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      Drugs & Diseases > Psychiatry

      Primary Hypersomnia Treatment & Management

      Updated: Sep 04, 2018
      • Author: Adrian Preda, MD; Chief Editor: Ana Hategan, MD, FRCPC  more...
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      Treatment

      Approach Considerations

      Severe idiopathic hypersomnolence is a disabling problem that often leads to permanent unemployment and responds poorly to medical treatment. [3, 83] Moreover, because the underlying cause of idiopathic hypersomnolence is unknown, treatment remains symptomatic in nature.

      Some limited evidence postulates that a CSF “somnogen” potentiates GABAA inhibitory effects and may increase excessive daytime sleepiness (EDS). Flumazenil is thought to competitively antagonize activity at the benzodiazepine recognition site, though it does not impact all GABA-ergic neurons. In a small study, 7 hypersomnolent patients had improved vigilance with flumazenil. [84]  Another study from a single sleep center reported subjective improvement in EDS in 53 idiopathic hypersomnia (IH) patients that were refractory to traditional psychostimulants, who were given clarithromycin, an antibiotic that has GABAA inhibitory properties. Long-term treatment, however, has potential side effects of antibiotic resistance, GI problems, and infections. [37]

      The American Academy of Sleep Medicine practice parameters state that successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce maximum possible return of function, and regular follow-up to monitor response to therapy.

      Modafinil, armodafinil,sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy and primary hypersomnias. Scheduled naps can be beneficial to combat sleepiness in these patients. [85]

      Behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease.

      Consultations

      The diagnosis of hypersomnolence is made after excluding neurologic, pulmonary, and psychiatric disorders known to cause excessive sleepiness. Therefore, if an underlying cause is suggested, appropriate consultations with a neurologist, pulmonologist, and psychiatrist should be obtained.

      Activity

      Caution is recommended in activities in which hypersomnolence may be hazardous.

      Next:

      Pharmacologic Therapy

      Oxybates  

      The FDA approved calcium/magnesium/potassium/sodium oxybates (Xywav) for adults with idiopathic hypersomnia in August 2021. It is a CNS depressant that contains salts of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA.   

      Approval was based on statistically significant and clinically meaningful differences compared to placebo in change in the primary endpoint of Epworth Sleepiness Scale score (p < 0.0001), and secondary endpoints of Patient Global Impression of Change (p  < 0.0001) and the Idiopathic Hypersomnia Severity Scale (p value < 0.0001). [86]  

      Stimulants

      Therapy for idiopathic hypersomnolence involves maintaining the patient on daytime stimulants. The drug dose is titrated so that the patient stays alert during the day, but adverse effects should be avoided. Methylphenidate (Ritalin) and dextroamphetamine are the most commonly prescribed medications. Pitolisant, a wake-promoting agent that increases CNS histamine via blocking presynaptic H3 reuptake, appears promising, but is still in the new drug application (NDA) process in the United States pending FDA approval. [13]

      Modafinil and armodafinil

      Modafinil, a 1:1 racemic mixture of (R)-(-) and (S)-(-) enantiomers, and armodafinil, the isolated (R)-(-) enantiomer, have proved clinically useful in the treatment of narcolepsy and other causes of excessive daytime sleepiness, such as idiopathic hypersomnolence. [87] It is a psychostimulant that enhances wakefulness and vigilance, but its pharmacologic profile is notably different from the amphetamines, methylphenidate, or cocaine. Modafinil is less likely to produce side effects such as jitteriness, anxiety, or excess locomotor activity or to lead to a hypersomnolent rebound effect. Modafinil, with its 1:1 racemic mixture has an estimated elimination half-life of 4 hours for the S-enantiomer and 15 hours for the R-enantiomer, functionally producing an estimated 9–14 hours half-life. Given the enantiomeric differences, armodafinil has a longer elimination half-life of around 10–15 hours. [82, 88, 13]

      The mechanism of action of modafinil is not fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. Its dopamine-releasing action in the nucleus accumbens is weak and dose dependent; the likelihood of a euphoric response, and, therefore, the abuse potential and tolerance, is small.

      Modafinil has central alpha 1-adrenergic agonist effects (ie, it directly stimulates the receptors). Modafinil inhibits the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO). More significant, perhaps, is its ability to increase excitatory glutaminergic transmission and reduce local gamma-aminobutyric acid (GABA)–ergic transmission, thereby diminishing GABA(A) receptor signaling on the mesolimbic dopamine terminals. [88, 84]  

      Other Medications

      Other medications that have been used in the treatment of this disorder include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), clonidine, levodopa, bromocriptine, amantadine, and methysergide. Patients develop tolerance to their medications; exercise caution in prescribing drugs.

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      Physician Legal Responsibilities

      Physicians have a legal responsibility to know which medical conditions may impede driving ability, to diagnose these conditions in their patients, and to discuss the implications of these conditions.

      The requirement to report unfit drivers varies among different jurisdictions, and interpretations of the law vary among the courts. Therefore, a physician’s risk of liability is unclear. Physicians may face legal action by their patients if they fail to counsel the patients on the dangers of driving associated with certain medications or medical conditions.

      Physicians’ legal responsibilities to report patients with certain medical conditions, when required by law, override their ethical responsibilities to keep patients’ medical information confidential.

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