Table 2.

Summary of adverse events (AEs) of TTX in clinical trials for cancer-related pain.

Study	Mild Adverse Events	Severe Adverse Events
Hagen et al., 2007 [38] Phase IIa SCP	All 24 subjects in the 31 treatments experienced AEs (531 reported). Approximately 98% of the total were rated as mild, with paresthesia and hypesthesia the most repeated, followed by nausea. These AEs appeared to increase in frequency in a dose-dependent manner.	AEs in the 30 µg TID dose group led to three patients discontinuing treatment partway through the four-day treatment period and a subsequent decision to discontinue further dose escalation. One of these AEs was an episode of severe ataxia after the seventh injection of TTX, which resolved within 24 h.
Hagen et al., 2008 [39] MSCP	In total, 648 of 690 AEs were considered mild or moderate, and 38 of 41 patients in the TTX group presented one or more AEs (92.7%). Overall, treatment-emergent AEs were greater in the TTX arm than in the placebo arm, but almost all were mild and related to tingling, numbness, or other transient sensory symptoms.	Three patients discontinued TTX (1) due to moderately severe but transient ataxia; (2) due to the development of malignant epidural spinal cord compression; or (3) due to the development of transient moderate dysphagia with a 3½ h duration that was probably related to the studied drug.
Hagen et al., 2011 [40] MSCP	Most AEs were described as mild (82%) or moderate (13%) in severity; all were well tolerated and had short durations (from 20 min to 1 h). Close to half of the patients described mild peri-oral tingling or numbness. Transient nausea was also reported by approximately one third of patients.	Four serious AEs were reported. Only one was related to the studied drug. The patient started taking the studied drug at a dose of 30 μg BID, and an hour after the second dose on day 1, she experienced hypertension and dizziness. Both events resolved the same day, and the patient was discharged.
Hagen et al., 2017 [41] Phase III MSCP	AEs were generally mild to moderate and transient. In the TTX group, all 77 patients experienced at least one AE that was considered drug-related. The most common were nausea, dizziness, oral numbness/tingling, and injection site irritation.	There were 12 serious AEs. Five AEs that occurred in three patients were probably related to TTX: ataxia (2), nystagmus (1), other neurotoxicity (1), and aspiration pneumonia (1). The aspiration pneumonia occurred in a patient who was at risk of aspiration.
Goldlust et al., 2021 [42] Phase II CINP	Across the TTX cohorts, 80.0 to 92.3% of the patients experienced at least one AE. The most frequent were oral paresthesia (34/100 TTX patients) and oral hypesthesia (28/100 TTX patients). Other common AEs were headache (19/100 TTX patients) and nausea (13/100 TTX patients).	Four patients had serious AEs, three of which were possibly related to treatment (hypertension, paresthesia, extremity pain, and a burning sensation). Two patients withdrew due to AEs: one patient with moderate vertigo and another with vertigo and an influenza-like illness, which were possibly related.

SCP: severe cancer pain; MSCP: moderate to severe cancer pain; CINP: chemotherapy-induced neuropathic pain; BID: twice daily; TID: three times a day.