Modafinil In Patients Research Articles

Evaluation of the effect of Modafinil in the improvement of the level of consciousness in patients with COVID-19 encephalopathy: A randomized controlled trial.

COVID-19 can lead to encephalopathy and loss of consciousness. This double-blinded randomized clinical trial conducted in Tehran, Iran, aimed to assess the potential effectiveness of modafinil in patients with COVID-19-related encephalopathy. Nineteen non-intubated COVID-19 patients with encephalopathy were randomized into two groups: a treatment group receiving crushed modafinil tablets and a placebo group receiving starch powder. Modafinil was administered at a dose of 100 mg every 2 h, reaching a peak dosage of 400 mg. The level of consciousness was assessed using the Glasgow Coma Score (GCS) at multiple time points on the day of medication administration. The trial was registered under IRCT20170903036041N3 on 23/5/2021. The average age in the modafinil and placebo groups was 75.33 and 70 years, respectively. No significant differences were observed between the two groups in terms of chronic conditions, clinical symptoms, or laboratory data. GCS scores were similar between the groups at baseline (p-value = 0.699). After four doses of modafinil, GCS scores were slightly higher in the treatment group, but this difference was not statistically significant (p-value = 0.581). GCS scores after each round of drug administration didn't significantly differ between the treatment and placebo groups (p-value = 0.908). Modafinil exhibited a slight improvement in the level of consciousness among COVID-19 patients with encephalopathy, although this improvement did not reach statistical significance when compared to the control group. Further research with larger sample sizes and longer treatment durations is recommended to explore modafinil's potential benefits in managing altered consciousness in COVID-19 patients.

Pitolisant-supported bridging during drug holidays to deal with tolerance to modafinil in patients with narcolepsy

Study objectivesModafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil. MethodsNarcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to “bridge” the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients’ diaries. Results41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly. ConclusionPatients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil. Clinical trial registration numberClinical Trials.gov Identifier NCT05321355.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

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.

Gap Junctions Modulate The Effects Of Modafinil On Cocaine Self‐Administration Behavior In A Dopamine‐Independent Fashion In Rats

Modafinil and methylphenidate are among the few clinically available medications that block the dopamine (DA) transporter (DAT), a mechanism shared by abused psychostimulants like cocaine. Modafinil is FDA approved for the treatment of narcolepsy and other sleep disorders, while methylphenidate is approved as a medication for neurological disorders (e.g., attention deficit hyperactivity disorder). Both drugs have been reported for their non‐medical use as “smart drugs”, raising concerns regarding their potential for abuse by populations that may also be exposed to illicit substances. In this preclinical study, we compared the potential for abuse of modafinil with that of methylphenidate and their interactions with the reinforcing effects of cocaine in rats trained to self‐administer cocaine (0.03–1 mg/kg i.v., Fixed‐Ratio 5) with 5 doses assessed within each session. Since changes in DA levels in the nucleus accumbens shell (NAS) have been related to reinforcing effects of drugs, we monitored extracellular DA concentrations using microdialysis procedures in rats. Methylphenidate (0.03–1.0 mg/kg) maintained intravenous self‐administration behavior at comparable levels to active doses of cocaine (0.03–1.0 mg/kg). Modafinil (0.1–10 mg/kg) failed to maintain self‐administration behavior at any dose tested. However, pre‐session treatments (i.p.) with both modafinil (10–32 mg/kg) or methylphenidate (1.0–10 mg/kg) potentiated cocaine self‐administration behavior. Administration of cocaine, at self‐administered doses, produced dose‐related stimulation of NAS DA levels. Methylphenidate (1.0–10 mg/kg, i.p.), but not modafinil, (10–32 mg/kg, i.p.), enhanced cocaine‐induced stimulation of DA levels. These microdialysis results suggest that the effects of methylphenidate on cocaine actions are DA‐dependent, while those of modafinil are not. Modafinil is known to facilitate electrotonic coupling between cells by actions on gap junctions. Thus, we assessed the effects of carbenoxolone pretreatments, a gap junction inhibitor, on the potentiation of cocaine self‐administration produced by modafinil or methylphenidate. Carbenoxolone (1 mg/kg i.p.) attenuated modafinil, but not methylphenidate, potentiation of cocaine self‐administration behavior, suggesting that the facilitation of electrotonic coupling plays a role in modafinil’s potentiation of cocaine’s effects. In conclusion, modafinil shares with cocaine and methylphenidate important actions at the DAT, but the present data suggest a unique pharmacological stimulant profile, lacking abuse potential and facilitating electrotonic coupling. These results, together with clinical studies, further suggest a potential therapeutic use of modafinil in patients with cocaine use disorder.Support or Funding InformationThis research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, DHHS

Cognitive effects of modafinil in patients with multiple sclerosis: A clinical trial.

To assess the efficacy of modafinil for the treatment of new learning and memory deficits and fatigue in multiple sclerosis. Only 1 previous study in the literature, to our knowledge, examined the effect of modafinil on cognition specifically in persons with multiple sclerosis. Sixteen patients with a diagnosis of multiple sclerosis (MS) and documented new learning impairment completed the study. In a 5-week randomized, double-blinded, crossover design, participants received either a single daily oral dose of modafinil (200 mg) or placebo for 2 weeks. A 1-week washout period was included between study arms. No effect of modafinil was noted on learning and memory performance. Participants taking 200 mg of modafinil showed improvement in 1 of the 2 working memory measures administered, the Wechsler Adult Intelligence Scale-III (WAIS-III) Letter-Number Sequencing task, as compared with those on placebo. Treatment with modafinil did not have a beneficial effect in reducing self-reported fatigue. No changes were noted on the Modified Fatigue Impact Scale or the Fatigue Severity Scale with the treatment of modafinil, as compared with placebo. Findings indicate that 200 mg of modafinil has the potential to improve working memory in persons with MS. These findings suggest that modafinil may enhance aspects of cognition in persons with MS and may be an effective adjunct to clinical rehabilitation interventions.

Effects of modafinil in patients with obstructive sleep apnea: A systematic review and meta-analysis

Effects of modafinil in patients with obstructive sleep apnea: A systematic review and meta-analysis

Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy

Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy. Docetaxel is associated with fatigue that may lead to premature therapy withdrawal. We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy. This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy (every 21 days; minimum dose 50 mg/m(2)). At the start of their third or subsequent chemotherapy cycle, patients with significant docetaxel-associated fatigue were randomized to receive concurrent modafinil 200 mg/day or placebo for 15 days ("treatment periods" (TP)). Docetaxel was continued for up to four further cycles. Fatigue was evaluated with the fatigue component of the MD Anderson Symptom Inventory (MDASI). The primary endpoint was cumulative MDASI area under the curve (AUC) during the first 7 days of study medication during TP1 and TP2. Evaluable data were available from 83 patients (65 with prostate cancer). There was no statistically significant difference between the two treatment arms for the primary endpoint (MSADI AUC3-10 35.9 vs 39.6; 95 % confidence interval -8.9, 1.4; P=0.15). Overall toxicity was comparable between treatment groups; however, the incidence of grade ≤ 2 nausea and vomiting was higher in the modafinil arm (45.4 vs 25 %). Assessing and managing chemotherapy-related fatigue remains a major challenge. There was a lack of difference between the two arms in the planned primary endpoint. However, there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil. Based on the study findings, modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements. Larger, longer term, randomized, controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue.

Safety Profile of Modafinil Across a Range of Prescribing Indications, Including Off-Label Use, in a Primary Care Setting in England

Modafinil (Provigil) was marketed in the UK in 1998 to promote wakefulness in the treatment of narcolepsy. In April 2004, the licence was extended to include chronic pathological conditions; 2years later, the prescription of modafinil was restricted to patients with shift work sleep disorder, narcolepsy and obstructive sleep apnoea/hypopnoea syndrome. Following a recent review of the safety data, the licence has been further restricted to only treat patients with narcolepsy. The review highlighted the degree of off-label usage of modafinil, including patients with multiple sclerosis. The aim of this study was to examine the safety profile of modafinil in real-world clinical usage and across a range of prescribing indications, including multiple sclerosis. The study was conducted using the observational cohort technique of Modified Prescription-Event Monitoring. Patients were identified from dispensed prescriptions issued by primary care physicians from July 2004 to August 2005. Patient demographics and information on prescribing behaviour were included in the questionnaire sent to the prescribing general practitioner (GP) 6months after the initial prescription for each patient. The questionnaire sought data on any events that patient may have experienced during that time, reasons for stopping treatment with modafinil, adverse drug reactions (ADRs), potential interaction with contraceptives, and pregnancies. Incidence densities (IDs) were calculated for all events, and stratified according to indication and dose. Specific events were evaluated by requesting further information. Of the 4,023 questionnaires sent to GPs, 2,416 were returned (response rate 60.1%). Of these, only those patients issued modafinil after April 2004 (with the associated broadening of the indications for treatment) were included in the study, resulting in a final cohort of 1,096 patients: 497 (45.3%) male, median age of 52years (interquartile range [IQR] 41-63), and 599 (54.7%) female, median age of 47years (IQR 38-57). Nine patients were aged 16years or younger; no serious skin reactions were reported in this group. Thirty-four percent of the cohort had an indication of multiple sclerosis. In this study, the majority of the clinical events that were most frequently reported as ADRs or reasons for stopping or that occurred in month 1 have been previously documented with modafinil. The results of the study show that less than half of the women of child-bearing potential were established on a recommended contraceptive programme; three women became pregnant whilst taking modafinil and the oral contraceptive pill. Stratification of IDs by dose revealed certain additional events occurred during month 1 of treatment at the higher dose only. Assessment of individual cases of cardiac, psychiatric and skin events indicated causal associations with modafinil. This study provides important additional safety data on the use of modafinil in patients in 'real-world' use, including those for whom the prescribing indication is outside the terms of licence, as per recent changes to the licensed indications for treatment. In addition to safety data, our study provides useful utilization data. Results from this study indicate that a significant number of women of child-bearing potential had not been commenced on appropriate contraceptive programmes prior to starting modafinil. There were three pregnancies that occurred whilst taking contraception, highlighting the necessity of ensuring effective contraceptive cover for women during and after stopping treatment with modafinil. Analysis of the data showed that the majority of events reported as ADRs or reasons for stopping and ranked events during the first month of treatment had been previously documented with the use of modafinil. Stratification of events according to dose revealed a number of events that occurred at the higher dose only, including serious events such as psychosis. The targeted events for which causality assessments were undertaken confirmed the potential of modafinil to induce certain types of events in individual patients, including cardiac and psychiatric events.

Armodafinil and Modafinil in Patients With Excessive Sleepiness Associated With Shift Work Disorder: A Pharmacokinetic/Pharmacodynamic Model for Predicting and Comparing Their Concentration‐Effect Relationships

Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses. Pooled Multiple Sleep Latency Test (MSLT) data from 2 randomized, double-blind, placebo-controlled trials in 463 patients with SWD, 1 with armodafinil 150 mg/d and 1 with modafinil 200 mg/d (both administered around 2200 h before night shifts), were used to build a pharmacokinetic/pharmacodynamic model. Predicted plasma drug concentrations were obtained by developing and applying a population pharmacokinetic model using nonlinear mixed-effects modeling. Armodafinil 200 mg produced a plasma concentration above the EC(50) (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg did not exceed the EC(50). Consequently, armodafinil produced greater increases in predicted placebo-subtracted MSLT times of 0.5-1 minute (up to 10 hours after dosing) compared with modafinil. On a milligram-to-milligram basis, armodafinil 200 mg consistently increased wakefulness more than modafinil 200 mg, including times late in the 8-hour shift.

Use of modafinil in patients with epilepsy

Fatigue and excessive daytime sleepiness are common symptoms in patients with neurological injury. Modafinil has been shown to ameliorate these symptoms, but its use in patients with seizures has been limited because of safety concerns. Using a large centralized clinical registry, we performed a retrospective chart review of patients with a diagnosis of epilepsy who were given modafinil over a 10-year period. A total of 205 patients were analyzed. There were 91 patients who had seizures while taking modafinil; there was no relationship between modafinil dosage and whether the patient had seizures. There were 6 patients in whom modafinil was discontinued because of concern for seizure exacerbation, and 4 patients had de novo seizures after starting modafinil. In 29 patients with epilepsy only, no major seizure exacerbation was seen. Modafinil is potentially safe in patients with epilepsy, but further prospective studies are needed to fully determine its safety and efficacy.

Armodafinil versus Modafinil in Patients of Excessive Sleepiness Associated with Shift Work Sleep Disorder: A Randomized Double Blind Multicentric Clinical Trial

Aim. To compare the efficacy and safety of armodafinil, the R-enantiomer of modafinil, with modafinil in patients of shift work sleep disorder (SWSD). Material and Methods. This was a 12-week, randomized, comparative, double-blind, multicentric, parallel-group study in 211 patients of SWSD, receiving armodafinil (150 mg) or modafinil (200 mg) one hour prior to the night shift. Outcome Measures. Efficacy was assessed by change in stanford sleepiness score (SSS) by at least 2 grades (responder) and global assessment for efficacy. Safety was assessed by incidence of adverse events, change in laboratory parameters, ECG, and global assessment of tolerability. Results. Both modafinil and armodafinil significantly improved sleepiness mean grades as compared to baseline (P < .0001). Responder rates with armodafinil (72.12%) and modafinil (74.29%) were comparable (P = .76). Adverse event incidences were comparable. Conclusion. Armodafinil was found to be safe and effective in the treatment of SWSD in Indian patients. The study did not demonstrate any difference in efficacy and safety of armodafinil 150 mg and modafinil 200 mg.

Modafinil Improves Functional Outcomes in Patients with Residual Excessive Sleepiness Associated with CPAP Treatment

The objective of this secondary analysis was to examine the effects of modafinil on the Functional Outcomes of Sleep Questionnaire (FOSQ) in patients with obstructive sleep apnea and residual excessive sleepiness with continuous positive airway pressure (CPAP) use. We also explored the association of improvement of functional status with the presenting level of subjective sleepiness. Data were pooled from 2 randomized placebo-controlled studies (4-week and 12-week interventions) of modafinil in patients with residual sleepiness (Epworth Sleepiness Scale score > or =10 on CPAP). The analysis included 480 patients (FOSQ efficacy data n=442 patients), 292 in the modafinil group and 188 in the placebo group. The mean age (SD) of the analyzed sample was 49.7 (9.2) years; 76% were men. Following administration with modafinil, there were greater improvements from baseline in the Total score (p < 0.0001) as well as 4 of the 5 domains (p < 0.05), compared with placebo. A greater proportion of patients who received modafinil were considered responders, compared with patients who received placebo (45% vs. 25%; p < 0.001). Responder analysis based on the individual FOSQ domain items demonstrated that 18 of the 30 FOSQ items increased by at least 1 point for significantly more patients who received modafinil (p < 0.05). Improvements in functional status were not found to depend on patients' degree of subjective sleepiness at baseline. In this secondary analysis of data from patients with OSA and excessive sleepiness despite CPAP use, modafinil was associated with improvements in patients' functional outcomes and their ability to engage in a broad array of everyday activities.

Modafinil Augmentation of Selective Serotonin Reuptake Inhibitor Therapy in MDD Partial Responders with Persistent Fatigue and Sleepiness

Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue. This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4). Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI. Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.

Poster 223: The Effect of Modafinil on Self-Esteem in Patients With Spinal Cord Injury: A Report of 2 Cases

Setting: Outpatient rehabilitation clinic. Patients: A 33-year-old man with history of polysubstance abuse and a C6 American Spinal Injury Association (ASIA) grade A injury and a 36-year-old woman with history of depression and a T11 ASIA grade A injury. Case Descriptions: The first patient presented for follow-up to the outpatient rehabilitation clinic for depression, decreased motivation, and lowered self-esteem. The patient had tried a selective serotonin reuptake inhibitor (SSRI) without success and reported increasing social and legal stressors. His mood also negatively affected his rehabilitation efforts, and he began neglecting his self-catheterization regimen. The second patient had tried various SSRIs for depression and adjustment issues with only modest success. She was frustrated by the pace of her rehabilitation and complained of being a burden to her family. She also complained of weight gain and decreased self-esteem. Assessment/Results: The patients were started on modafinil, a medication used to treat narcolepsy, which has been shown to increase self-esteem in other patient populations. Within 1 month of starting on modafinil, the first patient reported increased self-esteem and motivation, as well as decreased self-consciousness. He was motivated enough to date and ask his employer for a raise. The second patient lost weight and became more assertive and less self-conscious within 1 month after starting on modafinil. Discussion: These are the first reported cases, to our knowledge, of successful use of modafinil in patients with spinal cord injury (SCI) and lowered self-esteem. Conclusions: These 2 cases suggest that modafinil should be studied as a therapeutic option for treating lowered self-esteem in patients with SCI.

Modafinil Elicits Sympathomedullary Activation

The autonomic effects of modafinil (Provigil), a psychostimulant widely used to attenuate fatigue and promote wakefulness, are currently unexplored. We assessed the effect of modafinil on autonomic nervous system. We compared oral modafinil (400 mgx1) versus placebo in 12 healthy hospitalized normal subjects in a randomized double-blind, placebo-controlled cross-over study for 3 days each with subjects in 150 mEq sodium, 70 mEq potassium balance at the Vanderbilt General Clinical Research Center. Modafinil increased resting heart rate (9.2+/-2.0 bpm; mean [+/-SE]; 95% confidence interval [CI], 4.7 to 13.6; P=0.001), resting systolic blood pressure (7.3+/-3.2 mm Hg; 95% CI, 0.2 to 14.4; P=0.044), and resting diastolic blood pressure (5.3+/-1.7 mm Hg; 95% CI, 1.4 to 9.1 mm Hg; P<0.012). Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8+/-0.3 nmol/L; 95% CI, 0.2 to 1.3; P=0.01), and caused a 33% increase in urine norepinephrine (5.1+/-1.1 nmol/L creatinine per day; 95% CI, 2.7 to 7.4, P=0.001), and an 81% increase in urine epinephrine (1.3+/-0.2 nmol/L creatinine per day; 95% CI, 1 to 2; P<0.001). The peroneal microneurographic sympathetic activity was attenuated by modafinil during orthostatic tilt (P<0.001). alpha1-Adrenoreceptor function was maintained. Modafinil substantially perturbs autonomic cardiovascular regulation by increase in heart rate and blood pressure. Autonomic changes of this magnitude encourage caution in use of modafinil in patients with cardiovascular disease.

Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy

Patients with myotonic dystrophy frequently suffer from excess daytime sleepiness, which can be a significant cause of disability. Previous studies have indicated that this excess daytime sleepiness is only occasionally due to obstructive sleep apnoea and may be principally of central nervous system origin. Modafinil has been successfully used to treat narcolepsy, a central disorder causing excess daytime sleepiness. We have investigated the use of this drug in myotonic dystrophy patients with excess daytime sleepiness. Patients were recruited from a clinic population on the basis of screening with the Epworth Sleepiness Scale. Patients scoring 10 and above were invited to participate in a randomized double-blind crossover trial of modafinil versus placebo, with four weeks in each arm of the study separated by a 2-week washout period. Patients were assessed by polysomnography at baseline. The primary outcome measures were change in both the Epworth Sleepiness Scale and a modified Maintenance of Wakefulness Test, which were measured at the start of each arm of the trial and in week 3 of each intervention period. In agreement with previous smaller studies, sleepiness is not correlated with CTG expansion size. Treatment with modafinil showed a non-significant reduction in median Epworth Sleepiness Scale. However, the median Maintenance of Wakefulness Test score was prolonged by treatment (31.7–40 min, P=0.006). There were no significant adverse cardiac effects of the drug in this group of patients (resting 12 lead and 24 h ECG monitoring). Selected patients with myotonic dystrophy and excess daytime sleepiness may benefit from modafinil. In this patient group the Epworth Sleepiness Scale may not be the most reliable measure of sleepiness. Despite the potential for cardiac disease in these patients, the drug was well tolerated with no adverse effects.

Chiral Analysis of d- and l-Modafinil in Human Serum: Application to Human Pharmacokinetic Studies

Modafinil is a novel stimulant approved by the FDA for use in the management of excessive sleepiness associated with narcolepsy. Utility for other indications includes attention deficit-hyperactivity disorder (ADHD), depression, and management of cocaine dependence. To investigate the pharmacokinetics of modafinil in these patients, the authors improved and validated an HPLC method to separate and quantitate the separate enantiomers of modafinil in human serum. d- and l-Modafinil and the internal standard 3,3-diphenylpropylamine were extracted from serum, separated by gradient elution on a beta-cyclodextrin column, and then detected by UV absorbance at 225 nm. The elution gradient was developed to eliminate interferences by other drugs used to manage narcolepsy, ADHD, and stimulants of abuse, and endogenous substances in human serum. Validation studies included determination of stability, selectivity, precision, accuracy, and recovery. The method was used to investigate the pharmacokinetics of d- and l-modafinil in a volunteer after receiving 400 mg twice daily of racemic modafinil for 5 days. Interday and intraday assay variability (CV) typically ranged from 3% to 4%. The limits of detection (0.01 microg/mL) and quantitation (0.5 microg/mL) were well below the concentration expected in serum from patients receiving therapeutic doses of modafinil. The method was free from interference by methylphenidate, cocaine, commonly used antidepressants, and amphetamines. An example of apparent stereoselective disposition is presented as d-modafinil was eliminated more rapidly than l-modafinil from human serum. The validation data support the use of this method for human pharmacokinetic studies of modafinil in patients with known or suspected use of common antidepressants, psychostimulants, and drugs of abuse.

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.

Visual P300 latency predicts treatment response to modafinil in patients with narcolepsy

Objective: To evaluate the hypothesis that visual P300 latency (VL) predicts treatment response to modafinil (a new wake-promoting agent) in patients with narcolepsy.Methods: Design: Comparison of responders and non-responders in a double-blind randomized placebo-controlled trial. Setting: Private practice referral sleep disorders center. Patients: Twenty one patients with narcolepsy (ages 17–65 years). Interventions: Auditory and visual P300 testing using 31 evenly spaced scalp electrodes, and baseline polysomnograms and objective and subjective tests of daytime sleepiness, followed by modafinil treatment for 9 weeks. Polysomnograms and tests of sleepiness were then repeated. Main outcome measure: The Maintenance of Wakefulness Test (MWT). Response defined as a final MWT>7.3min (normative sample mean−3 SD), plus an increase >1SD based on normative sample (3.6 min) over baseline MWT.Results: Non-responders had longer age-adjusted 31-electrode mean VL (448.4 ms vs. 410.8 ms, P=0.024), and larger auditory P300 amplitude, with no topographical P300 differences. Non-responders and responders did not differ on any other baseline clinical variable. Using a cut-off of 0.5 SE from normal regression constant, shorter age-adjusted VL predicted modafinil response, with specificity of 0.71 and sensitivity of 0.86.Conclusions: VL predicts treatment response to modafinil in patients with narcolepsy.