Abstract
Intrathecal (IT) drug delivery technology has become one of the key arsenals in treating both nonmalignant and malignant chronic pain. However, only three compounds have been officially approved for use in IT pumps for pain management. The recent focus on the incidence and prevalence of serious adverse effects associated with opioids has renewed interest in searching for alternative compounds with improved side-effect profiles and efficacy. In this chapter we consider six candidate compounds for use in IT pumps. Review of the candidate compounds suggests that more research and clinical experiences are needed, and ultimately their approval for use by the United States Food and Drug Administration (FDA). Furthermore, review of each compound also suggests that future IT therapy might benefit from a combination therapy of FDA-approved IT compounds and other nonFDA-approved compounds for optimal pain management while mitigating side-effects, including potentially fatal side-effects associated with single-compound use in IT drug delivery systems.
Keywords
Adenosine, Chronic pain, Gabapentin, Intrathecal drug delivery systems, Intrathecal pump, Midazolam, Neostigmine, Oxytocin, Resiniferatoxin
Introduction
Intrathecal drug delivery systems (IDDSs) for chronic pain work by delivering a solution of an analgesic compound directly into the cerebrospinal fluid (CSF) for greater analgesic efficacy and minimal side-effects, as opposed to administering it through the systemic route. This mode of therapy has been in use for more than 30 years, but to this day only two analgesic compounds, morphine (Infumorph) and ziconotide (Prialt), and one antispasmodic compound, baclofen (Lioresal), have been officially approved for use in IDDS by the Food and Drug Administration (FDA) in the United States. Despite this fact, clinicians have been using various combinations of both FDA-approved and nonFDA-approved compounds, with varying degrees of success, to manage both chronic nonmalignant and chronic malignant pain for as long as IDDSs for the delivery of intrathecal (IT) agents have been on the market. Recent data published by Medtronic Inc. (Minneapolis, MN, USA) estimated that 66% of implanted IDDSs are filled with nonFDA-approved drugs, and Medtronic estimates that the actual number may be higher ( ).
The use of a single IT compound to treat chronic pain (monotherapy) is a relatively straightforward proposition in theory. IT monotherapy has its drawbacks, as both compounds approved by the FDA for IT use carry serious side-effects that can potentially be fatal and often lead to cessation of IT therapy ( ). Risks of respiratory depression, opioid-induced hyperalgesia, constipation, granuloma formation, and hypogonadism, among others, exist with IT infusion of opioids ( ). For ziconotide the one systemic side-effect is hypotension, and most of its known side-effects are related to the central nervous system (CNS). Additionally, ziconotide struggles to find a wider audience due to its narrow therapeutic window, the need to titrate infusion rates up slowly to avoid psychologic side-effects when titrated aggressively, and last but not least relatively high cost of medication compared to other IT agents ( ).
Chronic pain, whether from nonmalignant or malignant cause, is an amalgamation of pathophysiologic processes that may not be optimally managed with a single IT compound. Thus optimal pain management may require targeting of different pathophysiologic processes with multiple IT compounds in combination to bring pain relief and reduce chances of more serious side-effects associated with IT monotherapy, such as morphine when given alone. Thus compounding various drug combinations for IT delivery may be advantageous, if not necessary ( ). However, compounding must take into account key issues for IT drug delivery, such as the physiochemical property of the agent to be compounded (solubility, pH, stability at room temperature solution, and implanted device), its stability at body temperature, its compatibility with the delivery system, and its clinical efficacy and safety, any of which can be challenging to manage.
Recently there has been a strong public and political focus on the incidence and prevalence of serious adverse effects with the taking of opioids ( ; ). The need to search for and research candidate nonopiate compounds to develop for IT therapy and approval by the FDA, is now greater than ever. In this chapter we discuss six different classes of compounds that have shown promise to be used for targeted drug delivery in IDDSs, as either monotherapy or combination therapy. Some of these compounds have already been through phase 1 trials 1
1 Clinical trials are conducted in a series of steps, called phases – each phase is designed to answer a separate research question. Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Taken from the internet: https://www-nlm-nih-gov.easyaccess1.lib.cuhk.edu.hk/services/ctphases.html .
and have shown promise of clinical efficacy, while others show promise in animal studies and warrant further research to decipher their efficacy and safety. For each compound we give a brief history, its mechanism of action (MOA), and clinical experiences with closing remarks.Adenosine
Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule, and it plays an important role in biochemical processes such as energy transfer and signal transduction. More importantly, in the CNS it is a potent neuromodulator that helps in promoting sleep, suppressing arousal, and regulating anxiety, cognition, and memory in normal conditions ( ). In physiologically stressful situations, such as CNS ischemia, physical trauma, or seizure, adenosine acts as a neuroprotective agent by regulating blood flow and attenuation of inflammatory reactions, acting on neurons directly. In the spinal cord (SC), adenosine affects both presynaptic and postsynaptic membrane changes that modulate sensory input ( ) to affect the phenomena of hyperalgesia and allodynia. These actions are critical for neuronal survival and viability during stroke, epilepsy, degenerative conditions, and changes in the CNS after mechanical/chemical injury.
IT administration of adenosine for pain relief was first performed in a seminal study by . In a rodent study that looked at the effect of IT adenosine (ITA) on spinal regulation of pain, the authors demonstrated that an adenosine analogue increased thermal thresholds in mice, which could be reversed by the administration of an adenosine receptor antagonist. Additional research involving animal models of nociceptive, inflammatory, and neuropathic pain in humans also shows that the administration of ITA analogues produces analgesia and/or reduced hyperalgesia and allodynia ( ).
Mechanism of Action
Adenosine modulates the physiologic changes in the SC after SC injury or peripheral nerve injury. Such injuries can cause certain spinal neurons, such as interneurons and projection neurons, to assume an excitatory tone, which subsequently leads to hyperalgesia and allodynia ( ). ITA has been evaluated for analgesic actions against both acute pain and chronic pain, specifically for its effect on hyperalgesia and allodynia. Both animal and human studies have shown that adenosine had minimal and transient analgesic effect against acute noxious stimuli ( ). Additionally, IT delivery of adenosine was found to have a more potent, long-lasting antiallodynic and antihyperalgesic effect in animal models of mechanical hypersensitivity ( ), but not when it was administered intravenously ( ).
Both preclinical and clinical evidence has shown that adenosine exerts its antiallodynic and antihyperalgesic effects via spinal adenosine receptors. There are four known adenosine receptors, A1, A2 A , A2 B , and A3, that are expressed in the SC. It is postulated that A1 is the main receptor responsible for the antiallodynic and antihyperalgesic effects of adenosine ( ). The other receptor types, both A2 subtypes and A3, play a minor role in reversing allodynia and hyperalgesia. They may contribute to antihyperalgesia or antiallodynia when the SC is subjected to chronic exposure to adenosine ( ). The analgesic effect of ITA can last anywhere from minutes to weeks, yet the half-life of ITA in CSF is in the range of hours ( ). Preclinical evidence suggests that while A1 receptor ligand binding provides acute pain relief, the agonist binding of A2 receptor subtypes A and B may be responsible for prolonged analgesic effects through second-messenger pathways ( ). Specifically in chronic pain, which is thought to be mediated via glial cell activation, A2 A activation provokes activation of protein kinases A and C that increases cyclic adenosine monophosphate in glial cells and leads to downregulation of proinflammatory cytokine and chemokines, such as tumor necrosis factor alpha, and upregulation of antiinflammatory cytokines such as interleukin-10 (IL-10) ( ). The majority of evidence from preclinical and clinical studies on ITA is limited to bolus delivery, and data on continuous infusion of ITA is lacking at this time.
Clinical Evidence
In Rane et al. performed a phase 1 study of ITA in Sweden, and reported that R-PIA, an A1 receptor-specific agonist, when administered to human subjects via the IT route reduces neuropathic pain and allodynia, consistent with animal study findings ( ). In a neurotoxicity trial of ITA by Chiari et al. in , in both rats and dogs, the authors found no disturbances in neurologic function in either animal species. ITA did cause transient sedation in rats and increased muscle tone in dogs, but these symptoms resolved with continued exposure to the drug. In the same study, no acute thermal analgesia was observed with either adenosine or saline-treated rats or dogs. Furthermore, there were no differences between adenosine and placebo groups with regards to histopathology of the SC; both groups showed moderate fibrotic and inflammatory changes, believed to be secondary to use of the IT catheter.
In 2002 Eisenach et al. performed a phase 1a and 1b study with the United States formulation of adenosine; this differed from the European formulation, which contains mannitol. The United States formulation is prepared in preservative-free saline ( ). Adenosine in the United States is commercially available in two distinct formulations, for the treatment of dysrhythmia or for myocardial scanning, and the authors chose adenosine formulated for myocardial scanning due to the endotoxin unit testing that supports a larger number of milligrams of drug for acute administration ( ). found that ITA did not affect blood pressure, heart rate, end-tidal carbon dioxide, or neurologic function. The authors found headache and back pain were the two most common complaints with ITA administration, but neither was a dose-limiting side-effect. The same side-effects of headache and back pain were not reported by the saline-treated subjects, and the authors recommended further investigation of ITA-mediated analgesia in humans. Additional studies in human subjects showed that a maximum bolus dose of 2 mg of ITA produced 40 min to 4 days of antiallodynic and antihyperalgesic effects by reduction in areas of allodynia and hyperalgesia. However, the data varies as to the size of reduction of the reported area of allodynia and/or hyperalgesia, ranging from 30% or 40% to as high as 90% ( ).
The half-life of ITA in human CSF is approximately 1–2 h, which is significantly longer than its plasma half-life, but short in comparison to other IT compounds ( ). The relatively short half-life of ITA is likely mediated by various mechanisms, including reuptake and enzymatic breakdown via deaminases and kinases. Regardless of ITA’s half-life in the CSF, ITA has been shown to produce prolonged antihyperalgesic and allodynic effects in neuropathic pain models in both animals and humans ( ).
Closing Remarks
Despite showing promise in animal models of neuropathic pain and early on as a candidate for IT monotherapy or combination therapy, the human data suggests marginal effectiveness in reducing areas of hyperalgesia or allodynia and providing analgesia. Thus adenosine may not be an ideal candidate as an IT monotherapeutic agent for neuropathic pain, but given its favorable side-effect profile, further investigations are needed to evaluate ITA’s efficacy and safety as an adjunct therapy that may have a synergistic effect with other IT agents.
Adenosine
Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule, and it plays an important role in biochemical processes such as energy transfer and signal transduction. More importantly, in the CNS it is a potent neuromodulator that helps in promoting sleep, suppressing arousal, and regulating anxiety, cognition, and memory in normal conditions ( ). In physiologically stressful situations, such as CNS ischemia, physical trauma, or seizure, adenosine acts as a neuroprotective agent by regulating blood flow and attenuation of inflammatory reactions, acting on neurons directly. In the spinal cord (SC), adenosine affects both presynaptic and postsynaptic membrane changes that modulate sensory input ( ) to affect the phenomena of hyperalgesia and allodynia. These actions are critical for neuronal survival and viability during stroke, epilepsy, degenerative conditions, and changes in the CNS after mechanical/chemical injury.
IT administration of adenosine for pain relief was first performed in a seminal study by . In a rodent study that looked at the effect of IT adenosine (ITA) on spinal regulation of pain, the authors demonstrated that an adenosine analogue increased thermal thresholds in mice, which could be reversed by the administration of an adenosine receptor antagonist. Additional research involving animal models of nociceptive, inflammatory, and neuropathic pain in humans also shows that the administration of ITA analogues produces analgesia and/or reduced hyperalgesia and allodynia ( ).
Mechanism of Action
Adenosine modulates the physiologic changes in the SC after SC injury or peripheral nerve injury. Such injuries can cause certain spinal neurons, such as interneurons and projection neurons, to assume an excitatory tone, which subsequently leads to hyperalgesia and allodynia ( ). ITA has been evaluated for analgesic actions against both acute pain and chronic pain, specifically for its effect on hyperalgesia and allodynia. Both animal and human studies have shown that adenosine had minimal and transient analgesic effect against acute noxious stimuli ( ). Additionally, IT delivery of adenosine was found to have a more potent, long-lasting antiallodynic and antihyperalgesic effect in animal models of mechanical hypersensitivity ( ), but not when it was administered intravenously ( ).
Both preclinical and clinical evidence has shown that adenosine exerts its antiallodynic and antihyperalgesic effects via spinal adenosine receptors. There are four known adenosine receptors, A1, A2 A , A2 B , and A3, that are expressed in the SC. It is postulated that A1 is the main receptor responsible for the antiallodynic and antihyperalgesic effects of adenosine ( ). The other receptor types, both A2 subtypes and A3, play a minor role in reversing allodynia and hyperalgesia. They may contribute to antihyperalgesia or antiallodynia when the SC is subjected to chronic exposure to adenosine ( ). The analgesic effect of ITA can last anywhere from minutes to weeks, yet the half-life of ITA in CSF is in the range of hours ( ). Preclinical evidence suggests that while A1 receptor ligand binding provides acute pain relief, the agonist binding of A2 receptor subtypes A and B may be responsible for prolonged analgesic effects through second-messenger pathways ( ). Specifically in chronic pain, which is thought to be mediated via glial cell activation, A2 A activation provokes activation of protein kinases A and C that increases cyclic adenosine monophosphate in glial cells and leads to downregulation of proinflammatory cytokine and chemokines, such as tumor necrosis factor alpha, and upregulation of antiinflammatory cytokines such as interleukin-10 (IL-10) ( ). The majority of evidence from preclinical and clinical studies on ITA is limited to bolus delivery, and data on continuous infusion of ITA is lacking at this time.
Clinical Evidence
In Rane et al. performed a phase 1 study of ITA in Sweden, and reported that R-PIA, an A1 receptor-specific agonist, when administered to human subjects via the IT route reduces neuropathic pain and allodynia, consistent with animal study findings ( ). In a neurotoxicity trial of ITA by Chiari et al. in , in both rats and dogs, the authors found no disturbances in neurologic function in either animal species. ITA did cause transient sedation in rats and increased muscle tone in dogs, but these symptoms resolved with continued exposure to the drug. In the same study, no acute thermal analgesia was observed with either adenosine or saline-treated rats or dogs. Furthermore, there were no differences between adenosine and placebo groups with regards to histopathology of the SC; both groups showed moderate fibrotic and inflammatory changes, believed to be secondary to use of the IT catheter.
In 2002 Eisenach et al. performed a phase 1a and 1b study with the United States formulation of adenosine; this differed from the European formulation, which contains mannitol. The United States formulation is prepared in preservative-free saline ( ). Adenosine in the United States is commercially available in two distinct formulations, for the treatment of dysrhythmia or for myocardial scanning, and the authors chose adenosine formulated for myocardial scanning due to the endotoxin unit testing that supports a larger number of milligrams of drug for acute administration ( ). found that ITA did not affect blood pressure, heart rate, end-tidal carbon dioxide, or neurologic function. The authors found headache and back pain were the two most common complaints with ITA administration, but neither was a dose-limiting side-effect. The same side-effects of headache and back pain were not reported by the saline-treated subjects, and the authors recommended further investigation of ITA-mediated analgesia in humans. Additional studies in human subjects showed that a maximum bolus dose of 2 mg of ITA produced 40 min to 4 days of antiallodynic and antihyperalgesic effects by reduction in areas of allodynia and hyperalgesia. However, the data varies as to the size of reduction of the reported area of allodynia and/or hyperalgesia, ranging from 30% or 40% to as high as 90% ( ).
The half-life of ITA in human CSF is approximately 1–2 h, which is significantly longer than its plasma half-life, but short in comparison to other IT compounds ( ). The relatively short half-life of ITA is likely mediated by various mechanisms, including reuptake and enzymatic breakdown via deaminases and kinases. Regardless of ITA’s half-life in the CSF, ITA has been shown to produce prolonged antihyperalgesic and allodynic effects in neuropathic pain models in both animals and humans ( ).
Closing Remarks
Despite showing promise in animal models of neuropathic pain and early on as a candidate for IT monotherapy or combination therapy, the human data suggests marginal effectiveness in reducing areas of hyperalgesia or allodynia and providing analgesia. Thus adenosine may not be an ideal candidate as an IT monotherapeutic agent for neuropathic pain, but given its favorable side-effect profile, further investigations are needed to evaluate ITA’s efficacy and safety as an adjunct therapy that may have a synergistic effect with other IT agents.
Resiniferatoxin
Resiniferatoxin (RTX) is a naturally occurring compound found in a cactus-like plant, Euphorbia resinifera , most commonly found in the African continent ( ). First isolated in 1975, RTX is a very powerful capsaicin analogue that is reported to be approximately 500 times more potent than capsaicin ( ). What makes RTX interesting from a pharmacological perspective is that, along with capsaicin, it is a vanilloid receptor (VR) agonist. Preclinical studies show that VR activation is one of the first steps in the inflammatory pathway that detects and conveys the nociceptive signals from either damaged or inflamed peripheral tissue which can ultimately lead to chronic pain ( ).
Soma of nociceptive afferents that express the VR and are involved in signal transduction (Aδ and C fibers) are located in the dorsal horn (DH) of the SC ( ). The role of the VR in the pathophysiology of chronic pain and modulation of VR responses has been extensively researched, and the VR is now known as the transient receptor potential vanilloid 1 (TRPV1) ( ). TRPV1’s functions have been well characterized; they include thermal regulation, and detection and signal transduction of nociceptive information following exposure to noxious thermal stimuli. Thus in the SC small-diameter neurons, such as Aδ, and C fiber neurons are primarily responsible for detecting and conveying thermal nociception through activation of TRPV1 expressed on the cell surface ( ).
Mechanism of Action
As stated, RTX is a vanilloid compound and a potent agonist to TRPV1. As with capsaicin, a TRPV1/ligand complex opens the sodium/calcium, permeable, nonselective cation channel, leading to and influx of Ca 2+ ions, which produces a hyperpolarized state of nociceptive afferents and subsequent analgesia ( ). Due to its greater potency, the RTX/TPRV1 complex will lead to greater receptor recruitment and longer duration of channels being open. This leads to loss of cell membrane integrity due to Ca 2+ ions and eventual apoptosis of nociceptive afferents ( ). It is estimated that RTX can achieve a similar level of analgesia at 1/500th of the dose of capsaicin ( ).
The implication of greater potency is that a lower dose of RTX is required to achieve equivalent analgesia to capsaicin, in both systemic and IT settings. The concentration of vehicle needed to deliver the equivalent dose will also be lower, which in theory leads to fewer nonspecific side-effects related to delivery vehicle concentration when compared to capsaicin ( ). When RTX is delivered systemically in rodents via the intraperitoneal route, it causes neurolysis of thermal nociceptive neurons leading to sensory loss ( ). RTX, when administered intrathecally, has been shown to ablate selectively the Aδ and C fibers in the DH while preserving dorsal root ganglion (DRG) neurons ( ).
Clinical Evidence
IT delivery of RTX was considered an ideal route for treatment of regional pain secondary to its limited site of action, selective neurolysis of primary afferents in the DH expressing TRPV1 receptors, and its potency and destructive characteristics when administered systemically ( ). The same preclinical studies showed significant pain relief and improvements in mobility following IT RTX injection, and demonstrated IT RTX to be a safe compound without evidence of neurotoxicity in animal models ( ).
Other TRPV1 receptor antagonists were developed for clinical evaluation, with disappointing results. Two major side-effects of the TRPV1 antagonists are significant and worrisome increases in core body temperature and the systemic loss of the ability to sense noxious heat, which can expose patients to thermal injury if they are placed on chronic antagonist therapy ( ). IT RTX causes similar thermal insensitivity to noxious heat, with the difference that IT RTX will not cause dangerous increases in core temperature and, due to localized exposure, reduction in sensitivity to noxious thermal stimuli is limited to the dermatome corresponding to the site of injection. Thus it preserves the body’s ability to detect and respond to noxious thermal stimuli and allows for thermal environmental sampling ( ).
The human experiences with IT RTX have been focused on malignant pain management, and clinical trials are in progress to assess efficacy and safety of IT RTX for the treatment of such pain ( ). In both preclinical and clinical trials bolus administration of IT RTX causes initial pain and discomfort at the onset of action due to neurolysis of TRPV1 + sensory afferents. This aspect of the treatment has necessitated subjects being placed under general anesthesia for 2 h while undergoing IT RTX administration. In clinical trials for treatment of refractory malignant cancer pain, administered 13 and 25 μg to subjects who were refractory to maximum doses of oral opioids. They found that IT RTX decreased baseline pain by 24.7% and worst pain by 19.5% at the end of 2 weeks, and there was a 1.6 average improvement in BPI assessment with improvements in mobility. As in previous findings, the authors did report two case of thermal insensitivity that was consistent with the cephalad spread of IT RTX. However, they found no dose-limiting toxicity at IT RTX doses of 26 μg, and are planning to do additional studies with higher doses ( ).
Closing Remarks
Bolus IT RTX has shown to be an effective treatment for chronic malignant pain when the subjects’ chronic pain is not responsive to maximally tolerated opioids. It is possible to treat nonmalignant pain with IT RTX, but as of this writing both literature and data supporting the treatment of nonmalignant chronic pain are lacking. Before the clinical efficacy of IT RTX for treatment of nonmalignant chronic pain is trialed, one must rationalize the utility of permanent neurolysis and sequelae in this treatment. Furthermore, IT RTX does not appear to interfere with the actions of opioids or other agents, thus making it an ideal drug to be used in an IT pump. However, there are several safety issues that need to be addressed, including thermal insensitivity following IT RTX administration and the need for patients to be placed under general anesthesia due to intense pain during IT injection from progression of neurolysis. Further studies are also needed to evaluate the suitability of IT RTX for continuous infusion and look at different baricities of IT RTX to prevent cephalad spread and thermal insensitivity.
Midazolam
Midazolam (MZ), a benzodiazepine, was first introduced in 1976 and has been used extensively by the intravenous route in anesthesia for procedural sedation, treatment of seizures, insomnia, agitation, and end-of-life care ( ). In the early 1980s Rigoli et al. first reported that epidural MZ produces significant analgesic effects for postoperative and chronic pain patients ( ). The relatively large dose of MZ used not only produced the said analgesic effect but also caused significant sedation. In the late 1980s Goodchild et al. provided the first clues to the analgesic effects of IT MZ by measuring pain thresholds against electrical stimulation in rats ( ). Subsequent studies showed that IT MZ was superior to IT prednisone for the treatment of mechanical low back pain ( ). Since the 1990s preclinical and clinical studies have focused on IT MZ in the context of analgesia synergy in the setting of acute postoperative pain, and deciphering the neurotoxicity of IT MZ in both animal models and humans ( ; ; ; ).
Mechanism of Action
Both preclinical and clinical studies in the early stages of evaluation for IT MZ reported that it reduces pain threshold in rodents and has analgesic effects in humans ( ). Additionally, synergistic effects of IT MZ with other IT analgesics such as opioids, bupivacaine, baclofen, and clonidine, among others, give superior pain relief for longer durations ( ; ; ). MZ exerts its therapeutic effect through binding with gamma-amino butyric acid (GABA) receptors, in particular GABA A receptors. GABA receptors exist as one of two subtypes (A and B). The GABA A receptor is a fast-responding ligand-gated ion channel that binds with MZ and opens a chloride ion-selective channel, leading to increased chloride conductance that drives the membrane potential toward the reversal potential and ultimately leads to inhibition of new action potentials. In contrast, GABA B metabotropic receptors are G protein-coupled receptors and do not produce analgesic effects ( ; ).
Much of the mechanism(s) behind the synergistic interaction between IT MZ and IT analgesics is not yet clearly delineated. Investigators postulate that the GABA A /MZ complex may lead to the release of endogenous opioids that act on one or all three combinations of the opioid receptor subtypes ( ). In Goodchild et al. reported that IT MZ caused up-regulation of endogenous opioids that bind to the δ opioid receptors. The synergistic interaction between IT MZ and IT analgesics is the result of increased production of endogenous opioids specific to δ opioid receptors regardless of the coadministered IT analgesics.
Clinical Evidence
The story of IT MZ has been fraught with controversy, due to contradictory findings in preclinical studies regarding neurotoxicity and clinical study data supporting its safety ( ). In a series of case reports in the late 1990s, reported their clinical experience with IT MZ and clonidine combinations in continuous infusion therapy in four human subjects with pain that was refractory to IT morphine. The investigators reported that all four subjects achieved a Visual Analog Score (VAS) of 0–1 with this therapy, with doses ranging from 1.5 mg/60 μg to 6 mg/450 μg. In Kim and Lee reported that in a double-blinded, randomized controlled trial (RCT) with a 45-subject cohort undergoing hemorrhoidectomy, the combination of IT MZ and bupivacaine was superior to IT bupivacaine alone. They observed no side-effects, including, but not limited to, bradycardia, hypotension, sedation, and dizziness.
Contrary to clinical and preclinical experiences describing therapeutic success and safety of IT MZ, several preclinical studies reported that IT administration of MZ produced microhistologic evidence of neurotoxicity in animal models, which sparked a debate regarding the safety of IT MZ in clinical settings ( ). Erdine et al. first described histological changes within the SC after the IT administration of MZ in rabbits, using both light and electron microscopy. Other studies reported similar histopathological findings ( ). In Johansen et al. studied the safety and toxicity of continuous IT MZ in a sheep model with histological postmortem examination of the SC. They found that all histological lesions in the SC were local. Inflammatory processes that were seen were consistent with catheter-related foreign-body inflammation, and lesions were present in both control and experimental groups. Furthermore, in 2004 Tucker et al. found no clinical evidence of lasting neurological symptoms that suggest pathophysiologic process in SC secondary to IT MZ administration in subjects who received an average IT MZ dose of 0.03 mg/kg. Yaksh commented on the controversy surrounding IT MZ, and recommended continued clinical investigations of IT MZ in published doses while exercising vigilance for correlation between clinical symptoms and histopathologic evidence for neurotoxicity ( ). In a metaanalysis by , the authors recommend cautious clinical use of IT MZ, either alone or in combination with other agents, and recommend large, multicenter RCTs with longer-term follow-up to assess safety and cost effectiveness of IT MZ in clinical use.
Closing Remarks
The use of IT MZ should be carefully weighed against potential side-effects and possible neurotoxicity. While there is animal data showing histopathological evidence of potential neurotoxicity, evidence to correlate those findings with clinical behavior is lacking. Future investigations will need to address the long-term clinical significance of histological findings of toxicity in animal studies. There is clinical data strongly supporting the efficacy of IT MZ, either alone or in combination with other IT agents, for both acute and chronic pain as well as procedural pain. However, its greatest utility appears to be in combination therapy to augment monotherapeutic agents and limit potential side-effects.
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