Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Mixed

Effect and Mechanism of Action

Anesthesia-induced PONV may be reduced by pretreatment with ginger extracts, which probably act at both central serotonergic and peripheral gastric levels to inhibit emesis.

Research

Six trials performed over 15 years specifically examined the effects of ginger pretreatment on the severity and incidence of PONV. ^31-36 All trials involved gynecological settings, and the majority (five of six) involved laparoscopic outpatient procedures, with a total of 668 subjects across all the studies. Powdered ginger in capsules was used in all cases, with oral doses ranging from 0.5 to 2.0 g of herb, administered 1 to 3 hours before the procedure, although one trial also administered ginger both before and after the procedure.

In a meta-analysis of only three of the trials, Ernst and Pittler ³⁷ concluded that the evidence for ginger efficacy in PONV was positive. However, a more recent meta-analysis by Morin et al. ³⁸ that included all six trials available to date concluded that the antiemetic effects of ginger were insufficient to consider the incorporation of the herb into the PONV clinical setting.

Visalyputra et al. ³⁵ examined 111 women undergoing laparoscopic gynecological diagnostic procedures, divided into placebo, ginger-only, droperidol, and droperidol/ginger groups. The dose of ginger was divided into 1.0 g before the procedure and another 1.0 g 30 minutes before discharge. No significant differences were found between placebo and the other groups. ³⁵ The only notably positive study was by Phillips et al., ³⁶ who used 1 g ginger 1 hour before anesthesia. The ginger appeared to be equally effective to metoclopramide (10 mg) in reducing nausea, both being significantly better than placebo. ³⁶

A recent meta-analysis of these trials concluded that there was definite evidence for a positive effect of ginger at 1.0 g per day for PONV. ³⁹

Integrative Therapeutics, Clinical Concerns, and Adaptations

Although the trial evidence is not conclusive, there would appear to be reasonable grounds for patients undergoing elective procedures who may prefer nonpharmaceutical options, when available, to utilize ginger pretreatment before procedures involving anesthesia. Data are not available for emetic rescue, and conventional use of metoclopramide or dexamethasone may be required after exposure to emetogenic anesthetics. The risks of bleeding to anticoagulant effects of the herb are discussed in the following sections on antiplatelet agents and phenprocoumon. Theoretical cautions against combining ginger with anesthetics have also been made on the basis of a single rodent study in which administration of isolated [6]-gingerol and [6]-shogoal at doses of 3.5 mg/kg induced increases in hexobarbital sleep time in rats. ⁴⁰ Equivalent human doses of ginger powder or fresh ginger would be orders of magnitude higher than normal therapeutic dose levels of the herb.

Potential or Theoretical Adverse Interaction of Uncertain Severity

Mixed

Effect and Mechanism of Action

A theoretical interaction extrapolated from the “NSAID-like” activity of ginger and its active compounds through inhibition of thromboxane-evoked platelet aggregation, creating an assumed additive disabling of platelets. The interaction has not been clinically demonstrated to date.

Research

Equivocal results have been obtained in experimental and in vitro studies attempting to characterize effects of ginger extracts and isolated ginger compounds on platelet aggregation, although there is evidence for a dual inhibitory effect on eicosanoid synthesis, with lipoxygenase as well as cyclooxygenase subject to inhibition. ^14,15,41-43 COX-2 effects may be mediated by the effect of [6]-gingerol on nuclear factor kappa B (NF-κB) activation. Kim et al. ⁴⁴ used a mouse skin model and found evidence of the ginger compound blocking phosphorylation of I-κBα as well as p65. This was reversed by a p38 mitogen-activating protein (MAP) kinase inhibitor, implicating the p38 MAP kinase signaling pathway of NF-κB as the upstream mediator of COX-2 downregulation. ⁴⁴

Four human studies have investigated the effects of ginger on platelet aggregation. Verma et al. ⁴⁵ examined the effects of a fatty diet (100 g butter for 7 days) on platelet aggregation in 20 healthy volunteers. Ten individuals also consumed 5 g dried ginger with the fatty meal. Adenosine diphosphate (ADP) and epinephrine-induced platelet aggregation was significantly lower in the butter-plus-ginger group than in the butter-only group. Lumb ¹² conducted a small, double-blind randomized trial with eight healthy volunteers who consumed 2 g ginger or placebo. No effect was found on any parameters of platelet activity (samples taken 3 and 24 hours after ginger administration), including bleed time, aggregometry, and platelet count. Srivastava ¹⁰ measured platelet thromboxane in human volunteers before and after 7 days consumption of 5 g/day fresh garlic or 70 g/day raw onion. Thromboxane B ² (TXB ² ) levels (measured after sample clotted by incubation for 1 hour) were reduced by approximately one third in the ginger group ( n= 7). The small sample size was statistically underpowered ( p<0.1). The onion-consuming group exhibited a trend to increased TXB ² after clotting.

Another study investigated the effects of ginger on TXB ² with higher doses of ginger administered by vanilla custard, with 15 g raw ginger daily or 40 g cooked stem ginger for 2 weeks, in 18 healthy volunteers of both genders. There was no washout period in the crossover design, and when venous blood samples were taken on both day 12 and day 14, no significant change in TXB ² levels was detected between either form of ginger and placebo. In contrast, an earlier pilot study by the same researchers had detected significant (39%) TXB ² reduction after only 3 mg/day administration of acetylsalicylic acid (ASA). ¹³ Bordia et al. ¹¹ used a placebo-controlled trial to examine the effects of powdered ginger administered at 4 g daily for 3 months in 60 patients with a history of coronary artery disease. Blood lipids and glucose, plasma fibrinogen, and fibrinolytic activity, as well as ADP and epinephrine-induced platelet aggregation, were measured at 1½ and 3 months. No significant differences were found between the placebo and ginger groups in any of the parameters measured. However, a single 10-g dose of ginger did produce significant reduction in platelet aggregation evoked by the two test agonists measured 4 hours after ginger administration.

Jiang et al. ⁴⁶ conducted a small, open-label trial (12 healthy male volunteers) and examined a range of pharmacokinetic and hemostasis parameters after administration of ginger or ginkgo, alone or with warfarin. Aggregation, INR, warfarin enantiomer concentrations in plasma and urine, and warfarin enantiomer binding were all measured at day 1 and day 7. The dose of ginger was three tablets of 0.4 g powdered rhizome three times for 1 week. Neither ginger nor ginkgo produced significant effect on clotting status or the pharmacokinetics and pharmacodynamics of warfarin.

Clinical Implications and Adaptations

The quality of the evidence is variable, partly because of small sample sizes, different forms of ginger tested (or different purified compounds), and differing doses used. However, the balance of available data suggests that the effects of ginger compounds on cyclooxygenase and lipoxygenase inhibition do not appear to have detectable clinical effects on primary hemostasis. By extension, it appears that ginger can be safely utilized at therapeutic doses along with antiplatelet and anticoagulant medications. Theoretically, for certain individuals with unique pharmacogenomic susceptibility or subclinical platelet disorders, ginger preparations might interact adversely with either antiplatelet or anticoagulant agents.

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Nausea and vomiting are predictable adverse effects of certain chemotherapies, typically cisplatin and nitrogen mustards, and often occur with various other agents. The established antiemetic activity of ginger may be effective against acute (<24 hours) chemotherapy-induced nausea and vomiting, possibly through serotonergic mechanisms.

Research

Morrow ⁴⁷ surveyed 442 oncology outpatients receiving consecutive chemotherapy and found that 16% who reported susceptibility to motion sickness were more likely to experience nausea and vomiting after chemotherapy than matched controls. Ginger has been investigated in numerous trials for the treatment of various kinds of nausea, including motion sickness, postoperative nausea, and morning sickness. The majority of studies have been positive, and a meta-analysis of six randomized double-blind placebo-controlled trials concluded that ginger was a “promising antiemetic remedy” in 2000, although more data are required to draw firm conclusions. ³⁷ Sharma et al. ^48,49 investigated preadministration of acetone and alcoholic extracts of ginger in rodent and canine models of cisplatin-induced emesis. Cisplatin inhibits gastric emptying, and the endpoint used is the delay in gastric emptying associated with the antiemetic agent. Acetone ginger extracts (200 and 500 mg/kg orally) were more significantly effective than the 5-hydroxytryptamine (5-HT ³ ) receptor antagonist ondansetron in delaying gastric emptying in rodents. In canines, researchers using a similar procedure, but with the ginger extracts (25-200 mg/kg) given 30 minutes after cisplatin, also caused a dose-dependent reduction in emesis and increase in emetic latency compared with controls. Aqueous extracts were ineffective. The acetone extract of ginger was more effective than the alcoholic extract, preventing emesis in 20% of dogs, compared to none for the alcoholic extract. Yamahara et al. ⁵⁰ found that oral administration of [6]-gingerol (25 or 50 mg/kg orally) or an acetone extract of ginger (150 mg/kg orally) pretreatment could completely prevent cyclophosphamide-induced emesis in a rodent model.

The antiemetic mechanisms of ginger compounds were investigated by Abdel-Aziz et al. ⁵¹ using three different molecular models. They concluded that although an effect on 5-HT ³ receptor ion-channel complex was definitely implicated, there were also indirect effects, possibly through substance P and muscarinic receptors. ⁵¹ Finally, in a wider context but still within the oncology setting, a rodent model was used to demonstrate that ginger may also be effective in radiation-induced taste aversion. ⁵²

Integrative Therapeutics, Clinical Concerns, and Adaptations

Three temporal phases of chemotherapy-induced nausea are distinguished: anticipatory(occurring before exposure), acute(onset within or lasting up to 24 hours of exposure), and delayed(onset more than 24 hours after exposure, typically 48 to 72 hours, with variable duration). The anticipatory type is independent of the specific agent of both the type of cancer and the chemotherapy regimen, essentially a conditioned response. The acute form is most susceptible to treatment with antiemetic agents, whereas delayed symptoms are less susceptible to antiserotonergic agents, suggesting that different mechanisms may be involved. ^53,54 Although human studies are lacking, ginger extracts have been used clinically by practitioners versed in botanical medicine to prevent and treat the acute phases of chemotherapy-induced nausea typified by the emetic effects of cisplatin.

	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Ginger and ginger extracts exert anti-inflammatory effects through multiple mechanisms, including cyclooxygenase and lipoxygenase inhibition. Adjuvant combination of ginger with NSAIDs for arthritis leads to increased symptom relief and allows the NSAID dose to be lowered and in some cases discontinued. Ginger has a superior adverse effect profile to known NSAIDs, and coadministration reduces adverse effects through lower NSAID dose or eventual substitution.

Research

In vitro evidence has established that ginger and some of its constituent compounds are effective inhibitors of cyclooxygenase and lipoxygenase and may downregulate transcription of cyclooxygenase and inducible nitric oxide synthase (iNOS) by inhibition of NF-κB. ^21,42-44 Two randomized placebo-controlled clinical trials have demonstrated small but significant effects for ginger treatment of osteoarthritis, although in the study by Bliddal et al. ¹⁹ the effect was small compared with ibuprofen and was confined to a first period of treatment in a crossover design. The trial by Altman and Marcussen ²⁰ showed a significant effect in 261 patients with osteoarthritis of the knee, although the ginger extract was administered in combination with the herb galangal (Alpinia galangia). Acetaminophen was permitted as a rescue medication in both studies. The ginger group had less use of rescue medication than the placebo group. Additionally, several rodent experimental model studies have shown that ginger extracts are directly protective against NSAID-induced gastric ulcers in a rodent model. ^55-58

Reports

Srivastafa and Mustafa ⁵⁹ reported a case series of seven patients who used ginger extracts combined with NSAIDs, but who were not taking other antiarthritic medications (e.g., gold) or steroids. Six patients were taking NSAIDs for 3 months but failed to experience symptom relief. After 3 months of oral ginger administration (up to 5.0 g fresh rhizome or 1.0 g powdered rhizome daily), while continuing NSAID therapy, the patients all experienced reduction in pain symptoms and improved range of motion, and two patients also experienced relief of myalgia. After 3 months of coadministration the NSAIDs were stopped; the patients continued with ginger alone and were able to maintain the same degree of symptom relief.

Integrative Therapeutics, Clinical Concerns, and Adaptations

The adverse effect profile of NSAIDs, including the COX-2 specific inhibitors, continues to present significant problems to the pharmaceutical anti-inflammatory strategies for arthritis. Ginger extracts may additively combine with NSAIDs and after a period of coadministration can substitute for them in some cases. Health care professionals versed in botanical medicine are more likely to incorporate ginger into polyherbal anti-inflammatory formulae rather than use it as a single agent. Typical associated ingredients might include curcumin, Boswellia serrata,resveratrol, and the salicylate-containing Salixspp.

Potential or Theoretical Adverse Interaction of Uncertain Severity

Mixed

Effect and Mechanism of Action

A theoretical additive effect between coumarin anticoagulants and ginger on hemostasis is hypothesized to increase INR and risk of bleeding. Unsupported by the currently known pharmacology of the herb, a single report of the possible interaction is available. The clinical significance of the proposed interaction is minimal.

Research

There are no human studies investigating pharmacodynamic effects of ginger on the vitamin K–dependent clotting factors II, VII, IX, and X. Weidener and Sigwart ⁶⁰ conducted a series of experimental investigations with EV.EXT 33 ginger extracts on Wistar rats, including a study of the effects of oral warfarin (0.25 mg/kg daily) alone and in combination with the ginger extract. Warfarin significantly increased prothrombin time (PT) and activated partial thromboplastin time (APTT) compared with normal controls. Coadministration of ginger extract at 100 mg/kg for 4 days had no effect on warfarin-induced changes in PT and APTT and did not alter these coagulation parameters in a control group receiving no warfarin. ⁶⁰

In a recent study described earlier under Antiplatelet Agents, Jiang et al. ⁴⁶ found that ginger and ginkgo had no significant effect on clotting status or the pharmacological profile of warfarin.

Pharmacokinetic data demonstrating any effect of the herb on drug-metabolizing enzymes mediating coumarin drug metabolism (cytochromes P450 1A2 and 2C9) are also unavailable. Further studies are required to establish definitively an absence of effect of ginger on coagulation, but the balance of currently available evidence suggests such effects are unlikely.

Reports

A single German case involving ginger and phenprocoumon was reported by Krüth et al. ¹⁷ in 2004. A 76-year-old woman with a history of mitral insufficiency, atrial fibrillation, congestive heart failure, and osteoporosis who was taking concurrent cholecalciferol, captopril, piretanide, digoxin, and a nitrate vasodilator was maintaining a stable INR (range, 2.0 to 3.0) while receiving long-term phenprocoumon therapy. Because of a peripheral bleed incident (epistaxis), she was admitted to hospital, and INR was greater than 10. Phenprocoumon was stopped, and she received three doses of vitamin K ¹ (initially 10 mg intravenously, then 5.0 mg and 3.0 mg orally after 3 and 6 days, respectively). By day 6, the INR and PTT normalized and phenprocoumon was resumed, with INR maintained at normal levels by the same dose used before the bleeding episode. A detailed history revealed “a regular ginger intake (pieces of dried ginger and tea from ginger powder)” for several weeks before the bleeding incident occurred. The patient was advised to refrain from ginger use, and no further episodes of bleeding were noted. The authors note that the current pharmacological data on ginger do not provide any obvious mechanism for the observed effects.

The report, although complete in some respects, lacks vital information. The exact form, amount, dose, frequency, and duration of ginger administration are not given, making the incident impossible to evaluate. Further, “Dried ginger pieces” is an unusual form of ingesting the herb given its pungent and acrid taste, and “ginger tea” does not exclude the presence of nonginger ingredients. The ginger was apparently consumed for several weeks before the INR elevation. Case data show a rapid elevation of INR between two measurements 7 days apart. Relating this to an unstated dose of ginger consumed several weeks earlier does not constitute a reasonable association by timing for the INR effect to be causally associated with the herb consumption. The INR plots show values maintained within therapeutic range for more than a week before the bleed episode, presumably during the “several weeks” consumption of ginger. The observed INR increase might be explained by excessive phenprocoumon levels caused by inadvertent drug misadministration, a dietary pharmacokinetic interaction, or sudden decrease in dietary intake of vitamin K–containing foods, none of which was considered by the authors. ¹⁷

Clinical Implications and Adaptations

The single available case report is insufficient to confirm the existence of a ginger–oral anticoagulant interaction, especially with the lack of a plausible pharmacological mechanism and inadequacies in the report data. In addition, some controlled trial evidence suggests that ginger has no measurable effect on warfarin pharmacokinetics or pharmacodynamics. Until further data are available, it cannot be assumed that moderate ginger consumption exerts clinically significant effects on the coagulation cascade and INR values. As normally occurs with coumarin-effected anticoagulation, monitoring of INR and alerting patients to report early signs of bleeding (e.g., epistaxis, ecchymoses) remain essential elements of vitamin K antagonist therapy. Possible antiplatelet activity cannot be ruled out completely at this time (see Antiplatelet Agents), but epistaxis or other serious bleeding episode would be expected with an INR higher than 10.

The use of cured ginger in Chinese medicine to arrest bleeding in certain conditions has already been mentioned. Anecdotal clinical experience also suggests that at normal therapeutic dose ranges for appropriate indications, ginger and ginger extracts present no significant risk of bleeding in patients on oral vitamin K antagonist anticoagulation.

Amikacin (Amikin), gentamicin (G-mycin, Garamycin, Jenamicin), kanamycin (Kantrex), neomycin (Mycifradin, Myciguent, Neo-Fradin, NeoTab, Nivemycin), netilmicin (Netromycin), paromomycin (monomycin; Humatin), streptomycin, tobramycin (AKTob, Nebcin, TOBI, TOBI Solution, TobraDex, Tobrex).

A preliminary in vitro study by Nagoshi et al. ⁶¹ found a potential synergy between aminoglycoside antibiotics and [10]-gingerol against vancomycin-resistant enterococci. The authors suggested that this may be caused by detergent-like effect of the gingerol increasing membrane permeability. Whether this preliminary finding can be replicated in vivo remains to be established.

Sulfaguanidine

Using an experimental rat intestine model, Sakai et al. ²³ demonstrated that ginger extracts enhanced the absorption of sulfaguanidine by 150% compared with controls. This has been identified as the sole possible ginger-drug interaction by two authoritative secondary reviews. ^2,62 Whether or not this is an example of general effects of ginger on intestinal absorption in rodents (see pharmacokinetics discussion earlier), the likelihood of this being a clinically significant interaction, given the limited contemporary use of this agent for enteric infections and the lack of human data, suggests that the interaction is overstated, particularly when identified as the only interaction of ginger with any pharmaceutical agent.