Long-Term Care Updates

October 2017

By Alyson Lozicki, PharmD

The treatment of migraine symptoms in elderly patients is similar to treatment in younger adults. For all patients, the selection of a pharmacological agent should be based on patient- specific factors and migraine severity, and greater caution should be exercised for older adults due to an increased prevalence of comorbid conditions and risk of adverse effects. Because of this, options for drug therapy in the elderly are limited, but this population tends to have a better response to acute treatment in comparison to a younger cohort.1-3 Of the drugs that have established efficacy in the treatment of migraine, acetaminophen, triptans, ergotamine, opioids, and antiemetics can be appropriate options for elderly patients. Acetaminophen is the safest option and is the drug of choice for most patients with non- debilitating symptoms of migraine.2-4 The choice of therapy for patients with moderate- severe symptoms should be based on comorbid conditions, potential drug-drug interactions, and the risk of serious adverse effects. However, the adverse effect profile of a medication does not preclude its use.3 General recommendations and safety considerations are outlined in Table 1; some of these medications do appear on the Beers List with a strong recommendation to avoid due to increased risk of falls and fracture. Additionally, certain medications used to treat migraine in younger patients should be avoided in older adults due to the increased risk of serious adverse events. These include acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), barbiturate-containing drugs, flunarizine, www.creighton.edu/ 1-5 and tricyclic antidepressants (Table 2). pharmerica Table 1. Effective Abortive Therapy for Elderly Patients with Migraine1-5

Drug Recommendation Precautions

Acetaminophen Drug of choice for mild symptoms Maximum daily dose of 3000mg (off-label use)

Not recommended in patients with Drug of choice for moderate-to- risk factors for cardiovascular Triptans severe symptoms with no disease; caution with drug-drug contraindications interactions

Increased risk of adverse effects compared to younger patients; Ergotamine* Use with caution worsening of hypertension; may cause coronary and peripheral vasoconstriction

May cause oversedation, cognitive Use lowest effective dose and Opioids* impairment, constipation, urinary longer dosing interval retention

May cause sedation, movement Antiemetics Use with caution disorders, decrease seizure (adjunctive for nausea/vomiting) threshold *Beers Criteria Recommendations: Ergotamine - avoid due to lack of efficacy; Opioids - avoid total of >3 CNS-active drugs

Table 2. Migraine Medications to Avoid in the Elderly1-5 Drug* Rationale

Acetylsalicylic Acid & Nonsteroidal Increased risk of gastrointestinal bleeding, NSAID-induced Anti-inflammatory Drugs (NSAIDs) hypertension, renal impairment, drug interactions

Lack of evidence supporting efficacy; increased risk of Barbiturates dependence or drug-induced headache syndrome

Flunarizine Drug-induced Parkinson's

Tricyclic Antidepressants (TCAs) Anticholinergic effects

*Beers Criteria Recommendations: NSAIDs - avoid chronic use unless alternatives are not effective and patient can take a gastroprotective agent; Barbiturates - high rate of physical dependence and greater risk of overdose at low doses; TCAs - highly anticholinergic and sedating; Biologics: Eptinezumab, Erenumab, Fremanezumab, and Galcanezumab

Mechanism of Action: Calcitonin gene-related peptide (CGRP) antibody which inhibits vasodilation, inflammation, and pain transmission; Erenumab is uniquely a CGRP receptor-specific antibody.6

These drugs are among the first to be developed specifically for the of migraine, and are unique in their ability to be dosed monthly or quarterly (Table 3). The promising results of phase-III clinical trials were presented at the American Headache Society Annual Scientific Meeting (AHS) 2017. Trials have compared several new CGRPs to placebo in patients with chronic and episodic migraine, and evaluated the change from baseline in monthly days of moderate-severe headache and impact on disability. Patients in both the chronic and episodic migraine studies experienced statistically significant reductions in the number of headache days and disability compared to placebo; however, the clinical impact was modest (a difference of 2-5 days headache free, and marginal improvement in disability, compared to placebo). Additionally, there was not a significant difference in benefit between various dosing regimens of the active drug in each trial. There is not one drug that appears to stand out within this class in terms of superior efficacy. All of the investigational agents are fully humanized monoclonal antibodies, and the most common adverse effect across all studies was injection site pain/irritation, although this was not significantly different when compared to the placebo injection. Studies of the long-term safety and efficacy of these drugs are underway.7-10

Table 3. Investigational CGRPs for the Prevention of Migraine7-10 Route and Migraine Clinical Drug (Manufacturer) Frequency Type* Trials Intravenous Eptinezumab injection, every 3 Chronic PROMISE (Alder Pharmaceuticals) months

Erenumab Subcutaneous Episodic STRIVE & ARISE (Amgen and Novartis) injection, monthly

Subcutaneous Fremanezumab Chronic and injection, monthly or HALO-CM & HALO-EM (Teva Pharmaceuticals) Episodic every 3 months

Galcanezumab Subcutaneous Chronic and REGAIN, EVOLVE-1 & (Eli Lilly and Co.) injection, monthly Episodic EVOLVE-2

*Chronic migraine defined as >15 headaches per month Serotonergic Agents:

Lasmiditan (Eli Lilly and Co.) is a selective serotonin-1F receptor agonist with no vasoconstrictive activity.6 This drug has been studied as an abortive agent for the of migraine. The phase-III SAMURAI trial compared the safety and efficacy of lasmiditan to placebo in patients with an average migraine severity of 7.5 out of 10, and a large majority of the patients had at least 1 cardiovascular risk factor. A greater proportion of patients achieved pain relief (sustained for an average of 2 hours after the dose) and resolution of “most bothersome symptoms,” such as nausea and photophobia, with lasmiditan versus placebo when taken within 4 hours of migraine onset. While these differences were statistically significant, it is interesting to note that a relatively high percentage of patients (~40%) experienced pain relief with placebo. The most common adverse effects associated with treatment included dizziness (12-16%), paresthesia (6-8%), somnolence (6%), fatigue (4%), nausea (3-5%), and lethargy (2%). Additionally, the cardiovascular adverse effects that were likely attributed to lasmiditan included palpitations and bradycardia, occurring in <1% of patients. The CNS adverse effects are comparable in frequency to those of triptans, which have a similar mechanism of action (targeting serotonin-1B/1D), but lasmiditan has demonstrated a far lower risk of cardiovascular effects. This new class of drug for abortive therapy may be a promising option for patients not eligible for therapy with triptans. Long-term safety and efficacy studies are expected to conclude in 2018.11

It has not yet been disclosed whether elderly patients were included in the clinical trials for these investigational drugs, and the mean age of the patient population ranged from 40-50 years. Barring any long-term adverse effects associated with the CGRPs, these may prove to be a safe and effective option for the geriatric population as they are well tolerated and can be dosed monthly. The serotonergic agonist lasmiditan has been associated with fewer cardiovascular effects, compared to the similar drug class of triptans, but the CNS depressant effects may not make this an ideal agent for older adults.

While the treatment of migraine in the elderly is similar to that of younger patients, selecting an appropriate and effective agent is inherently a more complex process due to the number of comorbid conditions and concomitant medications that must be considered. Acetaminophen remains the drug of choice for treating the acute symptoms of migraine in this population. Triptans, ergotamine, opioids, and antiemetics may also be considered, but should be used with caution. Additionally, several medications used to treat migraine in younger patients should be avoided in the elderly due to the significantly increased risk of adverse effects. The options available for treatment may be limited, but the investigational agents in the pipeline show promise as alternative therapy. 1. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. 2015;55(1):3-20. http://onlinelibrary.wiley.com/doi/10.1111/head.12499/full 2. Bravo T. Headaches of the elderly. 2015;15:30. https://link.springer.com/article/10.1007/s11910- 015-0552-2 3. Haan J, Hollander J, Ferrari MD. Migraine in the elderly: a review. 2016;27(2):97-106. http://journals.sagepub.com/doi/10.1111/j.1468-2982.2006.01250.x 4. Straube A. (2016) Pharmacotherapy for primary headache disorders in the elderly. In: Mitsikostas D., Paemeleire K. (eds) Pharmacological Management of Headaches. Headache. Springer, Cham. https://link.springer.com/chapter/10.1007/978-3- 319-19911-5_16 5. Identifying medications that older adults should avoid or use with caution: the 2015 American Geriatrics Society Updated Beers Criteria. American Geriatrics Society website. http://geriatricscareonline.org/toc/american-geriatrics-society-updated- beers-criteria-for-potentially-inappropriate-medication-use-in-older-adults/CL001. Accessed September 11, 2017. 6. Turner IM. Migraine Preventive therapy: what’s in the pipeline? National headache Foundation website. March 2017. http://www.headaches.org/2017/03/13/migraine-preventive-therapy-whats-pipeline/. Accessed September 8, 2017. 7. Anderson P. Drugs targeting CGRP show promise in migraine. Medscape website. June 2016. http://www.medscape.com/viewarticle/865233. Accessed September 8, 2017. 8. Brauser D. Phase 3 STRIVE and ARISE trials show efficacy, safety for erenumab in migraine prevention. Medscape website. April 2017. http://www.medscape.com/viewarticle/879161. Accessed September 8, 2017. 9. Brauser D. Fremanezumab effective in chronic, episodic migraine. Medscape website. June 2017. http://www.medscape.com/viewarticle/881584. Accessed September 8, 2017. 10. Brauser D. Galcanezumab reduces migraine days in phase 3 trials. Medscape website. June 2017. http://www.medscape.com/viewarticle/881657. Accessed September 8, 2017. 11. Brauser D. SAMURAI: Lasmiditan reduces pain in acute migraine. Medscape website. June 2017. http://www.medscape.com/viewarticle/881835. Accessed September 8, 2017.

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