Previous studies have shown that intrathecal methylprednisolone is an effective treatment for postherpetic neuralgia (PHN).1–4 Contemporary thinking is to reserve this therapy for individuals who have failed to respond to conventional, noninterventional approaches to manage their pain.1,2 There is also a possibility of unintentional intrathecal injection of methylprednisolone occurring during epidural steroid injections. The widespread use of epidural steroid blocks and occasional intrathecal methylprednisolone use are limited for physicians in the United States. The manufacturer (Pharmacia & Upjohn Company, Kalamazoo, MI) does not recommend the intrathecal use of methylprednisolone acetate (MPA). One of the reasons is the presence of polyethylene glycol (PEG) as a preservative in the commercial formulation. PEG is a nonionic detergent and polymer of ethylene oxide and has been used as an excipient for depot steroid formulations. It has been shown to cause necrosis of muscles, neuronal and connective tissues, as well as demyelination of peripheral nerves.5–7 Complications of high-concentration PEG in the intrathecal space include sterile meningitis, arachnoiditis, transverse myelitis, cauda equina syndrome, lumbar radiculitis, intractable headache, and urinary retention.5–10
Because there is no preservative-free, commercial formulation of MPA, we recently presented a case wherein we attempted to reduce the concentration of PEG in the MPA suspension by inverting the vial before sterilely aspirating the vial contents into a syringe for subsequent injection.4 The purpose of this brief study was to precisely quantify the concentration of PEG in the MPA suspension.
Single-dose vials containing 80 mg of MPA suspension (Depo-Medrol®; Pharmacia & Upjohn Company) were inverted to promote partition of the PEG away from the steroid component. After achieving 2 phases, we carefully extracted and aspirated only the steroid component. While keeping the vial inverted, a 3-mL syringe with an 18-gauge blunt-tipped needle was gently inserted into the vial, aspirating the bottom part containing methylprednisolone, until only the upper part containing PEG remained in the vial. We kept the vials inverted for different time points (0, 30, 60, 120, 240, 360, and 480 minutes), and we measured concentrations of PEG and methylprednisolone by using liquid chromatography and mass spectrometry at the Mass Spectrometry Laboratory, Research Resource Center, University of Illinois, Chicago. We used 6 different vials for each time point (total 42 vials), and each sample was tested 4 times.
Liquid chromatography was performed using an Agilent 1100 series binary pump, vacuum degasser, auto sampler, thermostated column compartment system (Agilent Technologies, Santa Clara, CA). A Discovery C18 column (30 × 2.1 mm inside diameter, 5 μm; Sigma-Aldrich, St. Louis, MO) was used in the isocratic, reversed-phase method. The mobile phase consisted of 75% acetonitrile and 25% H2O with a flow rate of 0.250 mL/min. Sensitivity was such that only 10 μL of each sample was injected for analysis. The entire chromatographic effluent was passed through the mass spectrometer's interface for subsequent detection. Under these conditions, retention time was approximately 0.4 minute resulting in a total time (injection-to-injection) of 3 minutes.
The mass spectrometer was an Agilent 1100 series MSD Single Quadrapole LC/MS (Agilent Technologies). The coefficient of variation is between 2% and 10%, depending on the type of solution and the size of the molecule. The mass spectrometer's drying gas temperature and nitrogen gas flow rate were set at 350°C and 12 L/min, respectively, and the nebulizer gas pressure was 35 psig. Protonated analyte ions were formed using electrospray in positive mode, with the source oriented perpendicular to the spray and orifice potentials of 3.5 kV positive and 3 kV negative. The detection was optimized by varying the fragmentor voltage and it became apparent the optimal fragmentor voltage was 100 V. The analysis was performed in Selected Ion Monitoring mode to maximize sensitivity and reduce matrix interference. The 4 most intense base ions were picked to focus on (m/z 89.1, 133.1, 177.1, and 221.1). The dwell time for each ion was set at 144 milliseconds. The results of the analysis were processed using Agilent Chem Station software. The pH of samples was measured by using the pH meter for small samples (Thermo Fisher Scientific, Waltham, MA).
Statistical analysis was performed using SPSS software (IBM SPSS Statistics 18, Chicago, IL). Differences in PEG and methylprednisolone concentrations as well as pH were analyzed by using 1-way analysis of variance with Bonferroni correction, to compensate for multiple comparisons. We had 6 comparisons because we compared only adjacent time points.
The average baseline concentration of PEG in the original vials was 28.68 ± 0.37 mg/mL. After inverting the vials for 30 minutes, the average concentration of PEG in the sample was 8.02 ± 1.51 mg/mL (Fig. 1), which means that 72% of PEG was removed by inverting the vial. The average concentration of PEG after inverting the vials for 60 minutes was 6.48 ± 1.19 mg/mL. By keeping the vials inverted a longer time (120 and 240 minutes), the average concentration of PEG was 4.30 ± 1.07 mg/mL and 4.13 ± 0.77 mg/mL, respectively. We removed a minimum of 78% of PEG (the Bonferroni-corrected lower confidence limit for overall reduction in PEG) by keeping the vials inverted from 2 to 4 hours, and the average amount removed was 85% per vial. By keeping vials inverted even longer (360 and 480 minutes), there was no additional reduction in the concentration of PEG (Fig. 1). One-way analysis of variance with post hoc analysis and Bonferroni correction showed a statistically significant difference (P < 0.0001) between baseline concentration and concentrations after inverting the vials for different times. However, by removing PEG, we did not remove methylprednisolone from the preparations. Concentrations of methylprednisolone were between 76.97 and 78.95 mg/mL in all samples. Addition of PEG may decrease the pH of the suspension, which means that by removing PEG, we could potentially create a more basic preparation of MPA. Our results showed that the pH of the solution was not changed by removing PEG and it was in the range between 6.91 and 6.97 at all time points. There were no statistically significant differences in the concentrations of methylprednisolone (P = 0.283) or pH (P = 0.959) between different time points, with the largest of the 95% Bonferroni-corrected confidence intervals for the differences −1.1 to 4.2 mg/mL for MPA and −0.13 to 0.2 for pH.
Epidural MPA injections have not been shown to provide effective symptomatic treatment of PHN,1 whereas the intrathecal administration of MPA has been found to be effective.1–4 However, intrathecal MPA administration has been implicated in causing neurological complications,5–10 which occurred mainly in patients who had repeated injections.
Increasing concentrations of PEG decreased the compound action potential (CAP) and prolonged the latency in isolated rabbit sheathed-nerve preparations, and 40% of PEG completely abolished CAPs.11 However, with washout of the PEG, CAPs recovered to at least 80% of their basal levels.11 Although a 40% PEG concentration is 14 times larger than that used in commercial preparations of MPA (2.8%), extrapolations from an isolated, in vitro rabbit sciatic nerve to the human intrathecal space in vivo is not possible, especially because there is no vascular uptake in in vitro studies.
Clinicians typically dilute MPA with either saline or local anesthetics (from 1:1 to 1:3 ratio) for epidural injection or with lidocaine (usually 1:1) for intrathecal administration, which can further decrease the concentration of PEG in an injected solution. Benzon et al.12 showed that dilution may increase the proportion of larger particles (because of flocculation of MPA with saline), which can cause catastrophic embolic-related side effects.13 However, there are no data implicating this phenomenon when dilution of MPA with lidocaine is undertaken.
There is no preservative-free, commercial formulation of MPA. By keeping a vial of MPA suspension inverted for >2 hours, we greatly reduced the concentration of PEG in the suspension. However, we did not change the concentration of methylprednisolone or the pH of the solution.
It is important to use a single-dose vial of MPA, because the multidose formulation contains benzyl alcohol, which may increase the risk of complications.14 The single-dose formulation, which we used in our study, contains myristyl-γ-picolinium chloride as a preservative in almost 47 times lower concentrations than the concentration of benzyl alcohol in the multidose formulation. Other depot steroids, such as triamcinolone acetonide, triamcinolone hexacetonide, and triamcinolone diacetate, contain either PEG, and/or benzyl alcohol (Table 1), which are both potentially neurotoxic. Even nondepot steroids, such as dexamethasone sodium phosphate and betamethasone acetate, which might be considered beneficial when a reduction in embolic phenomena is deemed essential such as during performance of cervical transforaminal injections, contain preservatives. Betamethasone (Celestone Soluspan®), which has small particles, contains benzalkonium chloride, whereas dexamethasone sodium phosphate, which has either small particles (Tiso et al.13) or no particles (Benzon et al.12), contains benzyl alcohol (Table 1).
We believe that by decreasing the PEG concentration using our method, MPA-related complications will potentially be reduced, and this should be considered in patients with PHN refractory to other treatments who might be candidates for repeated intrathecal steroid injections. In cases of unintentional dural puncture occurring during epidural steroid injections in which MPA is the drug being used, the concentration of PEG entering the subarachnoid space should be greatly minimized using this technique.
Name: Kenneth D. Candido, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Kenneth D. Candido has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Ivana Knezevic, MD.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Ivana Knezevic has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Jessen Mukalel, MD.
Contribution: This author helped design the study and conduct the study.
Attestation: Jessen Mukalel has seen the original study data and approved the final manuscript.
Name: Nebojsa Nick Knezevic, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Nebojsa Nick Knezevic has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Spencer S. Liu, MD.
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