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Spinal Exparel®—an extended duration of preclinical study needed

2018; Elsevier BV; Volume: 122; Issue: 3 Linguagem: Inglês

10.1016/j.bja.2018.11.021

1471-6771

James C. Eisenach, Tony L. Yaksh,

Pain Management and Opioid Use

This issue of the British Journal of Anaesthesia contains a pilot report1Zel J. Hadzik A. Cvetko E. et al.Neurological and histological outcomes after subarachnoidal injection of bupivacaine liposome injectable suspension in pigs: a pilot study.Br J Anaesth. 2019; 122: 379-387Abstract Full Text Full Text PDF Scopus (12) Google Scholar examining the safety of the commercially available liposome encapsulated formulation of bupivacaine (Exparel®; Pacira Pharmaceuticals, Inc., Parsippany-Troy Hills, NJ, USA) when injected intrathecally in pigs. Exparel® is approved as a local anaesthetic for wound infiltration and for some perineural injections, but is not indicated for epidural or intrathecal injection. This pilot report, funded by Pacira Pharmaceuticals, Inc., is the first step on a road to assess safety of this formulation when injected intrathecally and its potential use as a long acting spinal analgesic. The goals of this commentary are to review what is known about toxicity from spinally administered bupivacaine and to highlight the rationale and need for considerably more preclinical assessment before this formulation is administered intrathecally to humans. All local anaesthetics produce concentration-dependent neurotoxicity in vitro2Lambert L.A. Lambert D.H. Strichartz G.R. Irreversible conduction block in isolated nerve by high concentrations of local anesthetics.Anesthesiology. 1994; 80: 1082-1093Crossref PubMed Scopus (263) Google Scholar and in vivo3Yamashita A. Matsumoto M. Matsumoto S. Itoh M. Kawai K. Sakabe T. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits.Anesth Analg. 2003; 97: 512-519Crossref PubMed Scopus (132) Google Scholar in animals and many have been associated with neurotoxicity, especially cauda equina syndrome, in humans. Bupivacaine has been shown to cause neurotoxicity after intrathecal injection in rabbits,3Yamashita A. Matsumoto M. Matsumoto S. Itoh M. Kawai K. Sakabe T. A comparison of the neurotoxic effects on the spinal cord of tetracaine, lidocaine, bupivacaine, and ropivacaine administered intrathecally in rabbits.Anesth Analg. 2003; 97: 512-519Crossref PubMed Scopus (132) Google Scholar rats,4Li D.F. Bahar M. Cole G. Rosen M. Neurological toxicity of the subarachnoid infusions of bupivacaine, lignocaine, or 2-chloroprocaine in the rat.Br J Anaesth. 1985; 57: 424-429Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 5Takenami T. Yagishita S. Murase S. Hiruma H. Kawakami T. Hoka S. Neurotoxicity of intrathecally administered bupivacaine involves the posterior roots/posterior white matter and is milder than lidocaine in rats.Reg Anesth Pain Med. 2005; 30: 464-472Google Scholar dogs,6Ganem E.M. Vianna P.T. Marques M. Castiglia Y.M. Vane L.A. Neurotoxicity of subarachnoid hyperbaric bupivacaine in dogs.Reg Anesth. 1996; 21: 234-238PubMed Google Scholar and non-human primates.7Rosen M.A. Baysinger C.L. Shnider S.M. et al.Evaluation of neurotoxicity after subarachnoid injection of large volumes of local anesthetic solutions.Anesth Analg. 1983; 62: 802-808Crossref PubMed Scopus (59) Google Scholar Although neurotoxicity was evident in several of these studies only after injection of bupivacaine at concentrations in excess of those in commercially available preparations, these effects were observed in a system where the anesthetic was subject to relatively rapid clearance. The slow release nature of the formulation thus is morelikely to mimic the persistent exposure associated with continuous infusion where pathological sequalae were more likley to be observed. Of particular relevance, there are case reports of cauda equina syndrome in humans after bolus intrathecal injection of commercial isobaric8Moussa T. Abdoulaye D. Youssouf C. Oumar G.C. Karim T.S. Traore T.J. Cauda equina syndrome and profound hearing loss after spinal anesthesia with isobaric bupivacaine.Anesth Analg. 2006; 102: 1863-1864Google Scholar and hyperbaric9Chen X. Xu Z. Lin R. Liu Z. Persistent cauda equina syndrome after cesarean section under combined spinal–epidural anesthesia: a case report.J Clin Anesth. 2015; 27: 520-523Crossref PubMed Scopus (8) Google Scholar solutions. Animal studies demonstrate that a key risk factor for neurotoxicity is high, and sustained local concentrations caused by injection of very large doses7Rosen M.A. Baysinger C.L. Shnider S.M. et al.Evaluation of neurotoxicity after subarachnoid injection of large volumes of local anesthetic solutions.Anesth Analg. 1983; 62: 802-808Crossref PubMed Scopus (59) Google Scholar or continuous slow infusion,10Drasner K. Sakura S. Chan V.W.S. Bollen A.W. Ciriales R. Persistent sacral sensory deficit induced by intrathecal local anesthetic infusion in the rat.Anesthesiology. 1994; 80: 847-852Crossref PubMed Scopus (116) Google Scholar and cases of cauda equina syndrome have been reported after accidental intrathecal injection of large doses of lidocaine intended for epidural administration11Drasner K. Rigler M.L. Sessler D.I. Stoller M.L. Cauda equina syndrome following intended epidural anesthesia.Anesthesiology. 1992; 77: 582-585Crossref PubMed Scopus (103) Google Scholar or by continuous, slow infusion through a spinal microcatheter.12Rigler M.L. Drasner K. Krejcie T.C. et al.Cauda equina syndrome after continuous spinal anesthesia.Anesth Analg. 1991; 72: 275-281Crossref PubMed Scopus (566) Google Scholar In their study in this issue, Zel and colleagues1Zel J. Hadzik A. Cvetko E. et al.Neurological and histological outcomes after subarachnoidal injection of bupivacaine liposome injectable suspension in pigs: a pilot study.Br J Anaesth. 2019; 122: 379-387Abstract Full Text Full Text PDF Scopus (12) Google Scholar randomised young adult pigs (n=5 per group) to receive a single intrathecal injection of saline, 3 ml of 0.5% bupivacaine, or 1.5, 3, or 5 ml of liposomal 1.33% bupivacaine (Exparel®), which also contains 0.04% bupivacaine base. Behaviours were assessed hourly for 12 h, every 4 h until 48 h, and then daily for 21 days, including assessment of nociception (pinching), proprioception (knuckling reflex), ambulation, breathing patterns and urination. Antinociception and ataxia were present for 4 h after plain bupivacaine, as expected. Antinociception was slightly prolonged to 5 h after the highest dose of liposomal bupivacaine, and this plus ataxia reappeared 21 h after injection, lasting a few hours, presumably coinciding with peak release of bupivacaine into cerebrospinal fluid. There was no behavioural or histological evidence for neurotoxicity of the cauda equina or spinal cord 21 days after injection. It should be noted that the pathology observed in the above studies with intrathecal local anaesthetics is typically observed in the nerve roots and in spinal white matter. It is characterised using electron microscopy by oedema and axonal degeneration including swelling, atrophy, and loss of axons with macrophage infiltration within several days of intrathecal exposure,13Muguruma T. Sakura S. Kirihara Y. Saito Y. Comparative somatic and visceral antinociception and neurotoxicity of intrathecal bupivacaine, levobupivacaine, and dextrobupivacaine in rats.Anesthesiology. 2006; 104: 1249-1256Crossref PubMed Scopus (20) Google Scholar along with potential initiation of apoptosis in dorsal root ganglion cells.14Guo Z. Liu Y. Cheng M. Resveratrol protects bupivacaine-induced neuro-apoptosis in dorsal root ganglion neurons via activation on tropomyosin receptor kinase A.Biomed Pharmacothe. 2018; 103: 1545-1551Google Scholar, 15Gold M.S. Reichling D.B. Hampl K.F. Drasner K. Levine J.D. Lidocaine toxicity in primary afferent neurons from the rat.J Pharmacol Exp Ther. 1998; 285: 413-421PubMed Google Scholar These data suggest that a dose as high as 66 mg of liposomal bupivacaine does not cause overt or histologic neurotoxicity in pigs, although with a sample size of only five animals neurotoxicity could occur as commonly as 65% and be missed by chance. It is precisely for this reason that preclinical safety studies are typically designed to determine the dose or concentration at which toxicity reliably occurs and to estimate a margin of safety between this dose/concentration and the maximum one to be allowed for clinical use. Importantly, this report1Zel J. Hadzik A. Cvetko E. et al.Neurological and histological outcomes after subarachnoidal injection of bupivacaine liposome injectable suspension in pigs: a pilot study.Br J Anaesth. 2019; 122: 379-387Abstract Full Text Full Text PDF Scopus (12) Google Scholar does not inform us on the margin of safety of liposomal bupivacaine for intrathecal use. Although the initial assessment of pathology failed to reveal any adverse findings, additional work should require examination at earlier periods and include assessments of cell death and apoptosis that may be less evident after extended periods of survival.16Emami A. Tepper J. Short B. et al.Toxicology evaluation of drugs administered via uncommon routes: intranasal, intraocular, intrathecal/intraspinal, and intra-articular.Intl J Toxicol. 2018; 37: 4-27Google Scholar, 17Butt M.T. Evaluation of the adult nervous system in preclinical studies.in: Butt M.T. Fundamental neuropathology for pathologists and toxicologists: principles and techniques. John Wiley & Sons, Hoboken, NJ2011: 321-328Crossref Scopus (12) Google Scholar Bupivacaine is marketed for intrathecal use in a concentration (0.75%) that is 30–50% of that which reliably causes neurotoxicity in animals, yet neurotoxicity in humans is exceedingly rare when given through relatively large bore delivery systems, presumably because of rapid dilution of the water-based solute in cerebrospinal fluid upon injection. The distribution after intrathecal injection of bupivacaine after slow release from the commercially used multivesicular liposome formulation, DepoFoam®, is unknown. DepoFoam® encapsulated cytarabine is approved for intrathecal injection for chemotherapy, and the released cytarabine is widely distributed along the neuroaxis whereas the lipids from the degraded particles remain largely in lumbar spinal tissue near the site of injection.18Kohn F.R. Malkmus S.A. Brownson E.A. Rossi S.S. Yaksh T.L. Fate of the predominant phospholipid component of DepoFoam drug delivery matrix after intrathecal administration of sustained-release encapsulated cytarabine in rats.Drug Deliv. 1998; 5: 143-151Google Scholar This would suggest a margin of safety for bupivacaine should it diffuse in cerebrospinal fluid to this extent. However, bupivacaine is lipophilic, having an n-octanol/aqueous partition coefficient 5 orders-of-magnitude greater than the hydrophilic cytarabine.19Legoabe L.J. Breytenbach J.C. N'Da D.D. Breytenbach J.W. In-vitro transdermal penetration of cytarabine and its N4-alkylamide derivatives.J Pharm Pharmacol. 2010; 62: 756-761Google Scholar Assuming many of the lipophilic DepoFoam® particles adhere to the spinal cord and nerve roots after intrathecal injection, slow release of the water soluble cytarabine would result in drug primarily partitioning into cerebrospinal fluid from which it could be distributed to supraspinal sites of chemotherapeutic action. In contrast, slow release of the lipid soluble bupivacaine could preferentially allow partition into the neural structures, potentially setting up an extreme example of maldistribution and neurotoxicity. Importantly, we know nothing about the tissue distribution of bupivacaine after intrathecal injection of Exparel®. Liposomal bupivacaine may reduce cardiotoxicity and seizures after peripheral administration or accidental intravascular administration because of slow release or sequestration, respectively. However, the same property of slow release could enhance local toxicity when administered near unprotected spinal nervous structures. There are no clinical reports of intrathecal Exparel®, although a study was completed in 2006 of epidural Exparel® in volunteers.20Viscusi E.R. Candiotti K.A. Onel E. Morren M. Ludbrook G.L. The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers.Reg Anesth Pain Med. 2012; 37: 616-622Crossref PubMed Scopus (57) Google Scholar In that study, epidural injection of the formulation produced analgesia to pinprick with a biphasic response. Compared with the 12 h of analgesia produced by the control injection of 50 mg bupivacaine, 266 mg of Exparel® extended analgesia to 36 h whereas lower doses (89 and 155 mg) showed only 4–5 h of analgesia. This Pacira Pharmaceuticals, Inc.-funded study was performed in Australia where the regulatory agency (the Therapeutic Goods Administration) is notified of, but does not evaluate, the risks and benefits of clinical trials of unapproved drugs (https://www.tga.gov.au/clinical-trials). However, the authors mention that a United States Food and Drug Administration Investigational New Drug designation for epidural Exparel® had been approved in the past but had lapsed at the time of the study. Whether the sponsor had been required to provide toxicological assessment of intrathecal injection, which can occur by accident with epidural techniques, is unknown. Presumably, animal toxicology after epidural administration was provided for that approval, but it's important to note that drugs such as the older formulation of 2-chloroprocaine can be safe when delivered in a given dose and concentration in the epidural space but produce neurotoxicity when injected intrathecally. In summary, Zel and colleagues1Zel J. Hadzik A. Cvetko E. et al.Neurological and histological outcomes after subarachnoidal injection of bupivacaine liposome injectable suspension in pigs: a pilot study.Br J Anaesth. 2019; 122: 379-387Abstract Full Text Full Text PDF Scopus (12) Google Scholar provide an important first step on the ethical road towards investigating a novel spinal analgesic. Their results are encouraging, but critical information regarding safety margin and drug disposition are left unanswered. Until these issues are systematically addressed, clinical use for either research or practice is precluded. Whether an extended release intrathecal local anaesthetic, which potentially produces extended analgesia and which also potentially produces extended adverse events, is useful will await clinical application, assuming that adequate preclinical toxicology studies convince regulatory agencies to approve intrathecal injection of an extended release preparation of an agent with specified concentration-dependent neurotoxicity. Writing of first draft of the manuscript: JCE. Critical editing and additions to the first draft of the manuscript, generating the final draft: TLY. JCE consults to Adynxx (San Francisco, CA, USA) regarding preclinical and clinical analgesic development of analgesics. TLY has received contracts from Adynxx and Sintetica, SA (Mendrisio, Switzerland) to perform neurotoxicity testing of intrathecal analgesics, including a local anaesthetic other than bupivacaine. Supported in part by grant R37 GM48085 to JCE and R01 DA15353 to TLY from the National Institutes of Health, Bethesda, MD, USA.