Primidone …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.06.2021
Released 01.28.2003
Expires For CME 03.06.2024

Primidone

Author: K K Jain MD†

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Primidone

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Introduction

Historical note and terminology

After the introduction of phenytoin, a search for antiepileptic drugs with a structure like that of phenobarbital and phenytoin continued, and primidone was synthesized in 1949 (05). It was introduced into clinical use in 1952 and found to be effective for the control of complex partial and secondarily generalized seizures (08). There has been some controversy as to whether it is a distinct antiepileptic drug or simply a prodrug of phenobarbital. Most investigations now suggest that primidone has pharmacodynamic properties distinct from those of phenobarbital. The manufacturer of primidone has announced the discontinuation of this drug. Primidone was withdrawn from the market in the Netherlands in 2004 but was available for some time on a limited basis (06). In the United Kingdom, the drug will be available until an alternative source of manufacture is found.

Indications

Primidone, either alone or used concomitantly with other anticonvulsants, is indicated in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsants.

Off-label uses

Management of tremor. Primidone is still being used for the management of mild to moderate tremor. Primidone has even been recommended as one of the first-line therapies for essential tremor (16). Although tremor is not listed as an approved indication, the following are important points about its use:

	• Primidone is apparently a promising compound against tremor in Wilson disease (09).
	• Evidence-based guidelines for treatment of essential tremor of the American Academy of Neurology recommend primidone as Level A treatment (23).
	• Primidone is one of the most effective drugs for sustained tremor, but treatment must be individualized depending on the cause of tremor-related disability (15).
	• Decrease of GABA concentration in the dentate nucleus of patients with essential tremor, assessed by magnetic resonance spectroscopy, is a potential biomarker of the disorder. Primidone use in these patients has been shown to have no effect on dentate GABA concentration and should not interfere with interpretation of the results (11).
	• Primidone has been used for reducing severe cerebellar tremors in patients with multiple sclerosis (12).
	• Ocular flutter in essential tremor (02).
	• Essential vocal tremor (13).
	• A patient who presented with tonic-clonic seizures and who developed dystonia after being given phenytoin was successfully treated with intramuscular biperiden hydrochloride, and primidone was added to the treatment regimen (01).
	• Primidone educes unesterified cholesterol levels in cells and extends lifespan in mice. Studies on cell and mouse models of Niemann-Pick disease type C have shown beneficial effects of primidone, resulting in the accumulation of unesterified, free cholesterol in cells and tissues in Niemann-Pick disease type C (03).

Role of primidone in pain. In experimental animal studies, administration of primidone in doses lower than those required for anticonvulsive effect inhibited melastatin-related transient receptor potential (TRP) channel TRPM3, which is a nonselective cation channel expressed in nociceptive neurons and activated by heat (10). This indicated thermal exertion of antinociceptive properties of primidone.

Adverse effects

Initial treatment may cause somnolence during the first few days of treatment. The most frequently reported adverse effects are ataxia and vertigo, which subside with prolonged use. Life-threatening systemic side effects are rare. Depression is significantly associated with inadequate seizure control and use of primidone. There is a case report of acute suicidality following initiation of primidone for erroneously diagnosed essential tremor in a patient with Parkinson disease without risk factors for suicide, and suicidal ideation resolved after primidone was discontinued (07).

Impaired consciousness in children on phenobarbital has been reported, and over 130 μmol/L of the drug was detected in serum along with presence of primidone, although primidone had not been used (19). The explanation for this finding is that high-dose phenobarbital can convert to its prodrug primidone.

Megaloblastic anemia may occur as a rare idiosyncratic reaction to primidone. Primidone along with other hepatic enzyme-inducing antiepileptic drugs has been clearly associated with decreased bone mineral density (Pack and Morrel 2004).

Connective tissue disorders such as Dupuytren contracture have been reported after prolonged use of primidone, and drug withdrawal may result in improvement (20). In experimental studies on rats, primidone impairs male sexual behavior due to changes in erectile function (21). No such events have been reported in patients treated with primidone.

Management. Pretreatment with phenobarbital can minimize the occurrence of intolerable adverse events associated with the introduction of primidone because of a cross tolerance between the 2 drugs. If adverse effects do not subside, dosage may be reduced or the drug continued. Megaloblastic anemia can be treated with folic acid therapy after primidone is discontinued.

References

01: Acar T, Alkan G, Çaksen H, et al. Phenytoin induced dystonia. Turk J Pediatr 2018;60(1):111-2. PMID 30102491
02: Anagnostou E, Kararizou E, Evdokimidis I. Ocular flutter in essential tremor: clinical course and response to primidone. J Neurol 2013;260(10):2672-4. PMID 24061767
03: Ashikawa H, Mogi H, Honda T, Nakamura H, Murayama T. Beneficial effects of primidone in Niemann-Pick disease type C (NPC)-model cells and mice: reduction of unesterified cholesterol levels in cells and extension of lifespan in mice. Eur J Pharmacol 2021;896:173907. PMID 33503462
04: Bentue-Ferrer D, Verdier MC, Tribut O. Therapeutic drug monitoring of primidone and phenobarbital. [French] Therapie 2012;67(4):381-90. PMID 23110839
05: Bogue J, Carrington HC. The evaluation of "mysoline," a new anticonvulsant drug. Br J Pharmacol Chemother 1953;8(2):230-6. PMID 13066728
06: de Haan GJ, Carpay JA, van Donselaar CA. Antiepileptic primidone shortly to be withdrawn from sale: change medication now. Ned Tijdschr Geneeskd 2003;147(47):2325-6. PMID 14669538
07: Famina S, Tegin C, El-Mallakh RS. Acute primidone-induced suicidality: a case report running head: acute primidone induced suicidality. J Transl Neurosci 2016;1:2.
08: Handley R, Stewart A. Mysoline: a new drug in the treatment of epilepsy. Lancet 1952;1:742-4. PMID 14918421
09: Hölscher S, Leinweber B, Hefter H, et al. Evaluation of the symptomatic treatment of residual neurological symptoms in Wilson disease. Eur Neurol 2010;64(2):83-7. PMID 20606453
10: Krügel U, Straub I, Beckmann H, Schaefer M. Primidone inhibits TRPM3 and attenuates thermal nociception in vivo. Pain 2017;158(5):856-67. PMID 28106668
11: Louis ED, Hernandez N, Dyke JP, Ma R, Dydak U. Effect of primidone on dentate nucleus γ-aminobutyric acid concentration in patients with essential tremor. Clin Neuropharmacol 2016;39(1):24-8. PMID 26757316
12: Naderi F, Javadi SA, Motamedi M, Sahraian MA. The efficacy of primidone in reducing severe cerebellar tremors in patients with multiple sclerosis. Clin Neuropharmacol 2012;35(5):224-6. PMID 22821064
13: Nida A, Alston J, Schweinfurth J. Primidone therapy for essential vocal tremor. JAMA Otolaryngol Head Neck Surg 2016;142(2):117-21. PMID 26660910
14: Pack AM, Morrell MJ. Epilepsy and bone health in adults. Epilepsy Behav 2004;5(Suppl 2):S24-9. PMID 15123008
15: Rajput AH, Rajput A. Medical treatment of essential tremor. J Cent Nerv Syst Dis 2014;6:29-39. PMID 24812533
16: Sharma S, Pandey S. Treatment of essential tremor: current status. Postgrad Med J 2020;96(1132):84-93. PMID 31575730
17: Smith DB, Mattson RH, Cramer JA, Collins JF, Novelly RA, Craft B. Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone. Epilepsia 1987;28(Suppl 3):S50-8. PMID 3319543
18: Sun MZ, Deckers CL, Liu YX, Wang W. Comparison of add-on valproate and primidone in carbamazepine-unresponsive patients with partial epilepsy. Seizure 2009;18(2):90-3. PMID 18672385
19: Tanoshima R, 't Jong GW, Merlocco A, et al. A child exposed to primidone not prescribed for her. Ther Drug Monit 2013;35(2):145-9. PMID 23503440
20: Vasconcellos LFR, Nassif D, Spitz M. Dupuytren, ledderhose, and Peyronie diseases after primidone use for essential tremor. Neurologist 2019;24(5):150-1. PMID 31478998
21: Westerman AT, Roma PG, Creed ET, Hurwitz ZE, Dominguez JM. The antiepileptic primidone impairs male rat sexual behavior. Pharmacol Biochem Behav 2009;93(2):160-4. PMID 19447126
22: Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord 2014;16(4):409-31. PMID 25515681
23: Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology 2011;77(19):1752-5. PMID 22013182

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Primidone

Other Pertinent Drugs

carbamazepine
Mysoline
phenobarbital
phenylethylmalonamide
phenytoin

Also Relevant

Absence status epilepticus
Epilepsy with grand mal seizures on awakening
Essential tremor
Fetal anticonvulsant syndrome
High-pressure neurologic syndrome
- Mesial temporal lobe epilepsy
- Multiple sclerosis
- Neuropharmacology
- Pharmacological treatment of epilepsy in adolescents and adults
- Treatment of multiple sclerosis symptoms
- Tremors

Primidone …

Primidone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

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Neocortical temporal lobe seizures

Primidone

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

This is an article preview.
Start a Free Account
to access the full version.