Yea or Nay Do the Nose Have It?
ABSTRACTS & COMMENTARY
Sources: 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.
No medication has emerged as a unanimous choice to abort migraine headache. Oral preparations have important drawbacksonset 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 three intranasal (IN) medicines.
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 six of the 28 controls (P = 0.004). 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.
The mixed opiate agonist-antagonist butorphanol (Stadol) is another widely used intranasal preparation. Diamond and colleagues’ study from 1992 remains the definitive report (Headache Q 1992;3:160-167). They randomized 96 patients in a double-blind, double-dummy, placebo-controlled treatment protocol comparing IN butorphanol (1 mg), intramuscular methadone (10 mg), and placebo. At 15 minutes following administration and continuing for 4-6 hours, IN butorphanol proved significantly better to methadone and placebo by all pain response measurements (P £ 0.05). Nausea was more frequent in the butorphanol than the other two groups, but dizziness and drowsiness were similar after either butorphanol or methadone.
Gallagher et al report a randomized, double-blind, placebo-controlled trial comparing the effectiveness of IN DHE in 310 patients with acute migraine. After 2 mg of IN DHE, 27% reported complete resolution or mild residual pain by 30 minutes, and 70% experienced near or complete resolution by four hours compared with 28% in the placebo group (P < 0.001). Furthermore, 56% of the IN DHE group could function normally by four hours compared to 17% in the placebo group (P < 0.001). Headache recurrence was 15% in the DHE group vs. 33% in placebo (P = 0.05). Adverse reactions reported with DHE included: rhinitis (41%), dysgeusia (12%), nausea (11%), application site reaction (9%), and dizziness (6%). More severe adverse reactions with less efficacy was reported in the group that received 3 mg DHE. Overall IN DHE (2 mg) provided moderately fast (4 hours), effective relief in episodic moderate/severe migraine attacks.
Touchon et al compared efficacy of subcutaneous sumatriptan (6 mg) and IN DHE (1 mg plus optional 1 mg). A total of 266 patients were randomized in a double-blind, double-dummy, cross-over study. Subcutaneous sumatriptan proved faster and provided greater headache relief in all efficacy end points. By two hours, 76% in the sumatriptan group compared to 46% in the IN DHE group experienced near or complete relief (P < 0.001). 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 vs. 24% who preferred IN DHE (P < 0.001).
COMMENTARY
The nasal mucosa is a richly vascularized region ideal for the rapid uptake and absorption of therapeutic agents. IN lidocaine, DHE, and butorphanol all show favorable responses, but no clear choice emerges.
IN lidocaine administration is cumbersome. The patient must lie flat for 30 minutes post-treatment, with the head tilted back 45° and rotated 30° toward the affected side; 10 drops of 4% lidocaine solution are then dropped into one or both nostrils ipsilateral to a painful side. Despite this technical challenge, Maizels et al describe a favorable response but fail to demonstrate how IN lidocaine would fare in severe migraine attacks. The response they report was mainly in moderate/severe headaches, and the improvement was rarely complete. Furthermore, they do not report on the incidence of nasal numbness and burning, which, in our experience, poses a major obstacle. Their 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 found effective 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.
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 et al 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 DHE has the best potential. 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 sumatriptan’s dominance in the treatment of acute severe migraine. However, for patients who fail to respond to sumatriptan, IN DHE would be an alternative. The drug will soon be available, as Sandoz Pharmaceuticals currently awaits final FDA approval. In the meantime, specialty pharmacies can make it to order. Thayer Pharmacy in Orlando, Florida, (1-800-896-7001) will prepare a 5 mL device that can be used for about 10 doses. jr
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