Medication side effects among people with epilepsy taking phenobarbital in Zambia

Abstract

Phenobarbital remains one of the most widely used antiepileptic drugs worldwide, yet there are limited data regarding side effects associated with its use in routine clinical care settings in low-income countries. Available data suggests that phenobarbital is as effective as other first-line drugs for treating tonic-clonic seizures, but side effect reports differ widely between high and low-income settings. A better understanding of phenobarbital side effect profile and severity in low-income settings is warranted given its role in efforts to decrease the epilepsy treatment gap. We used the Liverpool Adverse Events Profile (LEAP) to assess side effects in consecutive patients with epilepsy on phenobarbital seeking care in rural Zambia. Data regarding age, gender, medication dose, and medication adherence were also collected. T-tests and Spearman’s correlation coefficient were used to assess predictors of LEAP score and medication adherence. Thirty-five patients receiving a mean dose of 2.1 mg/kg/day (SD: 2.78 mg/kg/day) of phenobarbital were assessed. All participants reported at least one side effect in the previous four weeks with a median of 6 symptoms (IQR: 4–8) and a mean side effects score of 28/76 (SD: 5.38). Over half reported sleepiness and dizziness. Memory problems and depression were also common (both 46%). Total LAEP score was not associated with age (p=0.88), gender (p=0.17), or phenobarbital dose (p=0.13). Medication adherence was not associated with side effects total score (p=0.56). Rural Zambian adults taking phenobarbital at doses recommended by the WHO report a significant number of side effects. The most common side effects reported were similar to those reported in high-income countries. The significant burden of phenobarbital-associated side effects in this African cohort is in contrast to data from non-randomized clinical trials in China that reported phenobarbital to be well-tolerated with few side effects. Additional investigations regarding phenobarbital side effects in routine care in low income settings is warranted.

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

“…PB was once the most widely used first-line antiepileptic drug, but its use has declined in wealthy countries given a number of side effects, chiefly cognitive and functional impairments (Elafros et al, 2014). The adverse effects of PB include sedation, hyperactivity, impaired cognition, depressed mood and affect, anemia, hepatotoxicity and teratogenicity (Kwan and Brodie, 2004).…”

Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure

“…Phenobarbital is also associated with side effects (Table 2) [40]. In addition, phenobarbital is more likely to be discontinued compared to other drugs (including carbamazepine, phenytoin, and valproate) due to its adverse reactions [44]. Due to overall limited evidence of efficacy in short-and long-term prevention of seizures as well as numerous adverse effects [44], this anticonvulsant should be used only after consideration of other therapeutic options.…”

Phenobarbital use and neurological problems in FMR1 premutation carriers

“…This is consistent with the World Health Organization (WHO) recommendations that phenobarbital be used as first-line monotherapy in lower income settings because of its relatively low cost, convenient dosing and broad spectrum of activity (World Health Organization, 2012). However, a recent clinical study of low-income patients in Zambia reported memory problems and depression associated with use of phenobarbital (Elafros et al, 2014). …”

“…More is known about the developmental neurotoxicity of phenobarbital (Verrotti et al, 2014; Bittigau et al, 2002). In rodent models, postnatal exposure to phenobarbital causes excessive neuronal apoptosis, presumably due to its GABA mimetic actions, impairs neurogenesis, causes focal mitochondrial degeneration in diverse brain regions and dysregulates the cortical proteome (Saldarriaga et al, 2014; Elafros et al, 2014; Merola and Eubig, 2012). Exposure to phenobarbital at levels that fall within the moderate to high range of clinically relevant doses impairs the morphological and physiological maturation of both excitatory and inhibitory synapses in the rodent striatum, a brain region that displays reduced volume in human imaging studies of adults exposed to AEDs early in life (National Pesticide Information Center Agency USEP, 2015).…”