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Randomized Controlled Trial
. 2015 Jun;156(6):1018-1024.
doi: 10.1097/j.pain.0000000000000115.

Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain

Dorothy C Brown  1 , Kimberly Agnello, Michael J Iadarola
Affiliations
Randomized Controlled Trial

Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain

Dorothy C Brown et al. Pain. 2015 Jun.

Abstract

Resiniferatoxin (RTX) is the most potent among all known endogenous and synthetic agonists for the transient receptor potential vanilloid 1 (TRPV1) receptor, which is a calcium-permeable nonselective cation channel, expressed on the peripheral and central terminals of small-diameter sensory neurons. Prolonged calcium influx induced by RTX causes cytotoxicity and death of only those sensory neurons that express the TRPV1 ion channel leading to selective targeting and permanent deletion of the TRPV1-expressing C-fiber neuronal cell bodies in the dorsal root ganglia. The goal of this project was to provide preclinical efficacy data, that intrathecal RTX could provide effective pain relief and improve function in dogs with bone cancer without significant long-term side effects. In a single-blind, controlled study, 72 companion dogs with bone cancer pain were randomized to standard of care analgesic therapy alone (control, n = 36) or 1.2 μg/kg intrathecal RTX in addition to standard of care analgesic therapy (treated, n = 36). Significantly more dogs in the control group (78%) required unblinding and adjustment in analgesic protocol or euthanasia within 6 weeks of randomization, than dogs that were treated with RTX (50%; P < 0.03); and overall, dogs in the control group required unblinding significantly sooner than dogs that had been treated with RTX (P < 0.02). The analgesic effect was documented in these dogs without any evidence of development of deafferentation pain syndrome that can be seen with neurolytic therapies.

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Conflict of interest statement

The authors declare no competing interests at the time of study design, funding, implementation, and analysis. As of 3/22/2014 Dr. Brown acts as a consultant for Sorrento Therapeutics, which is developing RTX for human and veterinary applications, as a key opinion leader with the FDA assisting in study design and data interpretation.

Figures

Figure 1
Figure 1
Anterior-posterior (A) and lateral (B) radiographic views of the left antebrachium of an 11 year old, female, Golden Retriever that was diagnosed with osteosarcoma. There is a moth-eaten lytic lesion in the distal radial metaphyseal region with sunburst periosteal reactions associated with it.
Figure 2
Figure 2
Core body temperature of dogs undergoing general anesthesia and intrathecal injection of resiniferatoxin shows the development of hypothermia that plateaus three to four hours following extubation.
Figure 3
Figure 3
Kaplan-Meier product-limit method and log rank analysis demonstrated that owners of dogs that received standard of care therapy analgesics alone (controls) sought additional intervention including additional analgesics or euthanasia for their dogs significantly (p=0.01) sooner than owners of dogs that received resiniferatoxin in addition to standard of care analgesics.
Figure 4
Figure 4
Seventy eight percent of dogs in the control group required unblinding and additional intervention within 6 weeks of randomization, while only 50% of dogs treated with intrathecal resiniferatoxin required unblinding and additional intervention during that same time frame. This was a statistically significant difference between groups (p<0.03).
Figure 5
Figure 5
On the owner completed Canine Brief Pain Inventory, there was no significant difference between treated and control groups in the pain severity and pain interference scores two weeks following intrathecal resiniferatoxin administration.
Figure 6
Figure 6
An orthopedist, blinded to treatment group, evaluated lameness through video analysis and determined that seven percent of dogs in the control group had improved lameness while 33% of dogs in the RTX treated group had improved lameness 2 weeks post randomization. This was a statistically significant difference between groups (p<0.03).
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