Lecture 62 Headache Therapeutics Reardon

GOALS OF THERAPY:

• Treat attacks rapidly & consistently, and prevent recurrence

• Restore the pt’s ability to function

• Minimize the use of backup and rescue medications

• Optimize self-care and reduce subsequent use of resources

• Have minimal or no adverse effects

• Be cost-effective in overall management

APPROACH TO TREATMENT:

• Take medications as early as possible when HA pain starts

• Select non-oral route of admin for pts whose migraines present early with sig. N&V

• Not all agents work in all pts and not all agents work in the same pt all the time

• Use a stratified treatment approach

• Provide plan for “backup” or “rescue therapy”

• Encourage use of headache diary

• Guard against medication overuse headache

NON-PHARMACOLOGIC MANAGEMENT:

• Identify and avoid triggers o Lifestyle consistency: sleep, diet, hydration, caffeine,

alcohol, exercise, stress

• Application of cold/pressure

• Rest/stimulus deprivation

• Relaxation training, biofeedback, CBT

• Acupuncture, physiotherapy, chiropractic

ACUTE MIGRAINE TREATMENT:

SIMPLE ANALGESICS (ASA, ACETAMINOPHEN, NSAIDS):

Migraines • Reasonable first line choices for treatment of mild-moderate migraine attacks

• Not good if pt is vomiting, but could combine with antiemetic

• ASA + metoclopramide may be as effective as sumatriptan for mild-mod attacks

Tension • First line +/- caffeine

Cluster • No role

TRIPTANS:

Migraines • First line for moderate-severe attacks

Tension • Usually no role, may have benefit in patient with co-morbid migraines

Cluster • Sumatriptan subcut first line

Efficacy • Individual response varies considerably

• If pt fails a triptan, they can often be successfully switched to another

Admin • Consider subcut/nasal in pts who desire more rapid relief, have nausea, or fast onset of migraine

• May be synergy between NSAIDs and triptan

• If recurrence, repeat dose

Safety re: MI • Caution with CVD, but note no studies show increased risk of MI

Drug interactions

Triptans • Can’t use within 24h of dihydroergotamine (additive vasoconstriction)

• Because PRN, other theoretical interactions unlikely to be clinically significant

Frovatriptan, zolmitriptan

CYP1A2: cimetidine

Eletriptan CYP3A4: fluconazole, ketoconazole, erythromycin, verapamil

Serotonin syndrome

• Potentially life-threatening condition associated with increased CNS serotonergic activity

o Mental status changes, tachycardia, hyperthermia, NVD, hyperreflexia, incoordination

o Typically min-hrs after initiation/ dose increase in serotonergic drugs

• Selective action on 5HT1B/D = remote possibility o NOTE: routinely in combo with SSRIs/

SNRIs (depression/anxiety meds)

• Educate pts – stop triptan & seek medical help if symptoms occur

DIHDROERGOTAMINE:

Migraines • Mod-severe pain if triptans not an option

• Status migrainosus (migraine lasting >72h)

Tension • No role

Cluster • May be effective (IV) as second-line option

Admin • Nasal spray or IV/subcut

• Co-admin with antiemetic to reduce nausea

Efficacy • DHE IN less effective than sumitriptan IN

• Subcut similar to sumatriptan subcut o DHE slower onset but fewer

recurrences

• Role in treating medication withdrawal HA

Drug Interaction

• Can’t use within 24h of triptan (additive vasoconstriction)

• Avoid use with potent CYP3A4 inhibitors: cimetidine, clarithromycin, erythromycin, efavirenz, ritonavir, itraconazole, ketoconazole

ANTIEMETICS:

Migraines • PO or IV as adjunct with simple analgesics or migraine specific therapy

• IV for aborting migraine (usually hospital)

Tension • Limited role

• Small, low-quality trials suggest potential role for IV metoclopramide, chlorpromazine to abort headache

Cluster • Not part of standard management

• May be effective when given IV

Oral use • Adjuncts for nausea, increasing gastric motility to facilitate absorption of abortive therapies

IV use • Monotherapy for aborting migraines

• Dimenhydrinate ineffective for this

OPIOIDS:

• LAST RESORT

• More likely to experience recurrent headache within 7 days

MONITORING PARAMETERS:

Efficacy Acute attacks • Pain (0-10) at 1h (subcut, IN), 2 h (oral formulations)

• Resolution of N,V and other associated symptoms

• Resolution of attack

Acute med use

• Reduced

• Under threshold for medication overuse

MIDAS score • 50% reduction in frequency and/or severity of HA

QOL/fxn • As per individual pt goals

Safety • Medication side effects

Lecture 62 Headache Therapeutics Reardon

MEDICATION OVERUSE HEADACHE:

DIAGNOSIS: A. Headache occurring on ≥ 15 days per month in a patient with

a pre-existing headache disorder B. Regular overuse for >3 months of one or more drugs that can

be taken for acute and/or symptomatic treatment of headache

• Triptans 10-14 HA days/month

• Opioids: 8 days/month

• Barbiturates: 5 days/month

• Simple analgesics >14 days/month (protective if <10d/m) C. Not better accounted for by another diagnosis Suggested that highest risk if with opioids, butalbital compounds and ASA/acetaminophen/caffeine combos

MANAGEMENT:

• Stop offending agent o Taper if opioids or barbiturate o May stop cold turkey if triptans/simple analgesics

• Manage withdrawal according to agent o Bridge with NSAID or prednisone

• Educate pts that HA likely will get worse before getting better

• Start appropriate prophylaxis

HOSPITAL ADMISSION FOR MIGRAINE:

• Treatment of severe nausea, vomiting and subsequent dehydration

• Treatment of severe, refractory migraine pain (status migrainosus)

• Detoxification from overuse of combo analgesics, ergots or opioids

PREVENTION:

INDICATIONS:

• Contraindication/failure acute abortive therapy

• Use of abortive medication > twice per week

• Risk of medication overuse headache

• Frequent or long-lasting migraine headaches

• Significant disability or diminished QOL despite appropriate acute treatment

• Menstrual migraines

APPROACH TO TREATMENT:

• Optimize non-pharmacologic interventions

• Choice depends on co-morbidities, patient-specific factors

• Preventive medications are considered effective if the frequency and/or monthly headache days and/or severity of attacks are reduced by ≥ 50%

• Titrate meds over a few weeks o Start low and titrate up to minimize side effects o Allow 4-8 weeks for benefit once at target dose

▪ Adequate trial is 2-3 months at reasonable dose

• Reasonable to leave on prophylactic therapy for 6-12 months, then consider slowly tapering off with monitoring for worsening headaches

PREVENTIVE MEDICATIONS:

BBs • Propranolol > placebo

CCBs • Flunarizine, verapamil o Old studies, gaps in reporting o Weak, conflicting data

• Verapamil = CYP3A4 inhibition

TCAs • Amitriptyline o First line option based on decades of clinical

experience (limitations of available data) o Non-inferior vs. topiramate

• Nortriptyline may be considered due to lower risk of anticholinergic SEs, however not studied for migraine

Anti-convulsants

• Sodium valproate, divalproex sodium, gabapentin

• Topiramate caused paresthesia o Potential for oral contraceptive failure (unlikely at

≤ 100 mg daily)

Onbotulinum toxin

• Reserved for chronic migraine

• 2 weeks to benefit, typical duration 3 months

• Practical considerations; accessibility, affordability

PREVENTION OF MENSTRUAL MIGRAINE:

NSAIDs • Naproxen 550 mg BID 7 days pre-menses x 13 days

• Sig. reduction in pain index/frequency/severity/duration

Triptans • Start 2 days prior to menses x 5-7 days o Frovatriptan 2.5 mg po BID o Zolmitriptan 2.5 mg po BID-TID o Naratriptan 1 mg BID

Hormonal therapy

• Individualized

Chasteberrry Vitex agnus-castus

• Widely marketed for PMS symptoms; showed reduction in migraine frequency and monthly HA days

• No remarkable “side effects”

• Caution drug/disease interactions (theoretical) o Hormones/hormone sensitive cancers o Dopaminergic agents/PD/Schizophrenia

NHPS FOR MIGRAINE:

Dose Caution Preferred in AEs

Riboflavin 400 mg/d (od – BID) None None Yellow urine

Coenzyme Q10

100 mg TID Hypotension Hypertension GI upset

Mg citrate 300 mg BID Kidney failure, diarrhea

Constipation Diarrhea, GI upset

Butterbur 75 mg BID None Allergic rhinitis

GI (burping)

Feverfew NO EVIDENCE

Migraines Melatonin 3 mg IR HS > placebo = amitriptyline 25 mg HS Melatonin 2 mg ER HS = placebo

TENSION HEADACHES:

Acute • Ibuprofen, naproxen, acetaminophen o ASA weak evidence that > placebo o +/- caffeine (greater efficacy BUT also SE)

• Acupuncture, heat, ice, manual therapies, rest, biofeedback

DON’T USE: butalbital, codeine, muscle relaxants

Prophylaxis • Lifestyle measures

• Limited and inconclusive pharmacotherapy o Amitriptyline, mirtazapine, venlaxafine

CLUSTER HEADACHES:

Acute 1st line • Sumatriptan subcut, may repeat in 1h

• Oxygen 100% via facial mask x 15 min

2nd line • Sumatriptan IN; Zolmitriptan PO or IN; Lidocaine IN; DHE IV

Prophylaxis 1st line • Verapamil 360 mg div BID-TID

2nd line • Corticosteroids (prednisone, dexa) a) Pulse and taper b) Continuous therapy

SPECIAL POPULATIONS:

Pediatrics Acute • Similar to adults

• Caution metoclopramide (high risk of dystonic reactions)

Prophylaxis • Weak or no data to support benefit

Pregnancy • 60-70% have improvement in migraines

• Non-pharm measures first line (also in lactation)

Acute • Acetaminophen (1st line)

• Ibuprofen, naproxen (2ndline) – avoid 3rd trimester

• Severe nausea: metoclopramide or prochlorperazine

Prophylaxis • Propranolol, magnesium

Lactation Acute • Acetaminophen 1st line

• Ibuprofen NSAID of choice

• Antiemetics = safe

• Sumatriptan if migraines refractory

Prophylaxis • Propanol, magnesium (1st line)

• Divalproex/valproic acid = compatible

Lecture 62 Headache Therapeutics Reardon

OTHER HEADACHES:

Peri-menopausal /hormonal

• Migraines typically worsen initially (erratic menstrual cycles, disturbed sleep)

• With menopause, migraines may improve

• Acute treatment remains standard

• Hormone replacement may be considered for prevention depending on risk:benefit analysis (but no evidence)

Post-traumatic HA

• HA developing within 7 days of injury or after regaining consciousness post injury

• Mixed headache types: migraine, tension, other features

• Paucity of data to guide treatment; often treat as primary headache type based on clinical features o Standard acute treatment o Prophylaxis determined case by case