Antiepileptic Drugs, 5th Edition

Valproic Acid

87

Clinical Efficacy and Use in Other Neurological Disorders

Stephen D. Silberstein MD, FACP

Professor of Neurology, Department of Neurology, Jefferson Medical College; and Director, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Valproic acid is commercially available in the United States in three preparations: valproic acid, sodium valproate (Depakene syrup; Abbott Laboratories, Abbott Park, IL), and divalproex sodium (Depakote; Abbott Laboratories), an enteric-coated, stable coordination compound that contains equal proportions of valproic acid and sodium valproate (1). In this chapter, the term valproate is used for these formulations (2). An extended-release form (Depakote-ER; Abbott Laboratories), which allows once-daily dosing and decreased peak related side effects has just become available. The amide of valproic acid, valpromide (Depamide), is available in Europe.

Valproate is an anticonvulsant agent that shows broad-spectrum efficacy against partial and generalized seizure types (3). It is useful and well tolerated as a mood stabilizer in patients with bipolar and schizoaffective disorder, even those who have been unable to tolerate lithium or have failed to respond to this medication (4). Valproate is approved by the U.S. Food and Drug Administration for mania and migraine in the United States. Its use in psychiatric disorders is discussed in Chapter 88.

Five double-blind, placebo-controlled studies (5, 6, 7, 8, 9) have confirmed that valproate is an effective migraine treatment. Some investigators have suggested that valproate is especially useful for treating migraineurs who also have mania, seizures, aggressive behavior, or an anxiety disorder (4,10). In addition, studies have shown that it is effective for chronic daily headaches (11) and cluster headaches (12). This chapter reviews the evidence concerning the effectiveness of valproate in migraine and other headache disorders, and provides recommendations on its clinical use in these conditions.

MIGRAINE TREATMENT

The pharmacologic treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic) (13, 14), and patients who are experiencing frequent, severe headaches often require both approaches. Acute treatment attempts to abort (reverse or stop the progression of) a headache once it has started. Preventive therapy is given, even in the absence of a headache, to reduce the frequency and severity of anticipated attacks.

The United States Headache Consortium Guidelines (15) recommend preventive treatment under the following circumstances: (a) recurring migraines that, in the patient's opinion, significantly interfere with their daily routines, despite acute treatment; (b) frequent headaches (more than two per week); (c) contraindication, or failure or overuse of acute therapies; (d) use of acute medication more than twice a week; or (e) presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction (to prevent neurologic damage—as based on expert consensus). Medications for prophylactic treatment are more restricted during pregnancy, during which time severe, disabling attacks accompanied by nausea, vomiting, and possibly dehydration are required for chronic treatment to be prescribed (16).

The major medication groups of preventive migraine treatment include β-adrenergic blockers, antidepressants, calcium channel antagonists, serotonin [5-hydroxytryptamine (5-HT)] antagonists, anticonvulsants, and nonsteroidal antiinflammatory drugs (NSAIDs) (13,14). If preventive medication is indicated, the agent should be chosen from one of the major categories, based on side effect profiles and coexistent comorbid conditions (13,14).

MIGRAINE MECHANISMS

There is no certainty about how migraine medications work. Although there are no true animal models for

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migraine, a number of innovative models are available for the development of drugs for acute migraine treatment. These models were developed based on either the presumed pathophysiology of the migraine attack or the presumed mechanism of action of an existing migraine drug. Most migraine preventive medications were designed to treat other disorders. Methysergide, however, was developed as a migraine preventive agent, based on the concept that migraine is a serotonin excess disorder and methysergide is a serotonin antagonist. It has been suggested that downregulating the 5-HT2 receptor or modulating the discharge of serotonergic neurons may be involved in migraine prevention (17,18).

Antidromic stimulation of the trigeminal nerve releases substance P, calcitonin gene-related peptide, and neurokinin A from the sensory C-fibers and results in neurogenic inflammation (NI). The released neuropeptides interact with the blood vessel wall, producing dilation, plasma extravasation, and sterile inflammation. Platelet activation is seen on electron micrographs of the interior of these blood vessels (19).

The development of NI results in the breakdown of the blood-brain barrier in the dura mater. Sumatriptan and dihydroergotamine, drugs that are agonists at the presynaptic inhibitory 5-HT1D heteroreceptor, prevent leakage. Neither drug blocks the production of inflammation induced by direct application of neuropeptides to the dural vessels. Methysergide, after long-term, but not acute, administration, worked in this model, consistent with its clinical usefulness as a migraine preventive (20).

NI can be prevented by blocking neuronal transmission. Acute specific headache medications may work by blocking nerve fiber transmission in the trigeminal system rather than by vascular constriction. Elevated calcitonin gene-related peptide levels have been found in the jugular blood during a human migraine attack. The headache is aborted and calcitonin gene-related peptide reduced to control levels by 5-HT1D receptor agonists (21). Other drugs that block NI include valproate, neurosteroids, NSAIDs, and neuropeptide Y.

Diener's group reported brainstem activation in spontaneous migraine attacks (22). Using positron emission tomography to measure regional cerebral blood flow, nine patients who had migraine without aura and right-sided headaches were studied within hours of migraine onset. High regional cerebral blood flow values (compared with the headache-free interval) were found in the cerebrum in the cingulate cortex, the auditory association cortex, and the visual association cortex bilaterally, and in the inferior anterocaudal cingulate cortex on the left side only. There was increased regional cerebral blood flow lateralized to the left in the brainstem anterior to the aqueduct and posterior to the corticospinal tract. Sumatriptan relieved the headache and associated symptoms and reversed the cerebral increase in regional cerebral blood flow, but not the brainstem increase.

This is the first report of brainstem activation during a spontaneous attack of migraine without aura and is most likely a result of brainstem gray matter activation, including the dorsal raphe nucleus (a serotonergic nucleus) and the locus ceruleus (a noradrenergic nucleus).

Migraine may be due to abnormal activation of a network that has normal physiologic functions. The strong familial association of migraine and the association of some varieties of migraine with chromosome 19 suggest an underlying genetic basis with an unknown biologic basis. It is uncertain if migraine with aura and migraine without aura are distinct entities.

A preventive migraine drug could raise the threshold to activation of the migraine process either centrally or peripherally. Drugs could decrease activation of the migraine generator, enhance central antinociception, raise the threshold for spreading depression, or stabilize the more sensitive migrainous nervous system by changing sympathetic or serotonergic tone. Preventive drugs probably work by more than one mechanism. The drugs could, in part, have a peripheral mechanism of action, similar to specific acute medications. Because the prolonged use of most acute medications can cause daily headache and block the effect of preventive drugs, a theoretical problem is created. A clue to this problem may be found in the exceptions, long-acting NSAIDs and dihydroergotamine, which are both acute and preventive medications. Saxena (23) has postulated a primary peripheral mechanism for methysergide, which may work by closing cerebral AVAs, and Moskowitz (24) has shown that both methysergide and valproate block the development of NI in his model.

Valproate's mechanism of action in migraine prophylaxis may be related to facilitation of GABAergic neurotransmission (25, 26, 27). Valproate also attenuates plasma extravasation in the Moskowitz model of NI (24) by interacting with the γ-aminobutyric acid type A (GABAA) receptor. The relevant receptor may be on the parasympathetic nerve fibers that project from the sphenopalatine ganglia, where it attenuates nociceptive neurotransmission (28). Valproate-induced increased central enhancement of GABAA activity may enhance central antinociception (24). Valproate also interacts with the central 5-HT system and reduces the firing rate of midbrain serotonergic neurons (24).

PLACEBO-CONTROLLED, DOUBLE-BLIND TRIALS IN PATIENTS WITH MIGRAINE

In 1992, Hering and Kuritzky (5) evaluated sodium valproate's efficacy in migraine treatment in a double-blind, randomized, crossover study (Table 87.1). Thirty-two patients were divided into two groups and given either 400 mg of sodium valproate or placebo twice a day for 8 weeks. The patients were then crossed over to the opposite treatment for an additional 8 weeks. Three patients dropped out. Sodium valproate was effective in preventing migraine

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or reducing the frequency, severity, and duration of attacks in 86.2% of the remaining 29 patients, whose attacks were reduced from 15.6 to 8.8 a month. The drug was a well tolerated, effective migraine treatment.

TABLE 87.1. DOUBLE-BLIND PLACEBO-CONTROLLED CLINICAL TRIALS OF VALPROIC ACID IN MIGRAINE

Study

Patient Population (Diagnostic Criteria)

No.

Design

Dosage (mg/d) Medication

Plasma Valproic Acid Levels

Duration

Responder Rates

Hering and Kuritzky (1992)(5)

Migraine

29

crossover

800mg (400 mg bid)/sodium valproate

31.1 to 91.9µg/ml

8 Weeks each; total of 16 weeks

86.2% of patients responded better to valproate

Jensen et al. (1994)(6)

Migraine without aura

43

crossover

1,000 to 1,500 mg/sodium valproate

Mean 73.4µg/ml

32 Weeks

50% valproate
18% placebo

Mathew et al. (1995)(7)

Migraine with/without aura

107

Parallel-group

500 to 1,500mg/Divalproex

70 to 120µg/ml

16 Weeks

48% divalproex
14% placebo

Klapper (1995)(8)

Migraine with/without aura

176

Parallel-group

500 to 1,600 or 1,500 mg/Divalproex

??

10 Weeks

43% divalproex
21% placebo

Silberstein et al. (2000)(9)

Migraine with/without aura

237

Parallel-group

500 to 1,000 mg/Divalproex ER

 

12 Weeks

41% divalproex
28% placebo

Jensen et al., in 1994 (6), studied 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of slow-release sodium valproate. After a 4-week, medication-free, run-in period, the patients were randomized to sodium valproate (n = 22) or placebo (n = 21). Thirty-four patients completed the trial. Patients randomized to sodium valproate received 1,000 mg/day for the first week. Patients with serum levels below 50 µg/mL were blindly adjusted to 1,500 mg of sodium valproate a day and those with serum levels above 50 µg/mL were continued on 1,000 mg/day. The number of migraine days was 3.5 per 4 weeks during sodium valproate treatment and 6.1 during placebo (p = 0.002) treatment. The severity and duration of the migraine attacks that did occur were not affected by sodium valproate when compared with placebo. Fifty percent of the patients had a reduction in migraine frequency to 50% or less for the sodium valproate group, compared with 18% for placebo. During the last 4 weeks of valproate treatment, 65% of patients responded. The mean serum sodium valproate concentration was 73.4 µg/mL after 8 days and 64.2 µg/mL after 12 weeks of treatment. The most common side effects (33% valproate, 16% placebo) were intensified nausea and dyspepsia, tiredness, increased appetite, and weight gain; these usually were mild or moderate. Fifty-eight percent of the patients had no side effects. It was concluded that sodium valproate was an effective and well tolerated prophylactic medication for migraine without aura.

In 1995, in a multicenter, double-blind, randomized, placebo-controlled investigation, Mathew et al. (7) compared the effectiveness and safety of divalproex sodium and placebo in migraine prophylaxis. A 4-week, single-blind, placebo-baseline phase was followed by a 12-week treatment phase (4-week dose adjustment, 8-week maintenance). One-hundred seven patients were randomized to divalproex sodium or placebo (2:1 ratio), with 70 receiving divalproex sodium and 37 receiving placebo. Divalproex sodium and placebo dosages were titrated in blinded fashion during the dose adjustment period to achieve actual/sham trough valproate sodium concentrations of approximately 70 to 120 µg/mL. During the treatment phase, the mean migraine headache frequency per 4 weeks was 3.5 in the divalproex sodium group and 5.7 in the placebo group (p ≤ .001), compared with 6.0 and 6.4, respectively, during the baseline phase. Forty-eight percent of the divalproex sodium-treated patients and 14% of the placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from the baseline phase (p < .001). Among those with migraine headaches, the divalproex sodium-treated patients reported significantly less functional restriction than the placebo-treated patients and used significantly less symptomatic medication per episode. No significant treatment-group differences in average peak severity or duration of individual migraine headaches were observed. (A nonsignificant decrease in duration was noted.) Treatment was stopped in 13% of the divalproex sodium-treated patients and 5% of the placebo-treated patients because of intolerance, a statistically nonsignificant difference. The authors concluded that divalproex sodium is an effective prophylactic drug for patients with migraine headaches and is generally well tolerated.

Klapper et al. (8) evaluated the efficacy and safety of divalproex sodium as prophylactic monotherapy in a multicenter, double-blind, randomized, placebo-controlled study. During the 4-week, single-blind, baseline-placebo phase, patients completed a headache diary. Patients with two or more migraine attacks during the baseline phase were randomized to a daily divalproex sodium dose of 500, 1,000, or 1,500 mg, or placebo. The experimental phase lasted 12 weeks, the first 4 weeks for dose escalation and the remaining 8 weeks for dose maintenance. The primary efficacy variable was 4-week headache frequency during the experimental phase.

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During the experimental phase, the mean reduction in the combined daily divalproex sodium groups was 1.8 migraines per 4 weeks, compared with a mean reduction of 0.5 attacks per 4 weeks in the placebo group. Overall, 43% of divalproex sodium-treated patients achieved ≥50% reduction in their migraine attack rates, compared with 21% of placebo-treated patients. A statistically significant (p ≤ .05) dose-response effect across the dose range placebo, 500, 1,000, and 1,500 mg, was observed for both overall reduction in attack frequency and a ≥50% reduction in attack frequency. A nonsignificant decrease in headache duration was noted. With the exception of nausea, whose frequency was 24% in the divalproex groups combined (compared with 7% on placebo; p = .015), adverse events were similar in all groups, and most adverse effects were mild or moderate in severity. This study showed divalproex sodium to be an effective migraine prophylactic agent.

Silberstein et al. (9) recruited 237 patients with migraine 12 years of age or older. A 14-day washout period was followed by a 28-day baseline period. Divalproex sodiumextended release (DVS-ER) 500 mg once daily or placebo was administered for 7 days, then titrated up to 1,000 mg for an additional 7 days. After 14 days of treatment, patients could be reduced to 500 mg. During the next 70 days, 98 patients took 1,000 mg DVS-ER and 16 patients took 500 mg DVS-ER. After a total of 84 days of treatment, all patients were tapered to 500 mg, and all medication was stopped at 91 days.

There was a significant reduction in the 4-week headache rate from baseline in those taking DVS-ER compared with placebo (1.2 versus 0.6, p = .006; the primary efficacy measure). The secondary efficacy measure (reduction in the number of migraine headache days from baseline) showed a significant benefit for those in the DVS-ER group compared with those in the placebo group (1.7 versus 0.7, p = .009). The reduction in the number of migraine headache days during the last 4 weeks of the experimental phase also was substantially greater for the treatment group (2.0 versus 0.7, p = .001), and the percentage of patients with at least a 50% reduction in headaches was also greater in the treatment group (41% versus 28%, p = .024).

DVS-ER was well tolerated. There was no difference in premature discontinuation and abdominal pain between the two groups. Patients on placebo reported more asthenia, but there was more dyspepsia, nausea, vomiting, tremor, and rash in the DVS-ER group. However, none of the differences was significant.

DVS-ER had twice the efficacy in 4-week headache rate and produced a reduction in the number of 4-week headache days. There were significant decreases in migraine headache rate, migraine headache days, and patients with at least a 50% reduction in migraine headache rate in those who completed the study. DVS-ER is safe and well tolerated at dosages up to 1,000 mg once daily.

OTHER TRIALS IN PATIENTS WITH MIGRAINE

In 1988, in a prospective open trial of valproate, Sorenson (29) studied 22 patients who had severe migraine resistant to previous prophylactic treatment (Table 87.2). Seventeen patients had migraine without aura and five had migraine with aura. The attack frequency ranged from 4 to 16 per month in 21 patients (one had daily headache). The dose of valproate was 600 mg twice a day adjusted upward to a serum level of approximately 700 µmol/L. Follow-up in 3 to 12 months revealed that 11 patients were migraine free, 6 had had a significant reduction in frequency, 1 had had no change, and 4 had dropped out.

In 1991, Viswanathan et al. (30) conducted an open study of 16 patients who had resistant migraine and paroxysmal electroencephalographic changes. The patients were treated with sodium valproate, 200 mg three times a day as an add-on medication. After 2 weeks, 12 patients were headache free and the rest had 50% relief. The drug was continued for 3 months in the totally headache-free patients, whereas the other four patients increased their dose to 800 to 1,000 mg/day. Two of these dropped out, and the other two had complete relief.

Moore, in 1992 (31), reported a retrospective analysis of 207 patients with refractory headache who were treated with valproate 750 to 2,000 mg/day. Patients with either migraine (n = 125) or chronic daily headache (n = 82) were treated with the drug. Sixty-five percent of patients with migraine without aura and 50% of patients with migraine with aura had a good or excellent response (criteria not defined). Patients with mixed headache had a 52% response, whereas those with chronic tension-type headache (TTH) had a 73% response. The average duration of treatment was 246 days.

In 1993, Sianard-Gainko et al. (32) assessed the prophylactic effects of sodium valproate over 6 months in 56 patients with severe primary headaches. Thirty-two patients had migraine without aura, 3 had migraine with aura, 14 had both frequent migraine attacks and TTH, and 7 had only chronic TTH. Twenty-nine percent of the patients overused analgesics or ergotamine. The mean daily dose of sodium valproate (given twice a day) was 928.5 mg. Efficacy was assessed by comparing the number of headache days before treatment and during the sixth month of therapy. In the migraine-only group (n = 35), 60% had a 75% to 100% reduction and 20% had a 50% to 75% reduction in headache days. In the mixed or TTH group, only 33% had a >50% reduction in headache days. Clinical improvement significantly correlated with serum valproic acid levels. These results confirmed that sodium valproate is an effective prophylactic treatment for severe migraine, but is of limited value for TTH, at least when compounded by overuse of symptomatic medication. This study suggested aiming for a valproic acid plasma level between 70 and 90 µg/mL.

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TABLE 87.2. OTHER CLINICAL TRIALS OF VALPROIC ACID IN MIGRAINE

Study

Patient Population (Diagnostic Criteria)

No.

Design

Dosage (mg/d)/Other Medication

Plasma Levels

Duration

Responder Rates

Sorensen (1988)(29)

Resistant common or classic migraineurs

22

Open; prospective

600mg Valproate bid adjusted to serum level

100 µg/ml

3 to 12 Months

11 Headache free; 6 significant improvement; 4 dropped out; 1 no effect

Viswanathan et al. (1991)(30)

Migraine with EEG changes

16

Open

600mg/Valproate

??

14 Days

12 Headache-free

Moore (1992) (31)

Migraine; CDH

207

Retrospective review

750 to 2,000mg Divalproex

??

Average 246 days

Migraine with aura 50%; migraine 65%; CDH, mixed 52%; CTTH 73%

Sianard-Gainko et al. (1993)(32)

Migraine with/without aura

35

Open

928.5mg/Valproate mean dosage

70 to 90 µg/ml

6 Months

60%: 75-100% reduction; 20%: 50-75%

             

Reduction; improvement correlated to plasma level

Coria et al. (1994)(33)

Migraine with/without aura

62

Open

400mg/Valproate

Mean 30 µg/ml

12 Weeks

69.8% Substantial benefit; no correlation to plasma level

Rothrock (1994)(34)

Intractable headache; migraine; TM; TTH

75

Prospective; open

500mg bid/Divalproex titrate

<150µg/ml

10 Weeks

TTH 27%; TM 61%; Frequent migraine 85%

Czapinski (1995)(35)

Migraine without aura

32

Open; two groups

600mg,* titrate to 1,422mg**/Valproate

*<50µg/ml
**70 to 100µg/ml

26 Weeks

Better results with higher dose

Klapper (1995)(37)

Migraine with/without aura

12

Open, crossover

Highest dose tolerated

??

4.5 Months

92% had fewer headache on divalproex compared to propranolol

Kaniecki (1995)(36)

Migraine without aura

37

Single blind crossover comparison to propranolol

Mean dose divalproex 1,414mg; propranolol 168mg

Mean 68.5µg/ml

28 Weeks

Placebo 19%; propranolol 66%; divalproex 66%

Ghose and Niven (1998)(39)

Migraine with/without aura

27

Open

600 to 2,000 Valproate

<106µg/ml

12 to 24 Moths

50% reduction; 59% at 12 weeks

EEG, electroencephalogram; TM, transformed migraine; CDH, chronic daily headache; CTTH, chronic tension-type headache.

, Patients with serum levels less than 50 mcgr/ml remained on 600 mg/day.

** , Patients with serum levels above 50 mcgr/ml were titrated up to levels in range of 70 to 100 mcgr/ml (mean dose after titration 1,422 mg/day).

Coria et al., in 1994 (33), conducted an open-label trial of sodium valproate in which they assessed migraine prophylaxis in 62 consecutive patients with severe migraine with and without aura. The patients were given 200 mg of sodium valproate twice a day for 3 months and then asked to withdraw the drug for 3 months. The therapeutic response was measured with a scale of 15 items, which included the frequency and severity of migraine attacks. Substantial benefit was obtained by 69.8% of patients; it lasted 3 months after drug withdrawal in 67.6% of cases, perhaps because of a positive carry-over effect. No significant correlation was found between valproate levels and the therapeutic response as measured by the migraine assessment scale.

Rothrock et al., in 1994 (34), consecutively recruited 75 patients with intractable headache syndromes. They divided these patients into three groups [frequent migraine (FM; n = 18], transformed migraine (n = 43), and TTH (n = 14)] and treated all 75 with divalproex sodium. Thirty-six patients (48%) reported a ≥50% reduction in headache frequency. Significantly different treatment response rates were found in the three groups: patients with FM improved the most (61%); patients with transformed migraine less (51%); and patients with TTH the least (21%). They concluded that prophylactic

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treatment with divalproex sodium may be effective in selected patients with intractable headache syndromes and that identification of clinically distinct headache subtypes may assist in predicting response to treatment.

Czapinski, in 1995 (35), assessed the effect of valproic acid in a six-month open study of 32 patients (24 women and eight men) with migraine without aura. For the first month, valproate was slowly increased to a total divided dose of 600 mg/day. Serum valproic acid levels were obtained, and the patients were divided into two groups: (A) those with valproic acid levels below 50 µg/mL (n = 14); and (B) those with levels above 50 µg/mL (n = 18). In group B, the valproate dose was increased until the concentration reached 70 to 100 µg/mL (mean dose, 1,422 mg), whereas group A received the original dose. The outcome measure was the number of days with migraine before and after 2, 4, and 6 months of treatment. Valproate was found to be effective, with its beneficial effect increasing during the course of therapy. Efficacy correlated to serum valproic acid concentrations. Adverse events occurred in 10 patients (gastrointestinal complaints, loss of hair, weight gain), but did not necessitate the discontinuation of therapy.

In 1995, Kaniecki (36) enrolled 37 patients with International Headache Society-diagnosed migraine without aura in a randomized, single-blind, placebo-controlled, crossover study comparing divalproex sodium (mean dosage, 1,414 mg/day) and propranolol prophylaxis. After a 4- week baseline phase followed by a 4-week placebo phase, patients were randomized to either divalproex sodium or propranolol for 12 weeks. After a 4-week washout phase, they were crossed over to the opposite treatment. Thirty-two patients completed the study. Responders were defined as those patients who achieved a greater than 50% reduction in either mean migraine frequency (events per month) or mean number of days with migraine (days per month). Assessment of migraine frequency revealed a significant response to divalproex sodium in 66% of patients, to propranolol in 63% of patients, and to placebo in 19% of patients (compared with baseline). Similar results were seen in assessment of migraine days per month.

Klapper (37) compared divalproex sodium with propranolol in an open-label crossover study in which migraineurs randomly received either divalproex sodium or propranolol. The dose was titrated to the highest level tolerated, and the patients recorded their headaches for 2 months. They were then withdrawn from their first medication over a period of 2 weeks and the process was repeated for the second drug. Twelve patients completed both arms of the study. The number of headaches in the divalproex sodium arm was 10.9 per 2 months compared with 20.4 per 2 months in the propranolol arm, with 92% having fewer headaches when taking divalproex sodium. Nine of the patients who took divalproex sodium (38%) did not complete the study owing to side effects, compared with three patients (13%) who took propranolol. In this study, patients with migraine had significantly fewer headaches when taking divalproex sodium than when taking propranolol. However, the dropout rate was higher in the divalproex sodium group.

Silberstein and Collins (38) reported on 163 patients who (8) were enrolled in an open-label extension study after completion of either of the two placebo-controlled divalproex sodium trials (7). This represented 198 patient-years of divalproex exposure, with an average dosage of 974 mg/day. Forty-nine percent of patients experienced a ≥50% reduction in migraine headache rates from days 1 to 90. This increased to 70% from days 901 to 1,080, in part because of selective dropout.

A subset of patients who were treated for at least 12 months was analyzed. Patients who discontinued divalproex after 1 year failed to show this improvement up to days 361 to 500, in contrast to patients who remained in the study. Overall, 67% of the patients discontinued divalproex. Reasons included administrative problems (31%), drug intolerance (21%), and treatment ineffectiveness (15%). The most common adverse events were nausea (42%), infection (39%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), and somnolence (25%).

Ghose and Niven (39) studied 37 patients from a headache clinic who had a diagnosis of migraine with or without aura. They treated the patients with sodium valproate for 3 months. Response to therapy was defined as a ≥50% reduction in headache frequency. Four noncompliers were identified by plasma drug level monitoring and were excluded from the study. Seventeen (71%) patients improved within 4 to 6 weeks and maintained the improvement for 12 weeks. Between 12 and 24 months, two patients withdrew because of side effects and one because of non-drug-related problems. Twelve of the original 27 patients maintained their response for 12 months or longer. At 13 to 24 months, clinical improvement (percentage reduction in the frequency of migraine attacks) correlated inversely with the plasma drug levels and daily valproate dose among the responders. In this study, patients who did not respond to low-dose (600 mg) valproate were unlikely to benefit from higher doses.

Divalproex has been used in the acute treatment of migraine. Small open studies have suggested that intravenous (i.v.) valproic acid is effective in acute migraine treatment. Fourteen consecutive patients with moderate to severe headaches of 24 to 72 hours' duration were given 500 mg of valproate i.v. over 15 to 30 minutes or 10 mg metoclopramide with 1 mg DHE intramuscularly. In the i.v. valproate group, 71.4% of patients improved to a state of mild or no headache at 1 hour, 85.7% at 2 hours, and 71.4% at 4 hours. Migraine-associated symptoms of nausea, photophobia, and phonophobia showed similar improvement. In the DHE group, 42.8% of patients improved to a state of mild or no headache at 1 and 2 hours and 57.1% at 4 hours (40).

Czapinski and Motyl (41) studied 25 patients (18 women and 7 men) with an acute migraine attack, with or without aura, within 6 hours of onset. They were given either valproate

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i.v. for 5 minutes at the dosage of 15 mg/kg of body weight, or 0.9% NaCl according to the same protocol. Ten of 13 patients treated with valproate showed a decrease or subsidence of pain, in contrast to 4 of 12 patients in the placebo group. Complete pain relief occurred as soon as 10 minutes, with a range of 10 to 25 minutes (40, 41, 42).

STUDIES IN PATIENTS WITH OTHER HEADACHE TYPES

Some of these trials in patients with migraine also included patients with other headache types (31,32,34), and results are discussed in the previous section. Additional studies examined in greater detail the potential usefulness of valproate in other headache types. In 1989, Hering and Kuritzky (12) treated 15 patients with cluster headache (2 chronic and 13 episodic) with sodium valproate in an open pilot study (Table 87.3). The dosage ranged from 600 to 2,000 mg/day. Eleven patients (73.3%) improved: nine reported complete cessation of attacks and two reported marked improvement. There was no correlation between efficacy and valproate plasma levels.

Freitag et al. (43) enrolled 26 patients in a long-term, open-label, flexible-dose study of divalproex sodium for cluster headache prevention. Patients had an inadequate response or had experienced adverse events from preventive therapy. Twenty-one patients had chronic cluster and five had episodic cluster headache. Ten of 15 men and 5 of 6 women with chronic cluster headache had a ≥50% response. Six patients had a complete response and were able to discontinue treatment without recurrence of their cluster headache attacks. The mean degree of improvement was 53.9% for patients with chronic cluster headache and 58.6% for patients with episodic cluster headache. The mean dose of divalproex sodium was 850 mg for episodic cluster headaches and 826 mg for chronic cluster headaches. Five patients had adverse events: one each with a rash, hair breakage, tiredness, nausea, and tremor.

TABLE 87.3. CLINICAL TRIALS OF VALPROIC ACID IN OTHER HEADACHE TYPES

Study

Patient Population (Diagnostic Criteria)

No.

Design

Dosage (mg/d)/Other Medication

Plasma Levels

Duration

Responder Rates

Hering and Kuritzky (1989)(12)

Cluster, chronic episodic

15

Open

600 to 2,000 mg/Valproate

31 to 94 µg/ml

Until end of cluster

73.3% responded; 9/15 complete disappearance; 2/15 marked improvement

Mathew and Ali (1991)(11)

Chronic daily headache

30

Open

1,000 to 2,000mg Divalproex

75 to 100µg/ml

3 Months

2/3 Significant improvement

Freitag et al. (43)

Cluster, chronic and episodic

26
21-chronic

5-episodic

Open

Mean dose Divalproex
800mg—chronic
850mg—episodic

 

Until end of cycle or mean? Of 11.1 months

Chronic: 15/21 significantly improved
Episodic: 3/3 men improved; 2/2 women partially responded

Freitag et al.(45)

Chronic daily headache

132

Open

     

~75% had at least a 50% reduction in headache frequency

In 1991, Mathew and Ali (11) reported on 32 patients with chronic daily headache who were unresponsive to prior treatment. After a baseline observation period of 1 month, the patients were given divalproex sodium 1,000 to 2,000 mg/day for 3 months. Serum valproic acid levels were between 75 and 100 µg/mL. Two thirds of the patients showed a significant improvement in headache index and headache-free days. The most common side effects were weight gain, tremor, hair loss, and nausea. No liver function abnormalities were noted.

Delva et al. (44) suggested in a case report that valproate was useful to treat migraine induced by selective serotonin reuptake inhibitors.

Freitag et al. (45) assessed the safety and efficacy of divalproex sodium in the long-term treatment of chronic daily headache through a retrospective chart review with data extraction from headache diaries. Six hundred forty-two current patients under treatment with divalproex for chronic daily headache were reviewed; 132 were being treated with divalproex alone. The mean improvement was 47%, with migraine improving approximately 65%. Ninety-three of 132 patients had at least a 50% reduction in headache frequency. In patients who could differentiate their migraine from TTHs, the response of the migraine was better than the TTH component in 33 patients; in 47 patients, both changed at the same rate. Nine patients had an improved response for their TTH compared with their migraines. The remainder of the patients' headaches could not be differentiated clearly into migraine or TTHs, but

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met Silberstein's criteria for transformed migraine. The mean improvement in the migraine-differentiated component was 65.2%, whereas the patients with TTH demonstrated a mean improvement of 45.4% from baseline frequency. There was no correlation between response and age, sex, duration of treatment, and the dose of divalproex sodium given. Adverse events occurred in approximately 31% of patients; none was severe. Women were more likely to experience adverse events than men, but their weight gain was less (average weight gain was 1.9 pounds for women and 7 pounds for men). Divalproex sodium could be used for a long time as the sole drug for the successful treatment of chronic daily headache. Nearly three-fourths of patients had at least a 50% reduction in headache frequency; adverse events occurred in approximately one-third.

TREATMENT CHOICES FOR MIGRAINE

The goals of migraine preventive therapy are to (a) reduce attack frequency, severity, and duration; (b) improve responsiveness to treatment of acute attacks; and (c) improve function and reduce disability. The medications used to treat migraine have been put into the following treatment groups based on their established clinical efficacy, tolerability and safety profile, and the clinical experience of the United States Headache Consortium participants (15):

Group 1. Medications with proven high efficacy and mild to moderate adverse effects.

Group 2. Medications with lower efficacy (i.e., limited number of studies, studies reporting conflicting results, efficacy suggesting only “modest” improvement) and mild to moderate adverse effects.

Group 3. Medication use based on opinion, not randomized, controlled trials.

  1. Low to moderate adverse effects
  2. Frequent or severe adverse effects (or safety concerns) or complex management issues.

Group 4. Medication with proven efficacy but frequent or severe adverse effects (or safety concerns), or complex management issues

Group 5. Medications proven to have limited or no efficacy.

When deciding on a preventive drug, the clinician should choose a drug from one of the high-efficacy alternatives based on the patient's profile and the presence or absence of coexisting or comorbid disease. The clinician should use the drug with the best risk-to-benefit ratio for the individual patient, and take advantage of the side effect profile of the drug. An underweight patient would be a candidate for one of the medications that commonly produce weight gain; in contrast, one would avoid these drugs in the overweight patient. Sedating tertiary tricyclic antidepressants (TCAs) would be useful at bedtime for patients with insomnia. The older patient with cardiac disease may not be able to use TCAs, calcium channel blockers, or β blockers, but could easily use valproate. The athletic patient should not be prescribed β blockers. Patients who are dependent on their wits should not take medication that can impair cognitive functioning.

Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. In some instances, two or more conditions may be treated with a single drug (13,46). For example, valproate is a drug of choice for the patient with migraine and epilepsy (5,7) or migraine and manic-depressive illness (47,48). When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, β blockers should be used with caution in the depressed migraineur, whereas TCAs, neuroleptics, or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur.

CONCLUSIONS AND RECOMMENDATIONS ON THE USE OF VALPROATE IN MIGRAINE

In all of the clinical studies, whether open, retrospective, or placebo-controlled and double-blind, valproate was an effective preventive treatment for migraine. There was a reduction in the number of migraine attacks, and migraine duration and intensity also were reduced in some instances. There was some evidence that symptomatic medication use could be decreased. Some studies (6,32), but not all (39), suggested that clinical efficacy is correlated to serum concentration. Preliminary reports (36,49) suggest that divalproex sodium is as effective as the β blocker propranolol. The data from two multicenter, double-blind, placebo-controlled studies were combined and demonstrated that divalproex sodium was equally as effective in migraine with aura as in migraine without aura (49). It also appears to be effective in cluster headache and chronic daily headache, but it does not seem to be as effective for pure TTH. It is equally as effective in patients with severe, frequent migraines as in those with less severe migraines (50). The following recommendations can be made for the optimal use of valproate in migraine.

  1. Before initiating treatment, perform a physical examination and take a thorough medical history, with special attention to hepatic, hematologic, and bleeding abnormalities. Inform the patient about possible hair loss, weight gain, and teratogenic effects and the signs and symptoms of hepatic and hematologic dysfunction. Obtain screening baseline laboratory studies to help identify risk factors that could influence drug selection.

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Suggested studies include complete blood count, differential, and platelets; prothrombin time and partial thromboplastin time; serum chemistry, including glucose, blood urea nitrogen, electrolytes, calcium, potassium, magnesium, creatinine, urate, cholesterol, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total protein, and albumin (SMA profile).

  1. To minimize gastrointestinal side effects, use enteric-coated formulations of valproate. Begin with a dose of 250 mg at bedtime. If nausea still occurs, use the sprinkle formulation (125 mg) and increase the dose very slowly. Slowly increase the dosage to 500 to 750 mg/day (in two to three divided dose) to limit gastrointestinal side effects. Higher doses are needed at times.
  2. Obtain follow-up serum valproic acid levels to test for compliance, toxicity, and drug reactions as needed. Rigid adherence to the suggested optimal range for epilepsy (50 to 100 µg/mL) is not likely to benefit the patient; we occasionally push to trough levels of 125 µg/mL.
  3. See the patient on a regular basis (every 1 to 2 months) during the first 6 to 9 months of therapy.
  4. It is not necessary to monitor blood and urine in healthy and asymptomatic patients who are on monotherapy, despite the manufacturer's recommendation that liver function tests be performed at frequent intervals, especially during the first 6 months. Identify patients who belong to one of the high-risk groups at the inception of treatment. Obtain follow-up chemistry, if needed, particularly in patients on polypharmacy.
  5. If mild elevation of serum hepatic aminotransferase levels occurs, continue valproate at the same dose or a lower dose until the enzymes normalize. If the hepatic aminotransferase elevations are much higher (e.g., two to three times the upper limit of normal), discontinue valproate. If severe, abnormal pain suggestive of pancreatitis occurs, check serum amylase and lipase.
  6. Avoid valproate for headache in children younger than 10 years of age unless routine treatments have failed, in which case use it as monotherapy. Avoid valproate in patients with preexisting liver disease and metabolic disorders predisposing to liver toxicity. Avoid valproate for headache when women are pregnant or attempting to become pregnant.
  7. Ten percent of treated patients may experience tremor. If this is bothersome, decrease the dose of valproate or use propranolol, a β blocker that also is an effective migraine-preventive agent (51).
  8. Excessive weight gain can occur. Advise the patient to exercise regularly, obtain a dietary consultation, and avoid using other medications, such as TCAs, that can produce weight gain. The incidence of hair loss is 2.6% to 12% (25). Anecdotally, multivitamins and zinc supplements have been reported to control hair loss. We have our patients take 220 mg/day of zinc (mega zinc) and a multivitamin.

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