Abstract
Intractable cancer pain continues to be a difficult problem for pain management specialists. With current oral analgesics many patients have side-effects that limit their quality of life. Interventional treatments, such as intrathecal neurolysis with alcohol and phenol, can be effective, but have the potential for motor paralysis. Other potent intrathecal analgesics, such as ziconotide, opioids, bupivacaine, and clonidine, need to be administered by an external pump or internal implantable drug delivery system, which, with end-of-life care, can be hard to coordinate. Modern intrathecal alternatives, resiniferatoxin and saporin, offer prolonged analgesia, and their delivery avoids motor dysfunction. This chapter explores the history, data, and future studies of these novel natural compounds for cancer pain relief.
Keywords
Analgesic, Cancer pain, Euphorbia, Intrathecal, Neurolytic, Resiniferatoxin, Saporin, Substance P, TRPV1
Outline
Introduction 861
Resiniferatoxin 862
History 862
Mechanism of Action 862
Preclinical Data 862
Resiniferatoxin and Cancer Pain 863
Future Directions for Resiniferatoxin 864
Saporin 864
History 864
Pathophysiology 865
Safety and Efficacy of Saporin 866
Substance-P–Saporin and Cancer Pain 866
The Future for Substance-P–Saporin 866
Conclusion 867
References 867
Introduction
Intractable cancer pain continues to be a significant issue for oncological care. Although the spread of the disease may be controlled, symptom management for nausea, vomiting, lack of appetite, and pain control can be elusive. Interventional treatments, such as intrathecal (IT) neurolysis, may need to be utilized once conventional systemic therapies have been tried and failed.
IT neurolytic blockade to the sympathetic chain and spinal cord can significantly reduce refractory pain from cancer and oral analgesic requirements ( ). Use of IT neurolytic blockade for treatment of chronic pain was first described by Dogliotti in . However, a report of over 2000 subarachnoid blocks in 1981 demonstrated that neurolytic blockade is nonselective for sensory and motor neurons and can leave patients with transient (4.3%) or permanent (0.8%) paralysis ( ). IT neurolytic blockade has traditionally been performed using alcohol and phenol ( ). Alcohol at 50% is hypobaric to cerebrospinal fluid (CSF), and when injected there is rostral spread in the CSF when the head is down relative to injection site. When injected intrathecally there is a burning quality that many patients find difficult to tolerate, which may necessitate moderate sedation to general anesthesia. Phenol, often 6%–10%, is hyperbaric and viscous, tends to spread caudally, and can produce direct neural damage, vascular damage, and infarcts. Both alcohol and phenol can produce an estimated 3–6 months of significant relief of cancer pain, but their potential distribution to the anterior motor nerve roots can lead to paresis, urinary retention, and paralysis.
Modern alternatives derived from natural agents such as euphorbia and soapwort, which are synthesized to resiniferatoxin (RTX) and saporin, respectively, offer durable IT analgesia for cancer pain but avoid prolonged motor dysfunction. RTX, a TRPV1 agonist, and saporin, a ribosomal-inactivating protein, may produce long-lasting pain relief for more than 6 months after IT administration. This chapter explores the history, current research, and future studies of these novel natural compounds for cancer pain relief.
Resiniferatoxin
History
RTX comes from the genus of plants called Euphorbia. The most common of the species is sold during Christmas as the poinsettia ( Euphorbia pulcherrima ), and is indigenous to Mexico ( ). RTX ( Euphorbia resinifera ) is a cactus-like plant that comes from Morocco ( ); see Fig. 69.1 .
As a genus, all Euphorbia plants contain a viscous, milky-white latex, and this latex contains the potent TRPV1 agonist RTX. The synthesis of (+) resiniferatoxin was completed by the Wender group at Stanford University in 1997 ( ). RTX is one of the most potent TRPV1 receptor agonists and potentially one of the best agents to treat inflammatory and intractable chronic pain.
Mechanism of Action
TRPV1 receptors are nonselective cation channels that are sensitized from noxious stimuli, leading to inflammatory conditions and pain. In chronic pain states, vanilloid (TRPV1) receptors are up-regulated on neurons, have reduced stimulation thresholds, and cause an increased perception of pain. TRPV1 agonists, such as capsaicin, will activate and depolarize TRPV1 receptors, initially causing a burning sensation from stimulation of the nerve. After the TRPV1 receptors are completely depolarized, the nociceptive areas are desensitized and become analgesic, particularly to neuropathic pain ( ). Capsaicin, a less potent TRPV1 agonist than RTX, has been approved for the treatment of postherpetic neuralgia ( ). RTX, the most potent TRPV1 receptor agonist, is 1000–10,000 times more potent than capsaicin or 16 billion on the Scoville scale; see Fig. 69.2 .
RTX can reduce chronic pain without affecting normal pain perception, sensation, or motor function.
Preclinical Data
From preclinical animal models, RTX has been shown to have robust effects on TRPV1 cells.
In Olah et al. demonstrated that the effects of RTX were instantaneous and induced a large sustained influx of calcium in rat dorsal root ganglion (DRG) cell culture; see Fig. 69.3 .
Karai et al. in published work demonstrating that either periganglionic injections near the DRG or IT injections into the CSF would eliminate TRPV1 positive cells on spinal cord cross-sections after treatment ( Fig. 69.4 ).
A canine model ( ) was used to assess RTX effects on primary afferents in mammals. A single IT dose of RTX (1.2 mcg/kg) significantly attenuated thermal responses, with a sharp decrease in Visual analog scale for 14 weeks. Additionally, oral analgesics (opioids and Nonsteroid antiinflammatory drugs) were substantially decreased.
Resiniferatoxin and Cancer Pain
In humans, RTX has been tested for treating cancer pain by IT injection. The US National Institutes of Health opened a phase 1 study of IT RTX for treating severe refractory pain associated with advanced cancer ( ). An abstract of this study was presented in Tampa, FL, at the American Pain Society annual meeting in 2014 ( ). The study was an open-label, single-site, dose-escalation safety study for patients with severe pain due to cancer, rated at an average numeric rating scale (NRS) of >6/10 over a 7-day window. Eligible patients had to have histologically confirmed cancer with progressive disease after standard therapies and no effective palliative therapy to alleviate their pain. The targeted pain area was midchest (T5 dermatome) or below. Since TRPV1 agonists are known to cause profound burning pain, the RTX was administered under propofol general anesthesia. RTX injections were performed via a spinal catheter from a standard epidural kit placed in the lumbar region. Six patients between the ages of 29 and 68 ( Table 69.1 ) with advanced cancer had significant improvement in pain scores with 3, 13, and 26 mcg doses, respectively ( ); these doses were selected based on no-observed-adverse-effect dosages from animal data. Some patients at the 26 mcg dose reported thermal insensitivity changes in hands and feet.
| Demographics at Study Entry | Cancer Diagnosis | Target Pain Area |
|---|---|---|
| 49-year-old white female | Metastatic breast cancer | Low back and bilateral leg pain 2 degrees bone metastases |
| 56-year-old black male | Metastatic supraglottic squamous-cell cancer | Low back and bilateral hip pain 2 degrees bone metastases |
| 57-year-old black male | Metastatic pancreatic cancer | Bilateral abdominal (visceral) pain |
| 68-year-old white male | Lymphoma, small-fiber monoclonal gammopathy | Bilateral hip and buttocks (neuropathic) pain |
| 55-year-old white male | Metastatic small-cell lung cancer | Left hip pain 2 degrees bone metastases |
| 61-year-old white female | Metastatic endometrial cancer | Low back and left hip/groin pain 2 degrees bone metastases |
During this Phase 1 trial, patients with intractable pain associated with various cancer diagnoses were enrolled. Diagnoses included metastatic breast cancer to spine and pelvis, metastatic laryngeal cancer, lung cancer, and colorectal cancer. Most had significant loss of physical function and were using moderate to high opioid doses. IT treatment with RTX produced significant and long-lasting pain relief, reduction of opioids, and a profound increase in mobility ( Table 69.2 ). The nonambulatory patients were able to walk without the assistance walkers or wheelchairs. Overall, RTX in this study population was well tolerated with no unexpected side-effects.
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