Primidone

Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures, as well as essential tremors. It is taken by mouth.

Common side effects include sleepiness, poor coordination, nausea, and loss of appetite. Severe side effects may include suicide, psychosis, a lack of blood cells. Use during pregnancy may result in harm to the baby. Primidone is an anticonvulsant of the barbiturate class. How it works is not entirely clear.

Primidone was approved for medical use in the United States in 1954. It is available as a generic medication. In 2020, it was the 269th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Epilepsy

Licensed for generalized tonic-clonic and complex partial seizures in the United Kingdom. In the United States, primidone is approved for adjunctive (in combination with other drugs) and monotherapy (by itself) use in generalized tonic-clonic seizures, simple partial seizures, and complex partial seizures, and myoclonic seizures. In juvenile myoclonic epilepsy (JME), it is a second-line therapy, reserved for when the valproates or lamotrigine do not work and when other second-line therapies—acetazolamide work either.

Open-label case series have suggested that primidone is effective in the treatment of epilepsy. Primidone has been compared to phenytoin, phenobarbital, mephobarbital, ethotoin, metharbital, and mephenytoin. In adult comparison trials, primidone has been found to be just as effective.

Essential tremor

Primidone is considered to be a first-line therapy for essential tremor along with propranolol. In terms of tremor amplitude reduction, it is just as effective as propranolol, reducing it by 50%. Both drugs are well studied for this condition, unlike other therapies, and are recommended for initial treatment. 250 mg/day (low-dose therapy) is just as good as 750 mg/day (high-dose therapy).

Primidone is not the only anticonvulsant used for essential tremor; the others include topiramate and gabapentin. Other pharmacological agents include alprazolam, clonazepam, atenolol, sotalol, nadolol, clozapine, nimodipine, and botulinum toxin A. Many of these drugs were less effective (according to Table 1), but a few were not. Only propranolol has been compared to primidone in a clinical trial.

Psychiatric disorders

In 1965, Monroe and Wise reported using primidone along with a phenothiazine derivative antipsychotic and chlordiazepoxide in treatment-resistant psychosis. What is known is that ten years later, Monroe went on to publish the results of a meta-analysis of two controlled clinical trials on people displaying out-of-character and situationally inappropriate aggression, who had abnormal EEG readings, and who responded poorly to antipsychotics; one of the studies was specifically mentioned as involving psychosis patients. When they were given various anticonvulsants not only did their EEGs improve, but so did the aggression.

In March 1993, S.G. Hayes of the University of Southern California School of Medicine reported that nine out of twenty-seven people (33%) with either treatment-resistant depression or treatment-resistant bipolar disorder had a permanent positive response to primidone. A plurality of subjects were also given methylphenobarbital in addition to or instead of primidone.

Adverse effects

Primidone can cause drowsiness, listlessness, ataxia, visual disturbances, nystagmus, headache, and dizziness. These side effects are the most common, occurring in more than 1% of users. Transient nausea and vomiting are also common side effects.

Dupuytren's contracture, a disease of the fasciae in the palm and fingers that permanently bends the fingers (usually the little and ring fingers) toward the palm, was first noted to be highly prevalent in epileptic people in 1941 by a Dr. Lund, fourteen years before primidone was on the market. Lund also noted that it was equally prevalent in individuals with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not matter. However, only one quarter of the women were affected vs. half of the men. Thirty-five years later, Critcheley et al. reported a correlation between how long a patient had had epilepsy and his or her chance of getting Dupuytren's contracture. They suspected that this was due to phenobarbital therapy, and that the phenobarbital was stimulating peripheral tissue growth factors. Dupuytren's contracture is almost exclusively found in Caucasians, especially those of Viking descent, and highest rates are reported in Northern Scotland, Norway, Iceland, and Australia. It has also been associated with alcoholism, heavy smoking, diabetes mellitus, physical trauma (either penetrating in nature or due to manual labor), tuberculosis, and HIV. People with rheumatoid arthritis are less likely to get this, and Drs. Hart and Hooper speculate that this is also true of gout due to the use of allopurinol. This is the only susceptibility factor that is generally agreed upon. Anticonvulsants do not seem to increase the incidence of Dupuytren's contracture in non-whites.

Primidone has other cardiovascular effects in beyond shortening the QT interval. Both it and phenobarbital are associated with elevated serum levels (both fasting and six hours after methionine loading) of homocysteine, an amino acid derived from methionine. This is almost certainly related to the low folate levels reported in primidone users. Elevated levels of homocysteine have been linked to coronary heart disease. In 1985, both drugs were also reported to increase serum levels of high density lipoprotein (HDL) cholesterol, total cholesterol, and apolipoproteins A and B.

It was first reported to exacerbate hepatic porphyria in 1975. In 1981, it was shown that phenobarbital, one of primidone's metabolites, only induced a significant porphyrin at high concentrations ''in vitro''. It can also cause elevations in hepatic enzymes such as gamma-glutamyl transferase and alkaline phosphatase.

Less than 1% of primidone users will experience a rash. Compared to carbamazepine, lamotrigine, and phenytoin, this is very low. The rate is comparable to that of felbamate, vigabatrin, and topiramate. Primidone also causes exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis.

Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with bone diseases such as osteoporosis, osteopenia (which can precede osteoporosis), osteomalacia and fractures. The populations usually said to be most at risk are institutionalized people, postmenopausal women, older men, people taking more than one anticonvulsant, and children, who are also at risk of rickets. However, it has been suggested that bone demineralization is most pronounced in young people (25–44 years of age) and one 1987 study of institutionalized people found that the rate of osteomalacia in the ones taking anticonvulsants—one out of nineteen individuals taking an anticonvulsant (vs. none among the thirty-seven people taking none) —was similar to that expected in elderly people. The authors speculated that this was due to improvements in diet, sun exposure and exercise in response to earlier findings, and/or that this was because it was sunnier in London than in the Northern European countries which had earlier reported this effect. In any case, the use of more than one anticonvulsant has been associated with an increased prevalence of bone disease in institutionalized epilepsy patients versus institutionalized people who did not have epilepsy. Likewise, postmenopausal women taking anticonvulsants have a greater risk of fracture than their drug-naive counterparts.

Anticonvulsants affect the bones in many ways. They cause hypophosphatemia, hypocalcemia, low Vitamin D levels, and increased parathyroid hormone. Anticonvulsants also contribute to the increased rate of fractures by causing somnolence, ataxia, and tremor which would cause gait disturbance, further increasing the risk of fractures on top of the increase due to seizures and the restrictions on activity placed on epileptic people. Increased fracture rate has also been reported for carbamazepine, valproate and clonazepam. The risk of fractures is higher for people taking enzyme-inducing anticonvulsants than for people taking non-enzyme-inducing anticonvulsants. In addition to all of the above, primidone can cause arthralgia.

Granulocytopenia, agranulocytosis, and red-cell hypoplasia and aplasia, and megaloblastic anemia are rarely associated with the use of primidone. Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged red blood cells with abnormally high nuclear-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, into abnormal megakaryocytes and sometimes hypersegmented neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA replication. The anticonvulsant users who get this also tend to eat monotonous diets devoid of fruits and vegetables.

This antagonistic effect is not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.

In addition to increasing the risk of megaloblastic anemia, primidone, like other older anticonvulsants also increases the risk of neural tube defects, and like other enzyme-inducing anticonvulsants, it increases the likelihood of cardiovascular defects, and cleft lip without cleft palate. Epileptic women are generally advised to take folic acid, but there is conflicting evidence regarding the effectiveness of vitamin supplementation in the prevention of such defects.

Additionally, a coagulation defect resembling Vitamin K deficiency

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