The 2022 American Society of Pain and Neuroscience (ASPN) guidelines have summarized recommendations based on 36 randomized clinical trials (RCTs) for the use of epidural steroid injections (ESI) for treatment of low back pain. The panel recommends interlaminar or transforaminal epidural steroid injections (ILESI, TFESI) with high level of certainty for the treatment of back and radicular pain originating from disc disease, spinal stenosis, and for chronic back/leg pain after surgical intervention, with the option to provide caudal epidural injections when neither of the aforementioned approaches are feasible (grade A, level I-A). Particulate corticosteroids have a longer onset of action compared to non-particulate corticosteroids; however, the anti-inflammatory properties are shorter with particulates. Particulate corticosteroids include triamcinolone, methylprednisolone, and betamethasone acetate and are insoluble in saline, local anesthetic and iodinated contrast agents, while non-particulate corticosteroids (i.e., betamethasone sodium phosphate and dexamethasone) are soluble in all agents. Recommendations for specific corticosteroid injectable agents are not provided. [1]
For the treatment of radicular lumbosacral pain, the 2007 literature assessment from the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) suggests that ESI may yield improvement 2 to 6 weeks post-injection versus control, although the magnitude of effect is small and generalizability is limited due to the paucity of studies and comparable treatments (Level C, Class I-III evidence). The subcommittee does not recommend routine use of ESI for long-term functional improvement or pain relief beyond 3 months (Level B, Class I-III evidence). Additionally, there is insufficient evidence to make any recommendation for the use of ESI in the treatment of radicular cervical pain (Level U). [2]
The 2016 United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for low back pain and sciatica assessment and management recommend consideration of ESI in patients with acute and severe sciatica and consider it a relatively safe procedure with or without image guidance, based on evidence demonstrated by placebo-controlled trials examining efficacy of local anesthetic and steroid epidurals. In particular, evidence of benefit was found in trials with a combination of steroid plus anesthetic; there was no evidence of benefit found for either steroid or anesthetic alone when compared to a placebo or sham treatment for any critical outcome. Patients with acute and moderately severe sciatica would be most likely to benefit from epidural injection, as data were obtained from this particular patient population. Epidural injections are not recommended for neurogenic claudication in patients with central spinal canal stenosis. [3]
A 2021 systematic review and meta-analysis evaluated efficacy and safety of TFESI, including a total of 18 RCTs; sixteen evaluated efficacy in lumbar radicular pain, 4 evaluated efficacy in spinal stenosis, and 1 examined use in pain after lumbar surgery. Three studies evaluated both radicular pain and spinal stenosis. Of the non-randomized trials included, 8 studies evaluated use in lumbar radicular pain. Based on included studies, there is strong (Level 1) evidence supporting the use of TFESIs for radicular pain due to disc herniation. One meta-analysis noted significant improvement in both pain and function with particulate and non-particulate steroids at 3 and 6 months. The evidence is limited (Level 5) for radicular pain from central stenosis or failed back surgery syndrome, and consensus-based (Level 5) for radicular pain from foraminal stenosis and from axial low back pain with no radicular component. Although TFESIs are generally safe, the authors do acknowledge the risk of neurologic complications related to cord infarct. Still, they recommend that the use of blunt needles is the strongest preventative measure to neural catastrophes possible, with the alternative of an intraradicular approach should blunt needles be unavailable. [4]
A 2018 review on complications of cervical ESIs notes that risks of serious neurologic complications, although low and primarily documented in case reports, are not impossible to encounter. Risk of infarcting the spinal cord or posterior brain structures with cervical TFESI appears to be due to inadvertent arterial injection of particulate steroids, and the best way to mitigate this risk would be the use of dexamethasone (non-particulate) for cervical TFESI. Risk of neurological damage due to cervical ILESI is due to inappropriate needle placement or space-occupying lesions (e.g., epidural hematoma or abscess), and use of judicious caution, sterile technique, and proper anticoagulation are suggested to minimize this risk. Treatment-related adverse events, such as procedural-related pain, steroid side effects, and vasovagal reactions, are reportedly mild and transient. Overall, proper use of ESI to treat cervical radicular pain allows it to remain a safe and viable treatment option. [5]
The FDA issued a drug safety communication in 2014 warning of rare but serious neurologic complications following ESIs, including stroke, paralysis, spinal cord infarction, vision loss, and death. This followed reports and FDA adverse event data beginning in 2009 that identified serious neurologic events associated with both particulate and nonparticulate steroid preparations. In response, an FDA Safe Use Initiative expert panel in 2015 developed clinical recommendations aimed at reducing risk, emphasizing careful technique, imaging guidance, contrast use, and caution with particulate steroids, particularly in cervical transforaminal injections. Although ESIs are widely used for pain management, their safety and effectiveness for epidural use are not FDA-approved, and serious complications remain rare but well-documented. The FDA highlighted uncertainty regarding whether particulate steroids (such as methylprednisolone, triamcinolone, and betamethasone) carry higher risk than nonparticulate agents like dexamethasone, while expert consensus generally favored limiting particulate formulations in higher-risk procedures. Overall, both FDA and expert groups agreed that while these events are uncommon, strict procedural safeguards and informed consent are essential to minimize harm. [6]
A review of the safety profile of ESIs and their risk versus clinical effectiveness states ESIs are moderately beneficial for back pain relief on a short-term basis, but no long-term benefit is seen. Based on the literature, complications reported with interlaminar cervical ESIs include 11 cases of transient nerve root or spinal cord irritation, one vasovagal event and two cases of facial flushing. Another referenced retrospective analysis by Botwin et al which accounted for 16.8% of complications and most of these effects were due to an increase of neck pain, headache, insomnia and vasovagal reactions. The most common causes of neurologic injury include direct needle trauma to the spinal cord or nerve roots, compression of the spinal cord and roots due to epidural hematoma or abscess, and intravascular injection of steroids leading to infarction. Indirect compression or injury to the spinal cord or nerve roots due to inflammation or infection can also lead to neurologic injury. [7], [8]
A 2016 review evaluated available literature to determine safety profiles of different spinal injections, including corticosteroids and local anesthetics. Typically ESIs are performed using insoluble (particulate) corticosteroids. Methylprednisolone acetate (MPA), triamcinolone acetonide (TA), and betamethasone acetate are available as suspensions. Non-particulate preparations dissolve completely in water and include dexamethasone sodium phosphate (DSP) and betamethasone sodium phosphate. Insoluble suspensions have a delayed anti-inflammatory effect, but the effect is sustained for a longer period of time. Soluble corticosteroids, however, have a relatively rapid onset. Ischemic neurological injury from corticosteroid injections is thought to be caused by crystalline particles large enough to occlude arteries but also small enough to embolize distal to collateral vessels, blocking blood supply. Crystal morphological features vary with different corticosteroids, ranging from round to oval to rectangular in shape and 1-120 micrometers in size. It was stated that different excipients used, including polyethylene glycol and benzyl alcohol, found in MPA, may be potential sources of toxicity. The authors cited animal studies that found serious neurological effects associated with MPA but not with DSP or prednisone. It was hypothesized that this effect may have been due to MPA itself or excipients included in the formulation, such as benzyl alcohol. Studies comparing efficacy of DSP and TA in FTESI showed minimal differences in efficacy at 1 month. In the lumbar spine, the results were mixed; some studies showed similar efficacy, while others showed improved results with TA or the need for more frequent DSP injections to obtain similar results to TA. It was suggested that procedural techniques may also be modified to limit risks of vessel injury and intravascular injection. Based on the collected literature, the authors concluded that both particulate and non-particulate corticosteroids are acceptable choices in lower lumbosacral TFESIs. Additionally, preservative-free formulations, if available, may help minimize risk of adverse events. [9]
A 2015 article compiled consensus opinions from a multidisciplinary working group and national organizations to improve safety with ESIs and prevent potentially rare but severe neurologic injuries that have been associated with their use. Based on laboratory studies, particles or aggregates found in steroid formulations can function as emboli and result in the blockage of small terminal arterioles supplying blood to the brain or spinal cord, as seen in animal studies. Methylprednisolone, triamcinolone, and betamethasone all have particles, with methylprednisolone being the largest, triamcinolone intermediate, and betamethasone the smallest. Dexamethasone, however, does not form particles or aggregates. Animal studies have also revealed that the carrier used in steroid formulations might also be directly toxic to the central nervous system. However, it was stated that a review of animal studies found the concentrations of the preservatives polyethylene glycol and myristyl-gamma-picolinium chloride needed to cause such effects would have to be 2-10 times higher than the concentration found in commercial drug preparations. Additionally, it was stated that only non-particulate steroids should be used in therapeutic cervical transforaminal injections. The initial use of non-particulate steroid dexamethasone in lumbar transforaminal injections was recommended, but particulate steroids may be used in certain scenarios, such as in the event of failed treatment with a non-particulate steroid. [10]
A 2016 review describing the safety of TFESI suggested that the occurrence of rare, but devastating and permanent neurological infarctions may be underreported compared to their true frequency. The authors stated the complication had not been reported at the time with the use of non-particulate steroid solution betamethasone; however, it had been reported with the use of particulate steroid suspensions such as betamethasone, triamcinolone, and methylprednisolone. The authors mentioned that the mechanism of this complication had not been definitively identified, but it was hypothesized to be related to embolization and occlusion of the terminal arterioles by particles (steroid macroaggregates) larger than a red blood cell. Dexamethasone was not shown to be less effective for reducing pain and improving function compared to particulate steroids for lumbar TFESI. [11]
A 2013 review evaluated epidural, transforaminal, translaminar, and facet joint spinal injections for spinal pain. The review noted increasing use despite lack of FDA approval for epidural administration. Reported comparative studies included corticosteroids betamethasone, dexamethasone, methylprednisolone acetate, triamcinolone acetonide, and local anesthetics bupivacaine and lidocaine. Evidence was mixed: some studies showed short-term pain relief and reduced surgery rates, particularly with transforaminal injections, while others showed no meaningful long-term benefit compared with saline or local anesthetic alone. Overall, benefit was generally short-term and inconsistent across studies. The review also described complications associated with epidural and transforaminal procedures using the above corticosteroids, including meningitis, stroke, paralysis, death, spinal fluid leaks, positional headaches, adhesive arachnoiditis, hydrocephalus, air embolism, urinary retention, allergic reactions, intravascular injections, blindness, neurologic deficits, hematomas, and seizures; findings further highlighted concerns regarding contaminated steroid preparations involving these corticosteroids. The authors concluded that while epidural steroid injections may provide transient symptom relief, they carry significant risks that may outweigh benefits in many contexts. [12]
A 2017 systematic review evaluated epidural steroid injections using particulate and nonparticulate corticosteroids for cervical and lumbosacral radicular pain delivered via transforaminal and interlaminar approaches.The corticosteroids assessed across included studies were betamethasone (particulate), triamcinolone acetonide (particulate), and dexamethasone (nonparticulate). Across cervical and lumbar trials, both particulate and nonparticulate formulations showed reductions in pain and improvements in function, generally meeting minimal clinically important improvement thresholds in the short term (weeks to months). However, pooled analyses found no statistically significant differences in pain relief or functional outcomes between particulate and nonparticulate corticosteroids for cervical injections. In lumbar transforaminal injections, results were similarly mixed, with some studies showing comparable pain reduction and others showing inconsistent differences depending on outcome measures and follow-up duration. Across randomized and retrospective studies, both corticosteroid types produced short-term improvement in visual analog scale (VAS) pain scores and disability measures such as the Oswestry Disability Index, but long-term superiority of either formulation was not demonstrated. Adverse events reported were generally minor (e.g., transient complications such as post-dural puncture headache), with no consistent difference in complication rates between steroid types, though the review noted concern for rare severe neurological events in broader literature. Overall, the evidence concluded that efficacy between particulate and nonparticulate corticosteroids is largely equivalent for epidural injections, and there is no strong advantage of one formulation over another in improving long-term pain or function. [13]
A separate 2017 systematic review and meta-analysis similarly evaluated particulate versus nonparticulate corticosteroids in epidural steroid injections for cervical and lumbar radicular pain using transforaminal and interlaminar approaches. Across the included studies, particulate steroids included triamcinolone acetonide, betamethasone, and methylprednisolone, while nonparticulate steroids included dexamethasone. The analysis pooled level 1 evidence outcomes such as VAS, numerical pain scores, and Oswestry Disability Index (ODI), comparing changes from baseline through follow-up periods ranging from 2 weeks to 6 months. Across nine included studies (with 300 total participants in quantitative synthesis), results showed no statistically significant difference in pain reduction between particulate and nonparticulate steroids (standard mean difference 0.31 in favor of particulates, 95% confidence interval [CI] -0.68 to 1.30). Functional outcomes (ODI) were also not significantly different between groups. While some individual studies suggested a trend toward slightly greater pain improvement with particulate steroids such as triamcinolone acetonide, betamethasone, and methylprednisolone, overall pooled data did not demonstrate superiority over dexamethasone. The review concluded that nonparticulate steroids are not inferior in efficacy and may be preferred due to safety concerns associated with particulate formulations, with no clear evidence supporting a clinically meaningful advantage of one steroid type over another. [14]
In a 2019 review the authors evaluated the safety of the intrathecal route of methylprednisolone acetate (Depo-Medrol) use, focusing on potential toxicity related to the drug, device, and excipients. Notably, there are clinical and histological effects associated with polyethylene glycol and miripirium chloride following intrathecal exposure, as well as adverse reactions linked to particulate methylprednisolone acetate. Reported complications included arachnoiditis, bladder dysfunction, headache, and meningitis. The safety profile of intrathecal administration was assessed in the context of both on-label and off-label drug use, including excipient-related toxicity concerns. Additional findings highlight that additives in methylprednisolone acetate (Depo-Medrol) formulations, particularly polyethylene glycol and miripirium chloride, may be neurotoxic when administered intrathecally. Polyethylene glycol, widely used in pharmaceutical preparations, was also associated with systemic toxicity involving cardiovascular, hepatic, respiratory, and central nervous system effects. Overall, the authors concluded that intrathecal use of methylprednisolone acetate (Depo-Medrol) is not fully safe due to reported adverse events and excipient-related risks, and emphasized consideration of alternative corticosteroid therapies free of these excipients, such as methylprednisolone sodium succinate. [15]
A 2019 randomized, double-blind, placebo-controlled trial (see Table 1; N= 116) assessed if prophylactic epidural steroids decrease fetal exposure to hyperthermia and inflammatory cytokines following epidural analgesia. Term nulliparous women were randomized to receive 1 mL of 80 mg methylprednisolone diluted with 1 mL of preservative-free normal saline or placebo (2 mL preservative-free normal saline) via epidural catheter prior to epidural infusion. Interim results revealed no difference in the rate of maternal intrapartum fever or cord blood IL-6 levels between the study and placebo group. The study was terminated early due to the newly announced FDA warning regarding the use of epidural steroids. No complications included in the FDA warning had occurred during the study period. [16]
A 2019 randomized double-blind trial compared the therapeutic effectiveness of 3 techniques of ESIs in patients having unilateral lumbar radiculopathy (see Table 2; N= 65). Patients were randomized to receive 80 mg methylprednisolone acetate (Depo-Medrol injection) and 2 mL of 2% lidocaine via midline interlaminar (MIL; n= 21), parasagittal interlaminar (PIL; n= 20) or transforaminal (TF; n= 20) technique. Significantly more patients had effective pain relief in group PIL (80%) and group TF (75%) compared to group MIL (57%; p= 0.015 and 0.038, respectively). Visual analogue scale (VAS) scores at 3- and 6-month follow-up showed statistically significant difference in pain scores among the 3 groups (group MIL 3.81 ± 1.25, group PIL 2.7 ± 0.86, group TF 3.05 ± 0.75, p= 0.002 at 3 months; group MIL 3.86 ± 1.01, group PIL 2.35 ± 0.74, group TF 2.45 ± 0.51, p= 0.000 at 6 months). Additionally, patients receiving ESI in group PIL and group TF had significantly lower VAS scores compared to group MIL (p= 0.02, p= 0.5 at 3 months; p= 0.00, p= 0.02 at 6 months, respectively). No significant change in serum osteocalcin and bone mineral density occurred at 3 months in any group. The authors concluded that low-dose neuraxial steroids are safe in patients with lumbar radiculopathy, and the PIL technique may be the most preferable since it is associated with fewer complications and is easier to perform with equal effectiveness to the TF approach. [17]
A 2003 study (see Table 3; N= 40) compared epidural methylprednisolone (Depo-Medrol) to a non-depo form of betamethasone in patients with low back pain. Results showed patients with lumbar syndromes who received epidural Depo-Medrol reported a 40% reduction in pain, whereas only a 9% reduction was reported in betamethasone-treated patients (p= 0.018). Moreover, Depo-Medrol-treated patients showed significantly improved disability scores compared to the betamethasone-treated group (p= 0.047). The authors concluded that the aqueous steroid betamethasone is not an effective alternative to the commonly used Depo-Medrol when injected epidurally in patients with lumbar pain. The safety perspective of their use was not discussed. [18]
Preservative-free anesthetics are typically used in central nerve blockade (e.g., epidural or intrathecal administration); however, there is a lack of discussion or data for use in the setting of peripheral regional anesthesia. Incidence of adverse neurological events from intrathecal administration appear limited to case reports.While allergic reactions post-local anesthetic injections are likely attributable to both methylparaben and sulfites, there is a clear distinction between the two products. Methylparaben is the most commonly used antimicrobial preservative to prevent microbial growth in the multidose vials, whereas sulfites are antioxidants that are only included in local anesthetics if there is a component of epinephrine or levonordefrin to prevent oxidation. [19], [20], [21], [22]
A 2021 review on the safety of epidural steroid injections (ESI) noted that there are possible direct neurotoxic effects of additives and preservatives in commercially available corticosteroids that can lead to neurological complications following the administration of ESIs. The authors introduced some of these additives (benzyl alcohol, polyethylene glycol, polysorbate 80, edetate disodium, sodium sulfite, and myristyl-gamma-picolinium chloride) and stated that several reports in the literature (mainly animal studies) confirmed neurotoxicities of these preservatives. It was emphasized that since the selected preservative and the amount used is based on the need for antimicrobial activity (greater in the parental products for multi-use), a key factor in preservative use is whether the parental steroid is designed for the single-use or multi-dose use. It was also mentioned that commercially available dexamethasone sodium phosphate (DSP) and methylprednisolone acetate (MPA) contain warnings on the potential for neurotoxicity (regardless of having preservative or being preservative-free). Given the lack of data on the ingredient (e.g., drug or preservative) that can cause neurotoxicity, further research in this area is needed. The neurotoxic effects of different preservatives in corticosteroid injections are summarized in Table 1. [23]
From a 2020 case report, the authors cite a prior study that suggests benzyl alcohol administered in the central nervous system at 0.9% and 1.5% concentration can cause pain, anesthesia, and flaccid or spastic paraplegia. In some cases, the effects are transient and reversible. However, the reports included a rare case of paralysis causing respiratory and cardiac arrest, leading to death. Studies in rats also suggest irreversible damage to the nervous system when injected with 0.9% benzyl alcohol. The 2020 case report utilized benzyl alcohol at 0.07% concentration, a 10-fold lower amount compared to cited cases, which caused transient neurotoxicity in 2 patients. Therefore, the rate of toxicity may be influenced by the amount of preservatives administered intrathecally. [24]