How do you choose the appropriate migraine pharmacotherapy for an elderly person?

KEYWORDS:

• Aging
• elderly
• migraine
• pharmacotherapy
• treatment

1. Introduction

Migraine is ranked as the third most prevalent disorder, the eight most burdensome disease and the seventh cause of disability worldwide [1]. Although its prevalence decreases after the age of 60, it still affects 7% of women and 3% of men over 65. A successful treatment of a late-life migraine is particularly important due to the association with increased risk of ischemic stroke, white matter lesions and other transient neurological phenomena (migraine accompaniments) responsive to prophylactic medications [1]. A preventive treatment is recommended in case of frequent, severe, and long-lasting attacks, when symptomatic drugs are not effective or contraindicated or quality of life is seriously affected. Among prophylactic treatments, tricyclic antidepressants (TCAs), β blockers (propranolol, atenolol, or metoprolol), anticonvulsants (topiramate or sodium valproate), and calcium channel blockers (cinnarizine or flunarizine) received highest recommendation levels based on strength of scientific evidence and clinical effectiveness. Likewise, nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, ergotamine, triptans, and antiemetics are recommended as acute treatments for migraine attacks [2]. Although the variety of effective drugs allows personalizing treatment, it also increases the risk of underestimated drug-drug interactions (DDIs), adverse effects, lack of efficacy, and medication overuse or nonadherence. In older patients, choosing an appropriate migraine treatment is complicated by the increased risk of DDIs and adverse drug reactions (ADRs) related to the presence of comorbidities, polypharmacy, and decline of body functions [3]. Moreover, elderly patients are usually underrepresented in clinical trials with a lack of information on appropriate adaptations of drug prescription. Therefore, the aims of this editorial are to examine the main factors affecting migraine treatments efficacy and safety and to outline specific aspects of synthetic drugs pharmacological profile that should be considered to improve migraine treatment selection in older adults.

2. Pharmacokinetics and pharmacodynamics changes in the elderly

A decline of organs functions and age-associated illnesses characterize the aging process. The resulting pharmacokinetic (PK) and pharmacodynamic (PD) changes are the key source of variability in the interindividual response to drugs [4]. Drug distribution, metabolism, and elimination represent PKs alterations sensitive to aging. A decrease in body weight, hydration, muscle/fat ratio, and albumin levels affect drugs solubility and distribution. The preventive drugs propranolol, valproic acid, and TCAs free-fractions are increased with low albumin, α1-acid glycoprotein, and lipoproteins levels often seen in physiological aging and several elderly-associated illnesses (such as renal and hepatic diseases, myocardial infarction, arthritis). Similarly, ibuprofen, naproxen, valproic acid, and propranolol free-fractions change significantly in elderly patients, even if the clinical significance remains unclear [5]. Conversely, the reduction of drugs metabolism and elimination associated to declined renal and hepatic functions may be clinically relevant in the elderly [4,5]. Hepatic metabolism is the main elimination path through cytochromes P450 (CYP450s) that show a reduced enzymatic activity in the elderly [4]. These changes, together with a decreased renal and bile elimination, lead to a prolonged exposure to drugs and increase their potential toxicity. The clinical significance is often difficult to estimate due to the exclusion of older patients from clinical trials and depends on therapeutic range and the tolerability profile of the single drug. TCAs showed a lower clearance in the elderly [6] but the contribution of renal and hepatic impairments for a reliable estimation of drugs response were difficult to determine. Nevertheless, among TCAs, amytriptiline, and nortryptiline dose adjustment is not indicated even with a glomerular filtration rate lower than 15 mL/min [7]. Conversely, topiramate dose should be lowered in older adults even with normal creatinine levels (half of the dose should be prescribed with creatinine clearance < 70 ml/min/1.73 m²), whereas age-related changes in hepatic function alone did not result in significant clinical impact or the need for dose adjustments [8]. 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. In general, an estimate of GFR should be considered for dose-adjustments in geriatric patients and therapeutic drug monitoring (TDM, i.e. the quantification of serum drug/metabolites concentrations), when available, should be used to monitor blood concentrations of the prescribed medications. Moreover, every drug should be started at low doses and augmented with slow titration schedules.

PDs changes, usually linked to increased drugs sensitivity, are even more difficult to estimate due to the many molecular pathways involved in aging physiological changes. However, the clinical effect of drugs hypersensitivity is demonstrated by the increased risk of ADRs, specific for the drug category. Therefore, the greater risk of class- and drug-related adverse effects should be considered and balanced with pre-existing illnesses that might lead to severe ADRs (see Section 3).

3. Polypharmacy, comorbidities, preventive, and acute drugs DDIs and ADRs in the elderly

Polypharmacy is prevalent in elderly patients due to comorbidities and has been associated with lower treatment adherence, quality of life and suboptimal health outcomes [3]. Polypharmacy has been also associated with a higher prevalence of DDIs-related ADRs in the geriatric population, which has already an increased risk of ADRs and ADRs-associated mortality [9]. Therefore, one of the most important safety factors in frail geriatric patients is the preemptive identification of DDIs. The combination of a migraine preventive and acute drugs itself might lead to clinically significant DDIs, affecting both PKs and PDs drugs profile, responsible for altered response and development of ADRs [10]. PK interactions usually involve the modulation of specific CYP450 isozymes by coadministered drugs that inhibit or induce cytochromes activity and change their substrates metabolism. Accordingly, in patients treated with amytriptiline, cinnarizine, and flunarizine, metabolized mainly via CYP2D6, the administration of metoclopramide (an inhibiting CYP2D6 substrate) should be avoided due to the risk of increased adverse effects. Similarly, the valproic acid inhibitory effect on CYP2C9 rise the risk of increased diclofenac, flurbiprofen, and ibuprofen levels [11]. CYP450s interactions are largely known and free tools are available online allowing to check relevant DDIs of specific drug combinations before prescription [11,12]. DDIs can also arise from PD interactions occurring when concomitant drugs share the same molecular targets. Serotonin syndrome risk is higher when TCAs and triptans/ergot-derivatives are coadministrated due to their additive effect on the serotonin system and beta-blockers hypotensive effects might be diminished by NSAIDs inhibition of prostaglandin synthesis [10].

Besides DDIs evaluation, drug class selection should be primarily dictated by patients’ comorbidities. Among symptomatic treatments, triptans are not indicated in elderly patients with cardiovascular risk factors [13] while lasmiditan showed a favorable cardiac tolerability profile in phase 3 clinical trials [14]. Moreover, acetaminophen should be preferred to NSAIDs in patients with other risk factors for upper gastrointestinal bleeding and in patients with renal impairment [15,16]. TCAs are effective especially in patients with comorbid insomnia, mood, and anxiety disorders but not recommended in patients with glaucoma or prostatic hypertrophy. Additionally, TCAs should be avoided with prolonged QTc intervals, since a mean prolongation of 10–20 ms has been identified in treated elderly patients [17]. Beta-blockers are contraindicated in patients with diabetes, chronic obstructive pulmonary disease, heart failure and heart diseases and calcium-channel antagonists in patients with hypotension, parkinsonian syndromes, and heart failure. The unfavorable side effects profile usually limit also the use of antiepileptics in the elderly whereas OnabotulinumtoxinA is a safe and useful option in drug-resistant patients [13,15].

4. Conclusions

The choice of a safe and effective late-life migraine treatment is particularly challenging for clinicians. In fact, a physiological decline of body functions, medical comorbidities, polypharmacy, DDIs, and increased ADRs risk significantly affect migraine medications effectiveness and tolerability profile. Therefore, the careful personalization of treatment based on individual patients characteristics, the preventive evaluation of drug combinations DDIs, a low dose initiation and slow titration and, when available, a TDM of drugs blood levels are essential to choose a safe and effective migraine treatment among the many available pharmaceutical options.

5. Expert opinion

The fast demographic grow of the older part of the population is leading increasingly to face the health problem of proper drug prescription. In particular, the choice of an appropriate migraine pharmacotherapy in the elderly raises specific issues for both prophylactic and acute medications and their combinations. In fact, physiological aging is characterized by several factors that increase drug-related harmfulness and decrease the clinical efficacy of migraine pharmacotherapy. Moreover, the lack of information about the adaptation of drug prescribing to geriatric patients, often excluded from clinical trials, demands for additional strategies to improve the appropriateness of migraine treatment choice. 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 drugs interactions in elderly polypharmacy-treated patients. Future research should be directed to integrate the molecular data with the evaluation of older patients’ general and clinical data (comorbidities, organs function, and lifestyle) in order to prescribe migraine drugs combinations with a higher clinical efficacy and risk/benefit ratio and to include systematically geriatric patients in clinical studies on migraine treatment. Meanwhile, useful strategies to improve the appropriateness of a migraine polypharmacotherapy prescription include the exclusion of potentially harmful medications based on the presence of specific comorbidities, the preventive DDIs estimation supported by freely available tools, the individual PK, and PD profile evaluation and a low drugs dose initiation followed by the monitoring of blood drug levels.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This manuscript was not funded.