TREATMENT OF HEADACHE

Lifestyle Changes
Abortive Therapy
Prophylactic Therapy
Nonpharmacologic modalities

I. Lifestyle changes

1. Adequate sleep
2. Exercise
3. Avoid caffeine
4. Avoid known precipitants
5. Stress reduction
6. Discontinue daily analgesics, including opiates, barbiturates, ergotamines, caffeine, etc.
7. Headache diary for some pts

II. Treatment of medication overuse headache

1. In a study in 56 pts with medication overuse headache randomized to (3mo detox off abortive treatment then initiation of prophylactic treatment if inidicated) vs. (prophylactic treatment at start of study with no detox) vs. (no specific treatment), the initial-prophylaxis gropu had sig. greater reduction in headache schores at 3mos and 12mos than the initial-withdrawal group.  A reviewer at JW criticized the study as lumping all abortive treatment together rather than separating out use of opioids, triptans, NSAIDs, etc. (Cephalalgia 29:221, 2009-JW)

III. Abortive therapy--generally, effectiveness is greatest early in an attack

1. Serotonin-1 agonists (aka "Triptans")

1. Sumatriptan (Imitrex)
   1. Better than placebo for migraine in several studies though 30-65% of successfully treated pts had recurrence of HA in 24-48h; also shown effective for cluster HA
   2. Injectable form
      1. 6mg SQ, may repeat in 1h x 1 though published trials showed that if first shot didn't work, second injection was also ineffective; can, however, give a second dose for a second attack
      2. Max dose 12mg SQ per attack
      3. More effective than oral ergotamine for abortive tx of migraine; probably quicker onset of action too
      4. Probably more effective than oral or intranasal forms
   3. Oral form (25-100mg; can repeat in 2h) also available; better in migraine than ergotamine or ASA + metoclopamide in double-blind trials, but higher 48h recurrence rate in sumatriptan groups; max dose 200mg PO/24h
   4. Intranasal form (5 or 20mg, a single spray in either nostril, or can do 2 sprays of 5mg for a dose of 10mg--can repeat x1 after 2h)
      1. Better than placebo for migraine
      2. Better than intranasal DHE at producting initial improvement (327 pts randomized to one vs. other; incidence of relief at 2h sig. greater w/sumatritpan--63% vs. 51%; however, dose of DHE was only 1mg w/optional additional dose 30min later, not recc'd 2mg; abstract cited by UW Pharm letter)--however, may have increased rates of HA recurrence
      3. Adverse effects include bad taste, nausea, and vomiting

2. Zolmitriptan (Zomig) 2.5-5mg PO or 5mg intranasal; Can repeat either form x 1 after 2h; max 2 doses of either in 24h
   1. Unlike sumatriptan, closses blood-brain barrier readily
   2. 2.5mg PO better than placebo in 999 pts with mod-severe migraine (Neurol. 49:1210 and 1219, 1997--JW)
   3. PO form similarly effective to Sumatriptan 100mg PO (Med. Lett 40:28, 1998)
   4. Can give second dose at 2h with good results in some non-responders; max 10mg/24h

3. Naratriptan (Amerge) 2.5mg PO; may repeat after 2h; max 5mg/24h
4. Rizatriptan (Maxalt) 5-10mg PO; may repeat in 2h; max 30mg/24h
5. Almotriptan (Axert) 6.25-12.5mg PO; may repeat at 2h; max 2 doses/24h
6. Frovatriptan (Frova) 2.5mg PO; may repeat Q2h to max 7.5mg/24h; less effective than Sumatriptan in one unpublished randomized trial (Med. Lett. 44:20, 2002)
7. Eletriptan (Relpax) 20-40mg PO; may repeat after 2h; max 80mg/d

5. Adverse effects:
   1. Chest pain, nausea, dry mouth, flushing, weakness, drowsiness, dizziness, malaise, paresthesias; us. last 10-30min max
   2. Myocardial ischemia and MI--Association is unclear, but to avoid any potential serious CV adverse effects, some recommend giving first dose under supervision in postmenopausal women, men > 40yo, or other pts w/risk factors for CAD.
   3. May cause ischemic colitis with sx presenting from 6h-5d of administration--data from a small case series (Arch. Int. Med. 158:1946, 1998--JW)
6. Contraindications: certain meds (see below), pregnancy, CAD, h/o atypical chest pain, uncontrolled HTN, PVD, complicated migraine
7. Studies have not evaluated safety in children, pregnant women, or pts > 65yo
8. Drug interactions
   1. Don't use within 24h of any other "triptan" or ergotamine b/c of additive vasospastic effects
   2. Use w/caution in pts on SSRI's--may cause "serotonin syndrome" with weakness, hyperreflexis, and incoordination
   3. Don't use within 2 wks of an MAOI
   4. Cimetidine & OCP's may increase serum concentrations of Zolmitriptan

2. NSAIDS, including aspirin

1. In a randomized trial, naproxen vs. ergotamine tartrate was more effective in migraine in reducing severity of pain, n/v, and lightheadedness in pts w/migraine; no diff. in photophobia or duration of HA (Cephalalgia 5:107, 1985, cited in Med. Clin. N. Am. rvw)
2. Ibuprofen 400-800mg superior to ASA 650mg for tension-type HA in a randomized double-blind trial (Headache 23:206, 1983, cited in Med. Clin. N. Am. rvw)
3. Ketorolac IM-shown to be effective in acute tx of migraine
4. NSAIDs as an adjunct to Serotonin-1 Agonists
   1. In a study in 2,956 pts with acute mod-severe migraine randomized to sumatriptan 85mg PO, naproxen 500mg PO, both, or double-placebo, the combination group had sig. higher response rates at 2h and 24h than the sumatriptan-only, the naproxen-only, and the placebo groups.  No sig. diff. in incidence of adverse events between combination gropu and sumatriptan-only group (JAMA 297:1443, 2007--JW)

3. Calcitonin gene-related peptide antagonists
   1. No vasoconstrictive effects
   2. Similarly effective to zolmitriptan with fewer adverse effects in one randomized trial (Lancet 372:2115, 2008-JW)
4. Ergot alkaloids--nonspecific serotonin agonists

1. Alpha-adrenergic antagonists; have vasoconstrictive effects on sm. mm. of blood vessels
2. Dosage forms

1. Oral ergotamine tartrate1mg : 1-2 pills at onset of HA then repeat q30min PRN to max of 6/d or 10/wk

2. Rectal suppository: 2mg, 1 at onset to max 2/d or 5/wk

3. Combined ergotamine & caffeine
   1. Oral: ergotamine 1mg/caffeine 100mg (2 PO then 1 Q30min up to total 6 per attack)
   2. Rectal: ergotamine 2mg/caffeine 100mg (1 PR, may repeat x 1 after 1h)

Utility of oral and rectal forms of ergotamin for migraine are of questionable benefit (low biovailability, e.g. 2% for oral form; oral no better than placebo & increased n/v in 3 small placebo-controlled trials per Med. Clin. NA rvw, cites BMJ 2:325, 1970 and Cephalalgia 13:166, 1993; no controlled trials of PR or SL forms as of time of that rvw). Oral ergotamine tartrate may be effective for cluster HA; in that case, best to give shortly before anticipated onset of pain. These pts do not seem to experience problems w/rebound headaches with frequent use.

4. Parenteral dihydroergotamine (DHE):

1. 0.5-1.0 mg IV/IM/SQ over 2-3 min, may repeat in 30min; max 3mg/24h or 6mg/wk
2. Sig. better at migraine relief than placebo; similar relief of migraine to meperidine (Ann. Emerg. med. 32:129, 1998--JW)
3. If given IV, it is common to co-administer an antiemetic, e.g. metoclopramide 10mg IV
4. DHE is a less potent arterial vasoconstrictor and more portent venoconstrictor than ergoamine tartrate and thus has lower incidence of side effects; seems to have less risk of physical dependence
5. May cause nausea, sedation, and transient worsening of HA

5. Intranasal DHE:
   1. Much higher bioavailability than oral/PR forms
   2. Sig. better migraine relief than placebo in 6 of 9 placebo-controlled trials
   3. May be worse than intranasal Sumatriptan (see below)
   4. Adverse effects included nasal congestion and irritation, sneezing, and bitter taste
   5. Dose is 1 spray (0.5mg) in each nostril, then again after 15min, i.e. 2mg in 4 sprays; may give a max additional 1 spray each nostril in next 24h.

3. Adverse effects: vascular occlusion & gangrene, esp. w/overdosage, valvular heart disease after prolonged use (>5y)
4. Periodic heart auscultation to r/o murmur is indicated in pts on it long-term
5. Can produce tolerance and/or physical dependency with rebound HA w/discontinuation so avoid prolonged or frequent use
6. Contraindications: pregnancy, h/o CAD, renal failure, hepatic disease, PVD, uncontrolled HTN, and complicated migraine (see above)
7. Drug-drug interactions--Don't use w/vasoconstrictors, sumatriptan, beta-blockers, or macrolide antibiotics; use caution in pts on SRI's.

5. Acetaminophen
6. Opiates
7. 100% O2--shown better than placebo for cluster headache (though not for pts > 50yo or pts with chronic cluster HA; Arch. neurol. 42:362, 1985, cited in Med. Clin. NA rvw)
8. Cocaine (5-10%) + lidocaine (4%) instilled into nostril ipsilateral to pain--uncontrolled trials have suggested benefit
9. Capsaicin intranasal--one trial showed better results than placebo
10. Excedrin: ASA, caffeine, and acetaminophen
11. Midrin: isometheptene (a weak vasoconstrictor), dischoralphenazone (a sedative similar to chloral hydrate), and acetaminophen. Some addiction risk
12. Fiorinal: butalbital (a barbiturate), ASA and caffeine. Some addiction risk; also, frequent use of caffeine can result in rebound headaches.. Fioricet (akak Esgic) has acetaminophen instead of ASA
13. Beta-blockers: propanolol 80mg PRN
14. Ca-channel blockers
15. Botulinum toxin injected into scalp musculature
    1. Onabotulinum-toxin A injected at multiple sites in head and neck shown to reduce migraine frequency and improve headache-related disability over 6mos in two randomized trials involving over 1,300 pts  ("PREEMPT 1" and "PREEMPT 2" trials, reported in FP News 11/1/09)
16. For acute relief of migraine in the clinic/ER

1. Most commonly used abortive agents are sumatriptan, ketorolac, and DHE
2. Metoclopramide (10mg IM, 0.1mg/kg IV for 1-3 doses up to 10mg total) has been used to increase absorption of other abortive agents and has been shown to reduce n/v; also appears to reduce HA itself when given alone; can be used in office/ER parenterally or at home orally. it is pregnancy category B.
   1. In a meta-analysis of 13 randomzied trials of parenteral metoclopramide for acute migraine, metoclopramide was found to be sig. more effective for reduction of migraine pain & nausea (BMJ 329:1369, 2004--JW)
3. Chlorpromazine (12.5mg IV q20min up to 3x or 0.1mg/kg IM up to 3 doses) or Prochlorperazine (10mg IV or IM), if no response in 60min to first agent (ketorolac, sumatriptan, etc.); both are shown to be more effective than placebo in acute tx of migraine. They are pregnancy category C.
4. IV opiates if still no response
5. Some pts presenting for abortive therapy of migraine will also be volume depleted from n/v & require volume replacement; may also need antiemetics, e.g. prochlorperazine or metoclopramide
6. In a randomized study of prochlorperazine 10mg IV vs. sodium valproate 500mg IV for acute tx of migraine, prochlorperazine pts had sig. greater decreases in pain and nausea scores; no diff. in degree of sedation (Ann. Emerg. Med. 41:847, 2003--AFP)

• Complicated migrane
• > 2 headaches per month, severe enough to impair functioning
• Abortive Tx is unsuccessful or produces intolerable side effects

Note--

• For cluster HA, should usually start prophylaxis at onset of a cluster episode (in episodic cluster HA)

• Allow at least 2mos for effect and if successful, continue 6-12mos then try tapering
• For kids: A Cochrane review found one study each for propranolol and flunarizine with positive results of reduced headache frequency compared with placebo. Nimodipine, timolol, papaverine, pizotifen, trazodone, L-5HTP, clonidine, metoclopramide, and domperidone showed no efficacy in reduction of frequency of attacks (Victor S, Ryan SW. Drugs for preventing migraine headaches in children (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.)

1. Beta-blockers

1. Preferred agent in migraine; better than placebo in several double-blind studies
2. Effectiveness increases progressively beteen 3 and 12mos of tx so use for 6mos at least to determine efficacy
3. Don't relieve aura sx
4. Use with caution in complicated & classic migraine b/c may decrease cerebral blood flow
5. Contraindications: asthma or other COPD, CHF, heart block, overuse of ergotamines (may precipitate overt ergotism)
6. Specific agents:
   1. Propanolol starting with 80mg/d; increase in increments of 20-40mg to max 320mg/d; divided BID-QID
   2. Timolol 10-15mg BID
   3. Nadolol up to 160mg/d
   4. Beta-blockers with intrinsic sympathomimetic activity, e.g. pindolol, acebutolol, and alprendolol, are not effective
   5. Metoprolol is category B as of 1994 while others are category C

2. Ca-channel blockers
   1. Do relieve aura sx as well as reducing frequency/intensity of migraine; also better than placebo for prophylaxis of cluster HA
   2. May develop tolerance & need increasing dose; in pts successfully tx'd who develop tolerance and increasing dose was ineffective, switching to another ca-channel blocker resulted in effective control in majority of pts in one study
   3. Require 3-8 wks of tx for effectiveness
   4. Agents shown to be effective in double-blind, placebo-controlled studies:

   1. Nifedipine--though one study showed increase in migraine frequency in 71% of pts!
   2. Verapamil 80-240mg TID (for cluster HA can use up to 600mg sustained-release BID if tolerated)
   3. Nimodipine--No better than placebo per Neurol. Clin. rvw

3. Antidepressants

1. Amitriptyline (start w/25 HS increasing gradually to max of 150 HS) shown to be better than placebo for prophylaxis of tension-type HA's (e.g. JAMA 285:2208, 2001--JW)
2. Fluoxetine shown effetive in 1 placebo-controlled study but # of pts was small (Headache 32:101, 1992; cited in Med. Clin. NA rvw)

4. ACE Inhibitors and Angiotensin Receptor Blockers
   1. 60 pts 19-59yo with migraines 2-6/month in a randomized crossover trial if lisinopril 20mg QD vs. placebo; Lisinopril ass'd with sig. fewer days w/HA than placebo (BMJ USA 1:91, 2001)
   2. 47 adults with 2-6 migraines/mo randomized to lisinopril vs. placebo x 12wks then crossover x 12wks; lisinopril ass'd with sig. fewer days with HA (19.7 vs. 23.7) than placebo and sig. less use of abortive meds (BMJ 322:19, 2001--JW)
   3. Candesartan 16mg QD vs. placebo was ass'd with sig. lower headache frequency in a 24-week randomized crossover trial in 60 pts with migraine (JAMA 289:65, 2003--JW)

5. NSAIDs

1. Naproxen 550mg BID for migraine better than placebo in one study
2. Tolfenamic acid 100 TID--ditto
3. ASA 325mg QOD shown to be helpful
4. No other NSAIDs specifically studied

6. Methylsergide 2mg BID-QID

1. A serotonin-2 antagonist shown effective for prophylaxis of migrane in one uncontrolled study (NEJM 270:67, 1964; cited in Med. Clin. NA rvw) and of cluster HA in > 1 double-blinded study
2. May cause weight gain & peripheral edema
3. Must have 3-4wk drug holiday after each 6mo period of drug use to avoid risk of retroperitoneal, pleuropulmonary, and cardiac fibrosis; some do MRI of abdomen/chest q6mos to monitor for this; contraindicated in pts with atherosclerotic cardiovascular disease, severe HTN, PUD, pregnancy, and chronic pulmonary, hepatic, or renal disease

7. Riboflavin (vit. B2) 400mg QD--more effective than placebo in 55 pts with frequent migraines (about 4/mo at onset of trial) in 3mo f/u; 1 pt had diarrhea requiring withdrawal of the drug. Has no known toxicity. (Neurology 50:466, 1998--JW)
8. Valproate 200-250mg BID-TID--shown effective for migraine prophylaxis in two randomized, double-blind, crossover trial; no effect on mild headaches; promising results in open-label trials re: prophylaxis of cluster HA; contraindicated in hepatic disease & thrombocytopenia
9. Gabapentin
   1. 133 pts with chronic daily headache (> 4h/d on > 15/mo x > 6mos) randomized to gabapentin titrated up to 2400mg/d vs. placebo x 8wks then cross-over to other tx x 8wks.  % of headache-free days was 26.6% w/gabapentin and 17.5% w/placebo (sig.) (Neurol. 61:1637, 2003--JW)
10. Topiramate
    1. 468 pts with 3-12 migraines/month x 6mos randomized to topiramate 25-100mg BID vs. placebo x 26wks.  Decrease in migraine frequency was sig. higher in 50 and 100mg-dose topiramate groups than placebo (JAMA 291:965, 2004--JW)
11. Mirtazapine was ass'd with sig. improvement in HA symptomatology c/w placebo in 24 adults with chronic tension-type HA refractory to other treatments in an 8-week randomized trial (Neurol. 62:1706, 2004--JW)
12. Phenelzine (an MAOI) 15mg BID-QID
13. Cyproheptadine, an antihistamine w/antiserotonin properties; particularly effective for migraine prophylaxis in children
14. Clonidine 0.1mg TID--"ineffective in most cases" per Neurol. Clin. rvw
15. Prednisone 20-480mg/d tapered over 3wks; promising reults in open-label studies including in cluster HA
16. Lithium carbonate 300 BID-QID; promising results in open-label studies including in cluster HA
17. Feverview (Chrysanthemum parthenium) for migraine prophylaxis (per FP news 5/1/00)
    1. Has been shown to be more effective than placebo for prophylaxis of classic and common migraine
    2. Active ingredient may be the "parthenolides" which inhibit serotonin release, prostaglandin synthesis, and platelet aggregation
    3. Adverse effets may include abdominal pain, bitter taste in the mouth, diarrhea, fatigue, glossitis, arthralgias, and mouth ulcers
    4. Oral side f/x may be less if taken in capsule form
    5. Contraindicated in pts taking antiplatelet drugs (b/c it may have intrinsic antiplatelet effects); not recc'd in kids < 12yo or pregnant women
18. Butterbur (Petasites hybridus)
    1. 245 pts with frequent migraine randomized to butterbur extract 50 or 75mg/d (brand name = Petadolex) vs. placebo x 4mos; the 75mg group had sig. greater reduction of migraine frequency (45% vs. 32% with 50mg and 28% with placebo) (Neurol. 63:2240, 2004--JW)
19. Prophylaxis for "menstrual migraine"
    1. NSAIDS in midcycle commonly used
    2. Beta-blockers in midcycle as well
    3. Combination ethinyl estradiol and methyltestosterone has also been used, as has Danazol (I don't have any notes on clinical trials)
    4. Frovatriptan 2.5mg QD-BID started 2d before anticipated start of menstrually-associated migraine and continued x 6d was ass'd with a sig. reduction incidence of headache (67% w/placebo, 52% with 2.5mg QD, 41% with 2.5mg BID--all differences sig.) (Neurol. 63:261, 2004--abst)
    5. in a randomized trial in 546 women with menstrual migraine

1. Surgical treatment for cluster headaches
   1. Section of the trigeminal root, avulsion of branches of trigeminal nerve, and local anesthesia to trigeminal sensory root ganglion have been tried; no controlled studies as of 1995
   2. Occipital nerve stimulation
      1. Bilateral occipital nerve stimulation with implanted electrodes was associated with improvement in 10 of 14 pts in an uncontrolled study in pts with intractable chronic cluster headache; complications included muscle recruitment, neck stiffness, skin discomfort, and superficial infections (Neurol. 72:341, 2009-JW)
2. Psychotherapy/relaxation therapy/biofeedback
   1. Shown to increase the response rate to placebo Rx and to tricyclic antidepressnt Rx in pts with tension-type HA's (JAMA 285:2208, 2001--JW)
3. Physical therapy including traction, massage, correction of faulty posture, & application of heat, particularly in tension-type HA
4. Chiropractic manipulation
   1. 75 pts 20-59yo with episodic tension-type HA randomized to soft tissue therapy + spinal manipulation vs. soft tissue therapy + placebo laser tx; 8 tx over 4 wks. No sig. diff. in daily hours of HA, intensity of HA, or analgesic use (JAMA 280:1576, 1998)
5. Acupuncture
   1. 401 pts with > 1 headache/month randomized to usual care or usual care + acupuncture (up to 12 treatments over 3 months); over 12mo f/u, reduction in HA scores, doctor visits, medication use, and days off work were sig. greater in acupuncture group c/w control group (BMJ 328:744, 2004--JW)