ABSTRACT
INTRODUCTION: Multiple sclerosis (MS) is a debilitating neurological condition affecting nearly one million people across the United States. Among the most prominent symptoms of the condition are excessive fatigue and daytime sleepiness. Numerous clinical trials have investigated the efficacy of modafinil in addressing fatigue among these patients. OBJECTIVE: The objective of the present study is to assess the safety and efficacy of modafinil for the treatment of fatigue in MS. METHODOLOGY: An electronic search of PUBMED, ScienceDirect, and Cochrane Central was conducted for articles published from inception to December 2023 using search terms such as "modafinil," "fatigue," and "MS." RESULTS: Seven studies were included in our analysis. Modafinil leads to a meaningful reduction in fatigue when compared with placebo, as measured by Modified Fatigue Impact Scale [mean difference (MD) = -4.42 [-8.01, -.84]; I2 = 45%; p = .02] and Epworth Sleepiness Scale [MD = -.87 [-1.64, -.10]; I2 = 0%; p = .03]. Modafinil also demonstrated a greater risk of precipitating adverse events (e.g., insomnia, gastrointestinal symptoms) when compared with placebo [RR = 1.30 [1.03, 1.66]; I2 = 0%; p = .03]. In quality-of-life assessments, modafinil was associated with overall improvement in well-being [standardized mean difference = .18 [.01, .35]; I2 = 56%; p = .04]. CONCLUSION: The data indicates that modafinil confers a therapeutic benefit when treating fatigue in patients with MS and improves overall quality of life; however, there is a risk of precipitating adverse events. Ultimately, higher quality of evidence may be required to better inform clinical management.
Subject(s)
Fatigue , Modafinil , Multiple Sclerosis , Modafinil/therapeutic use , Modafinil/adverse effects , Modafinil/pharmacology , Humans , Multiple Sclerosis/drug therapy , Multiple Sclerosis/complications , Fatigue/drug therapy , Fatigue/etiology , Wakefulness-Promoting Agents/therapeutic use , Wakefulness-Promoting Agents/adverse effects , Wakefulness-Promoting Agents/pharmacology , Controlled Clinical Trials as TopicABSTRACT
BACKGROUND: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. PURPOSE: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. DATA SOURCES: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. STUDY SELECTION: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. DATA EXTRACTION: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. LIMITATIONS: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. CONCLUSION: Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. PRIMARY FUNDING SOURCE: None.
Subject(s)
Disorders of Excessive Somnolence , Sleep Apnea, Obstructive , Wakefulness-Promoting Agents , Humans , Autoreceptors , Disorders of Excessive Somnolence/drug therapy , Disorders of Excessive Somnolence/etiology , Modafinil/adverse effects , Network Meta-Analysis , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/drug therapy , Wakefulness-Promoting Agents/adverse effectsABSTRACT
To evaluate the ameliorating effect of Modafinil on neuroinflammation, behavioral, and histopathological alterations in rats induced by propionic acid (PPA). Thirty male Wistar rats were used in the study, divided into 3 groups of ten subjects. One group served as a control, the subjects in the other two were given 250 mg/kg/day of PPA by intraperitoneal injection over the course of 5 days to induce autism. The experimental design was as follows: Group 1: Normal control (orally-fed control, n = 10); Group 2 (PPA + saline, n = 10): PPA and 1 ml/kg/day % 0.9 NaCl saline via oral gavage; Group 3 (PPA + Modafinil, n = 10) PPA and 30 mg/kg/day Modafinil (Modiodal tablets 100 mg, Cephalon) via oral gavage. All of the groups were investigated for behavioral, biochemical, and histological abnormality. Autism-like behaviors were reduced significantly in the rats treated with PPA. TNF-α, Nerve Growth Factor (NGF), IL-17, IL-2, and NF-KB levels as well as MDA levels and lactate were significantly higher in those treated with PPA compared to the control group. Using immunohistochemical methods, the number of neurons and GFAP immunoreactivity was significantly altered in PPA-treated rats compared to the control. Using Magnetic Resonance Spectroscopy (MRS), we found that lactate levels were significantly higher in the PPA-treated rats, while creatinine levels were significantly decreased. In the rats administered with Modafinil, behavior, neuroinflammation, and histopathological changes brought about by PPA were significantly reversed. Our results demonstrate the potential role of Modafinil in ameliorating PPA-induced neuroinflammation in rats.
Subject(s)
Autistic Disorder , Rats , Male , Animals , Autistic Disorder/chemically induced , Autistic Disorder/drug therapy , Autistic Disorder/metabolism , Modafinil/adverse effects , Neuroinflammatory Diseases , Rats, Wistar , Lactates/adverse effectsABSTRACT
Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Methylphenidate , Mothers , Prenatal Exposure Delayed Effects , Adult , Child, Preschool , Female , Humans , Infant , Pregnancy , Amphetamines/adverse effects , Amphetamines/therapeutic use , Attention Deficit Disorder with Hyperactivity/drug therapy , Clonidine/adverse effects , Clonidine/therapeutic use , Cohort Studies , Denmark/epidemiology , Gestational Age , Methylphenidate/adverse effects , Methylphenidate/therapeutic use , Modafinil/adverse effects , Modafinil/therapeutic use , Mothers/psychology , Neurodevelopmental Disorders/chemically induced , Prenatal Exposure Delayed Effects/chemically induced , Prenatal Exposure Delayed Effects/epidemiology , RegistriesABSTRACT
Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil.
Subject(s)
Central Nervous System Stimulants , Disorders of Excessive Somnolence , Idiopathic Hypersomnia , Narcolepsy , Female , Humans , Modafinil/adverse effects , Narcolepsy/drug therapy , Narcolepsy/etiology , Disorders of Excessive Somnolence/chemically induced , Disorders of Excessive Somnolence/complications , Disorders of Excessive Somnolence/drug therapy , Central Nervous System Stimulants/adverse effects , Idiopathic Hypersomnia/complications , Idiopathic Hypersomnia/drug therapyABSTRACT
Antidepressants are known to cause sexual dysfunctions. Sexual side effects due to antidepressants negatively affect compliance with treatment. Modafinil is a stimulant drug used for narcolepsy and some other sleep disorders. It is also used in treatment of resistant depression, chronic fatigue syndrome, attention deficit hyperactivity disorder, and cocaine addiction syndrome. In this article, two female patients whose depressive complaints improved with antidepressant treatment, but who applied to the psychiatry outpatient clinic with complaints of sexual dysfunction and daytime sleepiness, will be presented. Both patients had loss of sexual desire, arousal and orgasm difficulties. The sexual histories obtained from the patients suggested that there was no sexual dysfunction in the period before they started using antidepressants. Both patients stated that they did not want to change the current antidepressant treatment. Modafinil 100 mg/day was prescribed to the patients for daytime sleepiness. One month after the initiation of modafinil 100 mg/day in the 39-yearold patient, there was a marked decrease in the complaints of loss of sexual desire, decreased sexual arousal and orgasm difficulties. In the other patient, 43 years old, a slight improvement in sexual functions was observed after the initiation of modafinil. In this case, after the modafinil dose was increased to 200 mg/day, there was a significant improvement in sexual dysfunctions. In both cases, the improvement in sexual dysfunctions and possible mechanisms as a result of the addition of modafinil to the treatment will be discussed. Keywords: Antidepressant, woman, sexual dysfunction, modafinil.
Subject(s)
Central Nervous System Stimulants , Disorders of Excessive Somnolence , Adult , Antidepressive Agents/adverse effects , Benzhydryl Compounds/adverse effects , Central Nervous System Stimulants/therapeutic use , Disorders of Excessive Somnolence/chemically induced , Disorders of Excessive Somnolence/drug therapy , Female , Humans , Modafinil/adverse effectsABSTRACT
BACKGROUND: Modafinil, as a wake-promoting agent, is commonly used to relieve fatigue during military operations. However, there is a lack of clarity regarding the effects of modafinil on the equilibrium and vestibular organs, especially when prescribing this drug to flight crewmembers. The objective of this study was to evaluate the equilibrium- and vestibular-related safety effects of modafinil.METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 10 healthy male volunteers received a single 200-mg oral dose of modafinil or placebo. Equilibrium and vestibular functions were assessed 2 h after oral administration by the sensory organization test (SOT), adaptation test (ADT), and video head impulse test (v-HIT).RESULTS: There was no change in the equilibrium scores of the six SOT conditions or the composite scores between the modafinil and placebo groups. Statistically significant differences were not observed for the sway energy score (SES) in the toe-down test. In the toe-up test, the SES decreased by 16.7% in the modafinil group relative to the placebo group in trial 2, while the differences in other trials were not statistically significant. In the v-HIT, there was no significant difference in the gain of each semicircular canal between the two groups.DISCUSSION: A single 200-mg dose of modafinil did not cause any impairment to vestibular function, equilibrium ability, or adaptive balance response; in fact, modafinil might have a positive effect on adaptation function in healthy volunteers. These findings preliminarily suggest that there is no hidden risk of vestibular dysfunction among aviation employees using modafinil.Liu F, Zhang M, Chen T, Zhai L, Zhang Z, Xue J. Equilibrium and vestibular safety of modafinil in healthy volunteers. Aerosp Med Hum Perform. 2022; 93(6):487-492.
Subject(s)
Central Nervous System Stimulants , Vestibule, Labyrinth , Benzhydryl Compounds/adverse effects , Central Nervous System Stimulants/pharmacology , Cross-Over Studies , Double-Blind Method , Healthy Volunteers , Humans , Male , Modafinil/adverse effectsABSTRACT
BACKGROUND: Patients receiving placebo in clinical trials often report side-effects (nocebo effects), but contributing factors are still poorly understood. PURPOSE: Using a sham trial of the cognition-enhancing "smart pill" Modafinil we tested whether medication beliefs and other psychological factors predicted detection and attribution of symptoms as side-effects to placebo. METHODS: Healthy students (n = 201) completed measures assessing beliefs about medication, perceived sensitivity to medicines, negative affectivity, somatization, and body awareness; 66 were then randomized to receive Deceptive Placebo (told Modafinil-given placebo, 67 to Open Placebo (told placebo-given placebo, and 68 to No Placebo. Memory and attention tasks assessed cognitive enhancement. Nocebo effects were assessed by symptom checklist. RESULTS: More symptoms were reported in the Deceptive Placebo condition (M = 2.65; SD = 2.27) than Open Placebo (M = 1.92; SD = 2.24; Mann-Whitney U = 1,654, z = 2.30, p = .022) or No Placebo (M = 1.68; SD = 1.75, Mann-Whitney U = 1,640, z = 2.74, p = .006). Participants were more likely to attribute symptoms to Modafinil side-effects if they believed pharmaceuticals to be generally harmful (incidence rate ratio [IRR] = 1.70, p = .019), had higher perceived sensitivity to medicines (IRR = 1.68, p = .011), stronger concerns about Modafinil (IRR = 2.10, p < .001), and higher negative affectivity (IRR = 2.37, p < .001). CONCLUSIONS: Beliefs about medication are potentially modifiable predictors of the nocebo effect. These findings provide insight into side-effect reports to placebo and, potentially, active treatment.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Cognition , Humans , Modafinil/adverse effects , Nocebo Effect , Pharmaceutical PreparationsABSTRACT
BACKGROUND: Status epilepticus (SE) is a continuous episode of seizures which leads to hippocampal neurodegeneration, severe systemic inflammation, and extreme damage to the brain. Modafinil, a psychostimulant and wake-promoting agent, has exerted neuroprotective and anti-inflammatory effects in previous preclinical studies. The aim of this study was to assess effects of modafinil on the lithium-pilocarpine-induced SE rat model and to explore possible involvement of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) pathways in this regard. METHODS: Status epilepticus was provoked by injection of lithium chloride (127â¯mg/kg, intraperitoneally [i.p]) and pilocarpine (60â¯mg/kg, i.p.) in rats. Animals received different modafinil doses (50, 75, 100, and 150â¯mg/kg, i.p.) and SE scores were documented over 3 hours of duration. Moreover, the role of the nitrergic pathway in the effects of modafinil was evaluated by injection of the non-selective NO synthase (NOS) inhibitor L-NG-Nitro arginine methyl ester (L-NAME, 10â¯mg/kg, i.p.), the selective neuronal NOS inhibitor 7-nitroindazole (30â¯mg/kg, i.p.), and the selective inducible NOS inhibitor aminoguanidine (100â¯mg/kg, i.p.) 15â¯min before saline/vehicle or modafinil. The ELISA method was used to quantify TNF-α and NO metabolite levels in the isolated hippocampus. RESULTS: Modafinil at 100â¯mg/kg significantly decreased SE scores (Pâ¯<â¯0.01). Pre-treatment with L-NAME, 7-nitroindazole, and aminoguanidine significantly reversed the anticonvulsive effects of modafinil. Status epilepticus-induced animals showed significantly higher NO metabolite and TNF-α levels in their hippocampal tissues, an effect that was reversed by modafinil (100â¯mg/kg, i.p.) treatment. Administration of NOS inhibitors resulted in excessive NO level reduction but an escalation of TNF-α level in modafinil-treated SE-animals. CONCLUSION: Our study revealed anticonvulsive effects of modafinil in the lithium-pilocarpine-induced SE rat model via possible involvement of TNF-α and nitrergic pathways.
Subject(s)
Pilocarpine , Status Epilepticus , Animals , Humans , Lithium/adverse effects , Modafinil/adverse effects , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Pilocarpine/pharmacology , Rats , Status Epilepticus/chemically induced , Status Epilepticus/drug therapy , Status Epilepticus/pathology , Tumor Necrosis Factor-alphaABSTRACT
Modafinil is a central nervous system stimulant that promotes wakefulness and is approved for the treatment of narcolepsy and several other conditions. However, there is a big concern about drug abuse, especially among students to enhance cognitive performance and to reduce the need for sleep. In this case report, we present a 23-year-old female admitted to the cardiology outpatient clinic owing to recurrent palpitations. She stated that she started modafinil 100 mg twice a day one month earlier to increase performance while studying for her exams. Her electrocardiogram (ECG) demonstrated sinus rhythm and a right bundle branch block (RBBB). No structural heart disease or metabolic pathology was detected. A 24-hour ambulatory ECG record showed 11 attacks of non-sustained ventricular tachycardia (NSVT), the longest of which was eight beats. The drug was discontinued and two weeks later, the patient was symptom-free, and her control ECG showed normal sinus rhythm with no RBBB. A control ambulatory ECG was performed, and no ventricular tachycardia was observed. Modafinil, which is considered safer than amphetamine derivatives in terms of cardiovascular side effects, rarely causes serious arrhythmic events, even in healthy subjects. Thus, we suggest evaluating patients for cardiac symptoms after starting on modafinil, and they should be also interrogated regarding the abuse of this drug.
Subject(s)
Arrhythmias, Cardiac , Tachycardia, Ventricular , Adult , Arrhythmias, Cardiac/diagnosis , Bundle-Branch Block/complications , Electrocardiography , Female , Humans , Modafinil/adverse effects , Tachycardia, Ventricular/diagnosis , Young AdultABSTRACT
IMPORTANCE: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG. OBJECTIVE: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue. DESIGN, SETTING, AND PARTICIPANTS: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019. INTERVENTIONS: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8. MAIN OUTCOMES AND MEASURES: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ2 tests were used and followed by confirmatory analyses. RESULTS: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (-0.7 [95% CI, -1.5 to -0.3] vs -1.7 [95% CI, -2.1 to -1.3]; P < .001). More patients (2 vs 7) reported insomnia with treatment with 250 mg of armodafinil. CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial found no meaningful benefit of using treatment with armodafinil to reduce cancer-related fatigue in patients with HGG. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01781468.
Subject(s)
Glioma , Quality of Life , Adult , Aged , Benzhydryl Compounds/adverse effects , Double-Blind Method , Fatigue/chemically induced , Fatigue/etiology , Female , Glioma/complications , Glioma/drug therapy , Glioma/radiotherapy , Humans , Male , Middle Aged , Modafinil/adverse effects , Treatment OutcomeABSTRACT
Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.
Subject(s)
Cytochrome P-450 CYP3A Inducers/administration & dosage , Cytochrome P-450 CYP3A/biosynthesis , Modafinil/administration & dosage , Biomarkers/blood , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A Inducers/adverse effects , Drug Administration Schedule , Drug Interactions , Enzyme Induction , Extracellular Vesicles/drug effects , Extracellular Vesicles/enzymology , Healthy Volunteers , Humans , Hydroxycholesterols/blood , Liquid Biopsy , Liver/enzymology , Modafinil/adverse effects , Models, Biological , Plasma/enzymology , Proteomics , Rifampin/administration & dosage , Rifampin/adverse effects , Time FactorsABSTRACT
Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.
Subject(s)
Attention/drug effects , Cognition Disorders/physiopathology , Modafinil/pharmacology , Morphine/pharmacology , Prefrontal Cortex/drug effects , Animals , Cognition Disorders/chemically induced , Dose-Response Relationship, Drug , Impulsive Behavior/drug effects , MAP Kinase Signaling System/drug effects , Mice , Modafinil/administration & dosage , Modafinil/adverse effects , Motivation/drug effectsABSTRACT
BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.
Subject(s)
Disorders of Excessive Somnolence , Flecainide , Modafinil , Parkinson Disease , Disorders of Excessive Somnolence/etiology , Double-Blind Method , Drug Combinations , Flecainide/adverse effects , Humans , Modafinil/adverse effects , Parkinson Disease/drug therapyABSTRACT
Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treatment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembolism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose replacement in subjects receiving metabolism-inducing drugs.
La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser desencadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.
Subject(s)
Adrenal Insufficiency , Acute Disease , Adrenal Insufficiency/chemically induced , Aged, 80 and over , Female , Glucocorticoids/adverse effects , Humans , Hydrocortisone/adverse effects , Modafinil/adverse effectsABSTRACT
Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.
Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.
Subject(s)
Humans , Female , Aged, 80 and over , Adrenal Insufficiency/chemically induced , Hydrocortisone/adverse effects , Acute Disease , Modafinil/adverse effects , Glucocorticoids/adverse effectsABSTRACT
The aim of this study was to compare the efficacy and safety of modafinil and dexamethasone in the management of cancer-related fatigue and their effects on quality of life (QoL). A prospective randomized controlled study was conducted, enrolling 80 cancer patients experiencing moderate or severe fatigue following at least three cycles of chemotherapy or a course of palliative/curative radiotherapy. Patients received either oral modafinil 100 mg or dexamethasone 4 mg daily for 14 days. Levels of fatigue, QoL and symptom severity were compared after 14-21 days. Both drugs were efficacious and safe in the management of fatigue and QoL. However, modafinil performed marginally better. Although modafinil demonstrated marginal superiority, both modafinil and dexamethasone can improve fatigue and QoL in cancer patients. Clinical trials registry of India: CTRI/2018/05/014046 (www.ctri.nic.in).
Lay abstract Cancer-related fatigue is a common and nagging problem that needs best evidence-based management. Modafinil, a brain stimulant, and dexamethasone, a corticosteroid, have been shown in separate studies to provide benefit, but there are little data regarding which one is superior. The present study compared modafinil with dexamethasone in a randomized controlled trial. Modafinil was found to be marginally superior in treating cancer-related fatigue and several domains of quality of life, though dexamethasone also demonstrated significant improvement of fatigue. This study provides a valuable guide for future larger studies for implementation of the findings in the form of better patient care.