Pharmacological Toxicological Effects 51 Gastrointestinal Effects

A study was conducted to evaluate the effect of ginger on the nystagmus response to vestibular or optokinetic stimuli, as measured by electro-nystagmographic (ENG) techniques (9). Study subjects were screened prior to study enrollment and were excluded if they responded abnormally to vestibular or optokinetic tests. A total of 38 subjects, 20 women and 18 men between the ages of 22 and 34, were given 1 g of ginger (Zintonaā„¢), 100 mg dimenhydrinate, or placebo in a double-blind, crossover fashion 90 minutes prior to each test. Ginger had no effect on the ENG, in contrast to dimen-hydrinate, which decreased nystagmus response to caloric, rotary, and optokinetic stimulations. Therefore, the authors considered a central nervous system (CNS) effect had been ruled out as ginger's antiemetic mechanism of action, and a direct gastrointestinal effect was proposed.

The antimotion sickness effect of ginger was also compared to that of dimenhydrinate (DramamineĀ®) in 18 male and 18 female college students who were self-rated as having extreme or very high susceptibility to motion sickness (10). The subjects were given either two ginger capsules (940 mg), one dimenhydrinate capsule (100 mg), or two placebo capsules (powdered chickweed herb [Stellaria media]). Subjects were led blindfolded to a previously concealed rotating chair 20 to 25 minutes after consuming the capsule(s). None of the dimenhydrinate or placebo subjects were able to remain in the chair a full 6 minutes, and three patients in the placebo group vomited. One-half of the ginger subjects stayed the full 6 minutes. It was concluded that 940 mg of ginger was superior to 100 mg of dimenhydrinate in preventing motion sickness. It is important to note that none of the subjects in the dimenhydri-

nate group specifically asked to have the test terminated; the test was stopped by the investigator because of the magnitude of the subjects' self-reported "intensity of stomach feeling." Although the study subjects were blinded not only to the treatments used, but also to the purpose of the study, it is unclear if the investigator was also blinded.

Anesthesiologists appreciate the fact that individuals who experience motion sickness are also at risk of having postoperative nausea and vomiting that may persist for days after surgery. Application of a scopolamine transdermal patch behind the ear for 3 days beyond surgery may serve as a useful adjunct to antiemetic therapy and eradicate this problem (11).

The efficacy of Ginger as a single agent was compared to various drugs alone or in combination to prevent motion sickness in a double-blind, placebo-controlled study (12). Three doses of ginger were investigated and, in the opinion of the authors, neither dose of ginger alone was more effective than placebo. Dimenhydrinate, promethazine, scopolamine, and d-amphet-amine were effective as single agents. The efficacy of the first three was enhanced by addition of d-amphetamine to the regimen. Most effective in preventing motion sickness with limited side effects in this study was a combination of scopolamine 0.6 mg and 10 mg d-amphetamine.

The efficacy of ginger as an antiemetic has been studied (13) and compared to metoclopramide after major gynecologic surgery in a double-blind, placebo-controlled, randomized study. Premedication with either powdered ginger or a placebo capsule and 10 mg intravenous metoclopramide or placebo was given 60 to 90 minutes prior to the operation. Surgical time lasted between 50 and 60 minutes and the anesthesia time exceeded 1 hour in all cases. Postoperative pain was managed with papaverine or acetaminophen, and postoperative nausea or vomiting was managed with metoclopramide. The incidence of postoperative nausea or vomiting was similar (28 and 30%) in the groups that had received ginger or metoclopramide and considerably greater in those who had received the placebo (51%).

Another placebo-controlled study tested the effectiveness of ginger in preventing postoperative nausea and vomiting (14). This randomized, doubleblind study included 108 subjects slated for elective gynecologic laparoscopy, a procedure generally shorter than that of the previous study. The number of subjects provided 80% power to detect a reduction in the incidence of nausea from 30 to 20%. All patients received 10 mg of diazepam orally and were randomized to receive two 500-mg ginger capsules, one 500-mg ginger capsule and one placebo capsule, or two placebo capsules 1 hour prior to surgery. Nausea, when present, was rated on a scale of 1 to 3 (mild, moderate, severe).

Although there was a trend favoring ginger, the difference was not statistically significant (p = 0.36). The investigators concluded that neither dose of ginger was effective in preventing postoperative nausea and vomiting. Blinding may have been problematic in this study because of the characteristic taste and smell of ginger, which was noted by one of the patients. Adverse effects were reported by five of the ginger patients and consisted of flatulence and a bloated feeling, heartburn (two patients), nausea, and burping. One patient in the placebo group complained of "feeling windy and having the urge to burp."

A third placebo-controlled study tested the efficacy of ginger in prevention of postoperative nausea and vomiting (15). This randomized, doubleblind study consisted of 120 subjects slated for elective gynecologic diagnostic-laparoscopy. The subjects were given either 1 g of ginger, 100 mg of metoclopramide, or a placebo (1 g of lactose) 1 hour prior to surgery. The incidence of nausea and vomiting with metoclopramide was 27%, 21% with ginger, and 41% with placebo. Ginger was similar in effectiveness to metoclopramide in preventing postoperative nausea and vomiting (p = 0.34) and significantly more effective than lactose (p = 0.006), the placebo.

Data from the previous three randomized controlled trials on postoperative nausea were appropriate for meta-analysis. The pooled absolute risk reduction for the incidence of postoperative nausea proved the difference between the groups treated with ginger and placebo to lack significance. These values indicate a point of the number-needed-to-treat of 19 and a 95% confidence interval that also includes the possibility of no benefit (16).

More recently, Visalyaputra and associates examined the efficacy of a 2-g dose of ginger root, compared to placebo and intravenous droperidol, and a combination of both oral ginger and intravenous droperidol to reduce postoperative nausea and vomiting. The authors concluded that neither ginger root capsules nor administration of a combination of intravenous droperidol and oral ginger lowered the incidence of postoperative nausea and vomiting in women having gynecologic diagnostic laparoscopy (17).

A randomized, double-blind crossover study was conducted to determine the efficacy of ginger in treating hyperemesis gravidarum (18). A total of 30 pregnant women at less than 20 weeks gestation previously admitted to the hospital for hyperemesis gravidarum participated in the study. The treatment included a 250-mg ginger capsule or a placebo (lactose) capsule three times a day for the first 4 days. After a 2-day washout period, the subjects received the alternate treatment for 4 days. Ginger was significantly more efficacious in reducing symptoms of hyperemesis gravidarum than placebo (p = 0.035).

Lastly, Vutyavanich and colleagues (19), conducted a randomized, double-blind, placebo-controlled trial to study 70 women with a lesser degree of nausea and vomiting who did not require hospital admission for hypereme-sis gravidarum. All had registered prior to 17 weeks gestation and met the author's criteria for exclusion of other medical causes of nausea and vomiting. Subjects received capsules containing 250 mg powdered ginger 4 times daily or an identical-appearing placebo capsule. Prior to the day of entry, each subject graded the degree of nausea and vomiting she experienced on a scale of 0 to 10. Subjects were dispensed 18 capsules of powdered ginger or placebo, advised to record the number of vomiting episodes twice daily (at noon and bedtime), and to return the 5-item Likert scale with packaging and unused capsules (if any) in a week. After a 2-day washout period, they started the second 4-day course of study drug. Outcomes: of the 32 women in the ginger group, all had one or more episodes of vomiting in the 24 hours before treatment. Only two of the placebo group had no vomiting during this time frame. Of those who received powdered ginger, vomiting was significantly less than in the placebo group. By calculating the exact number of vomiting episodes in the treatment group vs the placebo group, those receiving powdered ginger had a greater reduction in vomiting than those receiving placebo. Of the ginger-treated women, 87% were symptomatically improved as compared to 29% of the placebo group. All patients in the ginger group were compliant with the treatment regimen, as compared with 85% of the placebo group. Adverse affects in this study were minimal. Of those receiving ginger, one experienced heartburn, another abdominal discomfort, and a third had diarrhea for 1 day. The incidence of cephalagia in both groups was equal (19).

Ginger root has been studied as prophylaxis against seasickness (20) in a randomized, placebo-controlled trial. A group of 80 naval cadets who were inexperienced in sailing in heavy seas received either 1 g of powdered ginger root or placebo as the ship encountered heavy seas for the first time. Scorecards were kept for the next 4 hours regarding four symptoms of seasickness: nausea, vomiting, vertigo, or cold sweats. The cadets continued their assigned tasks throughout the study. All but one scorecard was valuable. Outcomes: 48 of the 79 cadets reported symptoms of seasickness (61%) and 31 (16 in the ginger group and 15 in the placebo group) reported no symptoms at all. Five subjects in the placebo group vomited more than once but none of the ginger group was so afflicted. Although all seasickness symptoms were less severe in the ginger group, the different was not statistically significant for nausea and vertigo.

A comparative study of motion sickness has been conducted (21) in which powdered ginger was compared with scopolamine or placebo. A group of 28

subjects sat in a rotating chair to an end point of motion sickness short of vomiting. Antimotion sickness was defined as activity allowing a greater number of head motions than the placebo. Electrical activity of the stomach was monitored by positioning electrodes over the epigastric area. Outcomes: Powdered ginger provided no protection against motion sickness; however, subjects were able to perform an average of 147.5 more head movements after receiving 0.6 mg scopolamine orally than placebo. The rate of gastric emptying was significantly delayed when tested immediately, but quickly recovered. The authors concluded ginger does not posess antimotion sickness activity nor does it significantly alter gastric function during motion sickness.

The effect of powdered ginger root on gastric emptying rate has been studied in a double-blind, random, controlled, crossover trial of 16 healthy volunteers. The subjects received either 1000 mg powdered ginger root or placebo, and gastric emptying was monitored using the oral acetaminophen absorption model. Powdered ginger did not alter gastric emptying. The authors concluded the antiemetic effect of ginger was not related to its effect on gastric emptying (22).

However, there is lack of consensus regarding the mechanism of the antiemetic effect of ginger. Is this effect a result of vestibular input to the vomiting center of the brain via muscarinic acetylcholine receptors, or is it a direct effect on the stomach? Studies in rats have shown 6-gingerol enhances gastrointestinal transport of a charcoal meal. It has been suggested Phillips' study failed to demonstrate this effect because of inadequate dose of 6-gingerol. Additionally, both 6-gingerol, shogaol, and galanolactone (23) have anti-5-hydroxytryptamine (5HT) activity in isolated guinea pig ileum. Lastly, available data is inadequate to clarify the significance of CNS activity (24).

Abrupt discontinuation or noncompliance with serotonin reuptake inhibitor (SRI) treatment regimens may result in a recently described "SRI Discontinuation Syndrome," characterized by disequilibrium, dizziness, vertigo, and ataxia. Although no randomized, placebo-controlled studies have been published regarding this entity, case reports of successful alleviation of its symptoms by ginger root have been emerging (25). The dose of ginger root most frequently utilized to treat this syndrome is 500 to 1000 mg three times daily.

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