Antiepileptic Drugs, 5th Edition

Phenytoin and Other Hydantoins

61

Clinical Efficacy and Use in Other Neurological Disorders

Ettore Beghi MD

Chief, Neurophysiological Unit, “San Gerardo” Hospital, Monza, Italy; and Head, Neurological Disorders Laboratory, Institute for Pharmacological Research “Mario Negri,” Milan, Italy

Phenytoin (PHT) reduces the frequency of sustained repetitive firing of action potentials in neurons through a use-dependent inhibition of sodium channels. The drug also exerts an action on calcium or sodium ions that regulate voltage-dependent neurotransmitter release at the synaptic cleft (1). These actions on neurotransmitter receptors and ion channels tend to explain the use of PHT and other anticonvulsants in neurologic conditions other than epilepsy. These mechanisms of action may explain the postulated efficacy of PHT in conditions such as neuropathic pain and pain syndromes, spasticity, myotonia, and other muscle disorders. Although several reports have been published on the use of PHT for the treatment of these and other nonepileptic conditions, evidence of efficacy from randomized clinical trials is scant.

NEUROPATHIC PAIN

Neuropathic pain is a spectrum of neuralgic pain syndromes including trigeminal neuralgia and neuralgias affecting other cranial or peripheral nerves (glossopharyngeal, superior-laryngeal, postherpetic), diabetic neuropathy, thalamic syndrome, phantom limb pain, tabetic pain, and cancer pain, among others.

Trigeminal and Other Cranial Neuralgias

Trigeminal neuralgia is a paroxysmal form of facial pain commonly affecting the second and third divisions of the trigeminal nerve. Unlike with carbamazepine (Chapter 24), evidence of efficacy of PHT in trigeminal neuralgia and similar conditions is based only on uncontrolled studies. In his extensive review of the neurophysiology of the main pain syndromes and the presumed mechanisms of actions of PHT and other anticonvulsants, Swerdlow (2) reported that PHT was effective as first-aid treatment in ≤80% of patients with trigeminal neuralgia. The drug was used in daily doses ranging from 300 to 600 mg/day. Because trigeminal neuralgia responds to carbamazepine, this is the drug of choice; if symptoms persist with carbamazepine, PHT should be added to the regimen. In contrast to trigeminal neuralgia, the response of glossopharyngeal neuralgia to PHT has been varied. Information on the safety and tolerability of PHT in these cases was insufficient. For these reasons, PHT can be considered an alternative to other treatments in patients with neuralgia, but other drugs such as carbamazepine are preferred.

Other Pain Syndromes

The results of five randomized clinical trials on the use of PHT in pain syndromes other than cranial nerve neuralgias are given in Table 61.1. The neuropathic conditions in these studies included diabetic neuropathy, Fabry's disease, and cold-induced pain. The drug was administered orally (average daily dose 300 mg/day) (3, 4, 5, 6) or as intravenous infusion (15 mg/kg) (7). The results of the two placebo-controlled studies in patients with diabetic neuropathy treated for 2 and 23 weeks were contradictory (PHT was superior to placebo in one study and was similar to placebo in the other study). The number needed to treat for effectiveness of PHT compared to placebo is 2.1 (95% confidence interval, 1.5 to 3.6) (8). In patients with Fabry's disease, PHT given for 3 weeks was better than aspirin 1,700 mg/day and placebo in reducing the intensity of pain (3). In diabetic neuropathy, the efficacy of PHT 300 mg/day was at best modest (4, 5). The analgesic

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activity of PHT on cold-induced pain in healthy volunteers was compared with that of lamotrigine and dihydrocodeine and was found to be similar (6). The three drugs did not show significant differences in sedation compared with placebo. In a double-blind placebo-controlled crossover study, intravenous infusion of PHT showed a significant analgesic effect in acute exacerbations of neuropathic pain, which outlived the infusion time and the plasma half-life of the drug. Based on the available findings, the evidence of efficacy of PHT ≤300 mg/day for the treatment of neuropathic pain is at best modest, even though the drug is thought to potentiate other analgesic agents (2), and it seems able to control acute exacerbations of neuropathic pain when it is given in intravenous infusion. PHT is well tolerated and does not seem to provoke sedation and cognitive impairment.

TABLE 61.1. RANDOMIZED CLINICAL TRIALS OF PHENYTOIN FOR NEUROPATHIC PAIN OTHER THAN TRIGEMINAL NEURALGIA

Reference

No. Treated (age) (Disease)

Treatment Duration (Double-Blind Period)

Daily Dose (mg) [Comparator]

Significant Results [No. Improved]

Adverse Eventsa [No. Withdrawals]

3

8 (13-32)
[Fabry's disease]

3 wk

≤300 or 4-6/kg
[ASP 1,700]

Mean subjective pain relief (score = 0-3)
PHT, 2.7; ASP, 0.5; PLC, 0.9

PHT, 1/8

4

12 (39-75)

23 wk

300

Mean pain score (distance in mm from “none”)

PHT, 10/12; PLC, 4/12

 

[Diabetic neuropathy]

 

[PLC]

PHT, 7.2 mm (PL, <5 mg/L), PLC, 8 mm; PHT, 19.1 mm (PL <5 mg/l), PLC, 20 mm

[PHT, 2/12; PLC, 0/12]

5

40 (?)
[Diabetic neuropathy]

2 wk

300
[PLC]

[PHT, 28/38; PLC, 10/38]

Ataxia: PHT, 4/38; PLC, 0/38

6

12 (20-26)
[Cold-induced pain]

Single

300
[LTG, 300; DHC, 90; PLC]

Main pain AUC changesb: PHT, +65; LTG, +37; DHC, +91; PLC, -17

PHT, 2/15; LTG, 1/15; DHC, 5/15: PLC, 0/15

7

20 (25-60)
[Radiculopathy, 10; neuritis, 5; diabetic neuropathy, 3; digital neuroma 2]

2 h

15/kg infusion
[PLC]

During PHT infusion: significant decrease of burning, shooting, and overall pain, sensitivity, and numbness
After infusion: significant decrease of overall pain (day 1), shooting pain (day 5), and sensitivity (day 3)
No change with PLC [PHT, 14/20; PLC, 0/20]

?

AMT, amitriptyline; ASP, aspirin; AUC, area under the drug plasma concentration; DHC, dihydrocodeine; LTG, lamotrigine; PHT, phenytoin; PL, plasma level; PLC, placebo; VAS, visual analog scale.

a No. with any event or, if unavailable, with commonest events.

b Positive value means pain decrease.

MYOTONIA

Myotonia is a clinical manifestation of different muscle disorders and is characterized by altered muscle membrane physiology. Treatment of myotonia with PHT 200 to 400 mg/day orally was investigated in two small double-blind comparative studies (Table 61.2) (9,10). The drug showed an efficacy similar to that of the two comparators (procainamide and carbamazepine) and was superior to placebo, as shown by the improvement of myotonic symptoms and the delay in muscle relaxation, documented ergographically. Based on the results of these studies, PHT and carbamazepine can be used interchangeably for the treatment of myotonia. Specific attention should be paid to adverse treatment events, which were not sufficiently documented in the randomized studies.

MOTION SICKNESS

PHT may be effective in motion sickness by acting on the central and peripheral vestibular pathways (11). The prophylactic action of PHT in 35 patients susceptible to motion sickness was tested in a double-blind trial (12). The patients received 200 mg of PHT or placebo in single dose. Based on clinical and electrophysiologic tests, PHT prevented gastric tachyarrhythmia and reduced the intensity of motion sickness symptoms.

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TABLE 61.2. RANDOMIZED CLINICAL TRIALS OF PHENYTOIN FOR MYOTONIA

Reference

No. Treated (age) (Disease)

Treatment Duration (Double-Blind Period)

Daily Dose (mg) [Comparator]

Significant Results [No. Improved]

Adverse Eventsa [No. Withdrawals]

9

9 (?)
[Myotonic dystrophy 7; myotonia congenita 2]

3 wk

300-400
[PCN, 2,000-4,000; PLC]

Grasp phase showed by PLC and PCN, not by PHT; relaxation affected by PHT and PCN (no difference), not by PLC
PHT and PCN both relieved myotonia [PHT, 5/9; PCN, 5/9; PLC, 2/9]

PCN, 6/9; PHT, 1?/9

10

6 (?)
[Myotonic dystrophy]

Two 15-day periods

200, 300 [CBZ, 600, 800; PLC]

Decrease in time of myotonic after-discharge (CBZ =PHT>PLC) with moderate effect of dose
Improved score of myotonic symptoms (CBZ =PHT>PLC) with no effect of dose

Asthenia and somnolence: PHT, 2/6; CBZ, 2/6
Increase of P-Q interval: CBZ, 1/6 [CBZ,0/6; PHT, 1/6]

PLC, placebo; PCN, procainamide.

a No. with any event or, if unavailable, with commonest events.

REFERENCES

  1. DeLorenzo RJ. Phenytoin: mechanisms of action. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1995:271-282.
  2. Swerdlow M. Anticonvulsant drugs and chronic pain. Clin Neuropharmacol1984;7:51-82.
  3. Lockman LA, Hunningghake DB, Krivit W, et al. Relief of pain of Fabry's disease by diphenylhydantoin. Neurology1973;23: 871-875.
  4. Saudek CD, Werns S, Reidenberg MM. Phenytoin in the treatment of diabetic symmetrical polyneuropathy. Clin Pharmacol Ther1977:22:196-199.
  5. Chadda VS, Mathur MS. Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy. J Assoc Physicians India1978;26:403-406.
  6. Webb J, Kamali F. Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers. Pain1998;76:357-363.
  7. McCleane GJ. Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blinded, placebo-controlled, crossover study. Anesth Analg1999;89:985-988.
  8. Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and chronic pain. In: Cochrane database of systematic reviews,2000:CD001133.
  9. Munsat TL. Therapy of myotonia: a double-blind evaluation of diphenylhydantoin, procainamide, and placebo. Neurology1967;17:359-367.
  10. Sechi GP, Traccis S, Durelli L, et al. Carbamazepine versus diphenylhydantoin in the treatment of myotonia. Eur Neurol1983;22:113-118.
  11. Knox GW, Woodard D, Chelen W, et al. Phenytoin for motion sickness: clinical evaluation. Laryngoscope1994;104:935-939.
  12. Stern RM, Uijtdehaage SH, Muth ER, et al. Effects of phenytoin on vection-induced motion sickness and gastric myoelectric activity. Aviat Space Environ Med1994;65:518-521.

SUGGESTED READING

Beghi E. The use of anticonvulsants in neurological conditions other than epilepsy: a review of the evidence from randomized controlled trials. CNS Drugs 1999;11:61-82.