The estimated prevalence of migraine among women and men older than 65 years is 7% and 3%, respectively.1 Although these rates are lower than those of younger adults, migraine in elderly patients is especially concerning, given their increased risk for associated events such as ischemic stroke, white matter lesions, and migraine accompaniments that may be prevented with treatment.

However, selecting the appropriate therapy for older patients presents several challenges, including a heightened risk for adverse drug reactions and drug-drug interactions (DDIs) resulting from declining organ function, an increased prevalence of comorbidities, and polypharmacy in this population. These can lead to alterations in drug distribution, metabolism, and clearance.

“Moreover, elderly patients are usually underrepresented in clinical trials with a lack of information on appropriate adaptations of drug prescription,” according to a new paper published in Expert Opinion on Pharmacotherapy.1 Noting the dearth of guidance on the topic, the authors conducted a review of the literature and reported the following recommendations and other points to consider in the selection of migraine therapies for elderly patients.

Pharmacokinetic and Pharmacodynamic Changes

Increased free fractions of propranolol, valproic acid, and tricyclic antidepressants (TCAs) are associated with the reduced levels of albumin, α1-acid glycoprotein, and lipoproteins that occur with aging and in various aging-related diseases. Free fractions of ibuprofen, naproxen, valproic acid, and propranolol also change significantly with advanced age.

“In general, an estimate of [glomerular filtration rate] GFR should be considered for dose-adjustments in geriatric patients,” as stated in the paper.1 “Atenolol and metoclopramide doses must be lowered with low creatinine clearance according to the drug monographs, while ketorolac should be avoided in patients with renal impairment.”

Although a lower clearance of TCAs has been demonstrated in elderly patients, dose adjustment of amitriptyline and nortriptyline is not indicated, even when glomerular filtration rate is <15 mL/min.2 However, the prescribed dose of topiramate should be halved in older adults with a glomerular filtration rate <60 mL/min/1.73 m2.

Polypharmacy Issues

Polypharmacy-related adverse effects often result from interactions with CYP450 substrates. “CYP450s interactions are largely known and free tools are available  allowing [clinicians] to check relevant DDIs of specific drug combinations before prescription,” the authors wrote.1,3 For example, metoclopramide, a CYP2D6 inhibitor, is contraindicated in patients taking amitriptyline, cinnarizine, or flunarizine, which are primarily metabolized via CYP2D6.

The authors note that significant DDIs may also result from the combination of preventive and acute drugs used to treat migraine. In addition, DDIs can arise from pharmacodynamic “interactions occurring when concomitant drugs share the same molecular targets,” such as the increased risk for serotonin syndrome associated with coadministration of TCAs and triptans/ergot-derivatives.

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The choice of drug class should also be based on each patient’s comorbidities, including these examples mentioned in the paper: Triptans are contraindicated in older patients with cardiovascular risk factors, and beta-blockers are contraindicated in patients with heart disease, diabetes, and chronic obstructive pulmonary disease. TCAs are particularly effective in “patients with comorbid insomnia, mood, and anxiety disorders but [are] not recommended in patients with glaucoma or prostatic hypertrophy…[or those] with prolonged QTc intervals, since a mean prolongation of 10–20 ms has been identified in treated elderly patients.”1,4

The authors concluded that various aspects of physiological aging increase drug-associated risks and reduce the efficacy of therapies for migraine. Additional studies on this topic are needed, as the lack of research involving this population further complicates treatment selection. Meanwhile, the “recent development of easy-to-use bioinformatics tools for big molecular data management offer a useful support to decision-making in drug prescription, particularly for the preventive evaluation of possibly harmful drug interactions in elderly polypharmacy-treated patients.”1

Neurology Advisor checked in with Laura Banks, MD, a neurologist at Natividad Medical Center in Salinas, California, and a member of the American Academy of Neurology, for a brief discussion about migraine treatment in elderly patients.

Neurology Advisor: What are some of the challenges pertaining to migraine treatment in elderly patients?

Dr Banks: Elderly patients are more likely to have several medical problems for which they take a plethora of medications. It is not unusual for these patients to be taking a dozen prescriptions. This puts them at greater risk for drug-drug interactions.

In addition, as a female migraineur ages, she is at greater risk of suffering neurological symptoms, which may mimic stroke symptoms, and they can be misdiagnosed.

Physiological decline of hepatic and renal function also places the elderly at greater risk for adverse effects, as they can develop toxicities at much lower doses.

Neurology Advisor: What are the key treatment recommendations for clinicians regarding this topic?

Dr Banks: It is critical to start elderly patients at lower-than-normal starting doses and initiate slower titration schedules to minimize adverse effects. Therapeutic drug monitoring can be helpful in monitoring preventive treatments.

Neurology Advisor: What should be the focus of further investigation in this area?

Dr Banks: Older adults have a different physiology than younger individuals. As such, I believe we should have separate prophylactic treatment studies in the elderly, just as we do in the pediatric population.

References

  1. Curto M, Capi M, Martelletti P, Lionetto L. How do you choose the appropriate migraine pharmacotherapy for an elderly person? Expert Opin Pharmacother. 2019;20(1):1-3.
  2. Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3–5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2012;27(10):3736-3745.
  3. Hoffmann MF, Preissner SC, Nickel J, Dunkel M, Preissner R, Preissner S. The Transformer database: biotransformation of xenobiotics. Nucleic Acids Res. 2014;42(1):D1113-D1117.
  4. Rochester MP, Kane AM, Linnebur SA, Fixen DR. Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence. Ther Adv Drug Saf. 2018;297-308.