Pain, whether neuropathic or functional, is one of the early symptoms of FD, and its occurrence may signal underlying organ deterioration [10, 20]. Fabry-disease-related pain has been studied in the past in a variety of settings, including by using registries or screening of medical records [7, 22]. However, the present study analyzed pain and pain crises from a patient’s perspective with moderate-to-severe pain across different FD phenotypes and for both sexes. The study demonstrated a heavy burden of neuropathic pain, abdominal pain, and pain crises experienced across sex and phenotype subgroups.
Neuropathic pain is a hallmark of FD [26]; participants in this study reported frequent pain, especially in the distal extremities. Most participants characterized their pain as either “triggered” or “sudden,” which is similar to prior studies that had demonstrated a predominance of evoked neuropathic pain caused by stimuli that may not trigger pain in healthy individuals, indicating a high burden of pain associated with FD [23, 30].
Additionally, the present study demonstrated the pain crisis experience (nature, frequency, and duration) to be highly varied with regard to sex, phenotype, and anatomical location. The study indicated a heterogenous distribution of the duration of pain crisis, ranging from a few hours to a full day. Half of the participants experienced neuropathic crisis, predominantly in the lower extremities, and described it as burning in nature, while abdominal pain crisis was often described as stabbing, which also correlates with a previous study reporting severe debilitating abdominal pain in patients with FD [20]. This novel characterization of crises in both sexes and for different phenotypes from a patient’s perspective furthers the understanding of the diverse experience of pain crises.
Prior data have often reported patients with later-onset FD phenotype to have less pronounced pain and sensory abnormalities when compared with the classic phenotype [9, 19, 31]. The present study, however, identified that among both phenotypes, the participants experienced neuropathic and abdominal pain; the participants from the later-onset phenotype even reported sudden pain in lower extremities in a higher proportion than the classic phenotype. Furthermore, contrary to published evidence that presents females experiencing mild and intermittent pain, the present study highlighted that females experienced severe pain in the upper and lower extremities as much as several times a day [30, 32, 33]. Thus, despite the previous and incorrect view of females with FD presenting with minimal symptoms [34], the present study showed that female participants had a high pain burden and experienced pain symptoms similar to that of male patients. Thus, greater attention is warranted to address disease management for patients with later-onset FD and female patients with FD.
Pain in FD is associated with various mechanisms and requires different therapeutic approaches through disease-specific treatment, supportive symptom management, and strategies to avoid pain triggers [26]. In the present study, most participants reported receiving pain medication (over the counter or prescription) in addition to Fabry-specific treatments for appropriate management of the multisystemic aspects of FD. Treatment guidelines recommend medications, such as carbamazepine, gabapentin, pregabalin, phenytoin, amitriptyline, duloxetine, and venlafaxine, and acute pain management with opioids (morphine, tramadol, and tilidate) [19, 22] for managing Fabry pain.
Further, looking at patient satisfaction with current treatment, participants in this study mostly reported agalsidase beta as their most recent Fabry-specific treatment and were consistently satisfied with overall symptom improvement as expressed by 82.2% of participants by 1 year after initiation of agalsidase beta. Previous studies also corroborated these findings, where agalsidase beta was beneficial in reducing pain and delaying the onset of renal, cardiovascular, and cerebrovascular events in patients with advanced FD [35, 36].
There are certain inherent limitations of cross-sectional studies that we acknowledge, such as potential participant bias. Further, since all data in this study were self-reported, participants may have misspecified their FD phenotype. This study focused only on the descriptive analysis; hence, the subgroup results do not imply any associations. The study enrolled patients who experienced moderate-to-severe neuropathic or abdominal pain, depicting a symptomatic population; therefore, the results are not generalizable to the overall Fabry population. The study could not characterize the impact of other treatments because of a small sample size. Nonetheless, this study provided a detailed analysis of pain and pain crises from a patient’s perspective, which may aid in better understanding and overall management of pain across Fabry patients.