Chronic high-dose dimenhydrinate use contributing to early multifactorial cognitive impairment.

Dimenhydrinate is an over-the-counter antihistaminergic medication with anticholinergic properties used to treat nausea or motion sickness worldwide. There is a well-established correlation between the use of anticholinergic medications and dementia, however, it is unclear if a causal role exists. We report a case of minor neurocognitive disorder in a woman in her 40s with several years of high-dose daily dimenhydrinate abuse who subsequently developed significant delusional beliefs. Her clinical presentation was confounded by numerous other factors that could have impacted her cognition, such as a longstanding presumed learning disability, ankylosing spondylitis with adalimumab treatment, extensive cannabis use or potential development of a primary psychotic disorder. Her workup was within normal limits, and she has not responded to first-line antipsychotic medications to date. This case report adds to the growing evidence supporting concerns about potentially irreversible cognitive deficits in chronic misuse of anticholinergic agents, an association previously observed only in the elderly population.

Efficacy and Safety of a Fixed-Dose Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in the Treatment of Patients with Vestibular Vertigo: An Individual Patient Data Meta-Analysis of Randomised, Double-Blind, Controlled Clinical Trials.

BACKGROUND AND OBJECTIVE: The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo. METHODS: Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted. RESULTS: Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (-1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either "good" or "very good". CONCLUSION: The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.

Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial.

BACKGROUND AND OBJECTIVE: Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with substantial impairment of health-related quality of life for the affected patients. Betahistine, a structural analogue of histamine and presumably the most widely prescribed anti-vertigo drug worldwide, has previously been shown to be an effective and safe treatment for these patients. The objective of the present study was to evaluate whether the fixed combination of cinnarizine and dimenhydrinate (Arlevert®) is non-inferior and thus a potentially useful alternative to betahistine dihydrochloride in the treatment of patients suffering from peripheral vestibular vertigo. METHODS: In this prospective, multicenter, double-blind, randomized, non-inferiority clinical trial, outpatients from 8 ENT clinics in Austria, Bulgaria, the Czech Republic and Russia were randomly assigned to receive three times daily one tablet of either the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg or betahistine dihydrochloride 16 mg for 4 weeks. Primary endpoint was the reduction of the mean vertigo score (MVS), a validated 12-item composite score defined as the mean of 6 vertigo symptoms (dystasia and walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and 6 trigger factors for vertigo (change of position, bowing, getting up, driving by car/train, head movements, eye movement), after 4 weeks of therapy, as judged by the patient on a 5-point visual analogue scale (VAS). The non-inferiority margin was set to 0.3. Secondary outcomes included the patient's and investigator's judgment of global efficacy, the patient's rating of impairment of daily activities, and safety/tolerability of the treatments. RESULTS: Three hundred and six patients (mean age 53.5 years, approximately 60% female) were enrolled and randomized to the fixed combination cinnarizine/dimenhydrinate (n = 152) or betahistine (n = 154) groups; 297 patients completed the study and 294 (146 and 148, respectively) were valid for the per-protocol analysis, which was used for the non-inferiority analysis. Treatment with cinnarizine/dimenhydrinate led to a stronger reduction of the MVS [least squares mean (LSM)] after 4-week therapy (primary endpoint) in comparison to betahistine (0.395 vs 0.488; difference: - 0.093, 95% CI - 0.180; - 0.007, p = 0.035); since the upper limit of the two-sided 95% confidence interval was not only below the non-inferiority margin of 0.3, but also entirely below 0, superiority of the fixed combination could be demonstrated. The combination preparation was also more effective after 1 week of therapy and received more favorable patient's ratings on overall efficacy and impairment of daily activities. Both treatments were very well tolerated. Only 12 patients (3.92%) reported 13 non-serious adverse events; 2 cinnarizine/dimenhydrinate-treated patients discontinued the study prematurely due to adverse events as compared to 5 betahistine-treated patients. CONCLUSION: The fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg was found to be not only non-inferior, but superior to betahistine 16 mg in the improvement of peripheral vestibular vertigo. Furthermore, taking into account a good and slightly favorable safety profile, the present study provides evidence that the fixed-combination preparation is a potent and even superior alternative to betahistine in the treatment of vertigo related to peripheral vestibular disorders. STUDY REGISTRATION: EudraCT No. 2011-004025-27.

Erythema multiforme secondary to dimenhydrinate in a patient with previous similar reactions to pamabrom.

OBJECTIVE: To report a case of erythema multiforme secondary to dimenhydrinate and pamabrom cross-sensitivity. CASE SUMMARY: A 22-year-old Chinese female presented with a complaint of lip mucosal ulceration with necrosis and stomatitis, worsening over the past 24 hours and associated with reduced oral intake and incomplete opening of the mouth. Presentation was accompanied by a generalized rash and genital mucosal involvement. The only new systemically ingested agent was dimenhydrinate approximately 4 days prior to admission. She had no significant medical history, but was labeled to be allergic to acetaminophen. She had a positive history of 2 similar presentations secondary to Panadol Menstrual (acetaminophen and pamabrom), once 3 years ago and again 5 months prior to the current admission. An objective causality assessment revealed that the adverse drug event was "probable" to dimenhydrinate. A detailed history revealed a negative drug challenge to acetaminophen. She had previously taken plain acetaminophen and Beserol (acetaminophen and chlormezanone) with no reaction. DISCUSSION: A comprehensive history taking facilitated the diagnosis of erythema multiforme secondary to dimenhydrinate without the need to perform invasive testing, and the removal of erroneous allergy labeling to acetaminophen. Dimenhydrinate and pamabron both contain theophylline-related structures in their chemical composition. Similar reactions to pamabrom strongly suggested cross-sensitivity to theophylline-related structures. CONCLUSIONS: To our knowledge, this is the first report of erythema multiforme due to dimenhydrinate with pamabron cross-sensitivity. We recommend that comprehensive medication-history taking be carried out for all drug-allergy patients to ensure greater informed decision making when choosing medications to use for that patient in the future.

Stevens-Johnson syndrome: report on a case with a strange complaint of allergy to bus.

Stevens-Johnson syndrome is an uncommon inflammatory skin disorder in which immune mechanisms, cytotoxic reactions, and delayed hypersensitivity seem to be involved. Herein, an unusual case with strange complaint of"bus allergy" is presented, suffering from severe generalized itching and skin lesions, followed by ulcers in his mouth and genitalia. The diagnosis of Stevens-Johnson syndrome was made and appropriate treatment was advised. However, detailed medical history revealed a completely different cause of his allergic reactions, as he had occasionally used dimenhydrinate because of motion sickness in his history. Therefore, adverse drug reaction to dimenhydrinate was considered as the main underlying cause of the disease. In conclusion, thorough medical history should be taken to make a definitive diagnosis and identify the underlying disease, since accurate diagnosis and appropriate treatment can prevent further complications.

Urticaria caused by dimenhydrinate

No disponible

Oral dimenhydrinate versus placebo in children with gastroenteritis: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of oral dimenhydrinate in the treatment of acute gastroenteritis. METHODS: This was a randomized, double-blind, placebo-controlled trial conducted in the emergency department of a pediatric university-affiliated center. Children 1 to 12 years old who presented to the emergency department with at least 5 episodes of vomiting in the previous 12 hours and diagnosed with acute gastroenteritis were block-randomized to receive oral dimenhydrinate (1 mg/kg; maximum: 50 mg) every 6 hours for 4 doses or placebo for 4 doses. The primary outcome measure was treatment failure as defined by the occurrence of ≥ 2 episodes of vomiting in the 24 hours after administration of the first dose of the study medication. RESULTS: During the study period, 209 patients met inclusion criteria, but 50 refused to participate and 7 were missed. Eight participants were lost to follow-up, and 144 were thus included in the primary analysis. Of these patients, 74 were randomized to receive dimenhydrinate and 70 placebo. The proportions of patients showing failure of treatment were similar for both treatment groups: dimenhydrinate, 31% (23 of 74); placebo, 29% (20 of 70) (difference: 0.02 [95% confidence interval: -0.12 to 0.17]). There were no differences between the 2 groups in rates of intravenous cathether insertion, mean number of episodes of vomiting or diarrhea, abdominal pain, nausea, duration of symptoms, revisit rates, or parental absenteeism. The proportions of adverse effects were similar in both groups (53% vs 54%). CONCLUSIONS: The prescription of oral dimenhydrinate did not significantly decrease the frequency of vomiting in children with acute gastroenteritis compared with placebo.

Dimenhydrinate use for children with vomiting.

QUESTION: Dimenhydrinate is an over-the-counter drug that is commonly used for the treatment of nausea and vomiting. Many of my adult patients use it, but is it safe and useful in the pediatric population? ANSWER: Dimenhydrinate appears to be safe for use in the pediatric population. While little literature has been published about adverse effects of this medication, family physicians need to identify the cause of the vomiting before considering if the drug will be effective and need to ensure that patients safely use the medication and avoid potential interaction of the drug with other products.

Assessment of the rewarding effects of dimenhydrinate using the conditioned place preference paradigm in mice.

Dimenhydrinate (DIM) is an over-the-counter antihistamine consisting of diphenhydramine (DIP) and 8-chlorotheophylline (CTP). Medical use of DIM is for prevention of nausea and motion sickness. Recently, it has been reported that DIM may be used alone or in combination with other drugs for recreational purposes due to its euphoric and hallucinogenic effects. To investigate the putatively rewarding properties of DIM and its constituents DIP and CTP, we used a conditioned place preference (CPP) test in mice. DIM significantly induced CPP at a dose of 30 mg/kg. Neither DIP (3, 10, and 30 mg/kg) nor CTP (3, 10, and 30 mg/kg) alone induced CPP. Because neither DIP nor CTP resulted in CPP, the rewarding property of DIM appears to be caused by the sum of the effects of its constituents. In addition, low doses of DIM (3 mg/kg), co-administered with low doses of cocaine (7.5 mg/kg), significantly induced CPP, while neither low-dose DIM (3 mg/kg) nor low-dose cocaine (7.5 mg/kg) administered separately induced CPP. This result suggests the liability of DIM use in combination with other abused drugs to create a stronger effect.

Protein S deficiency, epileptic seizures, sagittal sinus thrombosis and hemorrhagic infarction after ingestion of dimenhydrinate.

Congenital protein S deficiency is associated with an increased risk of venous thrombosis. A14-year-old boy presented with epileptic seizures and thrombosis of the superior sagittal sinus and frontal hemorrhagic venous infarction after ingestion of 50 mg of dimenhydrinate, an antiemetic drug. The patient was found to be heterozygous for the factor V Leiden mutation and had a functional protein S deficiency. He recovered completely within a month after conservative treatment. Dimenhydrinate may have disrupted a subclinical pre-existing condition in this case.

Efficacy and tolerability of a fixed low-dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: a 4-week, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study.

BACKGROUND: Most cases of vertigo are attributable to both peripheral and central vestibular disorders. Therefore, it would be of interest to determine whether a combination therapy having both peripheral and central actions would translate into more efficient symptom relief. OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of a fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg in the treatment of vertigo of central, peripheral, or combined central/peripheral origin. METHODS: This was a prospective, multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study in men and women (age >30 years) with central, peripheral, or combined central/peripheral vestibular vertigo. Patients who assessed > or =1 vertigo symptom as being of medium intensity (> or =2) on a 5-point visual analog scale (from 0 = no symptoms to 4 = very severe symptoms) and who had abnormal vestibulospinal movement patterns on cramocorpography were eligible. Patients were randomly assigned to receive 1 tablet of the fixed combination of cinnarizine 20 mg + dimenhydrinate 40 mg, cinnarizine 50 mg, dimenhydrinate 100 mg, or placebo 3 times daily for 4 weeks. The primary efficacy end point was the decrease in mean vertigo score (MVS), which was composed of 12 individual vertigo symptoms, each assessed on the 5-point visual analog scale after 4 weeks of treatment. RESULTS: The study enrolled 246 patients, of whom 239 were evaluable for efficacy. Approximately two thirds of the efficacy population were female and one third male. The mean age was 51.3 years, and the mean duration of vertigo was 2.6 years. The least squares mean (SD) change from baseline in MVS was significantly greater in the group receiving the fixed combination (1.37 [0.66]) than in any of the comparator groups (cinnarizine 50 mg: 0.87 [0.53]; dimenhydrinate 100 mg: 0.83 [0.66]; placebo: 0.76 [0.48]; all comparisons, P < 0.001). The differences were clinically relevant, based on the Mann-Whitney estimator. The incidence of vertigo-associated nausea was significantly reduced in the fixed-combination group relative to the comparator groups (P< or = 0.016). Thirty-four patients reported adverse events, 6 each in the fixed combination and placebo groups, 12 in the cinnarizine group, and 10 in the dimenhydrinate group. None of these adverse events were considered serious. After 4 weeks of treatment, the tolerability of treatment was rated as very good or good by 57 (96.6%) patients in the fixed-combination group; the values for cinnarizine, dimenhydrinate, and placebo were 54 (93.1%), 42 (72.4%), and 50 (87.7%), respectively. CONCLUSIONS: In this study, the fixed low-dose combination of cinnarizine 20 mg + dimenhydrinate 40 mg was effective, clinically beneficial, and well tolerated in patients with vestibular vertigo of central and/or peripheral origin. It was significantly more effective in reducing the MVS compared with placebo and the routinely prescribed higher doses of cinnarizine (50 mg) and dimenhydrinate (100 mg).