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Based on encouraging results from previous animal
studies, researchers at the US National Institutes of Health (NIH) are
currently conducting a Phase I clinical trial on an African spurge extract for
cancer-related pain.1,2 Resiniferatoxin — or “RTX,” as it is
commonly called — is an analgesic extracted from the white latex of the
cactus-like resin spurge (Euphorbia resinifera). A spurge is
a plant that emits a milky sap when cut; the word spurge is derived from the
Latin expurgare, which means to purge.3
German scientists isolated and attributed action to RTX in the 1970s, and NIH has
been researching it for almost 30 years.4 In previous studies, NIH scientists found that RTX successfully
decreased pain in rodents, as well as in dogs diagnosed with bone cancer. In
the canine study, all participating dogs had pain so severe and unresponsive to
other medications that their owners were considering having them euthanized. They
were given just one spinal fluid injection of RTX and the results, as described
in two scientific reports5,6 and a 2006 article in The NIH Catalyst, were “impressive.”7
“All
of the dogs experienced significant pain relief that lasted for the rest of
their lives,” stated the article’s author. “One dog that had only walked on
three legs due to pain from a large tumor on his foreleg trotted almost
normally through the clinic with his tail wagging several weeks after
treatment. Moreover, RTX did not negatively affect locomotion, coordination,
bowel and bladder function, or behavior in any of the animals.”7
Most
of this preliminary research was funded by an NIH Bench-to-Bedside Award given
to lead researcher Michael Iadarola, PhD,
now in the Department of Perioperative Medicine in NIH’s Clinical Center.
Through various studies, his team found that RTX destroys the neurons that communicate
pain sensations to the spinal cord while leaving other neurons alone — a highly
selective “killing the messengers” feat. Due to this action when administered in
the spinal fluid, RTX has been called a “single-shot dose of analgesic that
lasts forever,” and a “fire-and-forget missile.”8 While
RTX and capsaicin — the pain-killing component in peppers
(Capsicum annuum) — share similar molecular structures and attach
to the same vanilloid receptors in the human body, RTX
binds to these receptors much more strongly, leaving the channel open longer
and letting in an excess amount of calcium, which kills the cells that transmit
pain signals.
NIH
is now recruiting participants for the human study that will assess if RTX is
safe and can help treat pain in persons with advanced cancer who have not been
helped by available pharmaceutical drugs.2,4 The RTX used in the
study was obtained from Morocco, where native resin spurge grows. Interestingly,
the milky white latex within many Euphorbia
plants causes irritation — which sometimes can be severe — when handled or
consumed. Dr. Iadarola noted that if a person were to eat resin spurge, “It
would cause a lot of pain in the mouth and they would stop eating it,” and
explained that this is likely one of the plant’s evolutionary defenses against
predators. But, he said, this nerve ending activation lasts for just 30
minutes, after which the RTX compound goes on to produce a “long-term block of
pain.” In the current study, patients will be given a local anesthetic painkiller
so that the initial pain is not felt.
The
US Department of Health and Human Services — under which NIH operates — has received
a patent (# 8,338,457) from the US Patent and Trademark Office for RTX
administered into the spinal fluid.4 NIH licensed the patent to private
biopharmaceutical company Sherrington Pharmaceuticals, Inc. (New York, NY) for further phases of testing and the
commercialization part of the drug-development process.
“While RTX remains an investigational drug, the patent licensed to our
commercial partner provides further incentive to move the drug through clinical
development,” said an NIH representative in a press release. “The patent
increases the likelihood that RTX will not end up on a laboratory shelf as a
stalled or lost opportunity, but instead will have the potential to improve the
lives of people with intractable pain.”4
Depending
on this human study’s results, RTX could become an important option for
treating pain in people who do not respond to available interventions, as well
as an alternative for those wishing to avoid opioids’ myriad negative side
effects, including nausea, sedation, constipation, gradual decrease in
efficacy, addiction, etc. And because chronic pain often shortens or interferes
with patients’ cancer treatment, RTX could indirectly lead to improved disease
outcomes.9 If the current research, whose completion is expected in
December 2014, finds a positive therapeutic benefit, RTX would need to undergo
more rigorous late-phase clinical trials in order to apply for FDA drug
approval.
—Lindsay
Stafford Mader
References
1. Weintraub A. Prickly painkiller. Scientific American. July 2013.
Available here. Accessed June 25, 2013.
2.
Resiniferatoxin
to Treat Severe Pain Associated With Advanced Cancer. Identifier: NCT00804154.
Last updated May 1, 2013. ClinicalTrials.gov. Available here. Accessed June 25, 2013.
3.
About the genus Euphorbia. EuphORBia: a global inventory of the spurges
website. Available here. Accessed July 1, 2013.
4.
Method patent issued for
investigational new class of pain medication [press release]. Bethesda, MD:
National Institute of Dental and Craniofacial Research. January 29, 2013.
Available here. Accessed June 25, 2013.
5.
Brown DC, Iadarola MJ, Perkowski SZ, et
al. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a
canine bone cancer model. Anesthesiology.
2005;103(5):1052-9.
6.
Karai L, Brown DC, Mannes AJ, et al.
Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain
control. J Clin Invest. 2004;113(9):1344-52.
7.
Ross K. Novel strategy to vanquish
intractable cancer pain: resiniferatoxin at threshold of clinical trial. The NIH Catalyst. May-June 2006.
Available here. Accessed June 25, 2013.
8.
Profile 2009. NIH Clinical Center
Director’s Annual Report. US Department of Health and Human Services: National
Institutes of Health. Available here. Accessed June 26, 2013.
9.
Eastman P. Update on chronic pain
control at NIH symposium highlighting progress, unmet needs. Oncology Times. April 20, 2011.
Available here. Accessed June 25, 2011. |