Familial hemiplegic migraine is a rare disease characterized by generations of families with recurrent migraine associated with transient weakness.
1. Four missense mutations on chromosome 19 within the gene encoding for the alpha-1 subunit of the P/Q neuronal calcium channel (CACNL1A4) have been identified.1
2. The P/Q calcium channel is a voltage-gated ion channel that is widely expressed throughout the brain.
3. Defects in channel function could produce alterations in neuronal excitability, ultimately leading to cortical spreading depression?
4. Cortical spreading depression produces the clinical symptoms of migraine? Migraine as a "calcium channelopathy" is an appealing notion.
1. Ophoff RA, Familial hemiplegic migraine and eposodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACN1A4. Cell 1996;87:543-552.
YAY OR NAY,
DO THE NOSE HAVE IT?
Intransal migrane drugs
No unanimous choice has yet appeared among the medications used to abort migraine headache. Oral preparations have important draw backs: Onset is slow as GI absorption is erratic and often compounded by nausea and vomiting. On the other hand self-injected parenteral medications often present the patient with an anxious challenge. The need for fast, effective, and easy-to-use treatment has led to the development of 3 intranasal (IN) medicines.
Gallagher et al. report a randomized, double-blind, placebo controlled trial comparing the effectiveness of IN DHE in 310 patients with acute migraine. After 2mg of IN DHE 27% reported complete resolution or mild residual pain by 30 minutes and 70% experienced near or complete resolution by 4 hours compared with 28% in the placebo group (p<.001). Furthermore, 56% of the IN DHE group could function normally by 4 hours compared to 17% in the placebo (p<.001). Headache recurrence was 15% in the DHE group versus 33% in placebo (P=.05). Adverse reactions reported with DHE included: rhinitis (41%), dysgeusia (12%), nausea (11%), application site reaction (9%), dizziness (6%). More severe adverse reactions with less efficacy was reported in the group that received 3mg DHE. Overall IN DHE (2mg) provided moderately fast (4 hours), effective relief in episodic moderate/severe migraine attacks.
Ryan and colleagues report on the results of a randomized, double-blind, parallel group, placebo controlled, multicenter study using sumatriptan IN in the acute treatment of migraine. 926 patients were randomized to receive 20mg, 10mg or placebo. 63% of patients taking 20mg had mild to no headache two hours after dosing compared to improvement in 53% of patients taking 10mg and 35% given placebo (p<0.05). In the 20mg dosing group onset of relief was reported as fast as 15 minutes however 32% needed to redose within 24 hours. The most common adverse effects were taste disturbance, nausea/vomiting, rhinitis. Nonetheless, the authors concluded that the 20mg provided the most effective dose with favorable overall tolerance.
Touchon et al. compared efficacy of subcutaneous sumatriptan (6mg) and IN DHE (1mg plus optional 1mg). 266 patients were randomized in a double-blind, double-dummy, cross-over study. Subcutaneous sumatriptan proved faster and greater headache relief in all efficacy end points. By 2 hours 76% in the sumatriptan group compared to 46% in the IN DHE group experienced near or complete relief (p<.001). Though more adverse effects were reported after sumatriptan (malaise/fatigue, flushing and nausea) than after IN DHE (nausea, rhinitis) about 90% from both groups reported that each were well tolerated. By the end of the study 64% preferred sumatriptan versus 24% who preferred IN DHE (p<.001).
The mixed opiate agonist-antagonist butorphanol (Stadol) is another widely used intranasal preparation. Diamond and colleagues' study from 1992 remains the definitive report. They randomized 96 patients in a double blind, double-dummy, placebo controlled treatment protocol comparing IN butorphanol (1mg), intramuscular methadone (10mg) and placebo. At 15 minutes following administration and continuing for 4 to 6 hours, IN butorphanol proved significantly better to methadone and placebo by all pain response measurements (p< .05). Nausea was more frequent in the butorphanol than the other two groups, but dizziness and drowsiness were similar after either butorphanol or methadone.
Maizels and colleagues report the results of a randomized, double-blind placebo controlled trial evaluating intranasal (IN) lidocaine to treat acute migraine. Eighty-one patients were studied, 53 of whom received 0.5 ml IN of a 4% lidocaine solution. Twenty-nine of those treated had at least a 50% reduction of headache compared with 6 of the 28 controls (P=.004). Significant reductions in nausea/vomiting and photophobia were reported in the treatment group. Headache relapse, usually within the first hour, occurred in 42% of the lidocaine responders. Adverse effects included local burning, numbness, and unpleasant taste.
Comment: The nasal mucosa is a richly vascularized region ideal for the rapid uptake and absorption of therapeutic agents. DHE, sumatriptan, butorphanol and IN lidocaine all show favorable responses but no clear choice emerges.
In the "triptan" migraine revolution sumatriptan nasal spray provides another option. Although 6mg subcutaneous dose alleviates headache in nearly 80% of patients within 2 hours some find this procedure difficult. Glaxo-Wellcome has smartly packaged the nasal spray in an easy to use single-dose ampule.
IN DHE presents a valuable alternative. The 70% response rate as demonstrated by Gallagher et al. is compelling. In direct comparison to sumatriptan it proves not to work as fast and it is unlikely to challenge sumatriptans dominance in the treatment of acute severe migraine. However, for patients who fail to respond to sumatriptan, IN DHE would be an alternative in the acute severe migraine.
IN butorphanol remains useful in a subset of patients particularly refractory to other abortive modalities in whom rapid opiate analgesia is required. The side effect profile was not well characterized in the Diamond report but poor tolerance is often the limiting factor. Patients find the nausea, drowsiness and dizziness prohibitive for routine use. A few, however, have discovered benefit for nocturnal migraines after which they can sleep once the pain resolves.
IN lidocaine administration is cumbersome. The patient must lie flat for 30 post-treatment minutes, with the head tilted back 45° and rotated 30° toward the affected side. 10 drops of 4% lidocaine solution is then dropped into one or both nostrils ipsilateral to a painful side. Despite this technical challenge Maizels describes a favorable response but fails to demonstrate how IN lidocaine would fare in severe migraine attacks. The response he reports was mainly in moderate/severe headaches and the improvement was rarely complete. Furthermore he does not report on the incidence of nasal numbness and burning which in our experience poses a major obstacle. His speculation that lidocaine may block neurovascular inflammation similar to the mechanism of the 5-HT1d agonists may be ambitious. I suspect this phenomenon is similar to the observation in acute trigeminal neuralgia in which ipsilateral corneal anesthetic eye drops will dramatically abort the pain. Nasal analgesics have been foundeffective in treating a variety of head-face pains. A likely reason seems that nonspecific suppression of afferent inputs in a richly innervated region will dampen the overall level of nociceptive "noise". It remains to be seen what niche IN lidocaine will find.
Maizels M, et al. Intranasal lidocaine for treatment of migraine, a randomized, double-blind, controlled trial. JAMA 1996; 276: 319-321.
Gallagher RM, et al. Acute treatment of migraine with dihydoergotamine nasal spray. Arch Neurol 1996; 53: 1285-1291.
Touchon J, et al. A comparison of subcutaneous sumatriptan and dihydroergotamine nasal spray in the acute treatment of migraine. Neurology 1996;47:361-365.
Diamond S, et al. Transnasal butorphanol in the treatment of migraine headache pain. Headache Quarterly 1992;3:160-167.
Ryan R, et al. Sumatriptane nasal spray for the acute treatment of migraine. Neurology 1997; 49:1225-1230
1. Peikert A, Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 1996; 16:257-263.
2. Schoenen J. Effectiveness of high-dose riboflavin in migraine prophylaxis, a randomized controlled trial. Neurology 1998;50:466-470.
The Headache is a publication from the Cornell Headache Service, New York Presbyterian Hospital-Cornell Campus
Editor: Jeffrey B. Reich, MD (212) 746-2334
This issue was funded by an educational grant from Novartis.