Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is pathologically defined by the loss of dopaminergic neurons within the substantia nigra, along with the formation of Lewy bodies (Olanow et al., 2009). The neuronal depletion leads to a significant reduction in the neurotransmitter dopamine (DA), which causes a range of hallmark motor symptoms in individuals with PD, including tremor at rest, bradykinesia, muscular rigidity, and postural instability (Armstrong and Okun, 2020). These symptoms progressively worsen over time, significantly impairing the quality of life and daily functioning of affected individuals. Globally, PD affects over six million people and is a leading cause of disability, imposing a substantial burden on healthcare systems and society at large (Dorsey et al., 2018).

The cornerstone of PD management has long been the administration of levodopa (LD), a precursor to dopamine (Connolly and Lang, 2014). In the bloodstream, levodopa is primarily converted into dopamine and 3-O-methyldopa through the actions of decarboxylase and catechol O-methyltransferase (COMT), respectively. As a result, a mere 1% of orally administered levodopa reaches the dopaminergic neurons (Jankovic, 2002; Contin and Martinelli, 2010). To address this, levodopa is often given in combination with a decarboxylase inhibitor (DCI), such as benserazide (BSZ) and carbidopa (CD), in a single tablet form (Tolosa et al., 1998). This combined administration enhances the availability of levodopa in the brain by ten-fold and extends its peripheral half-life to roughly 90 min (Cedarbaum, 1987). This strategy increases the bioavailability of LD in the central nervous system but also allows for lower dosing, thereby reducing peripheral side effects such as nausea and hypotension (Rinne and Molsa, 1979; Hauser, 2009; Salat and Tolosa, 2013). Since its introduction in the 1970s, LD + DCIs have remained the gold standard in PD treatment due to its remarkable efficacy in alleviating motor symptoms (LeWitt and Fahn, 2016).

Patients often experience significant improvements in their ability to perform daily activities, as LD + DCIs effectively mitigates the debilitating symptoms of PD. However, prolonged use of LD therapy leads to non-physiological stimulation of dopamine receptors, which is consequently linked to motor complications such as motor fluctuations and dyskinesia (Obeso et al., 2000; Dewey, 2004). Motor complications frequently occur in early PD, with a 30%–40% incidence within 5 years of treatment, and the number accumulates to 60% by the 10th year as the disease progresses (Ahlskog and Muenter, 2001; Turcano et al., 2018; Prange et al., 2019). Some patients develop motor fluctuations, such as the “wearing-off” phenomenon, where the drug’s effects become transient and less durable. Moreover, patients may experience sudden “off” periods, where they switch unpredictably from an ‘on’ state of mobility to a significantly impaired ‘off’ state, known as the “on-off phenomenon.” Additionally, during the “freezing phenomenon,” patients may suddenly feel as though their feet are glued to the ground, making it difficult to initiate movement, especially in situations like turning or passing through narrow spaces. What’s more, involuntary movements known as dyskinesias can emerge, further complicating the clinical management of PD and diminishing patients’ quality of life (Chapuis et al., 2005).

The development of motor complications associated with oral LD therapy is a complex process influenced by multiple factors. These include the pulsatile stimulation of dopamine receptors due to fluctuating LD levels, the progressive degeneration of dopaminergic neurons, and individual patient characteristics such as genetic predispositions and disease severity (Bhidayasiri and Truong, 2008; Warren Olanow et al., 2013; Ray Chaudhuri et al., 2018). While BSZ and CD both aim to enhance LD efficacy by inhibiting its peripheral conversion, they contributed to different pharmacokinetic profiles of LD (Iwaki et al., 2015). These differences may affect the incidence and severity of motor complications. Therefore, we hypothesized that BSZ and CD may impact the emergence of these complications in a differential manner.

In this pharmacovigilance study, we seek to comprehensively analyze the safety profiles of BSZ and CD in combination with LD by utilizing data from the FDA Adverse Event Reporting System (FAERS) database. This database provides a valuable repository of spontaneous adverse event reports, offering insights into the real-world experiences of patients and healthcare providers (Poluzzi et al., 2012). Our objective was to systematically review the risk of levodopa-induced motor complications associated with BSZ and CD in PD and provide a reference for clinical decision making.

The present pharmacovigilance study of the FAERS database aimed to compare the safety profiles of BSZ and CD when used in conjunction with LD for the treatment of PD. We identified a total of 8,744 AERs related to motor complications, where 19,482 AEs were recorded. The present study highlighted the AEs related to motor complications as follows: dyskinesia, on-off phenomenon, freezing phenomenon, and wearing-off, all of which was identified to be associated with oral administration of both BSZ and CD by disproportionality analysis using three different methods. Further analysis of the statistical measures, particularly RORs, revealed distinct safety signals associated with each DCI, with BSZ showing a higher risk of certain motor complications compared to CD. Specifically, we identified stronger signals for dyskinesia, and on-off phenomenon with BSZ, while CD was more strongly associated with wearing-off.

Our subgroup analysis found that dyskinesia was significantly more prevalent in female patients than in male patients across both drug groups. This observation aligns with studies on levodopa pharmacokinetics, which indicate that women tend to have higher plasma concentrations of levodopa, as reflected by significantly higher area under curve (AUC) and maximum plasma concentration (Cmax) compared to men (Conti et al., 2022; Contin et al., 2022). For instance, Conti et al. (2022) found that female sex significantly predicted AUC and Cmax by assessing levodopa pharmacokinetics in 35 patients with PD at their first-ever intake of levodopa (Conti et al., 2022). Similarly, Conti et al. (2022) demonstrated that the AUC for levodopa was 27% higher in females than in males using data from a large series of levodopa therapeutic monitoring (Contin et al., 2022). Furthermore, the same study indicated that female patients required a 25% lower weight-normalized dose of levodopa to achieve the same bioavailability as their male counterparts (Contin et al., 2022). These pharmacokinetic differences likely contribute to the increased risk of dyskinesia observed in female patients. The findings underscore the importance of considering sex when assessing the risk of dyskinesia in PD patients treated with levodopa.

The pharmacokinetic differences of LD observed when combined with BSZ or CD provide valuable mechanistic insights into the varying safety profiles of these DCIs. As detailed in the study by Da Prada et al. (1987), the combination of levodopa with BSZ results in more rapid elevation and reduction of LD concentration compared to CD. Additionally, the study by Shiraishi et al. (2020) highlights the significance of high levodopa plasma concentrations in the development of levodopa-induced dyskinesia (LID) in patients with PD. The findings suggest that a higher Cmax and AUC are associated with an increased risk of LID, which aligns with the pharmacokinetic characteristics of BSZ (Iwaki et al., 2015), potentially explaining the higher incidence of dyskinesia observed with this combination. The rapid increase, high Cmax, and subsequent drop in levodopa levels, as seen with BSZ, result in a more pulsatile and excessive dopaminergic stimulation, potentially leading to a greater risk of LID and on-off phenomenon. On the other hand, the relatively limited potency of CD (Iwaki et al., 2015) might contribute to higher risks of wearing-off.

The comparison of two DCIs, BSZ and CD, in combination with levodopa has a history dating back to the 1970s, with the majority of studies focusing on their efficacy and short-term complications (Greenacre et al., 1976; Rinne and Mölsä, 1979). While these investigations have not revealed statistically significant differences in effectiveness, there has been a noted patient preference for one over the other due to variations in individual responses. Some researcher suggested combined use of BSZ and CD may be useful for individuals with PD (Lieberman et al., 1984). When it comes to long-term complications, such as motor fluctuations, there is a dearth of research. A notable exception is a retrospective cohort study from Japan (Baba et al., 2022) that analyzed 52 patients and concluded that LD/CD therapy with a CD to LD ratio of 1:10 might delay the onset of motor fluctuations compared to LD/BSZ therapy with a ratio of 1:4. This finding highlights the potential impact of LD/DCI dosing ratio on disease progression in PD. However, the effects of different selection of DCIs could not be established. With the focus on DCI components, our study revealed distinct motor complication signals in a real-world setting by leveraging the FAERS database. The large sample size and the use of disproportionality analysis algorithms allow for detection and assessment of specific motor complications between BSZ and CD in combination with oral LD, offering new insight for the clinical management of PD. Consistent with previous studies (Iwaki et al., 2015; Baba et al., 2022; Chaudhuri et al., 2013), the present study indicates LD/BSZ can be beneficial for individuals needing rapid relief from motor symptoms, and LD/CD might be advantageous for those experiencing significant dyskinesia due to overstimulation of dopamine within the striatum. Further, the results indicate those with unpredictable off episodes could consider switching their oral levodopa formula from LD/BSZ to LD/CD.

The core concept in the management of PD is the principle of continuous dopaminergic stimulation, which is designed to maintain a stable and therapeutic level of dopamine in the brain to prevent and manage motor complications. Despite various pharmaceutical advancements and innovative delivery methods for levodopa, including intrajejunal (Olanow et al., 2014) and subcutaneous infusion (Soileau et al., 2022), oral administration of LD/DCI remains the mainstay in clinical practice. However, clear guidelines on the selection of oral LD/DCIs have not been established. Our study, therefore, holds significant value as it offers a comparative analysis of motor complication profiles of BSZ and CD, the two most frequently used DCIs in conjunction with oral LD. To our knowledge, the present study is the first pharmacovigilance analysis of the FAERS database concerning levodopa-induced motor complications associated with BSZ and CD in PD. With the drugs orally administered, the confounding effects of levodopa delivery could be excluded. However, different formation of LD + DCIs could also influence AERs in both BSZ and CD due to distinct LD pharmacokinetics, which awaits exploration in the future.

The present study is not without limitations. Firstly, the FAERS database, while comprehensive, is subject to reporting biases, and the lack of standardized grading of AEs may limit the accuracy of our risk estimates. Secondly, the spontaneous nature of the reports means that our findings cannot be used to establish causality but rather to generate hypotheses that require further investigation in controlled studies. Thirdly, the interactions between the selected medication and concomitant drugs awaits further investigation, as patients with PD often take multiple anti-parkinsonian drugs simultaneously. Lastly, the cumulative levodopa equivalent daily dose (LEDD) (Jost et al., 2023) could not be calculated in each case report, so that the dose-effect relations was not evaluated. Therefore, our results should be interpreted with cautions. Future research should focus on prospective, randomized studies comparing BSZ and CD in terms of their impact on motor complications in PD. Further exploration of the pharmacokinetic and pharmacodynamic differences between these two DCIs, as well as their impact on the progression of PD, is warranted. Such studies will provide a more definitive understanding of the comparative safety and efficacy of BSZ and CD, guiding clinicians in the selection of the most appropriate DCI for individual patients with PD.

In conclusion, our disproportionality analysis of the FAERS database highlights the differential motor complication profiles of BSZ and CD when co-administered with levodopa in the treatment of PD. The findings suggest that BSZ is more strongly associated with dyskinesia and on-off phenomenon, while CD is linked to a higher risk of “wearing-off”. These results underscore the importance of choosing DCIs when tailoring treatment plans for patients with PD, as this choice may influence the incidence of motor complications. Further research is needed to elucidate the mechanisms underlying these differences and to optimize the management of motor complications in PD.