Factors influencing extent of nausea in the patients on oral iron therapy

Background/Aim. Nausea after oral administration of iron is frequent phenomenon (11% of patients) and it is believed to be consequence of accumulation of free radicals in mucosa of gastrointestinal tract. The aim of our study was to measure the extent of nausea in outpatients taking oral supplementation with iron, and to investigate possible factors that may have an influence on it. Methods. The study was of the cross-sectional type, and conducted on a sample of outpatients on oral iron supplementation. The sample was consecutive, including all patients coming to a community pharmacy for oral iron supply during the study period. Frequency and severity of nausea were measured by the 5-item Drug-Induced Nausea Scale (DINS). Results. The mean score of the DINS from the sample of 128 patients was 8.56 ± 5.07 (range from 5 to 25). Each additional cup of coffee per week increased the DINS score for 0.143 points, the history of gastrointestinal disease had protective effect and decreased the DINS score for 5.923 points. Conclusion. Frequency and severity of oral iron-induced nausea are not dependent on oral iron burden, but rather on coffee intake and previous experience of patients with symptoms of gastrointestinal diseases. Modification of diet and education about types and severity of symptoms of gastrointestinal diseases could be useful preventive measures to avoid or at least mitigate oral iron-induced nausea and/or vomiting.


INTRODUCTION
Nausea after oral administration of iron salts happens in 11% of patients [1], and it is believed to be consequence of accumulation of free radicals in mucosa of gastrointestinal tract [2].Almost 50% of patients who take iron salt orally become eventually non-adherent to the treatment, primarily due to gastrointestinal side effects, which makes nausea caused by oral iron salts to be significant public health problem, too [1].Especially ferrous sulfate causes nausea, about 2.32 times more often than other drugs or placebo [3].Type of oral iron salt may affect rate and severity of nausea, as was reported that ferrous salts (+2) were better tolerated, especially ferrous gluconate in liquid form [3].However, recent systematic review of efficacy and safety of oral iron preparations did not confirm existence of differences in rate of nausea and vomiting among different iron salts [4].Other factors that may influence rate and severity of nausea after oral iron therapy were nor investigated up to date.
The aim of our study was to measure the extent of nausea in outpatients taking oral supplementation with iron, and to investigate possible factors that may have an influence on it.

METHODS
Our study was of the cross/sectional type, and conducted during year 2016 on a sample of outpatients on oral iron supplementation in the town Osečina, Serbia.The sample was consecutive, including all patients coming to a community pharmacy for oral iron supply from January the 1 st to December the 31 st , 2016.The inclusion criteria were: age over 18 and below 75 years, diagnosis of iron deficiency anemia, oral supplementation of iron lasting at least two weeks prior visit to the community pharmacy and literacy.The exclusion criteria were previous gastrectomy, cognitive disorders (score at Mini-Mental State Examination below 24), mood disorders and mental retardation.The investigator was pharmacist employed in the same community pharmacy where the study took place.The study was approved by the Ethics Committee of Faculty of Clinical Center Kragujevac, Serbia.The patients were enrolled only after they had signed the informed consent form.
Existence and extent of oral iron-induced nausea were measured by 5-items Drug-Induced Nausea Scale (DINS) which we had constructed, with the following questions rated on 1-5 Likert's scale [5]: (1) Did you feel nausea during drug therapy?; (2) During drug therapy, did you feel nausea aways in the same time during a day?; (3) During drug therapy, how often you could not perform your daily activities due to nausea?; (4) Was your appetite decreased due to nausea during drug therapy?; and (5) Did you feel an urge to vomit during drug therapy?Presence of both independent (type of iron salt in an oral preparation, daily dose of iron, timing of oral iron in relation to a meals, timing of oral iron during a day, smoking, intake of alcohol and intake of coffee) and confounding (sex, age, education, employment status, place of living, pregnancy, knowledge about gastrointestinal adverse effects of oral iron, previous experience with nausea after taking drugs orally, comorbidities (diabetes, asthma, chronic obstructive pulmonary disease, chronic heart failure and hypertension), oral intake of other drugs, concomitant gastrointestinal disease (gastroesophageal reflux disease, peptic ulcer, chronic pancreatitis or inflammatory bowel diseases), chronic renal failure and liver cirrhosis) variables was established by an openended questionnaire offered to the patients.

Statistics
The data were primarily processed with descriptive statistics, calculating

RESULTS
In total 128 patients with iron deficiency anemia and taking oral supplementation with iron took part in the study.Characteristic of the study sample are shown in the Table1.
Mean score of the DINS was 8.56 ± 5.07 (range from 5 to 25).Optimal multiple regression model (R 2 = 0.114, F = 2.204, p = 0.039) after backward deletion included the following variables: oral intake of other drugs , knowledge of adverse effects of oral iron, experience with nausea after oral intake of drugs, sex, average number of coffee cups weekly, history of gastrointestinal disease and type of iron salt.However, only two variables showed significant influence on the DINS score: average number of coffee cups weekly (B = 0.143, range 0.022 -0.264, p = 0.021) and history of gastrointestinal disease (B = -5.923,range -11.814 -0.033, p = 0.049).

DISCUSSION
Many drugs have significant potential to induce nausea and/or vomiting.Main center for vomiting in medulla oblongata is stimulated by certain blood-borne substances, by input from nerve endings in gastrointestinal tract and by projections from chemioreceptor zone.There are several neurotransmitters which are involved in functioning of center for vomiting: acetylcholine, histamine, 5-hydroxytriptamine, dopamine, endogenous cannabinoids and substance P [6].The patients receiving cytostatic drugs experience nausea in 10% (low emetogenic drugs) to 90% (highly emetogenic drugs) of chemotherapy sessions [7], while the patients on opioids feel nausea in 48% of cases when these drugs were used for treatment of cancer pain and in 27% when used for postoperative pain [8].As already mentioned, nausea due to oral iron supplementation is also frequent phenomenon, occurring in 11% of patients [1].
Our study revealed only two factors with significant influence on frequency and extent of nausea after oral iron supplementation: coffee intake and history of gastrointestinal disease.While each additional cup of coffee per week increased the DINS score for 0.143 points, the history of gastrointestinal disease had protective effect and decreased the DINS score for 5.923 points.
It seems that coffee somehow augments nausea as adverse effect of drugs.It was shown in a group of patients receiving emetogenic chemotherapy that intense aversion to coffee develops after first cycle of therapy, and the patients avoided to take coffee in order to avoid nausea [9].Patients who were treated by prostaglandin inhibitors for premenstrual syndrome in a small observational study benefited from avoidance of coffee, and they experienced nausea as side effect of the therapy less frequently [10].Pregnant females who suffer from morning sickness also have strong aversion to coffee [11].Mechanism of emetogenic action of coffee remains obscure, but probably caffeine increases cholinergic transmission within the vomiting center, as it was recently shown that it blocks acetylcholinesterase [12].
History of gastrointestinal disease means that a patient has experience with nausea and possibly vomiting.It was shown that psychological treatments, like autogenic training, help patients to control nausea due to motion sickness more effectively [13], which could be an explanation why the patients in our study had lower DINS scores if previously exposed to some gastrointestinal disease.Probably experience with nausea helps them to be less anxious when they feel it after taking oral iron, and therefore score lower on the DINS.
Our study did not find an association between type of iron salt, daily dose or dosing regimen with severity of nausea, which is the same finding as those published in the two systematic reviews of the studies with this topic [4,14] .Although it seems logical that oxidative stress imposed to mucosa of the stomach by iron depends on its dose and relation to meals, probably this is not the only mechanism how oral iron causes nausea.It was shown that iron produces a clearly different sensation from the traditional basic tastes, including both olfactory and oral sensations [15], so taste of metal and not gastric irritation may be main factor in pathogenesis of oral ironinduced nausea.Whether intermittent (once weekly) iron supplementation could decrease problems with nausea in comparison to daily iron intake remains unclear, and further studies are necessary to give answer to that question [14,16].
CONCLUSION: Frequency and severity of oral ironinduced nausea are not dependent on oral iron burden, but rather on coffee intake and previous experience of patients with symptoms of gastrointestinal diseases.Modification of diet (avoidance of coffee during oral iron supplementation) and educating a patient about types and severity of symptoms of gastrointestinal diseases could be useful preventive measures to avoid or at least mitigate oral ironinduced nausea and/or vomiting.
Limitations of the study: Our results should be taken with caution, since almost two-thirds of patients did not intake iron before the meal, what is recommended dosing regimen.Non-adherence to the prescribed regimen could have influenced indirectly emetogenic action of oral iron and confounded the effects of other factors, including coffee and experience with gastrointestinal diseases.
frequencies and percentages of different values of categorical variables, as well as means and standard deviations of continuous variables.Total score of DINS was calculated as simple summation of scores on individual questions.Effects of independent and confounding variables on total DINS score were estimated by multiple linear regression, through sign and size of coefficients of variables with significant statistical influence.Optimal regression model was established by backward deletion method.All calculations were performed by Statistical Program for Social Sciences (SPSS), version 18.

Table 1 .
Characteristic of the study sample.