In the late 1940s, the Nobel laureate Philip Hench described the anti-inflammatory effects of glucocorticoids.1 In that same period, an inflammatory process was described to be an important component in the development of sciatic pain in patients with disk herniation.2,3 The appreciation of this inflammatory component in the development of nerve compression pain states, along with the insight that steroids served to diminish the inflammatory cascade, led to the use of epidural glucocorticoids in controlling the pain related to disk avulsion.4 It was not clear, however, whether the analgesic effect was related to the reduction in swelling of the injured tissue after disk protrusion or to an effect on neural tissue itself.
By the late 1960s, a number of articles had been published, reporting treatment of back pain with epidural delivery of glucocorticoids.5 Searching PubMed for “epidural glucocorticoids AND pain” results in >1000 published articles.
In the early 1960s, less hydrophilic glucocorticoid formulations such as methylprednisolone acetate (MPA) began to be used in the management of spinally originating pain states.6,7 The rationale was that low water solubility essentially creates a slowly eluted drug depot that permitted extended tissue exposure after a single application.8 In this review, we will broadly consider the mechanisms whereby synthetic glucocorticoids might be expected to exert their action on the inflammatory and neuropathic pain cascade and critically review the literature on intrathecal use of the depot glucocorticoid formulation MPA.
MOLECULAR MECHANISMS OF ACTION OF GLUCOCORTICOIDS
Many components of an inflammatory process are modified by the local action of glucocorticoids.9,10 Glucocorticoids exert their actions after entering a cell, where they may bind to their glucocorticoid receptor and form a complex (GR). The GR is a ligand-driven transcription factor. In the unbound form, it resides in the cytoplasm. Its binding with a glucocorticoid triggers translocation of the GR to the nucleus.11 In the nucleus, the GR binds as a homodimer to DNA sequences called glucocorticoid response elements (GREs). GREs transcriptionally activate (transactivation) or repress (transrepression) genes.12 In addition to transcriptional regulation, glucocorticoids also have fast nongenomic effects on the inflammatory process. These actions jointly have been shown to impact on the expression of >6500 genes.13
Below, we describe in more detail these 3 mechanisms by which glucocorticoids alter cellular responses to inflammatory stimuli and discuss the potential effects on nociceptive processing. (see also Fig. 1)
Transrepression of Proinflammatory Gene Cascades
Transrepression is the best known mechanism of action of glucocorticoids. By binding of the GR to a GRE, transcription of inflammatory genes can be blocked. One of the important transcriptional regulators in this process is nuclear factor kappa B (NFκB). NFκB is activated by inflammatory signals such as lipopolysaccharide or proinflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF).14 When activated, NFκB stimulates the transcription of a variety of products, including enzymes such as cyclooxygenase (COX)-2, IL-1β, IL-2, IL-6, IL-8, TNF, interferon γ (IFNγ), inducible nitric oxide synthase (iNOS), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1.14,15 These products all play a role in the inflammatory response, leading to localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leukocytes into the affected tissue. GR can antagonize NFκB, thereby blocking transcription of inflammatory genes and synthesis of these proinflammatory products.
A second important transcriptional regulator is activator protein (AP)-1. It is a collection of related transcription factors belonging to the Fos (c-Fos, FosB, Fra1, Fra2), Jun (c-Jun, JunB, JunD) or activating transcription factor ATF (ATF2, ATF3) families, which dimerize in various combinations through a region known as a leucine zipper. AP-1 regulates various aspects of cell proliferation and differentiation. GR interacts directly and indirectly with AP-1. Interaction of GR with AP-1 and NFκB16 leads to downregulation of inflammatory processes in the face of stimuli that would otherwise result in their upregulation and synthesis of inflammatory products.12 Inflammatory products such as COX-2, IL-1β, IL-2, IL-6, IL-8, TNF, IFNγ, and iNOS are well-known and important components in neuropathic pain pathways, and reduction of these products has led to attenuation of the hyperpathic state.
Transactivation of Anti-inflammatory Gene Cascades
Gene products upregulated by glucocorticoids and playing a role in resolution of inflammation include lipocortin I and p11/calpactin-binding protein.
Lipocortin I (annexin-1A) is involved in the inhibition of phospholipase A2 (PLA2).17 PLA2s hydrolyse phospholipid bonds, releasing arachidonic acid. Arachidonic acid plays a major role in the inflammatory cascade, and increased levels of arachidonic acid have been observed after disk avulsion as well as after nerve injury.18 By activating lipocortin I, glucocorticoids inhibit PLA2s, thereby reducing the inflammatory response. In addition, components such as β2-adrenoceptors, secretory leukocyte protease inhibitor, IL-1ra, and REDD1 (Regulated in Development and DNA Damage-1; a stress-induced gene linked to repression of mammalian target of rapamycin [mTOR] signaling) are upregulated by glucocorticoids.19–21 β2-agonists reduce neuropathic pain symptoms.22 IL-1ra reduce inflammatory signs in degenerative joint disease.23 mTOR activation plays a facilitatory role in pain states after peripheral tissue and nerve injury.24–26
Glucocorticoids have been shown to have rapid (milliseconds to minutes) excitatory and inhibitory effects on a variety of neuronal systems. This rapidity emphasizes actions that are independent of gene transcription modulation. Evidence suggests that nongenomic effects of glucocorticoids can be classified in 3 ways: (a) effects not mediated by a receptor, (b) effects mediated by a membrane-bound receptor, and (c) effects mediated by the cytosolic GR.27
1. Nonreceptor-mediated glucocorticoid signaling consists mainly of specific, direct effects of glucocorticoids on cell membranes. Alterations in physicochemical properties of the plasma membrane could change the activity of membrane-bound proteins (affecting calcium trafficking), or result in altered permeability of the membrane to ions.28 These effects have been demonstrated in vitro using high dosages of glucocorticoids. Clinically, this mechanism of action is often discussed in the treatment of spinal traumas where high glucocorticoid dosages might stabilize cell membranes in the injured area to such a degree that secondary damage is less compared with untreated patients.29
2. Actions mediated by membrane-bound receptors. Glucocorticoids exert rapid, transcription-independent actions through G-protein coupled receptors (GPCR) in various cells.30 One example is the GPR30, a nongenomic estrogen receptor, discussed later in more detail. There is also some evidence that activity of the chloride ionophore γ amino butyric acid (GABA)-A-receptor is enhanced by glucocorticoid binding and may mediate some of the nongenomic effects of glucocorticoids, an effect that could modulate after nerve injury hyperpathia.
3. Actions mediated by cytosolic GR. Glucocorticoids interact with cytoplasmic proteins such as mitogen-activated protein kinases (MAPKs), phosholipases (cPLA), and protein kinases (SRC), influencing the inflammatory cascade. The SRCs and MAPKs have been widely shown to play a facilitatory role in changes in spinal function initiated by tissue injury and inflammation.31,32
Perhaps unexpectedly, proinflammatory effects by glucocorticoids have also been described. Dexamethasone increased adenosine triphosphate-induced IL-6 in epithelial cells,33 an effect mediated through GR. It has been suggested that the effect of glucocorticoids, either an enhancement or suppression of the inflammatory response, is dependent on the timing and context of target cell exposure.34 Glucocorticoids are clearly not uniformly immunosuppressive.
In conclusion, the overall effect of glucocorticoids is dominated by suppression of inflammatory cascades, either through a direct suppression of inflammatory processes or by enhancement of anti-inflammatory mechanisms. However, in several instances, proinflammatory effects of glucocorticoids have been reported.33–35 We note that such proinflammatory effects could be a result of the glucocorticoid action itself or owing to other components of the glucocorticoid formulation. This issue is considered in more detail below.
ECTOPIC GENERATORS: TARGETS OF GLUCOCORTICOIDS IN NEUROPATHIC PAIN
After injury to primary afferents (by, for example, trauma, local inflammatory, or chemical products), a pain syndrome may arise often composed of (1) sharp-shooting pain sensations referred to the peripheral distribution of the injured nerve and (2) allodynia (abnormal sensations in response to light tactile [Aβ] stimulation of the skin). The origin of the afferent traffic associated with neuropathic pain reflects ectopic activity arising from the neuroma, for example, at the injury site and importantly, from the dorsal root ganglia (DRG) of the injured axon.36,37 These observations emphasize that after a variety of nerve injuries, trophic changes occur in the DRG and proximal root. In contrast to the peripheral afferent axon, where mechanical compression can initiate transient depolarization in the axon, such compression in the DRG has been shown to be able to produce persistent discharges.38–40 Also, local inflammatory products, such as TNF, IL-1β, and cytokine-induced neutrophil chemoattractant-1 that can arise from an avulsed disc, can initiate activity in DRG and injured roots.41–43 These inflammatory products activate local DRG cell populations such as the satellite cells and pericellular glia, initiate the migration of inflammatory cells (macrophages and neutrophils) into the DRG,42,44 and initiate downstream signaling though transcription factor activation.45,46 The inflammatory cascade results in a further increase of the local expression of proinflammatory substances such as cytokines (TNF/IL1β), chemokines,41,45,47,48 and growth factors.45 Blocking production or action of cytokines such as TNF and IL1β reduces inflammation-induced pain states.49–51
It is important to note that activation of the DRG by these mechanical and chemical stimuli initiates a variety of downstream cascades that lead to major changes in the phenotype of the DRG. On an acute basis, for example, TNF enhances excitability of sodium channels through phosphorylation by p38 MAPK, leading to enhanced excitability.52,53 Over a longer period of time, these DRG cascades can lead to prominent, time dependent, changes in transcription factors such as MAPKs and ATF354,55 and the activation of a myriad of genes through multiple downstream pathways such as those mediated by NFκB.56,57 Specifically, there is an increase in the expression of voltage-sensitive sodium and calcium channels and a decrease in potassium channels.58–60 This altered expression profile, often referred to as the neonatal phenotype, has the common property of enhancing membrane excitability. Although the injury is limited to the primary afferent and/or DRG, these interventions can lead to persistent changes in the spinal cord dorsal horn (SDH), including glial activation.61,62 It is important to note that this ongoing activity, along with expression of the proinflammatory cytokines generated by injury in the nerve and DRG, leads to a facilitation of SDH responses49,63,64 and hyperpathic states.65
The above commentary focuses on the events that transpire after frank injury or chronic compression of the peripheral nerve or the DRG. This sequence of events is also seen after other widely differing modes of nerve injury, studied in preclinical models. Chemotherapeutics66,67 or viral inflammation (as in postherpetic neuralgia)68–70 cause surprisingly similar changes in the SDH and DRG. Given the anti-inflammatory actions of glucocorticoids, these agents are thus expected to be able to intervene in the cascades that lead to those anomalous pain states.62,71,72
Preclinical Studies Considering Glucocorticoid Effects on Molecular Mechanisms Contributing to Pain Secondary to Nerve Injury
Given the wealth of potential glucocorticoid targets, systematic preclinical assessments of the effects of spinal glucocorticoids on system function and surrogate markers (e.g., transcription) are unexpectedly rare.
In various models of chronic pain, spontaneous nerve activity is one of the earliest abnormalities observed, and blocking this spontaneous activity is an effective way to block development of ongoing pain behaviors. Systemic triamcinolone acetonide reduced the incidence of bursting pattern ectopic discharge in DRG neurons.73 Local (perineural) application of either triamcinolone hexacetonide, triamcinolone diacetate, or dexamethasone substantially reduced the incidence of spontaneous ectopic discharge generated in experimental nerve end neuromas and prevented the later development of ectopic impulse discharge in freshly cut nerves.74 There is also evidence that locally applied glucocorticoids inhibit signal transmission in nociceptive C fibers directly after application, but this did not seem to have a long-term effects on the electrical and structural properties of peripheral nerves.75,76 Sympathetic sprouting and basket formation in the DRG was decreased after perineural application and after systemic administration of triamcinolone acetonide in the spinal nerve ligation (SNL) model.73,77 In hippocampal slices, dexamethasone rapidly increased expression of proteins that regulate actin polymerization and produced increases in dendritic spines containing pERK but reduced other populations of spines.78 At the spinal level, such regulation of spines would be considered to be important components, contributing to synaptic plasticity underlying facilitated pain states.79
Glial Cell Activation
Activation of spinal glia after peripheral nerve injury is a common finding.80,81 It has been reported that glucocorticoids attenuate the activation of glial cells. The activation of astrocytes was reduced in the SNL model and the spared nerve injury (SNI) model.77,82,83 Microglia activation was attenuated after perineural treatment with triamcinolone acetonide in the SNL model but not after intrathecal administration of dexamethasone in the SNI model.77,84
Inflammatory Factor Production
After SNI, intrathecal and perineural betamethasone reduced concentrations of proinflammatory cytokines TNFα and IL-1β involved in development and maintenance of central sensitization and neuropathic pain.83 In the chronic constriction injury (CCI) and SNL models, cytokines (TNF, MCP-1, IL-6) were reduced after systemic triamcinolone acetonide.73,85 In the development of neuropathic pain, these cytokines and chemokines are regulated by the activation of transcription factor NFκB. An inhibition of NFκB function was observed after a single epidural administration of betamethasone at the time of nerve injury in a spinal nerve transsection model.86 It partially inhibited development of hyperalgesia and attenuated levels of proinflammatory cytokines (TNFα, IL-1β) in the brain while stimulating expression of the anti-inflammatory cytokine IL-10. Timing of these changes correlated with the development of neuropathic pain.86
After chronic compression of the DRG, a time-dependent upregulation of neuronal nitric oxide synthase and N-methyl-D-aspartate (NMDA) receptor 2B (NR2B) subunits within the ipsilateral SDH was significantly diminished in a dose-dependent fashion by intrathecal prednisolone acetate. This effect was accompanied by inhibition of thermal hyperalgesia and tactile allodynia.87
Paradoxical Effects of Glucocorticoids
Surprisingly, there is also evidence that glucocorticoids can increase neuropathic pain behavior. Preclinical evidence shows that after nerve injury there is an increased expression of glucocorticoid receptors ipsilateral to nerve injury in the SDH, with a time course parallel to that of the development of neuropathic pain behaviors.83,88 The administration of intrathecal glucocorticoids is reported to further increase this GR expression.83 In a subsequent preclinical study,89 intrathecal dexamethasone exacerbated thermal hyperalgesia and mechanical allodynia in CCI rats, whereas intrathecal RU38486, a GR antagonist and potent progesterone receptor antagonist, reversed nociceptive behaviors.89,90 In addition, an inhibition of central GR with RU38486 reduced upregulation of NMDA subunits (NR1 and NR2), which is the reverse of what has been previously noted.87,89 There is also literature stating that the GR: (1) downregulates expression of a spinal glutamate transporter (EAAC1), causing an increased level of extracellular glutamate (enhancing neuropathic pain), (2) upregulates NFκB, the transcription factor that mediates production of proinflammatory cytokines such as TNFα, IL-1β, IL-6, etc., and (3) is involved in upregulation of the cannabinoid-1 receptors (CB1R) within the SDH after CCI in rats.91,92 There is no clear explanation for these results. Drug dosages appear comparable, and all studies have used the neuropathic pain models SNL, CCI, or SNI in male rats. Additional research is necessary to unravel the origin of these varying results and to further clarify the mechanisms by which glucocorticoids and their receptor influence the neuropathic pain cascade.
From research in asthmatic patients, we know that with increasing severity of the disease the beneficial response to glucocorticoids decreases.93 Also in other inflammatory diseases such as acute respiratory distress syndrome, cystic fibrosis, and severe rheumatoid arthritis, no clinical benefit of glucocorticoid treatment is observed in some patients. These disease entities have a severe state of inflammation in common. Studies have shown that this clinical phenomenon is caused by “glucocorticoid resistance.”14,93 The glucocorticoid resistance has several distinct molecular mechanisms and perhaps genetically related components that may contribute to the decreased anti-inflammatory effects of glucocorticoids, including: (1) defective GR binding and translocation to the nucleus and (2) increased expression of GR β, known to influence the cell’s sensitivity to glucocorticoids.14,93–95 We hypothesize that glucocorticoid resistance might play a role in severe neuropathic pain states, reducing the analgesic properties of glucocorticoids and perhaps contributing to the heterogeneous results in neuropathic pain studies.
Preclinical Studies on Intrathecal Delivery of Glucocorticoids in Neuropathic Pain Models
Of the 6 reports on intrathecal administration of glucocorticoids (methylprednisolone, prednisolone acetate, dexamethasone, or betamethasone) in neuropathic pain models (SNL, CCI, or SNI) in rats, 3 reports mention a reduction of thermal hyperalgesia and mechanical allodynia.82–84,87,88,96 (Table 1) After local (perineural), epidural, or systemic administration of glucocorticoids in neuropathic pain models (SNL, CCI, or SNI) in rats, most report a reduction of nociceptive behavior.73,77,83,86,97–100 Also in the formalin model, suppression of phase 2 formalin flinching was observed after repeated (× 4) but not single bolus dosing of intrathecal triamcinolone diacetate.101
Sex Differences and the Effects on Neuropathic Pain
Current work has emphasized the potential contribution of sex differences in neuropathic pain cascades.102 It has been shown that activation of the spinal innate immune receptor toll-like receptor (TLR)-4 produces hyperalgesia in men but not in women103,104 and that mutation of the TLR4 receptor in men, but not women, reverses the allodynic effects of nerve injury.103 The GPR30, a nongenomic estrogen receptor, was found to accumulate after selective spinal dorsal rhizotomy in the outer layer of the SDH after it was transported from the DRG to terminals. In ovariectomized female rats, GPR30 expression was downregulated in DRG neurons.105
Mechanistic Rationale for the Intrathecal Delivery of Glucocorticoids in Neuropathic Pain States
Many of the above targets in the inflammatory cascade, leading to a pain state that are potentially affected by the genomic and nongenomic actions of glucocorticoids, are located within spinal cord and/or the DRG. At present, it is not feasible to parse the relative contributions of these 2 principal sites. Such theoretical considerations are, however, of particular importance as it relates to the issue whether the glucocorticoid delivered in the intrathecal space has access to cascades in the DRG that are relevant to the injury-evoked processing. It is important to note that epidural MPA is not believed to pass through the dura into the intrathecal space and/or spinal cord.106 Hence, an intrathecal injection may be able to gain access to these intradural neuraxial systems and suggests the potential utility of the intrathecal route. If the target of glucocorticoid action is instead the DRG, there may be an issue of whether that target is reached more effectively by local application or the epidural versus the intrathecal route (Figure 1). Regarding the epidural route of delivery, if the mechanistic target is a DRG, an additional speculative consideration would be whether the interlaminar versus the transforaminal route of delivery might be more appropriate. The preclinical literature provides no specific insights into this question of either route of delivery.
Clinical Use of Intrathecal Steroids
Glucocorticoids such as MPA, triamcinolone acetonide, and dexamethasone have been given in the intrathecal space in humans for different clinical pain syndromes.7,107–109
In the following sections, we focus on the use of intrathecal methylprednisolone, with an emphasis on the acetate that is the depot formulation as compared with the succinate that is water soluble. MPA is of interest because it is the most commonly used glucocorticoid in pain practice. It is primarily used for epidural injections, but as mentioned, it has also been used intrathecally in a limited fashion. Intrathecal use in pain patients has yielded contradictory results. Here we systematically review (Appendix 1 for method section) literature on the clinical efficacy of intrathecal administration of MPA in pain patients and shall elaborate on its safety, characteristics, and pharmacokinetics to clarify the contradicting findings. A short note is made on the epidural use of MPA.
Intrathecal Clinical Reports
More than 50 years ago, Sehgal and Gardner6 described the use of epidural and intrathecal glucocorticoids for the relief of sciatica. The use of 80 mg intrathecal MPA in 75 sciatica patients was reported to result in 70% to 100% pain relief in 45 patients during 4 or more months.110 Aside from an exaggeration of back or leg pain during the first 24 hours after the injection, no side effects were described. Use of intrathecal MPA was also described in other neurological disorders including arachnoiditis, multiple sclerosis, and postherpetic neuralgia. In a timespan of 4 years, >1000 patients with various neurological disorders were treated. Positive effects were observed in patients with arachnoiditis and acute exacerbation of multiple sclerosis. No benefit was noted in postherpetic neuralgia patients, amyotrophic lateral sclerosis, and trigeminal neuralgia.7 It is important to note that none of these studies was randomized, controlled, or blinded and as such should be considered as case series rather than clinical trials. Studies providing sufficient information on their study domain, treatment regimen, and outcome in English are summarized in Table 2.110–115
Shortly after these initial reports, the use of intrathecal MPA increased, and reports of serious adverse events including cerebral hemorrhage, meningitis, conus syndrome, progressive weakness, reversible bladder dysfunction, and paresthesia began to appear.116–121 Most of the side effects were reported in patients with multiple sclerosis who had received repeated administrations of MPA at short intervals. Owing to the severity of the adverse events and the frequency of their occurrence, the use of intrathecal MPA declined. Thirty years later, intrathecal glucocorticoid treatment regained interest when 2 randomized controlled trials (RCTs) were published in high impact journals, showing a markedly high efficacy in patients with intractable postherpetic neuralgia.122,123 Of the 89 patients treated with 4 intrathecal injections of MPA combined with lidocaine, 82 (92%) had “good or excellent” pain relief during 1-year follow-up, against 5 of 91 (5%) treated with lidocaine only.123 Several Letters to the Editor warned against this potentially harmful treatment, noting that the safety issues had not been adequately addressed.124–128 Besides 2 positive case series, no other reports confirming the efficacy of MPA were published in the years after publication of these 2 trials.113,114
Recently, 2 negative RCTs were published.129,130 One RCT in 21 patients with chronic complex regional pain syndrome was ended prematurely because of a lack of efficacy and a high rate of adverse events.129 The other RCT was also stopped early because the 6 MPA-treated patients suffering from postherpetic neuralgia showed no clinical benefit from their MPA treatment.130 Taken together, the data suggest that the efficacy of intrathecal MPA administered according to the treatment regimens described in the trials is at best doubtful and associated with a measurable risk.(RCTs are summarized in Table 3)
Epidural MPA in Neuropathic Pain
Administration of MPA is a widely used therapy for radiculitis. The treatment is regarded as safe, though its efficacy remains debated.131–133 In a systematic review, half of the RCTs showed benefit from epidural glucocorticoid injections and half did not.131 In the RCTs that do show a positive effect of epidural MPA, the effect is often short lived.132 Nevertheless, the popularity of the treatment is high among clinicians and paramedical personnel, and it is used as standard practice in the treatment work-up of low back pain in most clinics. MPA is mainly used for lumbar epidural injections. For cervical epidural injections with a transforaminal approach, MPA is replaced by dexamethasone after reports of cerebrovascular events after inadvertent intravascular injection of MPA. Animal studies examining the effects of carotid artery injections demonstrate that MPA and its nonparticulate carrier and methylprednisolone succinate can produce significant injury to the blood-brain barrier.134,135
Recently, in the United States, there have been issues regarding contaminated vials of compounded MPA with the fungus Exserohilum rostratum that led to >600 fungal infections of which >300 were meningitis cases, leading to 40 deaths by January 2013.
Safety of Neuraxial MPA
Despite the risk of inadvertent intravascular injections of MPA or of injecting contaminated MPA in the epidural space, the risk of epidural administration of MPA has been considered low after safety studies in preclinical models.136 There are, however, several preclinical safety studies with intrathecal glucocorticoids reporting neurotoxicity137–140 (Table 4). In all these studies, preservatives were not removed from the glucocorticoid formulation. Accordingly, one explanation for the observed neurotoxicity is the presence of preservatives. However, in dogs, repeated intrathecal delivery (× 4 at weekly intervals) using a reformulated MPA formulation with minimal preservatives yielded dose-dependent histological indices of intrathecal toxicity.35 Although possible, we believe it is unlikely that the extent of the neurotoxic reaction is caused solely by the small concentrations of preservatives and have hypothesized, as have others,134 that the particulate nature of the formulation or the glucocorticoid itself may play a role. In the following section, we shall discuss the properties and pharmacokinetics of the MPA formulation and their potential contributions to intrathecal drug efficacy and safety.
MPA Drug Formulation
As noted, methylprednisolone formulations may be broadly divided amongst those that are soluble (methylprednisolone succinate) and those that are only modestly soluble (methylprednisolone acetate (MPA); 0.001% weight by volume). This lack of solubility leads to an extended release of the active product, methylprednisolone, when placed in a biological matrix (e.g., the intrathecal or epidural space), endowing the injectate with depot characteristics. The commercially available depot formulation of methylprednisolone, 1 mL of 40 mg/mL, Depo-medrol® (Pfizer, New York, NY) is a suspension of the active substance MPA as particles in a solution containing 29 mg/mL polyethylene glycol and 0.195 mg/mL myristyl-gamma-picolinium chloride. In theory, each of these components could be, individually or in combination, responsible for the observed neurotoxicity. We shall discuss each component of the drug formulation separately.
1. Particles in suspensions can cause a chemical irritation in tissue. An extensive literature search emphasizes that in systems such as the lung and prosthetic interfaces of joints, particulate materials such as carbon particles, particles from biomaterials, and other environmental toxins including nanoparticles can initiate cytokine release that in turn leads to activation of a variety of cell adhesion factors, resulting in macrophage and neutrophil immigration.141–143 In different study systems, particulates drive robust inflammatory reactions. The extent of the inflammatory reaction is inversely proportional to particle size and directly proportional to surface area.141,143 In the MPA suspension, 30% to 40% are larger than 20 μm in diameter.135,144 After dilution of MPA with saline, the proportion of large particulates increases144 owing to aggregation. The diameter of the particles does not exceed 60 μm in a lidocaine mixture.130 The critical size range for wear particles from prosthetic joint to cause an inflammatory response has been estimated to be from 0.2 to 10 μm.145 This suggests that most particles in the MPA suspension may be too large to cause a severe inflammatory response. Nevertheless, increased levels of IL-8 have been observed in the cerebrospinal fluid (CSF) after intrathecal administration of MPA in humans.130 It is important to note that IL-8 has been hypothesized to be a pivotal mediator of particle-induced neutrophilic inflammation.142,146 We hypothesize that the larger particles of MPA could contribute to mechanical irritation when injected into the intrathecal space. In postmortem examinations in cows, 24 hours after administration of MPA into a joint, a significant quantity of white material believed to be MPA precipitated at the bottom of the synovial cavity embedded in a fibrin-like deposit.147 Also after intrathecal MPA suspension, white deposits were observed after 1 week.35 Accordingly, it is probable that these white deposits remain present in the intrathecal space for an extended period of time. This could be a possible explaining cofactor for the inflammatory actions observed after intrathecal administration of MPA. An inflammatory response in the intrathecal space has not been observed with nonparticulate glucocorticoids such as methylprednisolone succinate.
2. Additives. Two additives are present in the formulation: polyethylene glycol (PEG) and myristyl-gamma-picolinium chloride (MPC).
1. Polyethylene glycol (PEG) is used as an excipient in pharmaceutical products such as solvents in oral liquids and soft capsules, ointment bases, and laxatives (e.g., movicolon, duclolax). PEG is one of the additives in MPA, and although it is often considered to be a preservative,125,148 it is added to enhance the viscosity of the drug to increase its stability. Concerns about neurotoxicity of PEG have been voiced.108 However, there is a substantial body of evidence indicating otherwise; PEG has been studied in spinal cord injury models because it is reported to promote restoration of functional and structural integrity of nerve tissue by direct application onto the spinal cord.149,150 In addition, PEG is used for dural repair in humans.151 In high concentrations, its prolonged focal application on the cord induces a conduction block.152,153 No inflammatory responses or neurotoxicity have been observed in any of these neurosurgical applications. Although the long-term effects of intrathecal PEG have not been assessed specifically, these results suggest that PEG may not account for any evident signs of toxicity in the models thus far examined, though clearly specific studies are required to support this assertion.
2. MPC is added to enhance solubility of the MPA formulation. It maintains the stability of the particle size and reduces the likelihood of aggregation.154 MPC is a cationic surfactant with emulsifying properties. It also has antibacterial activity. There have been no specific studies on the intrathecal safety of this agent. However, there are data on intravitreal delivery of MPC. Intravitreal delivery gives direct drug exposure to local neuronal systems (e.g., retina) in a low flow situation. In this regard, it has been shown that the intravitreal delivery of small volumes of MPC, in concentrations similar to those used in the MPA formulation, resulted in loss of photoreceptors, thinning of the retina close to the injection site, and irreversible effects on electroretinograms in rabbits.155 Comparable retinal effects are also seen with other cationic detergent surfactants such as benzalkonium chloride.156 Such observations raise strong concerns about potential neuraxial toxicity. The spinal and neural delivery of other detergents has been reported to result in demyelination and ultrastructural changes.157,158 Electrophysiologic studies have indicated that the local delivery of small amounts of lysophospholipids, the major component of detergents, into the dorsal part of the spinal column produces significant signs of increased electric activity, axonal cross talk, and mechanical sensitivity of the dorsal columns, presumably reflecting the underlying histopathologic changes.159 These results suggest a potential deleterious effect of detergent-like molecules, such as MPC on neural tissues at high concentrations, and their safety should be called into question until specifically shown otherwise at relevant concentrations.
Given the above commentary, it is important to note that there are no preservative-free, commercial formulations of MPA.148,160 Accordingly, several groups have attempted to reduce the adjuvant burden of the commercially available formulation using various “bedside” separation protocols. Two practical methods have been described to decrease the concentrations of PEG and MPC in the commercial MPA formulation;
1. Centrifugation of the vial and aspirating and discarding the supernatant. The residual pellet, the MPA, can then be resuspended with, for example, saline, lidocaine.35
2. Inverting the vial for 2 hours to let the MPA sink against the lid and then carefully aspirating the precipitate (glucocorticoid) component.148
The concentration of MPC was markedly reduced to 0.01 mg/mL (from 0.2 mg/mL in the commercial formulation) using method 1.35 Unfortunately, the concentration of PEG was not measured in the reformulated dosage form. PEG, however, is completely soluble in water, and because the concentration of MPC was reduced by nearly 20-fold, the concentration of PEG is estimated to be reduced accordingly to <2 mg/mL. With the use of method 2, the concentration of PEG decreased to 4.30 ± 1.07 mg/mL.148 The concentration of the preservative MPC was not measured. The concentration of PEG in both formulations is considered to be too low to induce a nerve induction block (seen at PEG concentrations above 40%)152,153 or cause inflammation.149 We cannot completely exclude that the MPC concentration is low enough to prevent any toxicity from occurring.
Pharmacokinetics of MPA
An extremely important component of the rationale for intrathecal versus epidural delivery is the observation that in normal neuraxial kinetics, methylprednisolone injected systemically or in the epidural space does not lead to measurable methylprednisolone levels in the CSF.8,106 It has been suggested that this phenomenon is caused by the effective exclusion at the blood-brain barrier by P-glycoprotein (mdr1 gene product), an efflux transporter for which methylprednisolone has been identified as a substrate.106 Thus, it is hypothesized that the poor bioavailability of glucocorticoids after IV administration results from active exclusion of the drug from the spinal cord by P-glycoprotein.
When MPA is injected in the intrathecal space, it is hydrolyzed by cholinesterases to become soluble and thus clinically active.161 Although relative to plasma, the concentrations of cholinesterases in CSF are very low, it is not clear whether these CSF concentrations present a limiting factor in bioavailability, resulting in the depot properties.162,163 Free methylprednisolone enters cells, gets transported to the systemic circulation, and/or gets metabolized. There is a considerable individual variation in the rate of absorption of the glucocorticoid from the spinal fluid into the blood after intrathecal MPA administration.8 Peak methylprednisolone plasma concentrations were observed between 3 and 6 hours after intrathecal MPA injection in dogs.35 Although plasma levels decreased after 6 hours, methylprednisolone was still measurable after 7 days but went below the detection threshold 3 weeks after the last injection.35 In humans, a similar timeframe was described; after 80 mg MPA, intrathecal peak plasma and CSF levels were observed after 1 day and were measurable until 21 days.8,130 After intra-articular injection of MPA, methylprednisolone plasma levels peak at a similar point in time, 8 hours after administration.164 However, the plasma levels decreased below the detection level much earlier, after 24 to 192 hours.164 In a study on intra-articular injections in a bovine model, this timeframe was observed, but when measuring the methylprednisolone concentration in the synovial fluid itself, pharmacologically significant concentrations were observed for >3 months after administration, and a significant quantity of white material believed to be MPA was present at the bottom of the synovial cavity.147 Besides methylprednisolone plasma and CSF levels, other variables, such as blood glucose levels, total white blood cells, and decreases in endogenous hydrocortisone have been used to determine the length of effect after intrathecal MPA administration.165 The effects on the variables were dose dependent. With intrathecal MPA dosages above 80 mg, an increase in CSF protein levels occurred.8 After intra-articular administration, untoward reactions and decreased plasma concentrations of endogenous glucocorticoids for a period of 3 days in horses, as long as 1 week in humans, and 12 weeks in cows have been reported.147,166
Summarizing the MPA formulation characteristics regarding their effect on safety and efficacy, we believe that the spinal/meningeal reactions observed after intrathecal administration have a multifactorial etiology. Both the particulate nature of the formulation, the presence of a minimal amount of the preservative MPC and the extremely long exposure of spinal tissue to methylprednisolone owing to its pharmacokinetics properties could all contribute to the observed neuroinflammatory phenotype. Regarding efficacy, because we do not have a clear picture of the effects of glucocorticoids on neuropathic pain pathways and the positive effects could be nullified by the potential neurotoxic effects, the efficacy of intrathecal MPA remains debated.
The reports on the efficacy of intrathecal administration of MPA in patients with neuropathic pain are contradicting. Considering the doubtful clinical benefits and the potential risks of the treatment, intrathecal administration of MPA in neuropathic pain patients is not recommended. However, we do not disregard all glucocorticoids for the treatment of chronic pain. There is evidence that at least a short-term beneficial effect may be expected after epidural administration in patients with radiculitis.
We find it strange, however, that in spite of; (1) the vast amount of work that has been accomplished with neuraxial glucocorticoids, (2) the evident role of biological targets sensitive to glucocorticoid modification and (3) the well-defined role played by these neuraxial targets in tissue and nerve injury pain processing, we continue to be uncertain of either the likely mechanism of action of glucocorticoids in the neuropathic pain cascade or whether at therapeutic dosages in clinical or preclinical models we can demonstrate surrogate marker changes (e.g., cytokine release, genomic activation in the DRG, and change in glial activation in the SDH). A better understanding of the mechanism of action of these drugs in the neuropathic pain cascade could possibly improve the clinical effect that they should theoretically have by modifying their use in current clinical practice. Finally, this review further emphasizes the critical important of appropriate preclinical safety assessments in the development of drugs and formulations for clinical delivery and the emphasis placed by the peer-reviewed literature on such robust assessments.167–169
APPENDIX 1. SEARCH STRATEGY Cited Here...
The databases Pubmed, Embase, and the Cochrane library were systematically searched to answer the research question; Does intrathecal administration of glucocorticoids decrease neuropathic pain? The search syntax contained the domain, all possible synonyms for neuropathic pain, and the determinant, synonyms for intrathecal glucocorticoids. We decided not to limit the determinant to the administration of methylprednisolone acetate only based on the small amount of studies retrieved during our first systematic search.
((“neuropathic pain” OR neuralgia OR allodynia OR allodynic OR hyperalgesia OR hyperalgesic OR neurogenic OR neuralgias OR “nerve pain” OR “nerve pains” OR neurodynia OR neurodynias OR phn OR crps OR “complex regional pain syndrome” OR sciatica OR “low back pain” OR radiculopathy) AND (neuraxial OR intrathecal OR spinal OR subdural OR arachnoidal OR intraspinal OR intradural) AND (steroids OR steroid OR corticosteroid OR corticosteroids OR glucocorticoid OR glucocorticoids OR methylprednisolone OR “depo medrol” OR “solu medrol” OR “depomedrol” OR triamcinolone OR dexamethasone OR hydrocortisone OR prednisolone OR prednisone OR cortisone OR betamethasone))
In all databases, we only searched for the above described terms in the study title and/or the abstract; In Pubmed [Title/Abstract] was added, in EMBASE & Cochrane Library ab,ti.
In total, 498 articles were retrieved of whom 6 were selected for Table 2 and 4 for Table 3. The references and the related articles (first 20 hits) of the selected articles were screened for missing articles in Pubmed en Google scholar. This revealed no extra articles.
Name: Mienke Rijsdijk, MD.
Contribution: This author helped in research of literature, preparation of the first draft of the manuscript, and preparation of revisions of the manuscript after review by the coauthors.
Attestation: Mienke Rijsdijk approved the final manuscript, attests to the integrity of this manuscript, and is the designated archival author who is responsible for maintaining the study records.
Name: Albert J. M. van Wijck, MD, PhD.
Contribution: This author helped in critical revision of the manuscript.
Attestation: Albert J. M. van Wijck approved the final manuscript.
Name: Cornelis J. Kalkman, MD, PhD.
Contribution: This author helped in critical revision of the manuscript.
Attestation: Cornelis J. Kalkman approved the final manuscript.
Name: Tony L. Yaksh, PhD.
Contribution: This author has supervised the research of literature, prepared the first draft of the manuscript, and critically reviewed the manuscript.
Attestation: Tony L. Yaksh approved the final manuscript.
This manuscript was handled by: Martin S. Angst, MD.
We thank Jorrit Huisman for his technical support with the illustration. This review was prepared while research and financial support was provided by the Department of Anesthesiology of the University Medical Center Utrecht to MR and TLY.
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