Table 1
Summary of the studies that reported adverse effects of primidone and/or PEMA in patients with essential tremor.
| AUTHORS AND PUBLICATION YEAR | STUDY TYPE | NUMBER OF PATIENTS | AGE (YEARS) | DOSE | NUMBER OF PATIENTS WITH ADR (%) | ADR DETAILS |
|---|---|---|---|---|---|---|
| O’Brien et.al.1981 [5] | OL | 20 | 15–78 | Not mentioned | 6 (30) | Vertigo, unsteadiness, nausea (Details of acute and chronic ADRs were not provided) |
| Chakrabarti and Pearce 1981 [6] | OL | 5 | 47–80 | 125 mg/d for 2–3d (max 750–1000 mg/d) | 0 | No ADRs |
| Calzetti et.al.1981 [7] | RDBPC (PEMA) | 8 | 28–69 | week 1: 400 mg/d week 2: 800 mg/d | 0 | No ADRs |
| Findley and Calzetti 1982 [8] | RDBPC cross-over | 11 | 15–82 (max 250 mg TID) | 62.5 mg/d | 4 (36.3%) | Sedation, tiredness, nausea, giddiness (Details of acute and chronic ADRs were not provided) |
| Findley et.al 1985 [9] | RDBPC cross-over (Extension of previous study) [8] | 22 | 16–82 | 62.5 mg/d (max 250 mg TID) | 5 (22.7%) withdrew due to ADRs (FDE). 11 (50%) had less severe ADRs | Nausea, vomiting, ataxia, giddiness (both acute and chronic toxicities had similar spectrum of ADRs) |
| Koller and Royse 1986 [10] | OL | 22 (P+) 10 (drug-naïve) | 56.5 (average) 52.3 (average) | 50 mg at bedtime (max 1000 mg/d) | 3 (9.3%) had FDE. 9 (32.1%) had Chronic ADRs. | FDE: Ataxia, confusion. Chronic: vertigo, sedation. |
| Dietrichson and Espen 1987 [11] | SBPC (Primidone vs propranolol) | 13 | 34–77 | 62.5 mg/d (max 250 mg TID) | 6 (46%) had FDE. 13 (100%) had chronic ADRs. | FDE: Ataxia, vomiting, blurred vision, headache, dry mouth. Chronic: nausea, dizziness, sedation. |
| Seyfert et.al. 1988 [12] | OL | 11 | 29–68 | single dose 750 mg | 11 (100% had FDE). | FDE: nausea, postural disturbance, headache, confusion. No chronic ADRs were Reported. |
| Sasso et.al. 1988 [13] | DBPC cross-over (primidone vs. phenobarbital) | 16 | 60–78 | 62.5 mg (max 250 mg TID) | 10 (62.5%) not specified how many had FDE and chronic ADRs | FDE: Nausea, vertigo. Chronic: sedation and fatigability. |
| Sasso et.al. 1990 [14] | OL | 11 | 63–77 | 62.5 mg (max 250 mg TID) | 8 (72.7%) had FDE. 72.7%, 36.3%, and 18.1% had chronic ADR at 3, 6, and 12-months, respectively. | FDE: malaise, headache, dizziness, drowsiness, nausea vomiting. Chronic: drowsiness, dry mouth, sexual dysfunction. |
| Nida et.al. 2015 [15] | OL (study on VT patients) | 30 | 71.9±11.8 | 25 mg/d (increased by 25 or 50 mg/month as tolerated) | 22 (73%) not specified how many had FDE and chronic ADRs. 9 (31%) stopped treatment due to ADRs. | Fatigue, nausea, headache, dizziness (details of FDE or chronic toxicity were not specified) |
[i] ADR: Adverse drug reactions; FDE: First dose effect; Max: Maximum; mg/d: milligrams/day; OL: Open label; P+: Patients on propranolol; PEMA: Phenyl ethyl malonamide; RDBPC: Randomized double blinded placebo-controlled trial; SBPC: Single blinded placebo-controlled trial; TID: Three times/day VT: Voice tremor.
Table 2
Results of search for articles from PubMed using various key words and their combinations.
| KEY WORDS AND COMBINATIONS | NUMBER OF PUBLICATIONS | ||
|---|---|---|---|
| TOTAL IDENTIFIED | INCLUDED | EXCLUDED | |
| “Essential tremor” AND “Primidone” | 168 | 22 | 146 (NE+NH = 37, unrelated to the review = 109) |
| “Epilepsy” AND “Primidone” | 854 | 16 | 838 (NE+NH = 289, unrelated to the review = 549) |
| “Seizure” AND “Primidone” | 185 | 2 | 183 (NE+NH = 57, unrelated to the review = 126) |
| Total number of articles included for review after removing the duplicates | 33 | ||
| Total number of articles included from the reference sections of the shortlisted articles | 8 | ||
| Total number of articles obtained from the authors’ personal collection | 11 | ||
| Final total number of articles included for review | 52 | ||
[i] NE: Non-English language, NH: Article on non-human subjects.
Figure 1
Summary of the factors that could potentially explain the primidone intolerance in essential tremor relative to patients with epilepsy.
Table 3
Strategies for future studies to explore the neurobiology of primidone intolerance in ET.
| • Prospective study exploring the emergence of primidone-associated ADRs in ET patients with and without certain clinical features including fatigue, excessive daytime sleepiness, ataxia, and cognitive impairment. |
| • Comparison of ADR profile of primidone in younger and older ET patients. |
| • Structural and functional neuroimaging studies on ET patients with and without primidone intolerance to explore neural correlates of such ADR. |
| • Large clinical trials to test the cross-tolerance theory (longitudinal assessment to explore for ADR after primidone treatment with and without pre-treatment with phenobarbital). |