A Phase I clinical trial has demonstrated that a single injection of resiniferatoxin, a potent plant-derived neurotoxin, may offer sustained pain relief in patients with intractable cancer pain, according to research.

Trial Design and Patient Population

The study, conducted at the National Institutes of Health Clinical Center, included 19 patients with histologically confirmed metastatic cancer and refractory pain. The first four patients were treated under a pilot feasibility protocol, while 15 patients were enrolled in the Phase I, open-label, dose-escalation trial. Eligible participants had progressive disease, were not pursuing curative therapy, and reported “worst” pain ratings ≥6 on a 0–10 scale, localized at or below the T6 dermatome.

Efficacy and Dosing Findings

Resiniferatoxin (RTX) was administered as a single intrathecal injection in doses ranging from 3 µg to 100 µg, in volumes of either 1 mL or 2 mL. The primary outcome was safety, while secondary outcomes included changes in pain and opioid use, measured as oral morphine equivalents (OME).

Across 15 evaluable patients, the mean “worst” pain score declined by 38%, from 8.4 (95% CI, 7.8–8.9) at baseline to 5.8 (95% CI, 4.8–6.8) at 15 days. Greater reductions were seen in those who received a 1-mL injection: mean scores dropped from 8.4 to 5.2 (Cohen’s d = 1.48), compared to 8.3 to 6.6 (Cohen’s d = 1.37) in the 2-mL group.

Median opioid use also decreased overall, from 306 mg (95% CI, 123–1140) to 209 mg (95% CI, 90–660) at 15 days. All nine patients in the 1-mL group showed a reduction in opioid use, versus only two of six in the 2-mL group.

Prespecified Efficacy Criteria

The trial defined efficacy as a ≥50% reduction in either “worst” pain or opioid use. Three patients (20%) met the pain criterion, and six (40%) met the opioid criterion; all patients who met the pain threshold also met the opioid one.

Mechanism of Action and Target Engagement

“RTX is a small, plant-derived molecule that is a highly specific agonist of the transient receptor potential vanilloid 1 (TRPV1) ion channel,” the authors explained. When administered intrathecally, RTX “produces a highly selective calcium overload in TRPV1+ sensory axons in the cauda equina that leads to a calcium-induced chemoaxotomy, thereby blocking peripheral nociceptive signals.”

Because TRPV1 is not expressed on motor or proprioceptive fibers, RTX spared motor, sensory, and cognitive functions. NSE increases in 3 of 14 patients at 24 hours post-treatment indicated successful TRPV1+ axon chemoaxotomy, supporting effective target engagement.

Safety and Adverse Events

Across 188 days of follow-up, 213 adverse events were reported, including 37 serious events in 14 patients (74%). Most AEs were consistent with advanced cancer progression. Fifteen patients (79%) experienced AEs considered possibly or probably treatment-related.

Expected on-target effects included thermal sensitivity loss in RTX-exposed dermatomes in 3 patients (grades I–III). Urinary retention occurred in 7 patients (3 grade III); one required surgical intervention. Transient hypertension and tachycardia, expected physiologic responses to RTX, occurred in 3 patients and resolved within 10–20 hours. QTc prolongation was seen in 5 patients and resolved within 24 hours.

Nine patients died during the study (mean time from injection to death: 70 days), all attributed to disease progression. The only grade IV AE was an unstageable decubitus ulcer, likely resulting from diminished pain signaling in the affected area.

One patient on extremely high-dose opioids (9,376 mg OME/day) experienced multiple seizures postinjection, attributed to opioid toxicity and resolved with dose reduction and anticonvulsants.

Clinical Implications and Future Research

Investigators emphasized the importance of administration technique: “We observed that a lower volume delivered slowly to prevent spread in the intrathecal space was associated with better clinical outcomes with RTX. This is consistent with a concentration-dependent lesion of TRPV1-containing axons in the intrathecal space.”

Although dose escalation had not reached the maximum planned dose, investigators stopped further escalation due to favorable outcomes at lower volumes without reaching the maximum tolerated dose or encountering dose-limiting toxicities (DLT).

“The chemoaxotomy mechanism of action produced analgesic effects that were durable at all time points examined, consistent with expectations for interventional neurolytic approaches,” the authors concluded.

This study offers preliminary evidence supporting RTX as a novel, nonopioid analgesic for patients with refractory cancer pain. Further controlled studies are needed to validate these results and refine dosing strategies and patient selection.

Disclosures can be found in the published study.

Source: NEJM Evidence