Brief Therapeutic Report: Papaverine Prophylaxis of Complicated Migraine Nazhiyath Vijayan, M.D. Department of Neurology School of Medicine, University of California, Davis (Dr. Vijayan). Reprint requests to: N. Vijayan, M.D., Department of Neurology, School Medicine, University of California, Davis, California 95616. Accepted for publication: 6/27/77 SYNOPSIS Use of vasoconstrictor agents for treatment of migraine associated with prolonged neurologic manifestations has been controversial because permanent sequelae, though rare, occur most commonly in these patients. A slowly released form of Papaverine, 150 mg twice a day prevented the premonitory neurologic symptoms in seven patients with complicated migraine. Four of these patients also became headache-free and the remaining three were considerably improved. Papaverine therapy was effective in patients in whom the use of ergotamine or other potent vasoconstrictor agents might be hazardous. (Headache 17: 159-162, 1977) Migraine is classified into 'classic' and 'common' forms depending on neurologic manifestations. These result from reduced cerebral blood flow due to intracranial vasoconstriction.1-4 This phase is usually brief and ends before the headache develops. However, in a few patients the neurologic symptoms are prolonged and may outlast the headache by hours or days. This type is called 'complicated migraine'.5 Recent blood flow studies showed dangerously low regional cerebral perfusion during this migraine phase.6,7 Permanent neurologic sequelae, though rare, occur more often in this group of patients.8,9 Ergot preparations are the mainstay of therapy for acute migraine attacks. For maximum benefit this drug should be used at the onset of symptoms. Ergot compounds act directly on vascular smooth muscles and constrict extracranial vessels preventing vasodilatation.1 The effect of ergot on intracranial vessels is controversial. Evidence indicates that ergot produces intracranial vasoconstriction in animals and man.2,10-12 Some physicians, therefore, hesitate using ergot in patients with complicated migraine. One alternative is the prophylactic use of methysergide. This drug is not always effective and cannot be given indefinitely because of side effects.13 It also is a weak vasoconstrictor.14 Papaverine in a slowly-released form was reported effective in treatment of patients with classic migraine resistant to the usual drugs.15 Because of this, papaverine might also be safe for the treatment of complicated migraine. MATERIALS AND METHODS During a two year period, patients from an outpatient headache clinic with complete histories, general and neurologic examinations were examined. Seven patients with complicated migraine were studied. Five migraineurs were selected because of focal neurologic symptoms lasting 4-24 hours. The symptoms continued into or outlasted the headache. A sixth patient had essential hypertension and migraine. In this patient the neurologic manifestations lasted 8 hours. The seventh patient had complicated migraine controlled with ergotamine tartarate which had to be discontinued when she became pregnant. The details of the neurologic manifestations are given in Table 1. Three patients had brain scans and cerebral angiography because of prolonged neurologic symptoms. Others had skull x-rays, electroencephalograms, and computerized axial tomography before therapy. Detailed history with emphasis on the features of the neurologic manifestations was taken at the first visit. Frequency and duration of headaches and associated neurologic symptoms were documented for a period of 12 weeks after the initial visit. During this period, specific anti-migraine

TABLE 1 RESULTS OF PAPAVERINE THERAPY OF COMPLICATED MIGRAINE 12 Weeks Before Treatment 12 Weeks During Treatment NUMBER OF HEADACHES

AVERAGE DURATION OF HEADACHES

NUMBER OF HEADACHES

AVERAGE DURATION OF HEADACHES

CASE NUMBER

12

10 hrs

Hemianopsia

4-6 hrs

None

-

1

18

4 hrs

Hemisensory loss

6 hrs

3

1 hr

2

3

11 hrs

Hemiparesis

24 hrs

None

-

3

2

6 hrs

Hemiparesis Hemisensory loss

6 hrs

1

11/2 hrs

4

6

12 hrs

Hemisensory loss Hemianopsia

9-12 hrs

None

-

5

14

5 hrs

Hemianopsia Hemisensory disturbances (essential hypertension)

8 hrs

8

2 hrs

6

18

7 hrs

Hemiparesis sensory and visual symptoms (pregnancy)

4-6 hrs

None

-

7

SYMPTOMS

DURATION OF NEUROLOGIC SYMPTOMS

medications were not prescribed and the patients were advised to use only aspirin and anti-emetic agents when necessary. Patient cooperation was very good because vasoconstrictors in the past had not been effective and most were anxious to avoid the potential risks associated with these drugs. Total number of headaches, average duration of each headache and duration of neurologic manifestations for the pre-treatment period is shown in Table 1. Informed consent for this study was obtained in each case. Similar observations were recorded for 12 more weeks, beginning two weeks after starting therapy with papaverine 150 mg b.i.d. (slowly released form). This two week time delay was necessary before evaluation because therapeutic effectiveness was apparent only after such an interval. Patients were again allowed to use aspirin and anti-emetic agents when necessary. RESULTS Statistical evaluation was not attempted because of the small number of patients and the obvious differences in results between the pre-treatment and treatment periods. Headaches were completely controlled in four patients and were much less severe and frequent in the other three. In the pre-treatment period, 73 headaches were present compared to 12 during treatment. Headaches may be shortened by aspirin, but it was used in the pre-treatment and treatment periods. During treatment with papaverine most patients used less aspirin or anti-emetics. The most significant response was complete cessation of neurologic manifestations in all patients including three who continued to have occasional headaches. Neurologic symptoms disappeared before gradual improvement in headaches. Attempts to withdraw the medication during later follow-up resulted in gradual return of pre-treatment clinical features. A delay of 2-4 weeks before symptoms returned with initial severity was observed. Results of treatment are given in Table 1. No side effects were observed during this study. DISCUSSION The results show that papaverine is effective in controlling prolonged neurologic manifestations in patients with complicated migraine. In addition, the frequency and duration of headaches were

significantly reduced in all patients. The mechanism of action of papaverine in complicated migraine is not clear. Pharmacologically, papaverine (6, 7-dimethoxy-1-veratryl isoquinoline hydrochloride) is a classic example of a non-specific smooth muscle relaxant acting independent of innervation. It has been used as a vasodilator in cerebrovascular disease, even though its therapeutic effectiveness is doubtful. Poser suggested that the initial vasoconstrictor phase of classic migraine may be obligatory and that papaverine, a vasodilator, prevents this phase thereby aborting the episode.15 However, it is doubtful that papaverine produces significant cerebral vasodilation with the dose used,16 even though experimentally it decreases cerebrovascular resistance.17 Papaverine has recently been shown to have a central pharmacologic action which may be responsible for its anti-migraine activity. It has a direct anti-dopamine effect in the caudate nucleus of rats.18 Normally, direct application of dopamine or electrical stimulation of substantia nigra produces inhibition of caudate neurons. Papaverine prevents this inhibition, and may block dopamine receptors in the caudate nucleus. Parkinsonian patients, adequately controlled on levodopa also deteriorated after the administration of papaverine given for cerebrovascular insufficiency.19 Excessive amounts of catecholamines or their metabolites act as precipitating agents in migraine. A classic example is tyramine which is the offending agent in some dietary migraine.20 Tyramine liberates norepinephrine and dopamine from their binding sites. Another vasoactive amine is phenylethylamine, the offending agent in patients who develop headaches following chocolate ingestion.21 Increased excretion of 4-hydroxy-3-methoxymandelic acid, a major metabolite of norepinephrine and epinephrine, occurs during migraine,22 and increased dopamine beta hydroxylase activity has been noted in patients with migraine.23 Other observations support the idea that abnormal catecholamine metabolism is present in migraine. These include the therapeutic effectiveness of propranolol, a ß-adrenergic blocking agent, in some patients with migraine.24,25 Migraine worsens initially and is subsequently benefited by repeated parenteral doses of reserpine26 and the beneficial effect is attributed to depletion of norepinephrine.27 The role of catecholamine metabolism in the pathogenesis of migraine is uncertain. It has been suggested that catecholamines are responsible for the vasoconstrictor phase and thus for the prolonged neurologic manifestations in patients with complicated migraine. The therapeutic effectiveness of papaverine can then be explained on the basis of its catecholamine blocking effect. Whatever its mechanism of action, this compound is useful in treating patients with complicated migraine and controlled trials in more patients are warranted. REFERENCES 1.

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Brief therapeutic report: papaverine prophylaxis of complicated migraine.

Brief Therapeutic Report: Papaverine Prophylaxis of Complicated Migraine Nazhiyath Vijayan, M.D. Department of Neurology School of Medicine, Universit...
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