piperidines and Disorders-of-Excessive-Somnolence

Excessive daytime sleepiness (EDS) and fatigue are major complaints in patients with obstructive sleep apnoea (OSA) syndrome. Pitolisant is an orally active selective histamine H3 receptor (H3R) antagonist/inverse agonist, which enhances histaminergic transmissions in the brain and thereby elicits strong wake-promoting effects. This article assesses the efficacy and safety of pitolisant 20 mg in patients with OSA, based on existing randomised controlled studies.. An individual patient data (IPD) meta-analytical two-level (study-patient) hierarchical model was used assuming a random treatment effect. The Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSleR) tests were co-primary endpoints.. A total of 512 patients, including 384 treated with pitolisant and 128 with placebo, were included in the analysis. Compared with placebo, pitolisant reduced mean ESS by - 3.1 (95% CI [- 4.1; - 2.1]; p < 0.001) and improved OSleR by 1.18 (1.02; 1.35, p = 0.022); 30% more patients had reduced fatigue (risk ratio [RR] = 1.3, [1.11; 1.53]), p = 0.001) and 46% more patients had improved Clinical Global Impression (CGI) (RR = 1.46 [1.12; 1.89], p = 0.005). No significant differences in safety endpoints were found. These results proved homogeneous across studies and subgroups of the population.. The results provide evidence of a significant benefit of pitolisant in improving EDS and fatigue, irrespective of baseline conditions.

Topics: Disorders of Excessive Somnolence; Fatigue; Humans; Piperidines; Sleep Apnea, Obstructive; Treatment Outcome

Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI: -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI: 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI: 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI: 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.

Topics: Disorders of Excessive Somnolence; Histamine Antagonists; Humans; Narcolepsy; Piperidines; Placebo Effect; Quality of Life; Randomized Controlled Trials as Topic; Sleep Apnea, Obstructive

OSA is a highly prevalent sleep disorder, and subjective excessive daytime sleepiness (EDS) is the cardinal symptom for which many individuals seek medical advice. Positive airway pressure (PAP) devices, first-line treatment for OSA, eliminates EDS in most patients. However, a subset of patients suffers from persistent EDS despite adherence to therapy. Multiple conditions, some reversible, could account for the residual sleepiness and need to be explored, requiring detailed history, review of PAP data from the smart card, and sometimes additional testing. When all known causes of EDS are excluded, in adequately treated subjects, the purported mechanisms could relate to long-term exposure to the OSA-related sleep fragmentation, sleep deprivation, and hypoxic injury to the arousal system, shifts in melatonin secretion, or altered microbiome. Independent of the mechanism, in well-treated OSA, pharmacological therapy with approved drugs can be considered. Modafinil is commonly prescribed to combat residual EDS, but more recently two drugs, solriamfetol, a dual dopamine-norepinephrine reuptake inhibitor, and pitolisant, a histamine H3 receptor inverse agonist, were approved for EDS. Solriamfetol has undergone randomized controlled trials for treatment of EDS associated with both OSA and narcolepsy, exhibiting robust efficacy. Solriamfetol is renally excreted, with no known drug interactions. Pitolisant, which is nonscheduled, has undergone multiple RCTs in narcolepsy, showing improvement in subjective and objective EDS and one OSA trial showing improvement in subjective EDS.

Topics: Carbamates; Disorders of Excessive Somnolence; Humans; Modafinil; Phenylalanine; Piperidines; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents

Insomnia and hypersomnia are conditions with multifactorial causes that can be difficult to treat. There have been recent developments and changes in the treatment of both conditions, including the addition of some agents that have a novel mechanism of action. This review summarizes recent changes and highlights pertinent updates.. Benzodiazepine receptor agonists received a warning in 2019 regarding the possibility of complex sleep behaviors, such as sleepwalking. Zolpidem has been marketed in new dosage forms that include sublingual tablets and oral spray formulations. Orexin receptor antagonists appear to be well tolerated with a good safety profile. Suvorexant received an approval for the treatment of patients with comorbid insomnia and dementia. Lemborexant was demonstrated to be effective for maintenance insomnia. Trazodone was shown to affect the oligomerization of tau proteins thus suggesting potential implications in attenuating dementia pathology. Pitolisant, a novel histamine-3 receptor antagonist/inverse agonist, gained approval for the treatment of excessive daytime sleepiness in adults with narcolepsy as well as obstructive sleep apnea. Solriamfetol, a new norepinephrine and dopamine reuptake inhibitor, was approved for hypersomnolence based on good efficacy, but with cardiovascular warnings.. Recent advancements in the treatment of insomnia includes agents with novel mechanisms, new indications, and new dosage forms. Risk of complex sleep behaviors, and possible next-day driving impairment, should be discussed for all agents used for insomnia, including orexin receptor antagonists. Novel agents also are available for hypersomnia and there are options beyond traditional stimulants that may have great utility.

Topics: Azepines; Carbamates; Dementia; Disorders of Excessive Somnolence; GABA-A Receptor Agonists; Humans; Orexin Receptor Antagonists; Phenylalanine; Piperidines; Pyridines; Pyrimidines; Sleep Aids, Pharmaceutical; Sleep Apnea, Obstructive; Sleep Initiation and Maintenance Disorders; Trazodone; Triazoles; Zolpidem

Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person).. The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy.. This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy.. The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy.. The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy.. ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Topics: Adolescent; Adult; Aged; Cataplexy; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Piperidines; Treatment Outcome; Young Adult

Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects.. Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS?. In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety.. Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported.. Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.. ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.

Topics: Continuous Positive Airway Pressure; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Piperidines; Quality of Life; Receptors, Histamine H3; Sleep Apnea, Obstructive; Surveys and Questionnaires

First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting.. This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected.. 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%).. First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

Topics: Adolescent; Adult; Amines; Cataplexy; Child; Disorders of Excessive Somnolence; Female; Histamine Agonists; Humans; Male; Narcolepsy; Piperidines; Retrospective Studies

Modafinil 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.. Narcolepsy 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.. 41 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.. Patients 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 Trials.gov Identifier NCT05321355.

Topics: Benzhydryl Compounds; Disorders of Excessive Somnolence; Humans; Modafinil; Narcolepsy; Piperidines; Quality of Life

Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy).. We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study.. One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms.. Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

Topics: Cross-Sectional Studies; Disorders of Excessive Somnolence; Humans; Narcolepsy; Piperidines

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Uptake Inhibitors; Amphetamine; Animals; Carbamates; Corpus Striatum; Disorders of Excessive Somnolence; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Evaluation, Preclinical; Drug Inverse Agonism; Feeding Behavior; Histamine Antagonists; Locomotion; Mice; Modafinil; Narcolepsy; Neostriatum; Norepinephrine Plasma Membrane Transport Proteins; Nucleus Accumbens; Phenylalanine; Piperidines; Receptors, Histamine H3; Sleep Apnea, Obstructive; Wakefulness-Promoting Agents

Donepezil, an oral acetylcholinesterase inhibitor, is used to treat Alzheimer's disease and reportedly attenuates opioid-induced sedation in patients with cancer pain. Neuropathic pain is often treated with gabapentinoids (pregabalin, gabapentin), but gabapentinoid-induced somnolence sometimes prevents patients from using these agents. We conducted a retrospective chart review of patients with neuropathic pain to examine whether donepezil is useful for gabapentinoid-induced somnolence. We investigated pain severity in 13 patients before and after taking gabapentinoids and donepezil, the degree of gabapentinoid-induced somnolence before and after starting donepezil, and gabapentinoid dose escalation after taking donepezil. Donepezil was started at 3-5 mg/day upon experiencing gabapentinoid-induced somnolence. Likert-scale scores for somnolence (0 = no somnolence; 4 = severe somnolence with stumbling) improved significantly after starting donepezil (before: 2.3 ± 0.9, after: 0.5 ± 0.7; Wilcoxon's signed-rank test, P < .05), resulting in gabapentinoid dose escalation (before: 796.2 ± 564.3 mg, after: 1409.6 ± 526.9 mg; P < .05), which significantly decreased pain intensity (before: 7.4 ± 1.2, after: 5.0 ± 1.3; P < .05). Donepezil could be an alternative to psychostimulants for gabapentinoid-induced somnolence. The analgesic effect of gabapentinoids remained uncompromised by donepezil, which could enhance the dose-dependent analgesic effect of gabapentinoids.

Topics: Adult; Aged; Aged, 80 and over; Amines; Cholinesterase Inhibitors; Cyclohexanecarboxylic Acids; Disorders of Excessive Somnolence; Donepezil; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Indans; Male; Middle Aged; Neuralgia; Pain Measurement; Piperidines; Pregabalin; Retrospective Studies

To evaluate the benefits and risks of pitolisant (a wake-enhancing drug that increases the histamine release in the brain by blocking presynaptic H3 histamine reuptake) in patients with idiopathic (IH) and symptomatic (SH) hypersomnia plus sleepiness refractory to available stimulants (modafinil, methylphenidate, mazindol, sodium oxybate, and d-amphetamine).. Through retrospective analyses of patient files, the benefit (the score from the Epworth Sleepiness Scale [ESS], authorization renewal) and tolerance (side-effects) of pitolisant were assessed.. A total of 78 patients with IH (n=65%, 78% women) and SH (n=13%, 54% women) received pitolisant 5-50 mg once per day over the course of five days to 37 months. The median (interquartile range) ESS scores of patients with IH decreased from 17 (15.5-18.5) to 14 (12-17). There were 36% responders (ESS fall of > or =3). The improvement in ESS score (-1.9±2.6) was different from 0 in IH without long sleep time (P<0.002) and in IH with a long sleep time (P<0.0001), but not in SH. Forty-four (63%) patients with IH and 12 (77%) patients with SH stopped pitolisant, mostly due to a lack of efficacy. Side-effects included gastrointestinal pain (15.4%), increased appetite and weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%), as well as exceptional reports of depression and persistent genital arousal.. Pitolisant had a long-term favorable benefit/risk ratio in 23-38% of drug-resistant patients with IH and SH, suggesting that histamine neurons can be stimulated in severe idiopathic and symptomatic hypersomnia.

Topics: Adult; Disorders of Excessive Somnolence; Female; Histamine Agonists; Humans; Idiopathic Hypersomnia; Male; Middle Aged; Piperidines; Polysomnography; Retrospective Studies; Treatment Outcome

Topics: Adolescent; Disorders of Excessive Somnolence; Histamine; Humans; Male; Piperidines; Receptors, Histamine H3; Synaptic Transmission; Tourette Syndrome

Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.

Topics: Amphetamine; Animals; Benzhydryl Compounds; Brain; Central Nervous System Stimulants; Circadian Rhythm; Disorders of Excessive Somnolence; Food Deprivation; Histamine; Male; Modafinil; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Sleep; Sleep Deprivation; Synaptic Transmission; Wakefulness

Topics: Central Nervous System Stimulants; Depression; Depressive Disorder; Disorders of Excessive Somnolence; Fatigue; Piperidines