L52. Pharmacology - Tx of Migraines, Emesis and Sleep Disorders

• Migraine is a common and debilitating disease, affecting approximately 1 billion people worldwide, with a one-year prevalence of 15-18%.

Migraine Headaches

• Migraine headaches are unilateral, pulsatile or throbbing, associated with nausea or vomiting, of sufficient intensity to interrupt daily activities, and usually last 4-72 hours if left untreated.
• The presence of prodrome or aura distinguishes migraine from other types of headaches.
• Migraine affects 18% of women and 6% of men.
• Dietary triggers can cause migraines in approximately 20% of migraine sufferers.

Pathophysiology of Migraine

• The pathophysiology behind migraine attacks is not fully understood.
• Initial theories suggested migraines originated in the blood vessels irrigating brain membranes, known as the Vasogenic theory.
• Current research supports a primarily neural origin for migraine, particularly involving the sensitization and activation of the trigeminovascular system.

Migraine Attack Phases

• Migraine attacks progress through phases, but not all patients experience every phase.
• The earliest phases are the prodrome, which is a cluster of subtle symptoms that anticipate the migraine episode, and the aura, which is a perceptual, typically visual disturbance immediately preceding the migraine.
• Prodromes can occur a day or more before the headache, while auras occur hours before it.
• About a third of migraine patients experience a prodrome and/or aura, presenting an opportunity for early therapeutic intervention.Prodrome symptoms include:
  • Irritability
  • Depression
  • Yawning
  • Increased need to urinate
  • Food cravings
  • Sensitivity to light/sound
  • Problems in concentrating
  • Fatigue and muscle stiffness
  • Difficulty with speaking and reading
  • Nausea
  • Difficulty sleeping
• Aura symptoms include:
  • Visual disturbances
  • Temporary loss of sight
  • Numbness and tingling on parts of the body
• Headache symptoms include:
  • Throbbing
  • Drilling sensation
  • Feeling an icepick in the head
  • Burning sensation
  • Nausea
  • Vomiting
  • Giddiness
  • Insomnia
  • Nasal congestion
  • Anxiety
  • Depressed mood
  • Sensitivity to light, smell, and sound
  • Neck pain and stiffness
• Postdrome symptoms include:
  • Inability to concentrate
  • Fatigue
  • Depressed mood
  • Euphoric mood
  • Lack of comprehension

Pharmacotherapy of Migraine

• Migraine episodes vary widely in intensity and frequency.
• Non-opioid analgesics such as aspirin, acetaminophen, or NSAIDs (Ibuprofen, Naproxen) can be effective for mild to moderate migraine episodes.
• They can be supplemented with anti-nausea medications like metoclopramide.
• Triptans are the drugs of choice for treating moderate to severe migraine episodes.
• Triptans are selective agonists for 5-HT1B/D receptors targeted to neuronal presynaptic terminals, reducing neurotransmitter release (presynaptic inhibition), and thus are thought to elicit their therapeutic effect by inhibiting neurotransmitter release/synaptic transmission.
• Triptans are most effective when administered with a non-opioid analgesic like an NSAID.
• Patients should start treatment as soon as migraine symptoms are recognized to prevent the development of a full episode.
• Sumatriptan (Imitrex), available in self-injection, nasal spray, and oral formulations, is a classic triptan.
• Almotriptan (Axert), eletriptan (Relpax), and rizatriptan (Maxalt) are comparable to sumatriptan.
• Naratriptan (Amerge) and frovatriptan (Frova) have a slower onset and longer half-life, resulting in a lower initial response rate.
• Triptans can cause nausea, tingling, flushing, drowsiness, fatigue, chest pressure or heaviness, and dizziness, but angina, myocardial infarction, arrhythmias, and stroke are rare.
• Triptans are contraindicated for patients with arterial diseases or uncontrolled hypertension and should be used with caution in those with vascular disease risk, including diabetes.
• Triptans work best in combination with an NSAID, have relatively mild adverse effects.
• Triptans are not significantly better than NSAIDs for some, can be combined with antiemetics, and early intervention is important.

Lasmiditan

• Lasmiditan is a selective 5-HT1F receptor agonist approved by the FDA (2019) to treat acute migraine.
• It targets 5-HT1F receptors in trigeminal neurons, leading to their inhibition.
• It may be less effective than triptans but is safe for patients with vascular disease

Ergotamine and Dihydroergotamine

• Ergotamine and dihydroergotamine, broad-spectrum serotonin agonists, have been used in migraine treatments, with similar mechanisms to triptans but more severe adverse effects.

CGRP Antagonists (Gepants)

• CGRP release from trigeminal sensory endings is linked to migraine pathogenesis.
• First-generation CGRP antagonists were found to be hepatotoxic.
• Second-generation small molecule CGRP antagonists (Gepants) do not appear to cause significant liver toxicity.
• Ubrogepant and rimegepant were approved in 2020 for acute migraine treatment; they are somewhat less efficacious but better tolerated than triptans.

Preventive Pharmacotherapy of Migraine

• Recurrent migraines are managed by pharmacological approaches and lifestyle changes to avoid triggers.
• Menstrual migraines can be treated with triptans (naratriptan or frovatriptan) or NSAIDs.
• Patients with impairing/disabling migraine frequencies are at risk of medication overuse headaches and require preventive therapy.
• Continuous prophylaxis formerly included beta blockers, antiepileptic drugs, antidepressants, calcium channel blockers, ACE inhibitors, petasites (Butterbur), or botulinum toxin injections, but with limited effectiveness.
• Several immunotherapies for migraine have been FDA-approved since 2018 including:
  • Erenumab: a monoclonal antibody targeting the CGRP receptor.
  • Fremanezumab, galcanezumab, and eptinezumab: monoclonal antibodies targeting CGRP.
  • Altogepant and rimegepant: small molecule CGRP antagonists.
• Preventive therapies include:
  • mAbs targeting CGRP
    • Erenumab
    • Fremanezumab
    • Galcanezumab
    • Eptinezumab
  • Gepants
    • Altogepant
  • Beta Blockers
    • Propanolol
    • Timolol
    • Metoprolol
  • Antiepileptic drugs
    • Valproate
    • Topiramate
  • Antidepressants
    • Amitriptiline
    • SSRIs
    • SNRIs
• Behavioral therapies such as relaxation training, EMG biofeedback, and cognitive therapy are effective.

Pathophysiology of Emesis

• Nausea and vomiting are physiological responses to infections, pregnancy, vestibular dysfunction, radiation therapy, and chemotherapy.
• Emesis is mediated by the activation of the "vomiting center" in the brain stem, which integrates inputs from the GI tract, heart, meninges, forebrain, vestibular system, and the chemoreceptor trigger zone.

Pharmacotherapy of Emesis

• Treatment relies on targeting drugable neurotransmitter receptors in neuronal circuits; 5-HT3 receptors are in the nucleus of the tractus solitarius (vomiting center) and on vagal afferents.
• Serotonin, released from enterochromaffin cells after chemotherapy, activates these receptors, causing emesis.
• Neuropeptide substance P and NK1 receptors are abundantly expressed in the “vomiting center;" they are thought to play a role in emesis.
• Patients respond to chemotherapy with highly emetogenic drugs (cisplatin) with an acute phase of emesis followed by a delayed phase.
• 5-HT3 receptor antagonists combined with dexamethasone nearly completely protect against acute vomiting from chemotherapy.
• Available 5-HT3 receptor antagonists include ondansetron, granisetron, dolasetron, and palonosetron.
• 5-HT3 receptor antagonists are less effective in suppressing the delayed phase of chemotherapy-induced emetic response, which responds to Neurokinin 1 (NK1) receptor blockers (aprepitant, netupitant, and rolapitant) combined with 5-HT3 receptor antagonists and corticosteroids to inhibit both acute and delayed phases.
• Other drugs for emesis include:
  • Antipsychotics that inhibit dopamine receptors
  • Substituted benzamides (metoclopramide)
  • Cannabinoids
  • Antihistamines (diphenhydramine)
  • Anticholinergics (scopolamine), useful for motion sickness

Pharmacological Strategies for Sleep Disturbances

• Sleep disturbances are common and impact quality of life.

Insomnia

• Insomnia is a sleep disturbance characterized by difficulty falling asleep.
• Pharmacological approaches rely on short-acting benzodiazepines or benzodiazepine-like hypnotics:
  • Zoldipem (Ambien, half-life ~2.6 hrs)
  • Zaleplon (Sonata, half-life ~1-1.5hr)
  • Eszopiclone (Lunesta, half-life ~6hrs).
• These drugs quickly induce sleep with minimal next-morning somnolence. Lorazepam and temazepam are sometimes used, however, they have longer half-lives. FDA-approved options include the antidepressant doxepin and the melatonin receptor agonist ramelteon. Alternatively, H1 antagonists (diphenhydramine or trazodone) may be used. Cognitive behavioral therapy is also effective and may be preferred in the elderly.

Hypersomnia

• Hypersomnia is excessive sleepiness, including shift work sleep disorder and narcolepsy.
• Modafinil and armodafinil are FDA-approved Schedule 4 drugs, thought to have a lower abuse risk than stimulants like amphetamine.

Narcolepsy

• Narcolepsy is uncommon (prevalence ~25-50 cases per 100,000 people), characterized by a daytime urge to sleep, inappropriate daytime sleep, and fragmented nighttime sleep.
• Narcolepsy is associated with cataplexy, which involves weakened muscle tone with preserved consciousness
• Narcolepsy with cataplexy involves the loss of hypothalamic neurons that produce orexin A and B (hypocretins).
• Orexin neurons, by releasing orexin, maintain and stabilize sleep and wakefulness through two GPCR receptors (OX1 and OX2). Dual orexin receptor antagonists, such as suvorexant, lemborexant, and daridorexant, are approved for insomnia (schedule 4).
• Modafinil, armodafinil, and amphetamine are effective for narcolepsy, as is sodium oxybate (GHB), thought to condense sleep in a discrete period to counter sleep fragmentation caused by the loss of orexin neurons.

Drugs for Sleep Disorders

• Insomnia
  • Short acting hypnotics
    • Zoldipem
    • Zaleplon
    • Eszopiclone
  • Suvorexant
  • Doxepin
  • Ramelteon
• Hypersomnia (Shift work sleep disorders, breathing-related sleep disorders, narcolepsy, etc.)
  • Stimulants
    • Modafinil
    • Armodafinil
  • Hypnotic
    • Sodium oxybate (GHB)