In this article, we will discuss the pharmacologic treatments of sleep apnea, narcolepsy, restless legs syndrome, jet lag, shift work sleep disorder, and parasomnias.
Sleep Apnea
Sleep apnea is characterized by fragmented sleep and periods of apnea. This is a cycle of repetitive cessation of breathing and a brief arousal from sleep due to oxygen desaturation. This puts the body in the hyper-arousal state, but the patients don’t necessarily wake-up
There are three types of sleep apnea: central sleep apnea, which is the impairment of respiratory drive, and obstructive, which is the collapse of the upper airway, and mixed sleep apnea. Obstructive sleep apnea is the most common of the three.
The reason why it is important to treat this disorder is because the cycle of apnea puts the body in the hyper-arousal state, which drives blood pressure up. This can lead to treatment-resistant hypertension. Due to the lack of restful sleep, the patients are at an increased risk of depression, cancer, stroke, CV disease, and motor vehicle accidents.
Sleep apnea is also classified by severity, which goes by the number of apnea per hour.
- Mild: 5-15 per hour
- Moderate: 15-30 per hour
- Severe: >30 per hour
Treatment is indicated for moderate to severe. For mild, treatment should be considered if the patient is experiencing excess daytime sleepiness, hypertension, or other cardiovascular disease.
Obstructive Sleep Apnea (OSA)
Again, this is caused by partial or full closure of the upper airways. The most common cause is obesity. Other causes are hypothyroidism, neurologic conditions, and upper airway lesions.
Common question to ask the patient is, “Do you snore?”
The primary and preferred treatment of OSA is Positive airway pressure (CPAP, BiPAP, AutoPAP). In these patients, we would want to avoid the use of CNS depressants. Stimulants may be considered if there is an excessive daytime sleepiness.
Narcolepsy and Cataplexy
The narcolepsy symptom tetrad:
- Excessive daytime sleepiness (EDS)
- Cataplexy
- Hallucinations – this is especially hallucinations that centered around waking-up period, and seem to the patients very real.
- Sleep paralysis
There are two types of narcolepsy: Narcolepsy type 1 (with cataplexy) and narcolepsy type 2 (without cataplexy.) Patients diagnosed with type 1 needs to be treated with medication.
Cataplexy is seen in 60-70% of patients with narcolepsy. It can last anywhere from several seconds to a few minutes.
In some patients, they might present with sleep paralysis as well. Usually this happens while falling asleep (hypnagogic) or upon awakening (hypnopompin.). This is seen in about 60% of the patients.
Treatment Approach for Narcolepsy
Goal: Return to normal function with good sleep hygiene.
Non-pharmacology treatment includes scheduling daytime naps and managing expectations around patient behaviors.
There are two approaches that we can take when considering pharmacologic therapies:
- Treating excessive daytime sleepiness
- Treat REM sleep abnormalities and help them sleep better at night
If the patient is a type I, a treatment for cataplexy also needs to be considered.
The treatment recommendation can be made based on the 2021 American Academy of Sleep Medicine Clinical Practice Guideline.
- First-line: modafinil, pitolisant, sodium oxybate, and solriamfetol
- Second-line: armodafinil, dextroamphetamine, and methylphenidate
Modafinil and armodafinil
Both of these medications work to inhibit dopamine reuptake transporter (DAT). This leads to an increased in the dopamine levels and increased in alertness during daytime. They are considered the stimulants that are less stimulated than Adderall, which attacks both the NET and DAT.
They are effective for EDS, but not for cataplexy.
Due to their action on the DAT, the side effect profile includes headache, nausea, anxiety, insomnia, and increase blood pressure.
Sodium Oxybate (Xyrem)
Xyrem is derived from GHB. This medication work to depress the central nervous system. It is a liquid that can be taken at bedtime. The downside to this medication is that it doesn’t last long, so the dose may need to be repeated again in 2.5-4 hours.
This medication improved both EDS and cataplexy. It is also known to decrease sleep paralysis.
There is a formulation under Xywav that is formulated with lower amount of sodium.
ADR: nausea, somnolence, confusion, dizziness, incontinence.
Due to the abuse potential, this medication is part of the REMS program.
Histamine-3 Receptor Antagonist/Inverse Agonist – Pitolisant (Wakix)
This medication works well for both EDS and cataplexy. It can be prescribed with modafinil and other stimulants.
The key pearl with this medication is to start low and work your way up.
ADR: headache, nausea, insomnia, and anxiety
Stimulants
The two stimulants that are approved for narcolepsy are dextroamphetamine and methylphenidate. But, really, any stimulant can work. Some prescribers use Adderall, Vyvanse, or Methamphetamine.
These medications improve alertness, elevate mood, and prevent sleep
ADR: insomnia, hypertension, palpitation, and irritability
One caveat is that tolerance may develop with these medications.
Cataplexy treatment comment:
So far there are only two medications that can treat cataplexy: Xyrem and Wakix. If these don’t work, then we can consider antidepressants like SSRI or TCA. These are effective in 80% of the patients because they target serotonin
- TCA of choice: imipramine, clomipramine, nortriptyline
- SSRI of choice: Fluoxetine
Strattera may also be considered, but not commonly.
Restless Legs Syndrome (RLS)
Patients with RLS experience paresthesia, which pain from non-physical sources. Some have urges to keep limbs moving all the time. We don’t really know the etiology of RLS.
Studies have shown that patients with established iron deficiency, especially in the substantia nigra, have been known to have RLS. This is why in these patients, an iron supplementation is recommended.
RLS can be worsen by multiple factors, such as caffeine, alcohol, agents that block dopamine, antidepressants, and sedating antihistamines.
Some non-pharmacological options that can be tried are regular moderate exercise, improving sleep hygiene, participation in mentally alerting activities at times of rest
Magnesium and potassium supplementation do NOT help
Treatment of RLS
As mentioned before, in patients with established iron deficiency, iron supplementation is recommended. There is no good guideline on dosing though a regular ferrous sulfate 325mg once daily should be sufficient.
Gabapentinoid agents are the next options, such as gabapentin and pregablin.
The next option are dopamine:
- Dopamine precursor: Carbidopa and levadopa
- Dopamine agonists: ropinirole, pramipexole, rotigotine (Neupro Patch)
- ADR: nausea, fatigue, dizziness, and emergence of compulsive behaviors
- These medications can have tolerance develop. If this happens, stop the medication and switch to gabapentin.
Jet Lag
In travel lasting longer than 7 days, we can try to adjust sleep-wake times before departure.
If pharmacologic therapy is needed, the recommended agent is short-acting BZDs, ramelteon, or melatonin.
Shift Work Sleep Disorder
Non-pharmacologic treatments include scheduled naps, sleep hygiene, and extend daytime sleep.
Pharmacologic: Ramelteon or melatonin to consolidate sleep. Modafinil for EDS.
Parasomnias
These include sleepwaking, sleep talking, nightmares, enuresis, bruxism.
They usually go away on their own, but in patients who need treatment, they can be treated with BZDs if needed. This is the absolute last resort.