Safety Of Modafinil Research Articles

Efficacy and safety of modafinil in patients with idiopathic hypersomnia without long sleep time: a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study

BackgroundFew treatments are available for patients with idiopathic hypersomnia (IH). Modafinil, an established treatment for narcolepsy, was tested for efficacy and safety in Japanese patients with IH without long sleep time. MethodsThis multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study was conducted at 20 institutions in Japan. Patients who met the diagnostic criteria of IH in the International Classification of Sleep Disorders (second edition) were included. The study comprised a ≥17-day observation period and a 3-week treatment period during which modafinil (200 mg) or placebo was administered orally once daily (in the morning). The primary efficacy endpoint was change in mean sleep latency on the Maintenance of Wakefulness Test (MWT). Adverse events (AEs) were also recorded to evaluate safety. ResultsIn total, 123 patients were screened and 71 were randomized to receive modafinil (N = 34) or placebo (N = 37). Patients treated with modafinil experienced a significantly prolonged mean sleep latency on the MWT at the end of the study compared with placebo (5.02 min, 95% confidence interval: 3.26–6.77 min; p < 0.001). AEs occurred in 58.8% (20/34) and 27.0% (10/37) of patients in the modafinil and placebo groups, respectively. Frequent AEs in the modafinil group were headache (n = 6), dry mouth (n = 3), and nausea (n = 3); no clinically significant AEs occurred. ConclusionModafinil was shown to be an effective and safe treatment for excessive daytime sleepiness in patients with IH without long sleep time. Clinical trial registrationJapicCTI; 142539.

Modafinil for poststroke patients: A systematic review.

Stroke is a major cause of death and disability worldwide. The use of modafinil, a wakefulness-promoting agent, is hypothesised to benefit stroke patients. We performed a systematic review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions recommendations to assess the efficacy and safety of modafinil in poststroke patients. We prospectively registered the review protocol in PROSPERO (CRD42017078465) and reported the systematic review following the PRISMA statement. Two published studies (77 participants) and one ongoing randomised controlled trial, with limited methodological quality, assessed the effects of modafinil (200mg or 400mg) for adults from 14days poststroke up to 3months poststroke and fulfilled our inclusion criteria. The clinical and methodological variability between studies precluded meta-analyses. Overall, these studies showed some benefit of modafinil for fatigue, but no benefit for disability, cognition, and for subscores of stroke-specific quality of life. Data for adverse events were scarce and mortality was not considered by studies. Due to very low quality related to the evidence, we are uncertain about the effects of modafinil for all outcomes assessed by our systematic review. Based on two small randomised controlled trial, which provided very low quality evidence, the effects (benefits and harms) of modafinil for stroke patients are unclear and do not support its routinely use in clinical practice for this clinical situation. Number of Protocol registration in PROSPERO database: CRD42017078465 (available from http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017078465).

An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil.

Modafinil (MOD) is a wakefulness-inducing compound prescribed for treatment of excessive daytime sleepiness as a consequence of sleep disturbances such as shift work sleep disorder, obstructive sleep apnea, restless leg syndrome, or narcolepsy. While providing effective results in patients with sleepiness, MOD also produces positive outcomes in the management of fatigue associated with different conditions including depression, cancer, or tiredness in military personnel. Although there is clear evidence of the stimulant effects of MOD, current data also show that administration of this drug apparently induces positive neurobiological effects, such as improvement in memory. However, serious concerns have been raised since some reports have suggested MOD dependence. Taken together, these findings highlight the need to characterize the changes induced by MOD which have been observed in several neurobiological functions. Moreover, further work should follow up on the likely long-term effects of this drug if used for treatment of drowsiness and tiredness. Here, we review and summarize recent findings of the medical uses of MOD in the management of sleepiness and fatigue associated with depression or cancer as well as exhaustion in military personnel. We also discuss the available literature related with the cognitive enhancing properties of this stimulant, as well as what is known and unknown about MOD addiction.

Modafinil Treatment of Cocaine Dependence: A Systematic Review and Meta-Analysis

ABSTRACTBackground: Currently, there is none FDA-approved medication to treat cocaine dependency. Studies conducted with various medications, including antipsychotics, antidepressants, anticonvulsants, and others, revealed inconsistent results. Objectives: To meta-analytically investigate the efficacy and safety of modafinil in the treatment of cocaine-dependent patients. Methods: Randomized controlled trials with ≥20 subjects comparing the numerical therapeutic outcomes of modafinil with placebo were identified in databases, such as PUBMED, psycINFO, EMBASE, and Clinicaltrials.gov. Relevant data on efficacy and safety were extracted. Relative risk (RR) and standardized mean difference were applied for reporting dichotomous and continuous outcomes respectively. Random effects, subgroup, and meta-regression analyses were conducted to further explore the results and evaluate for any moderators. Results: In total, 11 studies (participants = 896, duration = 6.7 ± 1.9 weeks) comparing modafinil with placebo were systematically analyzed, which indicated that modafinil was not superior to placebo in improving the treatment retention rate (studies = 11, participants = 891, RR = 1.030, 95% CI = 0.918–1.156, p = .613). Similarly, data from 7/11 studies did not evidence superiority of modafinil in achieving cocaine abstinence (participants = 696, RR = 1.259, 95% CI = 0.813–1.949, p = .302). However, subgroup analysis of six studies conducted in the United States demonstrated superiority of modafinil in cocaine abstinence rate (studies = 6, participants = 669, 95% CI = 1.027–2.020, p = 0.035). In addition, no evidence suggested modafinil-related discontinuation or specific adverse events than placebo. Conclusions: Overall, there is no evidence to conclude superiority of modafinil in increasing cocaine abstinence and treatment retention rate. However, promising result in subgroup analysis of cocaine abstinence, secondary outcomes, and good safety profile urged the need of larger studies to derive more conclusive results.

Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and a debilitating neuro-behavior disorder in the pediatric population. Although numerous effective psychostimulants are available, more than 30% of patients still do not show adequate treatment response rendering diverse pharmacological options. We aimed at assessing the efficacy and safety of modafinil in the treatment of children and adolescents with ADHD by conducting a meta-analysis. An extensive search of databases and clinical trial registries resulted in five published short-term randomized, double-blind, placebo-controlled trials. Primary efficacy measures were mean change in ADHD Rating Scale-IV Home (ADHD-RS-IV Home) and School Version (ADHD-RS-IV School) from baseline to study end point. The results showed that modafinil more significantly improved ADHD-RS-IV Home (SMD, −0.77 [95%CI, −1.11 to −0.44]) and School (SMD, −0.71 [95%CI, −0.96 to −0.47]) than placebo. Dropout rate due to adverse event did not significantly differ between two groups. In terms of commonly observed side effects, modafinil showed significantly higher incidence of decreased appetite (RR = 5.02, 95% CIs, 2.55 to 9.89, P < 0.00001) and insomnia (RR = 6.16, 95% CIs, 3.40 to 11.17, P < 0.00001). Modafinil did not cause a clinically significant increase of heart rate, systolic blood pressure, and diastolic blood pressure. Although we found that modafinil may be another treatment option in children and adolescents with ADHD, the results should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of clinical trials.

A Method for Deciding About the Possible Safety of Modafinil and Armodafinil in Patients With Seizure Disorder

Modafinil or armodafinil (ar/mod) may be considered for patients with approved or unapproved indications, including excessive daytime drowsiness, fatigue, attention-deficit/hyperactivity disorder (ADHD), or addictions. Ar/mod is classified as a psychostimulant, and psychostimulants have been associated with a small risk of seizures. There is no guidance about the use of ar/mod in patients who are at risk of seizures. This article suggests how a physician may explore the safety of ar/mod if indicated in a patient at such risk. In summary, reading the prescribing information, writing to the drug manufacturer, and searching research databases suggest the following: Ar/mod and its metabolites and derivatives have dose-dependent anticonvulsant action in animal models; ar/mod is not associated with seizures as an adverse event in populations at risk, such as those with ADHD, head injury, and brain tumors; it is not associated with worsening of seizure disorder in patients with current seizure disorder; and it is not associated with seizures in overdose. These findings are reassuring. However, not all the data are of high quality, and potential ar/mod interactions with antiepileptic drugs (and other concurrent medications that affect the seizure threshold) need to be considered because ar/mod can induce the metabolism of some drugs and inhibit the metabolism of others. Decisions should be individualized, and decision-making should be a shared effort between patient and physician.

Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: A randomized, double-blind, placebo-controlled study

ObjectiveTo examine the efficacy and safety of modafinil on parkinsonism and excessive daytime sleepiness (EDS), as well as on negative symptoms and cognitive abilities in patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) in a randomized double-blind placebo-controlled 8-week study. MethodsTwenty-four male patients, who were aged 20–63years and on stable dose of second generation antipsychotic medications and with a negative symptom score of ≥20 on the Positive and Negative Syndrome Scale (PANSS), were randomized into either the modafinil (n=12) or placebo (n=12) group. The modafinil group received flexible does of modafinil 50–200mg/day. Primary measurements were the Simpson-Angus Scale (SAS) for extrapyramidal side effects (EPS), the Epworth Sleepiness Scale (ESS), the PANSS and a neuropsychological (NP) test battery. Data were collected on Days 0, 14, 28, 42 and 56 for rating scales, and on Days 0, 28 and 56 for NP tests. ResultsMixed model analyses showed a significant group-x-time interaction for total SAS scores (P<0.006), with scores decreasing in the modafinil group but remaining the same in the placebo group. There were no significant group-x-time interactions for scores of ESS (total), PANSS (total, positive and negative), and NP tests (composite and domains) (all P's>0.5). No significant adverse events were observed. ConclusionThe data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. Further studies in larger samples and with longer study time are needed to test/confirm the beneficial effects of modafinil on motor function.

Anesthetic management of a patient with narcolepsy for emergency caesarean section

Narcolepsy is defined as a neurological disorder and is characterized by excessive daytime somnolence, sleep paralysis and cataplexy [1]. The cause of this disorder is thought to be a loss of function of the neurones in the hypothalamus producing hypocretin/orexin peptides, which play an important role in the control of the human sleep-wake cycle [2]. Herein we present an emergency caesarean surgery of a narcoleptic patient under general anesthesia who was not receiving any treatment. A 35-year-old primigravida (weight: 82 kg, height: 165 cm) with a 13-year history of narcolepsy at 39 weeks gestation received emergency caesarean delivery due to failure of labor progression. She first experienced symptoms of excessive sleepiness when she was 22 years old, but she had been diagnosed by her neurologist at age 25 with narcolepsy. She was treated well with modafinil 200 mg and imipramine 10 mg. She stopped her medication of her own account 1.5 years ago. Bedside ultrasound, revealed fetal distress, and the patient was taken to the operating room for an emergency caesarean section. In the operating room, routine monitors (electrocardiogram, pulse oximeter, arterial blood pressure) were attached. Her blood pressure was 144/92 mmHg, heart rate was 88 beats/min, and pulse oximeter oxygen saturation was 97% at room air. Bispectral index (BIS) values of the patient were recorded using a BIS sensor applied to her left forehead. General anesthesia was induced with propofol 2 mg/kg, and rocuronium 0.6 mg/kg IV was administered to facilitate tracheal intubation. BIS values of the patient were above 95 before induction of anesthesia. Her trachea was intubated with a 7.5 mm-sized endotracheal tube in one attempt without difficulty. A live female baby weighing 3160 g was delivered (APGAR scores; at one minute: 9, and at five minutes: 10). Anesthesia was maintained with sevoflurane in 1 : 1 of oxygen and nitrous oxide mixture, with end tidal sevoflurane concentrations between 0.8-1.4%. BIS values ranged between 46 and 60. Hemodynamic parameters of the patient were stable during the surgery. The surgery lasted 50 minutes. Postoperative analgesia was provided with intramuscular diclofenac sodium. Neuromuscular blockade was antagonized with 100 mg sugammadex. When she responded to verbal commands with sufficient respiration and neuromuscular function, she was extubated successfully. Her BIS value was above 94 after extubation. She did not experience any complications such as cataplexy, apnea, or prolonged emergence associated with narcolepsy in the postanesthesia care unit. She was discharged home on the third postoperative day. There's no specific treatment for narcolepsy. While excessive daytime sleepiness is treated using central nervous system stimulants, cataplexy is treated with various tricyclic antidepressants or with fluoxetine. All of these drugs used to treat narcolepsy are metabolized in the liver by the cytocrome P 450 system as propofol and fentanyl. For this reason, the anesthesist should be aware of potential drug interactions [3]. Additionally, use of amphetamines may cause a depletion of catecholamines and reduce patients' ability to generate a sympathetic response to hypotension. Direct acting agents such as phenylephrine and/or epinephrine should be used to treat refractory hypotension instead of indirect acting agents such as ephedrine [4]. It has been reported that central nervous system stimulants like modafinil can be used safely during the preoperative period. However, limited information is available about the safety of modafinil in pregnancy. Embryo toxicity has been shown in rats, and the manufacturer recommends avoidance during pregnancy and while breastfeeding [5]. Our patient had been using modafinil 200 mg and imipramine 10 mg once daily before her current pregnancy, but she stopped taking her medication. In the present case report, we used sevoflurane in a 50% oxygen and 50% nitrous oxide mixture without complication. We used a BIS monitor for titrating sevoflurane concentrations. We did not use narcotics and long-acting agents. Our patient was extubated without any complication at the end of the operation. In conclusion, we found sevoflurane anesthesia safe to use for the management of an uncontrolled narcoleptic patient with BIS monitoring for emergence caesarean section.

A 9-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Finding Study to Evaluate the Efficacy and Safety of Modafinil as Treatment for Adults With ADHD

Objective: This study evaluated the efficacy and tolerability of modafinil at a range of doses, versus placebo, in alleviating symptoms of ADHD in adults. Method: Adult patients with ADHD were randomized in 1:1:1:1:1 fashion to double-blind treatment with modafinil 255, 340, 425, or 510 mg daily or placebo for 9 weeks. The primary efficacy outcome was the change from baseline at final visit in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. Results: A total of 338 patients were enrolled, of whom 330 received at least 1 dose of study medication (modafinil or placebo). No statistically significant difference in the AISRS total score was observed at final visit between any modafinil group and placebo; however, some observations among patients who completed the trial may warrant further investigation. Conclusion: Modafinil was reasonably tolerated but did not demonstrate a benefit on ADHD symptoms in adults.

Efficacy and Safety of Modafinil in the Treatment of Cancer-Related Fatigue

To review the efficacy and safety of modafinil in the treatment of cancer-related fatigue (CRF). DATA SOUCES: Literature was accessed via MEDLINE (1950-week 3, November 2008), International Pharmaceutical Abstracts, and Google Scholar using the terms modafinil, cancer, and fatigue. Reference citations from articles identified were reviewed. All English-language publications identified were analyzed for significance. Studies relevant to the objective were used, including 2 prospective open-label studies, one randomized double-blind, dose-controlled trial with an open-label extension, and one Phase 3 randomized, placebo-controlled, double-blind trial. Fatigue is a nearly universal adverse effect of cancer and its treatment that is unrelated to physical exertion, is not relieved by sleep or rest, and negatively affects quality of life. Modafinil is a central nervous system stimulant with minimal toxicity and a low propensity for abuse. Clinical data demonstrate that modafinil significantly reduces fatigue in patients who have received cancer treatment or are currently undergoing chemotherapy. Additional benefits include improvement in cognitive function, mood, general activity, walking ability, normal work ability, relations with other people, and enjoyment of life. Limitations of the available data include open-label design in 3 of the 4 studies; the absence of numerical results of fatigue assessments in the abstract of 1 trial, preventing the determination of clinical significance; and the full inclusion/exclusion criteria, which were not included in the published abstracts. These limitations leave readers without a clear picture of the study populations. Finally, different patient populations at different points in treatment with varying durations of therapy were used, which makes extrapolation of data to the general population challenging. Further randomized placebo-controlled trials are necessary to amass evidence for the effective and safe use of modafinil for CRF; however, if traditional therapies have failed or are intolerable, modafinil can be considered a treatment option.

Modafinil for the treatment of fatigue in lung cancer: a pilot study

Cancer-related fatigue is the most prevalent and distressing symptom experienced by patients with advanced cancer. Central nervous system stimulants have been shown to relieve fatigue in nonmalignant disease. Modafinil is a stimulant with a selective site of action in the brain that is better tolerated than traditional stimulants, such as methylphenidate. The aim of this study was to determine the feasibility of conducting a randomised controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer. Twenty patients with non-small cell lung cancer were recruited to this open-label study. Modafinil was taken in a fixed dose-titration schedule of 100 mg daily for 7 days followed by 200 mg daily for 7 days. Fifteen patients completed the study. During the study period, there was a rapid and statistically significant reduction in the primary outcome, fatigue (P = 0.001) and the secondary outcomes of daytime sleepiness and depression/anxiety. This improvement in fatigue was also clinically significant. Ten patients chose to continue modafinil after the study and the drug was well-tolerated. It would be both feasible and worthwhile to conduct a definitive randomised controlled trial to determine the role of modafinil in the treatment of cancer-related fatigue.

Long-term efficacy and safety of modafinil (PROVIGIL ®) for the treatment of excessive daytime sleepiness associated with narcolepsy

Objectives: To assess the long-term efficacy and safety of modafinil in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. Background: Modafinil has been shown to be effective and well tolerated for treating EDS associated with narcolepsy in two large-scale, well-controlled, 9-week clinical trials. Methods: Four hundred and seventy eight adult patients with a diagnosis of narcolepsy who had completed one of two 9-week, double-blind, placebo-controlled, multicenter, clinical trials of modafinil were enrolled in two 40-week, open-label, extension studies. A flexible-dose regimen (i.e. 200, 300, or 400 mg daily) was followed in one study. In the second study, patients received 200 mg/day for 1 week, followed by 400 mg/day for 1 week. Investigators then prescribed either 200- or 400-mg doses for the duration of the study. Efficacy was evaluated using Clinical Global Impression of Change (CGI-C) scores, the Epworth Sleepiness Scale (ESS), and the 36-item Medical Outcomes Study health survey (SF-36). Adverse events were recorded. Data from the two studies were combined. Results: The majority of patients (∼75%) received 400 mg of modafinil daily. Disease severity improved in >80% of patients throughout the 40-week study. At weeks 2, 8, 24, and 40, disease severity was ‘much improved’ or ‘very much improved’ in 49, 58, 59, and 58% of patients, respectively. The mean (±SEM) ESS score improved significantly from 16.5±0.2 at open-label baseline to 12.4±0.2 at week 2 and remained at that level through week 40 ( P<0.001). Quality of life scores at weeks 4, 8, 24, and 40 were significantly improved versus open-label baseline scores for six of the eight SF-36 domains ( P<0.001). The most common treatment-related adverse events were headache (13%), nervousness (8%), and nausea (5%). Most adverse events were mild to moderate in nature. A total of 341 patients (71%) completed the studies. Forty-three patients (9.0%) discontinued treatment because of adverse events. Conclusions: Modafinil is effective for the long-term treatment of EDS associated with narcolepsy and significantly improves perceptions of general health. Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment.

A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy

Objective: To assess the continued efficacy of modafinil in the treatment of excessive daytime somnolence (EDS) of narcolepsy. Background: Modafinil has been shown to be a safe and effective treatment for the EDS presented by patients with narcolepsy. However, the duration of treatment has been relatively brief, particularly considering the chronic nature of the disease. Methods: Sixty-nine patients with narcolepsy, who completed a 6-week crossover study of modafinil continued on modafinil for 16 weeks of open-label treatment (300±100 mg). This was followed by 2 weeks during which patients were randomly and blindly allocated to continue modafinil (M) at the same dose ( n=30), or placebo (P; n=33). Results: A mean dose of 330 mg of modafinil continued to produce a significant decrease in EDS as measured by the Maintenance of Wakefulness Test (9.7±7.9 for P; 16.4±13.7 for M; P=0.009), the Epworth Sleepiness Scale (15.4±5.8 for P; 13.2±5.7 for M; P=0.023), and the number of episodes of severe somnolence and sleep reported in patient diaries (8.2±7.2 for P; 4.2±5.2 for M; P=0.017). Modafinil had no significant effects on nocturnal sleep, blood pressure, heart rate, the electrocardiogram (ECG), weight, or mood. Conclusion: Modafinil continues to be an effective and well-tolerated drug after 16 weeks of treatment.