Narrative Review of Migraine Management in Patients With Renal or Hepatic Disease

Jennifer I. Stern MD; Shae Datta MD; Chia-Chun Chiang MD; Ivan Garza MD; Dorice L. Vieira MLS, MA, MPH; Carrie E. Robertson MD

Disclosures

Headache. 2023;63(1):9-24.

Abstract and Introduction

Abstract

Objectives/Background: Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system.

Methods: A detailed search for terms related to liver disease, renal disease, and migraine management was performed in PubMed, Ovid Medline, Embase, and the Cochrane Library.For each medication, product labels were retrieved and reviewed using the US FDA website, with additional review of IBM Micromedex, LiverTox, and the Renal Drug Handbook.

Results: This manuscript provides an overview of migraine drug metabolism and how it can be affected by liver and renal impairment. It reviews the standard terminology recommended by the US Food and Drug Administration for the different stages of hepatic and renal failure. The available evidence regarding the use of abortive and preventative medicines in the setting of organ failure is discussed in detail, including more recent therapies such as lasmiditan, gepants, and calcitonin gene-related peptide antibodies.

Conclusions: For acute therapy, the use of NSAIDS should be limited, as these carry risk for both severe hepatic and renal disease. Triptans can be selectively used, often with dose guideline adjustments. Ubrogepant may be used in severe hepatic disease with dose adjustment and lasmiditan can be used in end stage renal disease. Though non-medicine strategies may be the most reasonable initial approach, many preventative medications can be used in the setting of hepatic and renal disease, often with dose adjustment. This review provides tables of guidelines, including reduced dosing recommendations, for the use of abortive and preventative migraine medications in hepatic and renal failure.

Introduction

It is not uncommon for patients to present for migraine management with comorbid hepatic or renal impairment, given the high prevalence of each of these diseases. While migraine affects an estimated 12% of the population,^[1] chronic liver disease is estimated to occur in 1.5 billion people worldwide,^[2] and the global prevalence of chronic kidney disease (CKD) has recently been estimated at 11%–13%.^[3] Headache management in the setting of either hepatic or renal disease presents a challenge, as both can result in complex changes in biological and pharmacokinetic activities of headache medications and may increase risk for drug-related injury. This manuscript will provide a clinical guide and approach to headache management in patients with renal or hepatic disease.

Decisions on acute or preventative headache medicines for a patient with kidney or liver failure must consider not only how the drug's metabolism is changed depending on organ failure severity, but also whether the drug can create further organ toxicity or damage. This manuscript will therefore start with a brief overview of drug metabolism and how this may be affected by organ failure. Because the US Food and Drug Administration (US FDA) has recommended standard terminology be used for different stages of organ failure in pharmacokinetic studies, we will review the terminology recommended in the US FDA guidelines for industry. Each organ review will also be accompanied by some secondary headache considerations in the case of organ impairment. Finally, available evidence regarding the use of migraine acute and preventative medicines in the setting of organ failure will be discussed in detail.

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Abstract and Introduction
Methods
Summary and Discussion
References

Table 1. Acute migraine medications in renal impairment
Medication	Mild or moderate renal impairment (eGFR 60–89 or 30–59 respectively)	Severe renal impairment (eGFR 15–29)	End-stage renal disease (eGFR <15)	End-stage renal disease on dialysis	Selected pharmacokinetic comments
Acetaminophen (oral route)³³	eGFR>60: no dose adjustment eGFR 30–50: Increase dosing interval to every 6 h	eGFR 15–29: increase dosing interval to every 6 h	eGFR <10: increase dosing interval to every 8 h	Do not supplement after HD Not dialyzable⁶	Eliminated in urine (<5% unchanged) Renal impairment: accumulation of toxic metabolites
Ibuprofen³⁴	eGFR 30–50: no specific dose adjustment but avoid if possible⁶	No specific dose adjustment but avoid if possible⁶	Not recommended³⁴	Not recommended³⁴ Not dialyzable⁶	Primarily eliminated in urine (<1% unchanged) NSAIDs inhibit prostaglandins, leading to possible decreased renal perfusion
Naproxen³⁵	eGFR 30–50: no specific dose adjustment but avoid if possible⁶ Caution advised³⁶	Not recommended³⁵	Not recommended³⁵	Not recommended³⁵ Not dialyzable⁶	Primarily eliminated in urine (<1% unchanged) NSAIDs inhibit prostaglandins, leading to possible decreased renal perfusion
Naratriptan³⁷	Start at 1 mg. Maximum 2.5 mg in 24 h³⁷	Maximum 2.5 mg in 24 h⁶	Contraindicated in eGFR <15³⁷	Likely dialyzable⁶	Predominantly eliminated in urine (50% unchanged and 30% as metabolites)
Sumatriptan^{38, 39}	Dose as in normal renal function for eGFR 30–50⁶	Dose as in normal renal function for eGFR 20–29⁶ <20: use with caution	Use with caution⁶	Unknown whether dialyzable⁶	Oral: 60% eliminated in urine (mostly metabolites; only 3% unchanged) SC: 60% eliminated in urine (22% unchanged)
Frovatriptan⁴⁰	No dose adjustment⁶	No dose adjustment⁶	No dose adjustment⁶	No dose adjustment recommended⁶ Likely dialyzable⁶	<10% eliminated in urine
Rizatriptan⁴¹	No dose adjustment⁶	No dose adjustment⁶	Start 5 mg, may repeat after 2 h; maximum 15 mg in 24 h⁶	Start 5 mg, may repeat after 2 h; maximum 15 mg in 24 h⁶ Unknown whether dialyzable⁶ Exposure 44% higher in HD than in normal renal function	82% eliminated in urine (14% unchanged, remainder metabolites)
Almotriptan⁴²	No dose adjustment⁶	Limit individual dose to 6.25 mg; maximum dose 12.5 mg in 24 h⁴²	Limit individual dose to 6.25 mg; maximum dose 12.5 mg in 24 h⁴²	Limit individual dose to 6.25 mg; maximum dose 12.5 mg in 24 h⁴² Likely dialyzable⁶	75% eliminated in urine (40% unchanged)
Zolmitriptan⁴³	No dose adjustment⁴⁴	No dose adjustment⁴⁴	No dose adjustment⁴⁴	Unknown whether dialyzable⁶	65% eliminated in urine (8% unchanged)
Eletriptan⁴⁵	No dose adjustment⁶	No dose adjustment⁶	No dose adjustment but use with caution⁶	No dose adjustment but use with caution⁶ Unknown whether dialyzable⁶	10% eliminated in the urine Blood pressure elevation was seen in mild, moderate or severe renal impairment
Rimegepant⁴⁶	No dose adjustment⁴⁶	No dose adjustment⁴⁶	Avoid use⁴⁶	Avoid use⁴⁶	24% elimination in the urine
Ubrogepant⁴⁷	No dose adjustment⁴⁷	No more than 50 mg/dose. May use 2nd 50 mg dose 2 h after the 1st⁴⁷	Avoid use⁴⁷	Not defined by manufacturer	Renal elimination plays a minor role
Lasmiditan⁴⁸	No dose adjustment⁴⁸	No dose adjustment⁴⁸	No dose adjustment⁴⁸	Not defined by manufacturer	Renal elimination plays a minor role

Abbreviations: eGFR, estimated glomerular filtration rate; HD, hemodialysis; NSAID, nonsteroid anti-inflammatory drug; SC, subcutaneous.

Table 2. Migraine preventative medications in renal impairment
Medication	Mild or moderate renal impairment (eGFR 60–89 or 30–59 respectively)	Severe renal impairment (eGFR 15–29)	End-stage renal disease (eGFR <15)	End-stage renal disease on dialysis	Selected pharmacokinetic comments
Amitriptyline⁵⁴	No dose adjustment required; start low dose⁵⁵	No dose adjustment required; start low dose⁵⁵	No dose adjustment required; start low dose⁵⁵	No dose adjustment required; start low dose⁵⁵ Not dialyzable⁶	33%–50% eliminated in urine (majority metabolites)
Nortriptyline⁵⁶	No dose adjustment⁶	No dose adjustment⁶	No dose adjustment for eGFR 10–15⁶ Start low dose for eGFR <10⁶	Start low dose⁶ Not dialyzable⁶	Majority excreted in urine
Venlafaxine⁵⁷	Reduce dose by 25%⁵⁷	Reduce dose by at least 50%⁵⁷	Reduce dose by 50%⁶	Reduce dose by 50%⁵⁷ Not dialyzable⁵⁷	87% eliminated in urine (5% unchanged; remainder metabolites)
Topiramate⁵⁸	Reduce dose by 50% for eGFR<70⁵⁸	Reduce dose by 50%⁵⁸	Reduce dose by 50%⁵⁸	Supplemental dose may be required⁵⁸ Dialyzable⁶ Dialysis removes topiramate at a rate 4–6 times greater than normal	70% eliminated in urine (majority unchanged)
Valproic acid⁵⁹	No dose adjustment⁶	No dose adjustment⁶	No dose adjustment for eGFR >10; start low dose and titrate as needed for eGFR <10⁶	Start low dose and titrate as needed for eGFR <10⁶ 20% reduction in valproate concentrations with HD	30%–50% eliminated in urine (1.8% unchanged) Renal disease may decrease protein binding: may be misleading to monitor total concentration
Gabapentin⁶⁰	eGFR ≥60: max dose 1200 mg TID⁶⁰; eGFR 31–59: max dose 700 mg BID⁶⁰	eGFR >15–29: maximum 700 mg QD⁶⁰ eGFR 15: maximum dose 300 mg QD⁶⁰	eGFR <15: reduce dose proportionally below eGFR 15⁶⁰ (eGFR of 7.5 ml/min should get half dose of 15 ml/min)	Give maintenance dose based on eGFR estimate, and a post-HD supplement (125–350 mg) after each 4 h of HD⁶⁰ 50% of gabapentin is removed per 4-h HD session⁵⁵	100% eliminated unchanged in urine Gabapentin toxicity in the setting of renal impairment may be underrecognized⁶¹
Propranolol⁶²	eGFR 30–50: dose same as with normal renal function⁶	eGFR 15–20: start at low dose and titrate if needed⁶	Start at low dose and titrate if needed⁶	Adjustment not necessary⁶³ Not dialyzable⁶	< 1% eliminated in urine Chronic renal failure can also decrease hepatic metabolism by downregulating cytochrome P450 Non-selective beta blockers can decrease renal perfusion⁶⁴
Metoprolol⁶⁵	No dose adjustment⁶	eGFR >20: no dose adjustment⁶ eGFR 15–20: start low dose and titrate as needed⁶	Start low dose and titrate as needed⁶	Start low dose and titrate with caution⁶ Not dialyzable⁶	95% eliminated in urine (<5% unchanged; remainder metabolites)
Candesartan⁶⁶	No dose adjustment⁶	eGFR >20: no dose adjustment⁶ eGFR 15–20: start 2 mg and titrate as needed⁶	Start 2 mg and titrate as needed⁶	Start 2 mg and titrate as needed⁶ Not dialyzable⁶	33% eliminated in urine (26% unchanged)
Lisinopril⁶⁷	eGFR >30: start 10 mg; maximum 40 mg/day⁶⁷	Start 5 mg/day; maximum 40 mg/day⁶⁷	Start 2.5 mg/day; maximum 40 mg/day⁶⁷	Start 2.5 mg/day; maximum 40 mg/day⁶⁷ 10–40 mg 3 times/week after HD Do not supplement after HD Dialyzable⁶	100% eliminated in urine unchanged
Verapamil⁶⁸	No dose adjustment⁶ Monitor closely⁶⁸	No dose adjustment⁶	No dose adjustment, but monitor carefully for eGFR <10⁶	No dose adjustment, but monitor carefully for eGFR <10⁶ Not dialyzable⁶⁸	70% eliminated in urine (3%–4% unchanged; remainder metabolites)
Onabolutinum-toxinA⁶⁹	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Recommended doses are undetectable in blood suggesting no or minimal systemic absorption
Atogepant⁷⁰	No dose adjustment recommended⁷⁰	Maximum dose 10 mg daily⁷⁰	Maximum dose 10 mg daily⁷⁰	Take after dialysis⁷⁰	Renal excretion plays a minor role
Erenumab⁷¹	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Renal impairment is not expected to have an effect on pharmacokinetics based on mechanism; however, has not been studied in severe renal impairment
Galcanezumab⁷²	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer
Fremanezumab⁷³	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer
Eptinezumab⁷⁴	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer	Not defined by manufacturer

Abbreviations: BID, twice daily; eGFR, estimated glomerular filtration rate; HD, hemodialysis; QD, once daily; TID, three times a day.

Table 3. Acute migraine treatment in hepatic impairment
Medication	Mild or moderate impairment, Child-Pugh A or B	Severe impairment, Child-Pugh C	Selected pharmacokinetic comments
Acetaminophen³³	Less than 2–3 g/day, short term use⁷⁸	Avoid	Extensive hepatic metabolism with toxic metabolites
Ibuprofen³⁴	Avoid⁷⁹	Avoid⁷⁹	Extensive hepatic metabolism
Naproxen^{35, 36}	Avoid⁷⁹	Avoid⁷⁹	Extensive hepatic metabolism
Naratriptan³⁷	Start at 1 mg. Maximum 2.5 mg in 24 h³⁷	Contraindicated³⁷	Partial hepatic metabolism with inactive metabolites
Sumatriptan^{38, 39}	Maximum 50 mg PO per dose for mild to moderate hepatic impairment³⁸	Contraindicated (PO and SC)³⁸	Extensive hepatic metabolism
Frovatriptan⁴⁰	No adjustment needed in mild to moderate hepatic impairment⁴⁰	Caution advised⁴⁰	Partial hepatic metabolism
Rizatriptan⁴¹	Mild: dose not defined by manufacturer⁴¹ Moderate: caution advised	Caution advised⁴¹	Majority undergoes hepatic metabolism
Almotriptan⁴²	Moderate: maximum single dose 6.25 mg/dose; 12.5 mg/24 h⁴²	Maximum single dose 6.25 mg/dose; 12.5 mg/24 h⁴²	Partial hepatic metabolism
Zolmitriptan⁴³	Moderate: maximum single dose 1.25 mg; 5 mg in 24 h⁴³ Avoid ODT or nasal spray because dose cannot be reduced	Severe: Maximum single dose 1.25 mg; 5 mg in 24 h⁴³ Avoid ODT or nasal spray because dose cannot be reduced	Majority undergoes hepatic metabolism with both active and inactive metabolites⁶ Active metabolite is more active on 5HT_1B/1D receptors than parent compound Case reports of cholestatic hepatitis
Eletriptan⁴⁵	Dose not defined by manufacturer	Not recommended⁴⁵	Primarily undergoes hepatic metabolism into active and inactive metabolite⁶
Rimegepant⁴⁶	No dose adjustment⁴⁶	Avoid use⁴⁶	Partial hepatic metabolism
Ubrogepant⁴⁷	No dose adjustment⁴⁷	No more than 50 mg/dose. May use 2nd 50 mg dose 2 h after the 1st⁴⁷	Majority undergoes hepatic metabolism
Lasmiditan⁴⁸	No dose adjustment⁴⁸	Not recommended⁴⁸	Primarily eliminated via hepatic and extrahepatic metabolism

Abbreviations: PO, orally; ODT, orally disintegrating tablet; 5-HT, 5-hydroxytryptamine (serotonin)

Table 4. Preventative Treatment of Migraine in Patients With Hepatic Impairment
Medication	Mild or moderate impairment, Child-Pugh A or B	Severe impairment, Child-Pugh C	Selected pharmacokinetic comments
Amitriptyline⁹⁸	Reduce by 50% in chronic liver disease⁹⁹	Start lowest dose and titrate slowly; consider administering in conjunction with laxatives⁸²	Extensive hepatic metabolism with metabolites, including main active metabolite nortriptyline⁶
Nortriptyline¹⁰⁰	Reduce by 50% in chronic liver disease⁹⁹	Start lowest dose and titrate slowly; consider administering in conjunction with laxatives⁸²	Extensive hepatic metabolism, including active metabolite⁶
Venlafaxine⁵⁷	Reduce dose by 50%⁵⁷	Dose not defined by manufacturer	Extensive hepatic metabolism, including active metabolite⁶
Topiramate⁵⁸	Use with caution⁵⁸	Use with caution⁵⁸ 30% increase in plasma levels in patients with moderate to severe liver disease¹⁰¹	Partial hepatic metabolism
Valproic acid⁵⁹	Contraindicated⁵⁹	Contraindicated⁵⁹	Almost completely metabolized by the liver
Gabapentin⁶⁰	Dose not specifically addressed by manufacturer, but adjustment not expected to be required, as hepatic metabolism does not occur	Dose not specifically addressed by manufacturer, but adjustment not expected to be required, as hepatic metabolism does not occur	Not metabolized by liver
Metoprolol⁶⁵	Use with caution⁶⁵	Use with caution⁶⁵	Extensive hepatic metabolism
Propranolol⁶²	Use with caution⁶²	Use with caution⁶²	Extensive hepatic metabolism with active and inactive metabolites⁶
Candesartan⁶⁶	Child-Pugh Class A: no dose adjustment⁶⁶ Child-Pugh Class B: start 8 mg/day⁶⁶	Dose not defined by manufacturer	Hepatic metabolism is minor
Lisinopril⁶⁷	Dose not specifically addressed by manufacturer, but adjustment not expected to be required, as hepatic metabolism does not occur	Dose not specifically addressed by manufacturer, but adjustment not expected to be required, as hepatic metabolism does not occur	No hepatic metabolism
Verapamil⁶⁸	Give approximately 30% of normal dose⁶⁸ Consider avoiding ER dose	Give approximately 30% of normal dose⁶⁸ Consider avoiding ER dose	Extensive hepatic metabolism, including active metabolite
OnabotulinumtoxinA⁶⁹	Not defined by manufacturer	Not defined by manufacturer	Recommended doses are undetectable in blood suggesting no or minimal systemic absorption
Atogepant⁷⁰	No dose adjustment⁷⁰	Avoid use⁷⁰	Metabolism is main route of elimination; primarily CYP3A4 Avoidance was recommended in Child-Pugh class C because of adverse effect of liver enzyme elevation
Erenumab⁷¹	Not defined by manufacturer	Not defined by manufacturer	No dedicated studies of effect of hepatic impairment on pharmacokinetics were performed, but hepatic impairment is not expected to have an effect on pharmacokinetics, because it is thought to be eliminated through saturable binding to the CGRP receptor (at low concentrations) and proteolytic degradation (at higher concentrations)
Galcanezumab⁷²	Not defined by manufacturer	Not defined by manufacturer	No dedicated studies of the effect of hepatic impairment on pharmacokinetics, but hepatic impairment is not expected to impact pharmacokinetics, because it is thought to be eliminated through proteolytic degradation
Fremanezumab⁷³	Not defined by manufacturer	Not defined by manufacturer
Eptinezumab⁷⁴	Not defined by manufacturer	Not defined by manufacturer

Abbreviation: ER, extended release; CYP, cytochrome P450

Table 5. Summary of management options for end stage renal disease and severe cirrhosis
	End-stage renal disease	Severe cirrhosis	Non-medicine strategies to consider for either
Probably safe	Acute • Frovatriptan • Zolmitriptan • Eletriptan • Lasmiditan Preventative • Amitriptyline/nortriptyline • Valproic acid • Metoprolol • Candesartan • OnabotulinumtoxinA injections (for CM)	Preventative • Gabapentin • Lisinopril • OnabotulinumtoxinA injections (for CM)	• Cognitive behavioral therapy • Biofeedback • Neuromodulation devices • Nerve blocks • Filtered lenses (e.g., FL-41 lenses) • Acupuncture • Mindfulness • Exercise
Use with caution; either safety is unknown or medicine is likely to require dose adjustment	Acute • Acetaminophen (reduced dose) • Almotriptan (reduced dose) • Rizatriptan (reduced dose) • Sumatriptan (unknown safety) Preventative • Topiramate (reduced dose) • Gabapentin (reduced dose) • Propranolol • Verapamil • Lisinopril (reduced dose) • Venlafaxine (reduced dose) • Atogepant (reduced dose) • CGRP monoclonal antibodies (unknown safety)	Acute • Zolmitriptan (reduced dose) • Almotriptan (reduced dose) • Ubrogepant (reduced dose) Preventative • Topiramate (unknown safety) • Propranolol/metoprolol • Verapamil (reduced dose) Venlafaxine (reduced dose, unknown safety in severe disease) • Amitriptyline/nortriptyline (reduced dose) • CGRP monoclonal antibodies (unknown safety)
Unsafe/avoid	Acute • NSAIDs • Naratriptan (unknown safety) • Gepants (unknown safety)	Acute • NSAIDs • Acetaminophen • Naratriptan • Sumatriptan • Eletriptan • Rimegepant • Lasmiditan (unknown safety) Preventative • Valproic acid • Atogepant

Abbreviations: CGRP, calcitonin gene-related peptide; CM, chronic migraine; NSAID, nonsteroid anti-inflammatory drug.

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Narrative Review of Migraine Management in Patients With Renal or Hepatic Disease

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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