of patients with ginger, 64% with metoclopramide, and 86% with ondansetronCompared ginger to standard emetics as a standalone therapy
Complete control of nausea was achieved in 62% of patients with ginger, 58% with metoclopramide, and 86% with ondansetron. No data on withdrawals or adherence was specifiedThe assessment tool used in this study was not reported
  • Abbreviations: CINV, chemotherapy-induced nausea and vomiting; MANE, Morrow Assessment of Nausea and Emesis.

Sontakke et al.26 found 2 g of ginger to be effective in reducing acute CINV and equal to metoclopramide. Pillai et al.30 determined that 1–2 g of ginger was effective in reducing the severity of both acute and delayed CINV by 37–47%. Ryan et al.28 reported that all doses used in their intervention successfully reduced symptoms of acute nausea by 0.16–0.44 on a 1–7 Likert scale in patients experiencing mild baseline-CINV (P = 0.003), with 0.5 g and 1 g (P = 0.017 and P = 0.036, respectively) being the most effective doses; however, delayed nausea and quality of life were not affected by ginger supplementation. A 16% reduction in acute nausea during the first 6–24 h post chemotherapy was also found by Panahi et al.29 using 1.5 g of ginger (P = 0.04).

Manusirivithaya et al.27 reported that during the acute phase of chemotherapy, 1 g of ginger did not further reduce CINV when combined with metoclopramide, dexamethsone, and lorazepam. It did, however, perform equally to metoclopramide during the delayed phase (2–5 days post chemotherapy). Zick et al.18 and Fahimi et al.31 found no additional benefit when ginger was used as an adjuvant therapy to standard nausea and emetic control.

A variety of tools were used to assess nausea and vomiting in the studies reviewed. Two studies measured symptoms using a modified version of the Morrow Assessment of Nausea and Emesis (MANE),18,31 a validated instrument for assessing nausea in cancer patients32; Pillai et al.30 employed the Edmonton Symptom Assessment Scale and the National Cancer Institute Guidelines for Nausea and Vomiting, respectively; two studies used an unspecified tool26,27; Panahi et al.29 employed the Rhodes Index of Nausea, Vomiting, and Retching; and Ryan et al.28 utilized an unnamed tool used in previous studies.33

Five of the seven studies specifically included patients receiving highly emetogenic chemotherapy regimens; however, while all of the regimens were highly emetogenic, there was little consistency in the agent and protocol used. The remaining two studies included patients undergoing combination chemotherapy containing agents with different degrees of emetogenicity.18,28

Adverse events and adherence

Despite previous research indicating that ginger supplementation could theoretically cause excessive bleeding in susceptible patients, due to the inhibition of platelet aggregation,34 all adverse events that were attributed to the intervention were nonserious in nature. The most common reactions reported included heartburn, bruising or flushing, rash, and gastrointestinal discomfort. Adverse events were generally not significantly higher in the ginger group compared to the control group in any study.

Most studies (5/7) reported some degree of non-adherence during their investigations. Studies that included information regarding adherence reported rates between 75 and 90%.18,28,29,31 The exact method for determining adherence was not stated for five of the seven studies; however, Ryan et al.28 reported that adherence was measured by counting the amount of remaining pills at the end of each study cycle while Panahi et al.29 measured self-reported adherence.

Discussion

The currently available evidence is mixed in its support of ginger as an adjuvant or stand-alone treatment for CINV. Of the seven RCTs published to date, five reported favorable results while the results of two studies were unfavorable. Of the five favorable studies, three reported ginger as improving some measure of CINV when combined with standard anti-CINV treatment, with Ryan et al.28 and Panahi et al.29 reporting a reduction in acute nausea and Pillai et al.30 reporting a reduction in acute and delayed nausea and vomiting. The two other favorable studies found that ginger reduced some measure of CINV equal to metoclopramide, but due to the lack of a placebo group in both studies, it is difficult to determine the clinical significance of these results.26,27 This is due to the fact that, in both of these trials, the percentage of individuals in the ginger group who reported symptoms was still within the predicted emetic risk for the chemotherapy regimen used; therefore, without a placebo group, it is difficult to determine the intervention's true impact. Additionally, metoclopramide is no longer routinely used as a stand-alone antiemetic treatment, which reduces the clinical significance of these findings. Results from positive trials have found ginger to reduce measures of CINV by 16–47% and, while these findings need to be reconciled with the negative findings from other studies in this review, this magnitude of reduction could provide meaningful relief to patients experiencing CINV.

Using the NHMRC body of evidence assessment matrix, the present review indicates there is C-level evidence for the use of ginger as an antinausea agent in the chemotherapy setting. Therefore, while there is some supporting evidence for its use, the considerable inconsistency in study methods and outcomes reported here reflect genuine uncertainty about its use in this context. Until this uncertainty is resolved, professional opinion will continue to guide the healthcare team when choosing ginger as a treatment option.

Confounding factors within current literature

There are multiple factors that explain the mixed results reported in the literature. One possible explanation is that some ginger preparations have higher levels of certain active compounds when compared to the preparations used in other studies. Research investigating the concentration of active compounds in commercial ginger products indicates that the levels of these compounds can vary greatly among products, demonstrating a need to analyze ginger interventions for their active compounds and to utilize standardized extracts rather than powdered formulations.35,36 In order to improve the significance of future trials in this area, dose-finding studies using varied standardized extracts are required to determine the effective dose and preparation of ginger.

Recent studies have also determined that once a patient undergoing chemotherapy develops any form of nausea or vomiting (i.e., anticipatory, acute, delayed), regardless of the emetogenicity of that treatment, the likelihood of that patient experiencing nausea for the remainder of their treatment regimen is significantly higher and more difficult to treat with standard anti-CINV medication.37 This is due to the complex etiology of CINV, a response that is initiated by varying stimuli within the central and peripheral nervous systems. These include the effects of chemotherapy on both the central nervous system and gastrointestinal tract as well as the effect of sensory input (e.g., smell, sight) and the psychological conditions of the individual (e.g., fear, anxiety).38 These stimuli activate peripheral and central nerve signals, which are then received by the chemoreceptor trigger zone, an area within the brain that coordinates the body's emetic response base. Anticipatory nausea and vomiting is thought to be a conditioned response to previous chemotherapy exposure. Anticipatory CINV is mediated by the central nervous system and is caused by the coupling of neutral stimuli (such as the smell or sight of the hospital environment) with the undesirable effects of chemotherapy, which then results in the initially neutral stimuli eliciting a similar response to the cytotoxic treatment.39 Since many studies in this review included patients who had previously experienced CINV, the participants within these studies might have had an increased resistance to the intervention due to conditioning. This is of particular concern in the studies that used a crossover design, as patients who were initially in the control group could have established resistance to the intervention before being subsequently crossed over. Conducting a statistical analysis to ensure that the sequence of intervention does not influence the results, as undertaken by Manusirivithaya et al.27 and Zick et al.,18 will help monitor this effect. Alternatively, Roscoe et al.28,40 were able to determine that a self-assessed susceptibility to nausea and vomiting by chemotherapy patients was a predictor of CINV and might be a viable method of screening in future trials.

Research has found that female patients are significantly more likely to experience CINV than their male counterparts.41 The majority of studies (5 of 7) included a sample that was predominantly female, and four of those studies reported benefits from ginger treatment. This suggests that gender may have influenced the patients' response to the ginger treatment, possibly by decreasing the threshold at which CINV is experienced and thereby increasing the efficacy of anti-CINV treatments. In light of this, the null results reported by Fahimi et al.31 may be partially explained by the male-dominant sample. In that study, the severity of nausea in both the intervention and control groups was rated as low at all timepoints, indicating that the patients within the study may not have been experiencing CINV at a sufficiently high level of severity to have responded to anti-CINV intervention. This may also explain the results found by Pillai et al.30 When the gender distributions between the control and treatment groups were compared, there was a greater proportion of men within the experimental group compared to the control group, which almost reached statistical significance (P = 0.055). This may have also resulted in the experimental group being more resistant to CINV compared to the control group regardless of ginger treatment. Therefore, similarly to anticipatory nausea, future trials should either include screening protocols or conduct statistical analyses to account for gender variations within the study sample.

Additionally, because of the subjective nature of nausea, direct comparison of findings can be difficult and investigators should, therefore, aim to use validated tools such as the MANE, which would ensure that results are both validated and easily comparable to other studies. It should be noted that the two studies that failed to find any benefit from ginger supplementation both used the MANE as the assessment tool, which suggests that the use of different assessment tools used within each study might have been a factor contributing to the mixed results of the reviewed literature.18,31

Another concern is that due to the distinctive aroma of ginger, it is important to ensure that studies are properly blinded. For example, Zick et al.18 tested the effectiveness of the blinding in their investigation. While they had taken steps to ensure adequate blinding, the participants were able to discern the intervention group from the placebo at a statistically significant rate (P = 0.01). To overcome this problem, Ryan et al.28 utilized a combination of double encapsulation with a nitrogen cap to mask the odor and color of the ginger. While this is an example of a potentially effective blinding technique, they did not test its effectiveness. Interestingly, the study of Ryan et al.28 was one of the two that reported positive results when ginger was used as an adjuvant therapy; effective blinding may, at least in part, help explain the disparity of results among studies within this review. Future clinical trials should incorporate more stringent blinding procedures to avoid a potential placebo or nocebo effect from occurring.

Possible drug interactions at high doses

An interesting result reported from two studies in this review is that when subjects were given higher doses (1.5–2 g) of ginger, there was a statistically significant decline in CINV control when compared to the participants that either received lower doses or the placebo. Zick et al.18 reported that when subjects received a combination of 2 g ginger plus aprepitant (an NK1 inhibitor), the severity of delayed nausea increased when compared to control (P = 0.01). Similarly, Ryan et al.28 concluded that, while all doses of ginger were effective in reducing acute CINV, 1.5 g of ginger was less effective when compared to the 0.5 g and 1 g of ginger preparations. These findings corroborate those from previous studies in this field, which reported that higher doses of ginger were less effective when treating nausea from causes other than chemotherapy.42,43 This led Zick et al.18 to hypothesize that ginger reduces absorption of medication by increasing gastric emptying and intestinal motility, which has been demonstrated in animal models. However, the effect of ginger on gastric emptying in humans is unclear.44,45 Another hypothesis is that ginger competitively interacts with the same receptors that standard anti-CINV medication acts upon, thereby reducing the binding rate of medications when used in combination.28 Animal studies support this hypothesis, indicating that gingerols and shoagoals are able to bind to both 5-HT3 and substance P receptors, which are the receptors with which medications such as aprepitant and ondansetron interact.46,47 It should also be noted that these studies showed that different ginger compounds bound to these receptors with varying strengths and, therefore, different preparations of ginger could exert differing effects on nausea. This highlights further limitations to current understanding in this area, as there are multiple active compounds in ginger that appear to be responsible for these interactions. This poses a significant limitation to the current research as the majority of studies, excluding Zick et al.18 and Ryan et al.,28 used ginger preparations with unknown levels of these active constituents.

Clinical implications

The feasibility of ginger supplementation has not been extensively or rigorously studied in chemotherapy populations. Fatigue, mouth sores, and taste sensitivities are all common symptoms that chemotherapy patients experience while undergoing treatment. Given that some studies included in this review used up to eight capsules, consumed at multiple times throughout the day, this could place a significant burden on a population group that might already have a reduced functional capacity and quality of life. Future research is required to investigate areas of practice, such as participant tolerability and adherence to the intervention, in addition to its effect on quality of life and patient satisfaction with the intervention, in order to determine its real-world efficacy.

Review limitations

The exclusion of unpublished literature may have affected this review by introducing a publication bias; however, since the two unpublished studies that were identified and excluded from this review both reported positive results, this seems unlikely.24,25

Conclusion

Despite the widespread use of ginger in the treatment of nausea in other contexts, such as gestational nausea, the current literature provides mixed support for the use of ginger as a standard part of anti-CINV control for patients undergoing chemotherapy. Hence, standard recommendations for such use are premature. This review discussed some of the limitations of current understanding of this topic and highlights the need for further investigation. In particular, issues regarding rigorous blinding procedures, patient screening, the timing of intervention to encompass the range of CINV, and ginger preparation should be considered in future research. The present analysis of the evidence using NHMRC grading indicates that ginger may be useful for some patients undergoing chemotherapy but that care needs to be taken in its application until further studies are conducted.

Acknowledgments

Funding

This work was supported by a University of Queensland Summer Scholarship.

Declaration of interest

The authors have no relevant interests to declare.

References

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