The Neurotoxicity of Drugs Given Intrathecally (Spinal)

A growing understanding of the neuropharmacology of spinal cord processing of nociceptive input has led to intense interest in the use of spinal drugs in anesthesia and pain management. The direct application of receptor-specific therapeutics at the spinal cord can potentially interrupt specific pain pathways and limit systemic side effects, but this practice also carries the inherent risk of injury to the central nervous system. Thus, the neurotoxicity of spinal drugs is a central safety issue. Spinal cord or nerve root toxicity may manifest itself as histologic, physiologic, or behavioral/clinical derangements after exposure to a spinal drug. Neurohistopathology is broadly classified as neural injury, gliosis, or damage to the myelin sheath, and it also describes inflammatory changes and involvement of the arachnoid cell layers. Physiologic neurotoxicity of spinal drugs includes changes in spinal cord blood flow, disruption of the blood-brain barrier, and changes in the electrophysiology of impulse conduction. Behavioral and clinical signs of neurotoxicity include pain, motor and sensory deficits, and bowel and bladder dysfunction. Ideally, a complete roster of histological, physiologic, and behavioral testing would be performed on spinal drugs in several animal species, followed by safety trials in humans before widespread use. In practice, drugs have taken a variety of roads from conception to application, and often without safety data. In this article, we review available neurotoxicity data on drugs that have a clinical application, classified as spinal local anesthetics, spinal analgesics, or spinal adjuvants. Spinal Local Anesthetics The 100-yr history of spinal local anesthetic use in humans has typically involved self-experimentation, followed by widespread application with little or no controlled testing for neurotoxicity. Bier and Hildebrant [1] initially performed spinal anesthesia with cocaine on themselves in 1898, and essentially all of the earliest local anesthetics for spinal anesthesia were introduced in this fashion without toxicity studies. Despite a long history of clinical use, recent interest in neurotoxicity has arisen due to concerns over reports of cauda equina syndrome and transient neurologic symptoms (TNS) from spinal local anesthetics. We review animal data that have been used to assess the neurotoxicity of local anesthetics and summarize data available from human studies. In 1985, Ready et al. [2] evaluated the neurotoxic effects of single injections of local anesthetics in rabbits. They reported that spinal cord histopathology remained normal and that persistent neurologic deficits were not seen with clinically used concentrations of tetracaine, lidocaine, bupivacaine, or chlorprocaine. However, histopathologic changes and neurologic deficits did occur with higher concentrations of tetracaine (1%) and lidocaine (8%). In this model, extensive neurologic impairment was not necessarily accompanied by equally extensive lesions in the spinal cord and nerve roots, thus demonstrating the need for multiple models to fully assess neurotoxicity. Recent studies have used desheathed peripheral nerve models, designed to mimic unprotected nerve roots in the cauda equina, to further assess electrophysiologic neurotoxicity of clinically relevant concentrations of local anesthetics [3-5]. These models demonstrate that clinically used concentrations of 5% lidocaine and 0.5% tetracaine cause irreversible conduction block, whereas 1.5% lidocaine, 0.75% bupivacaine, and 0.06% tetracaine do not. Electrophysiologic toxicity of lidocaine in these models is concentration-dependent (Figure 1) beginning at 40 mM (approximately 1%) with irreversible ablation of the compound action potential at 80 mM (approximately 2%). Kanai et al. [4] subsequently demonstrated that generation of action potentials was more vulnerable than maintenance of resting membrane potential and that irreversible ablation of action and resting membrane potential by lidocaine seems to be both concentration- and time-dependent.Figure 1: The nonreversible effect of 40 mM lidocaine on the compound action potential (CAP) of frog sciatic nerve. Lidocaine was applied to a stable nerve preparation for 15 min, then washed with frog Ringer's solution for 2 h. Tracings represent CAPs in response to stimuli (1-Hz stimulus = heavy line, 40-Hz stimulus = thin line). Lidocaine 40 mM completely ablated the CAP when applied to the nerve. The 1-Hz CAP response began to return after 10-15 min of washing and reached a new level in 45 min, where it was stable for the subsequent 2 h of observation. The recovered 1-Hz CAP is only 65% of the original. Reprinted with the publisher's permission from Holman SJ. Anesthesiology: hyperbaric dye solution distribution. Anesthesiology 1997;86:969.Effects of local anesthetics on spinal cord blood flow seem benign. Spinal administration of bupivacaine, lidocaine, mepivacaine, and tetracaine causes vasodilation and increase spinal cord blood flow [6,7], whereas ropivacaine causes concentration-dependent vasoconstriction and reduction in spinal cord blood flow [6]. However, the effects of lidocaine on blood flow of in vitro peripheral nerve models are more concerning. Myers et al. [8] applied solutions of isotonic sodium chloride solution, 1% and 2% lidocaine with and without epinephrine, and epinephrine alone to isolated rat sciatic nerve and measured changes in blood flow with a laser Doppler flow probe. Blood flow was significantly depressed for all solutions except isotonic sodium chloride solution. Epinephrine by itself significantly reduced nerve blood flow, and, when added to local anesthetic solutions, it reduced blood flow to a greater extent than the reduction caused by local anesthetics alone. Although experimental studies in animals have provided ample evidence that some local anesthetics in clinically relevant concentrations can injure nerve tissue, the exact mechanisms of injury are unclear. Recent work on neuronal cell lines has attempted to determine the mechanism of local anesthetic neurotoxicity. Johnson and Uhl [9] have shown that direct application of 2.5%-5.0% lidocaine caused a >3-fold increase in intracellular calcium and up to a 20% incidence of cell death during 60 min of exposure in the neuronal cell line. They postulated that the mechanism of neurotoxicity was not likely from sodium channel blockade, because such a block would not lead to an increase in cytoplasmic calcium. Subsequent work in this model determined that 0.5% and 1.0% lidocaine, as well as 0.625% bupivacaine, lead to transient, moderate increases in calcium, probably from the endoplasmic reticulum, without cell death [10]. Thus, several different laboratory models have proven that all local anesthetics can be neurotoxic but that lidocaine and tetracaine are potentially more neurotoxic than bupivacaine (Table 1).Table 1: Local Anesthetic ToxicityDespite the knowledge that all local anesthetics can be neurotoxic in the laboratory model, large-scale surveys of the complications of spinal anesthesia attest to the relative safety of spinal local anesthetics in humans (Table 2). Retrospective [11], prospective [12], and historical studies [13-15] report 0%-0.7% incidence of postoperative neurologic injury in patients undergoing spinal anesthesia. Although lacking a denominator, information from closed-claims databases corroborate these findings [16,17]. Thus, the neurotoxic potential of spinally administered local anesthetics has not manifested itself in large-scale studies.Table 2: Large Epidemiologic Studies of the Neurologic Complications of Spinal AnesthesiaThere are few nonepidemiologic clinical studies evaluating the potential neurotoxicity of local anesthetics, and all have focused on electrophysiologic variables after spinal anesthesia. Somatosensory evoked potentials, monosynaptic H-reflex [18], and cutaneous current perception thresholds [19] have been used to evaluate recovery after spinal anesthesia. These measurements have shown complete return to baseline activity after 5% lidocaine spinal anesthesia in very small study populations. Histopathologic or other physiologic data in humans are lacking; thus, information from controlled studies in humans is essentially not available. Lidocaine Controversy about the use of single-injection spinal lidocaine began in 1993 when Schneider et al. [20] published four cases of short-lived neurologic symptoms after spinal anesthesia with 5% hyperbaric lidocaine. This was the first report to question the potential for neurotoxicity with standard clinical doses and concentrations of lidocaine after single-injection spinal anesthesia. Subsequent prospective, randomized studies reveal a 4%-33% incidence of TNS after lidocaine spinal anesthesia (Table 3) [21,22]. This incidence varies with the type of surgical procedure and is unaffected by baricity or the dilution of lidocaine to 0.5%. Contemporary reports of cauda equina syndrome after continuous lidocaine spinal anesthesia and the potential concentration-dependent neurotoxicity of lidocaine have led several authors to label TNS as a manifestation of subclinical neurotoxicity.Table 3: Incidence of Transient Neurologic Symptoms (TNS) with Spinal Anesthesia in Prospective Randomized StudiesAs previously discussed, laboratory work in both intrathecal and desheathed peripheral nerve models has proven that the concentration of lidocaine is a critical factor in neurotoxicity. Because concentrations of lidocaine <40 mM (approximately 1.0%) are not neurotoxic to desheathed peripheral nerve, such dilute concentrations of spinal lidocaine should not cause TNS if the syndrome is caused by subclinical concentration-dependent neurotoxicity. We recently examined whether spinal lidocaine concentrations of <1.0% might therefore decrease the incidence of TNS [21]. Patients undergoing knee arthroscopy were randomized to receive 50 mg of hyperbaric lidocaine as either a 2.0%, 1.0%, or 0.5% solution. There was no difference in the incidence of TNS (18%) among the three groups. The incidence of TNS with lidocaine concentrations further dilution in seem to the of a concentration-dependent neurotoxic potential for TNS include neural of local anesthetics to by or the of and of [21]. The of TNS is and further studies are to the In local anesthetics all have the potential to be in concentrations and doses than used In and neuronal cell models, lidocaine and tetracaine seem to have a greater potential for neurotoxicity than bupivacaine at clinically relevant large-scale surveys of the complications of spinal anesthesia attest to the relative safety of spinal local anesthetics. Spinal There is a of different for the and of in the spinal These include and The and as and of and pain that have been administered spinally in humans are to or this of and (Figure 2). the animal safety data and the human safety data are and in 2: of mechanisms and of of spinal = = type = = = = = = = = and = and = of of Spinal and to clinically relevant doses of intrathecal for several no histopathology of the spinal cord Spinal cord blood flow is unaffected by mg of intrathecal in with a of or physiologic behavioral effects reported in intrathecal did not include evidence of neurotoxicity studies in patients with after continuous intrathecal to the in histopathologic Electrophysiologic study of spinal is to of evoked potentials, are intense clinical to intrathecal were reported in these studies. Spinal has no published animal neurotoxicity In spinal has been reported as an for surgical anesthesia without clinical but no neurotoxicity testing has been Spinal has not been safety in A single report describes administered spinally with in a with pain without evidence of In available is administered However, is also from animal safety testing data. Histopathologic studies of isolated nerve in solution to evidence of neural damage with in isotonic solution. electrophysiologic neurotoxicity was reported with the available solution of caused conduction deficits to alone In only doses of would be to a intrathecal human safety data are also with spinal There are no published reports the histologic, physiologic, or clinical evidence of neurotoxicity with spinal report of persistent neurologic complications was from a widespread clinical use of spinal was administered to with intrathecal for without to clinically relevant doses of intrathecal for several also no histopathology However, to (approximately 50 and very (approximately doses of h for intrathecal evidence of spinal cord histopathology These findings may a neurotoxic effect at doses or an of the experimental due to the preparation used in this studies of spinal cord blood flow, blood-brain effects, or electrophysiology are available. The and used in the no persistent behavioral The demonstrated and motor deficits that There is no human neurotoxicity testing of but are also no clinical reports of impairment from widespread use. The spinal administration of to for and to for several intrathecal no histopathology There are no reports of human with intrathecal Spinal has been for in but no histopathology has been published other than were not and recovery was not There is no published human with spinal In the with as a solution of and caused and behavioral whereas in was with inflammatory neuronal changes at and transient other animal or human data are available. In laboratory studies and extensive clinical with and can the safety of intrathecal doses of these or are without animal and human safety testing data. is the spinal in animals no in or Spinal cord blood flow studies in and reveal on the do not normal clinical behavioral neurotoxicity have been with intrathecal There has been extensive and exposure of humans to spinal and pain with no clinical evidence of neurotoxicity Although no histopathologic or physiologic studies have been seems to be a spinal in a effect by and has been shown to cause in animal and human of and after intrathecal and without administration reveal no spinal cord toxicity not spinal cord blood flow in and were no behavioral changes neurotoxicity reported in the animal studies. safety in human have been performed for both and hyperbaric of spinal without clinical evidence of neurotoxicity Although the human with spinal is clinical trials performed thus have not reported evidence of neurologic (Table other is in an solution when to physiologic These have the spinal studies in animals have rat studies with intrathecal for 15 or isolated to of in solution no neurotoxic on or However, a subsequent study in after a single intrathecal of reported that three of animals spinal cord histopathologic changes after exposure The of the histopathologic that from to the of and persistent in the and the all a systemic of in the three these a study on the rat was performed cell and after intrathecal administration of for The spinal evidence of neuronal death and on in a preparation of was used in to the isotonic preparation used in all in nerve injury in isolated nerve and has been in the neurotoxicity of spinal in Although may be the of the reported neurotoxicity of spinal is a and of Spinal animal studies on spinal cord blood flow or electrophysiology have been The effect of on blood-brain was in the study on and in three of animals Despite some histopathologic evidence of no behavioral have been reported in of the animal neurotoxicity studies of intrathecal There are no or physiologic studies of humans to spinal are small reports of intrathecal for anesthesia and pain management. this human are no reports of clinical neurologic after continuous intrathecal use in four patients with pain neurotoxicity is Although the solution seems to be neurotoxic in of the solution may be than the in not seems to be neurotoxic in the but it may be in the There are studies in humans to determine the risk of neurotoxicity with spinal Spinal is to from of motor after motor can be with is a stable of and with the in 2 of the (Figure to spinal of either or doses of no to intrathecal for no spinal cord histopathology studies on spinal cord blood flow, blood-brain effects, or electrophysiology have been published with to intrathecal behavioral evidence of neurotoxicity There are no published human studies evaluating histopathologic or physiologic neurotoxicity of Spinal was in for without clinical evidence of neurotoxicity extensive review of cases intrathecal did not on animal studies and clinical spinal is not likely to cause neurologic studies the neurotoxicity of with the of some Studies performed in and after intrathecal injections with and without chloride did not histopathologic evidence of neurotoxicity In other rat studies reported histopathologic evidence of neurotoxicity with spinal study of the in nerve roots in of that on of However, it is to these findings to neurotoxicity the of rat study with single intrathecal injections of mg of with the chloride reported that of injury at from the injections on However, more than of the animals in the either after or single after the of the in animal studies have been published on the effect of spinal on spinal cord blood flow or a of blood-brain significantly from that of after single injections of with but not with The neurotoxicity of spinal is in a few use for spinal anesthesia and the and studies with intrathecal safety if used without a A small human that the anesthetic is well However, the available preparation of an and be for intrathecal use in animal testing of intrathecal is to a physiologic in A of intrathecal doses or with a the human did not spinal cord blood behavioral were reported except for transient with the of mg of The of mg of the intrathecal the animals for min, whereas mg intense and followed by death from causes in exposure and studies are reported to be in The of neurotoxicity further In intrathecal neurotoxic at or doses to with findings in and administered in doses to in did not changes Spinal in effects in the spinal cord and to reduced blood flow, and blood-brain spinal cord blood flow changes were seen in the behavioral changes were in the and but not in the in the neurotoxic to may these but is evidence for neurotoxicity in several animal In spinal has been to patients with pain were after injections of spinal histopathology was on the spinal of moderate of some roots the cauda equina, whereas the other demonstrated no histopathologic signs of neurotoxicity were not In has been shown to be neurotoxic in and at doses to that In small doses of have been reported to pain in the of neurologic on this demonstrated of neurotoxicity in several animal species, spinal should be a only in the are involved in the spinal cord of pain and spinal drugs can in animals Although the of spinal has been no animal neurotoxicity studies have been published However, the used for is potentially and should not be used has been shown to be and has been in the rat for neurotoxicity with Although by a spinal cord to rat study reported injury in of the intrathecal In histopathologic a persistent decrease in spinal cord blood flow were seen in rat study with doses of for at The study behavioral changes in after the spinal of to death from The subsequent study did not report behavioral Although the report the safety of intrathecal the single of and the behavioral in the are and In is evidence for safety of spinal administration of in either animals or spinal cord pain in by with the of inflammatory A recent study with intrathecal administration of and in did not or behavioral signs of neurotoxicity are administered in humans as a risk of intrathecal and intrathecal use before an the safety of this A recent review the of evidence that intrathecal administered at causes clinically In are that that intrathecal is the cause of and neurologic in available of and and Spinal in the of evidence of it seems that not be administered to humans the current is However, should a occur during for the at an and a standard of the dilution of in or local anesthetic solutions, would seem to the Spinal Spinal drugs are with to with to or with an or Despite the widespread use of is little prospective to Epinephrine Epinephrine is often used to spinal anesthesia and to increase block of spinal cord direct reduced spinal cord blood flow to and In studies have histopathologic evidence of spinal cord injections of epinephrine in doses of mg caused to then fully the animals were spinal cord changes were not different from after tetracaine or intrathecal epinephrine in caused no clinical signs of neurologic injury, were histopathologic changes different from in the epinephrine spinal cord blood flow is relevant doses of intrathecal epinephrine alone do not spinal cord blood flow in but do significantly blood flow may to the of some local anesthetics. administered with spinal lidocaine, tetracaine, or mepivacaine, epinephrine to the increase in spinal cord blood flow seen with these local anesthetics, in no in spinal cord blood flow the spinal administration of epinephrine alone or in with local anesthetics not seem to spinal cord blood flow or cause some peripheral nerve studies reveal different In for epinephrine alone in peripheral nerve blood epinephrine 2% lidocaine peripheral nerve blood flow by These may that spinal by or are at higher risk from a of epinephrine and lidocaine than from either alone. However, the of animal peripheral nerve studies to human spinal cord is unclear. local solutions for use are with a (approximately to epinephrine to of local anesthetic solutions not significantly Epinephrine added to spinal anesthetic may up to 20% of but it is is epinephrine concentrations added to of in do not significantly spinal cord blood flow human clinical or studies the of spinal cord Although a recent has the use of epinephrine with lidocaine spinal anesthesia large-scale prospective and clinical surveys have not a neurologic complications and intrathecal in and report of patients with neurologic after only of of spinal anesthetics in et review epinephrine, but of patients with neurologic complications The of from these and that spinal epinephrine is In is no animal or human evidence neurotoxicity. animal studies direct spinal cord histopathology to as with epinephrine, studies are with the of spinal cord to either not spinal cord blood flow in or it to a clinically extent cause vasoconstriction a mechanism for local anesthetic intrathecal lidocaine and no clinical or behavioral signs of neurotoxicity In was used as an to tetracaine in of spinal anesthetics reported by and but was not in postoperative Transient and pain after tetracaine spinal anesthesia was reported to occur more when was it is whether this neurologic injury Although are no animal data to that is neurotoxic or that it significantly spinal cord blood flow in However, human data that it may increase the risk of transient neurologic symptoms after tetracaine spinal anesthesia. is added to spinal anesthetics to increase of hyperbaric spinal anesthetics may be with the cauda equina syndrome A further is that causes may itself be and human studies have as a to neural spinal cord in and to intrathecal 5% with to demonstrate neuronal damage However, studies in do the that may to local nerve damage not cause sensory impairment after 5% lidocaine in the rat it the compound action potential in desheathed human studies have the of in the of transient neurologic symptoms after spinal but has it as a Thus, animal and human studies attest to the safety of spinally administered in concentrations and drugs for use as and or or are with as can when these drugs are in the some such as are the of where cause neural are added to local anesthetics to in the when it was with neural deficits after the of alone is in several animal the of sodium and was as neurotoxicity in response to concerns over sodium was introduced as an for In a rat model, causes behavioral and evidence of neural injury, is by with has been with transient, pain after administration This should be from the neural injury seen with intrathecal of with sodium and not neurotoxicity. The of patients spinal of to knowledge of the neurotoxic potential of in humans These patients doses of sodium mg and up to mg of over in concentrations than with neurotoxicity in animal The authors no new clinical or deficits to the intrathecal administration of these However, be taken when such because of the lesions to or have also been in animal models of toxicity are often added to local anesthetic and in and are added to drugs for single use. to caused of compound action potentials in nerve, but the animals recovered completely after subsequent and was no evidence of histopathologic changes and to intrathecal no evidence of neural damage on human studies have not reported behavioral evidence for toxicity with spinal administration of solutions of These findings that are when administered spinally in the small doses with use. has been with of or available include the Spinal has been shown to be in whereas intrathecal chloride causes no changes in There are no human studies these is a in at is practice to dilute before However, are neurotoxic at and safety studies should intrathecal use as in are used as in the preparation of some is with a This is with motor impairment when administered spinally to a continuous The mechanism of action is and are no human studies is used as an for and have been over potential neurotoxicity if were in with and desheathed nerve no or conduction in concentrations up to Histopathologic studies of the nerve were not and are no human studies Thus, concerns with and seem to be for human use. a of seems as and are the well of all spinal adjuvants. spinal drugs in clinical use have been for spinal cord and nerve root studies that all local anesthetics are neurotoxic in concentrations and that lidocaine and tetracaine have neurotoxic potential in clinically used However, spinal anesthesia lidocaine and has a long and history of Spinal such as and seem to have a potential for neurotoxicity on laboratory and extensive clinical use. and used in seem to have a potential for neurotoxicity. In to current we that this review on spinal drugs to a to potential neurotoxicity. an would histologic, physiologic, and behavioral testing in several species, followed by histologic, physiologic, and clinical testing in human and patients with to