Introduction

Epilepsy is the syndrome of two or more unprovoked seizures that occur more than 24 h apart1. Epilepsy is associated with adverse psychosocial outcomes, disability, higher rates of psychiatric comorbidity, and approximately threefold increased mortality2. In Life time one in 26 people develop epilepsy, and it is the fourth most common neurological disorder in the world3. Worldwide there are seventy million people with epilepsy, and 90% of people with epilepsy live in low- and middle-income countries4,5. Epileptic seizure has a lot of negative consequences on the patient’s psychology and social life such as education, relationships, and employment status6.

Antiseizure medications are standard treatment modalities with the primary goal of achieving seizure freedom ideally without adverse events, reducing morbidity, mortality, and seizure-related accidents, and improving quality of life7,7. In 70% of the patients with epilepsy, these goals are feasible with the optimum use of antiseizure drugs (ASDs)8. The centrally acting drugs like antiseizure, contribute to adverse drug reactions (ADRs) such as insomnia, sedation, increasing suicidal tendencies, and depression6. These ADRs compromise the benefits of ASDs6. The World Health Organization (WHO) defines adverse drug reaction (ADR) as “any noxious, unintended, or undesired effect of a drug that occurs at doses used in humans for prophylaxis, diagnosis, investigation, therapy, or for the adjustment of physiological function9,10.

ADR has long been a problem in the health industry and is a big worry in the healthcare system. ADR has impacted most individuals throughout medical history, significantly increased morbidity and mortality, and placed a heavy demand on healthcare resources11. Because of its potentially serious consequences, adverse drug reactions (ADRs) may have a significant impact on clinical practice and the economy. ADRs is either avoidable or unavoidable and it may resulted in transient or permanently debilitating effects, including death and financial costs for the patients, healthcare institutions and society as a whole12.

ADRs are a significant public health problem in the world. Not only do ADRs cause death and injury but they also affect the length of stay in hospitals which in turn leads to increased healthcare costs and decreased patient productivity13. In the United States (US) 44,000 to 98,000 deaths occur annually from medication errors. Of this total, an estimated 7000 deaths occur due to ADRs13.ADRs account for 4.2–30% of hospital admissions in Canada, 2.5–10.6% of admissions in Europe, 5.7–18.8% of admissions in Australia14, and 6.2% of all admissions in Southern Italy15. In Norway, 19.7% of patients had drug-related emergency visits and ADRs were the most common causes of these visits16.

The causes of adverse drug reactions are related to many factors including drug-related, patient-related, disease related, social, and adverse drug-related factors11,17. The patient’s physiological and illness status influence unfavorable drug response; very young and elderly patients are more vulnerable to an unfavorable drug response than adult patients. This is usually due to a significant difference in metabolism and excretion pattern at this level and the decreased functional reserve in the extremities of age17.

Studies showed that 22–31% of patients with epilepsy (PWE) developed antiseizure-associated ADR18,19,20. Adverse drug reactions of ASDs are a leading cause of treatment failure among people with epilepsy19. Fifteen to twenty five percents of patients with epilepsy discontinued ASDs within 6 months of therapy owing to intolerable adverse drug reactions20,21. The previous study across various settings identified factors associated with ADRs among people with epilepsy. These are polytherapy, age, alcohol intake, frequent seizure, gender, and pretreatment seizure numbers13,18,21,22. Despite these potentially modifiable factors related to ADR among PWE, no prior extensive study has been conducted in the current study setting. Therefore, this prospective observational study was designed to carried out the prevalence of ADR and its associated factors among patients with epilepsy at the ambulatory clinic of Jimma medical center (JMC).

Materials and methods

Study design, area, and period

A prospective observational study design was spanned from December 2020 to November 2021 at the ambulatory clinic of Jimma Medical Center (JMC). JMC is a referral and teaching governmental institution located in Jimma town of Oromia Regional State, Ethiopia. Currently, the center provides services for 20 million people from the Jimma zone and is a referral center for South Western part of Ethiopia.

Inclusion and exclusions criteria

Age of ≥ 18 years, on ASDs for a minimum of 1 year, and agreeing to give informed consent were inclusion criteria.

Patients with unstable psychiatric illness, not adhere to their next follow-up schedule, and incomplete medical records were excluded from the study.

Sample size and sampling technique

The sample size was calculated by using a single population proportion formula by considering the proportion of ADR, P = 0.2218, n = the desired sample size, Z = level of significance at 95% confidence interval which is 1.96, d = margin of error which is 0.05,

$${\text{n }} = \frac{{{\text{z}}^{{2}} {\text{p}}\,\,\left( {{1} - {\text{p}}} \right)}}{{{\text{d}}^{{2}} }} = \, \frac{{({1}.{96})^{{2}} \,0.{22}\,\,\left( {{1} - 0.{22}} \right)}}{{\left( {0.0{5}} \right)^{{2}} }} = { 264}$$

By adding a 10% non-response rate, the final sample size of 290 was calculated. A consecutive sampling method was used to include study participants.

Data collection tools and procedures

Data were collected through the patient interview and medication chart review. The data collection tools were prepared after reviewing relevant kinds of literature and modified to address the objectives of this study9,23,24,25,26. Patients were interviewed after leaving the physician’s office for medication refills. Information related to the ADR was collected through the patient interview and augmented by the review of the patient’s medical records. The Causal relationship between ADR and treatment was assessed by a researcher, with the Naranjo Algorithm24. Naranjo ADR probability scale is validated for the assessment of ADRs and produced the most consistent results27,28,29. The Naranjo Algorithm consists of 10 questions that are answered as either Yes, No, or “Do not know”. Different point values (− 1, 0, + 1, or + 2) are assigned to each answer24. Total scores range from − 4 to + 13; the reaction is considered definite if the score is 9 or higher, probable if 5 to 8, possible if 1 to 4, and doubtful if 0 or less24. Medication belief is assessed by belief about medication questionnaires (BMQ)26. Belief about Medications Questionnaire (BMQ) is a validated tool to assess the beliefs of patients about their medications30. This is 10 items self-reported Likert scale, which are further categorized as the medication necessity scale and medication concern scale, each containing five items. The patient’s belief was considered to be positive when the average sum of the 5-item patient’s medication necessity scale score exceeded the average 5-item medication concern scale, if not it was considered negative5. Three pharmacists, a bachelor of degree holders were participated in the overall data collection processes.

Data processing & analysis

The collected data were entered into Epidata Manager version 4.6.0.4 and then exported to SPSS version 25.0. A descriptive statistic was calculated for dependent and independent variables. To select candidate variables for multivariable analysis a bivariable logistic regression analysis was done and all variables with a p-value of < 0.25 were taken to multivariable analysis. A multivariable logistic regression analysis was performed to identify independent variables associated with ADR. From multivariable outputs variables with a p-value of < 0.05 were considered as statistically significant variables associated with ADR. A 95% confidence interval (CI) was used to assess the strength of association between the independent and the primary outcome of the variable.

Ethical considerations

The approval letter for this study was taken from the institutional review board (IRB) of Jimma University, College of Health Sciences. The objective of the study was explained and written informed consent was obtained from study participants. For the matter of patient confidentiality, the name and addresses of the patients were not included in the data collection tools. All methods were performed in accordance with relevant guidelines and regulations.

Results

Socio-demographic characteristics of study participants

A total of 310 patients were approached, eight patients were excluded from analysis due to incomplete medical records, five patients were excluded for instability of the illness, and seven patients were excluded for lost from follow-up. Of 290 studied patients, 54.48% were male, and 46.55% were within the age range of 18–25 years. About 27.93% had no formal education and only 12.76% of participants were employed (Table 1).

Table 1 Demographic characteristics of study participants at the neurology clinic of JMC, 2021.
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Clinical characteristics of the patients with epilepsy

Half (50.69%) of the participants had a seizure duration of more than 10 years and about three fourth of them had been diagnosed at the age of older than 10 years. Two third (65.52%) of the study subjects had no seizure episode since the last visit, whereas (47.58%) of patients had a seizure-free period of fewer than 2 years. The majority (62.75%) of the patients have no comorbid medical condition and half the participants were taking single ASD (Table 2).

Table 2 Clinical characteristics of study participants at the neurology clinic of JMC, 2021.
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Profile of adverse drug reactions among people with epilepsy

From 290 studied participants 98 were experienced at least one antiseizure associated ADR with an overall prevalence of 33.8% (95% CI 29.2–39.9%). The most commonly recorded ADRs were epigastric pain (27.55%) and central nervous system drowsiness (23.46%). According to the Naranjo probability scale of causality assessment in (52.72% and (39.09%) of the case the level of causality was possible and probable respectively. Patients counseling and decreasing the dose of ASD were the two common measures taken by pharmacists (Table 3). ADRs were frequently reported with the two most widely used ASDs:—phenobarbital (52.04%) and phenytoin (34.70%) (Fig. 1).

Table 3 Adverse drug reactions profile among epileptic patients at the neurology clinic of JMC 2021.
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Figure 1
figure 1

Antiseizure drugs associated with ADR at the neurology clinic of JMC 2021.

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Factors associated with ADR among patients with epilepsy

The results of multivariable analysis output showed that patients who had experienced seizure episodes in the last 2 years were 1.94 times more likely to have ADR as compared to patients without seizure episodes (AOR = 1.94, 95% CI (1.18–3.19)), patients with one or more comorbidity were 5.91 times more likely to develop ADR as compared to patients with no comorbid medical conditions (AOR = 5.91, 95% CI (2.14–16.32)). Additionally, those patients who were taking two or more ASD were 1.35 times more likely to have ADR as compared to patients who were on monotherapy (AOR = 1.35, 95% CI (1.80–2.26)) (Table 4).

Table 4 Multivariable logistic regression analysis of factors associated with adverse drug reactions among epileptics at JMC, 2021.
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Discussion

The overall aim of treatment in patients with epilepsy (PWE) is complete seizure freedom with little to no medication-related side effects31. However, the prolonged use of ASD is associated with various idiosyncratic reactions and clinically significant drug interactions, that may result in treatment letdown in about 40% of patients19. In this finding, ADRs were found in 98 (33.8%) of PWE, and most commonly occurred within the age category of 26–44 years. This finding was relatively similar to the study reported from Bishoftu general hospital32, and contrary to the results from various settings including India, Italy, and Hyderabad where the prevalence of ADR were 3.07%, 3.2%,4.67% respectively15,33,34. This variation might be due to the special considerations taken by the practicing physicians regarding the prescribing and titrating doses of ASD, and the availability of new ASD in the former settings.

Regards to the distribution of ADR, epigastric pain (27.55%), drowsiness (23.46%), and headache (20.40%) were the most commonly reported ADR. This is in line with the study conducted at the neurology clinic of UoGRH, Northwest Ethiopia, and Amanuel Specialized Mental Hospital (ASMH)18,35. In contrast to our study, headache, and Loss of appetite were the most commonest ADRs recorded in Bishoftu general hospital and Tertiary Care Hospital of India32,33.

From the total of 98 reported ADRs, phenobarbital was the primary cause (52.04%) followed by phenytoin (34.70%) and carbamazepine (7.14%). This finding was augmented by the prior reports from (ASMH) and UoGRH25,35, but it is in contrast to the other finding from Tertiary Care Hospital of India, where 42.5% of ADR were related to valproate33. The probable justifications for this disagreement could be in resource-poor settings like Ethiopia it is old-generation ASDs like phenobarbital and phenytoin that were frequently used in the management of epilepsy5.

Studies showed that 30–40% of patients with epilepsy suffered from uncontrolled seizures on a single antiseizure drug(ASD)36. For these patients, combination therapy is standard of practice rather than optional37. The combined use of ASD is usually not without problems. Previous studies established that polytherapy leads to a higher risk of adverse drug effects compared with monotherapy19,22,38. Similarly, in this study patients undergoing polytherapy tended 1.35 times (AOR: 1.35, 95% CI 1.80–2.26) at increased risk of ADR as compared to monotherapy. This finding is potentiated by the other study conducted at the Northwest Ethiopia and Wangaya Regional Hospital in Denpasar25,39. This is probably because of overlapping effects and drug interactions ADR increases as the number of co-administered ASD increases.

There is increasing recognition that epilepsy can be associated with a broad spectrum of comorbidities40. Several diseases, including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy than in the general population41. It is known that comorbidity is strongly associated with a higher risk of ADR15,42. In our finding also the risk of experiencing ADR among epileptic patients with one or more comorbidities was increased by 5.91 times (AOR: 5.91, 95% CI 2.14–16.32) as compared with no comorbid medical conditions. The probable justifications for this factor could be multiple disease conditions influence susceptibility to ADRs and predispose patients to ADRs due to the concurrent use of many medicines13,43.

Adverse drug reactions can contribute to treatment failure in up to 40% of patients and can affect the ultimate quality of life independent of seizure control44. In the present study, seizure-free periods of fewer than two years were significantly associated with ADR (AOR: 1.94, 95% CI 1.18–3.19). This finding is supported by the various literature across the globe5,7,45. The probable justification for this factor may be due to the negative effect of ADR on adherence that affects the seizure control status.

Strength and limitation

The quality of the data given in this study is significantly higher than in other studies because it is a prospective observational study. Patients' replies are used in the assessment of ADR, medicine belief, and Naranjo casual assessment, which may skew the results or alter their genuine value. Furthermore, because this study was only done in one location, it might not be very generalizable.

Conclusions

This study looks into a larger percentage of ADR than other national and international studies that have been done. ADR risk factors included polytherapy, comorbidities, and a seizure-free duration of less than two years. Healthcare providers who focus on patients with the aforementioned issues may be able to address or reduce the risk of ADR.