INTRODUCTION
Failed back surgery syndrome (FBSS) affects 10-40% of individuals who undergo spine surgery, highlighting its prevalence and significance. The International Association for the Study of Pain defines FBSS as a condition characterized by ongoing or recurring pain and/or disability 6 months or more after laminectomy or discectomy. This can occur with or without sensorimotor neurological deficits, or urinary/bowel incontinence, despite the anatomical success of the initial surgery [1].
The pathophysiology of FBSS is intricate, and comprehensive evidence remains elusive. Pre-, intra-, and postoperative factors significantly contribute to the development of FBSS. Preoperative determinants include psychological conditions such as anxiety and depression, as well as physical characteristics such as obesity [2]. Postoperative epidural fibrosis and psychosocial factors are strongly associated with the development of FBSS [3]. Other contributing factors include the chronic build-up of inflammatory mediators, which can alter nerve-sensitive functions and predispose patients to chronic spinal neuropathic pain [4]. Surgical-related causes include errors in accurately identifying the surgical site, suboptimal surgical techniques, disc fragmentation, spinal instability resulting from laminectomy, and complications such as discitis [5].
Epidural scarring and tethering due to surgical trauma are among the most common causes of FBSS [6]. These complications can entrain the nerve root and obstruct the vascular supply, leading to severe and persistent pain [7]. This chronic pain not only imposes substantial socio-economic burdens but also significantly compromises quality of life and exerts considerable pressure on the healthcare system [8]. Lumbar epidural injection with a long-acting particulate steroid under fluoroscopic guidance shows level II evidence with moderate-to-strong recommendations, owing to its anti-inflammatory actions. Excessive fibrosis and previously damaged anatomy can mechanically block this action [9].
In this context, we hypothesized that epidural hyaluronidase (HA) or dexmedetomidine (DEX) can augment and extend the therapeutic efficacy of steroid-based epidural injections in patients with FBSS. Epidural HA specifically breaks down glucosamine and hyaluronic acid, key components maintaining connective tissue integrity. This breakdown disrupts collagen bundles, helps reconstruct the peri-neural matrix, and functions as a pharmacological chemical adhesiolysis by reducing fibroplasia and removing mechanical barriers, thus facilitating drug distribution [10]. Conversely, DEX, through its pre- and post-synaptic alpha-2 agonistic effects, alleviates inflammatory responses, reduces chronic allodynia, and influences cognitive function [11]. DEX is a selective α2 agonist with sympatholytic properties. Alpha-2 receptors, located on postsynaptic dorsal horn neurons, mediate analgesia by inhibiting continuous pain signals from C fibers [12]. This study aimed to compare the therapeutic effects of magnesium and DEX with those of epidural particulate steroids on pain intensity, functional disability, and possible complications in a population with FBSS.
MATERIALS AND METHODS
This randomized, double-blind, single-center clinical trial was approved by Minia university local ethical committee council (IRB 278/5-2022) and registered on ClinicalTrials.gov under the identification number NCT 05370963. This study adhered to the principles outlined in the Declaration of Helsinki. Patients were recruited from the Rheumatology and Rehabilitation Department and received injections at a pain clinic between January 20, 2022 and October 2022. All patients underwent proper follow-ups. Each patient completed a surgical sheet detailing the procedure performed, preoperative complaints, level of surgery, and any significant events during or after the procedure. Written informed consent was obtained from all participants.
Inclusion criteria
Strict prerequisites involved a population aged between 30 and 75 years, of any sex, who experienced persistent back pain and/or lower limb radicular pain lasting at least 6 months following laminectomy. Patients experiencing persistent back pain after laminectomy for spinal canal stenosis and/or discectomy for herniated nucleus pulposus confirmed by lumbosacral magnetic resonance imaging (MRI) were included in the study.
Exclusion criteria
Patients were excluded because of sacroiliitis, diabetes, pregnancy, disc sequestration, surgically induced discitis, and/or allergies to any drug used. None of the enrolled patients were on opioid supplements during or after the procedure.
Concealment
All samples were prepared in advance by a designated study member. They were subsequently delivered to the interventional therapist in sealed envelopes, each of which was coded and sequentially numbered using a specific alphanumeric system (e.g., 1A, 2A, 1B, and 2B). This coding system was documented on patient identification cards to enable subsequent tracking. The key to this coding scheme remained confidential and was not revealed until the conclusion of the study; this was after the final patient follow-up was completed.
Study design
The outcome-assessing physician and patients were blinded to the group assignments. All patients provided informed consent and acknowledged their understanding of the nature and objectives of the procedure. Patients were given detailed explanations of the study protocol and instructions on how to use the visual analog scale (VAS). The scale ranges from 0 cm, indicating the absence of pain, to 10 cm, indicating intolerable pain. It encompasses gradations where 1-3 cm corresponds to mild pain; 4-6 cm, moderate pain; and 7-9 cm, severe pain. Additionally, the Modified Oswestry Disability Index (MODI), a validated questionnaire consisting of 10 items each scoring up to 5 points, was employed. The total score was divided by 50 and multiplied by 100 to yield a percentage score, with higher values signifying greater disability [13]. Follow-ups were performed by an independent therapist, with assistance from a senior nurse.
Study groups
In the HA group, patients received a combination of bupivacaine 0.5% 5 mg (5 mg/1 ml; Bupivacaine hydrochloride, USP), triamcinolone acetonide 40 mg (40 mg/1 ml; E.I.P.I.C.O Pharmaceuticals, Egypt under the license of Upjohn S.A), sterile saline (2 ml), and HA (1,500 IU; C-Hynidase, Shreya life sciences Pvt. Ltd) dissolved in 1 ml distilled water.
In the DEX group, patients received a combination of bupivacaine 0.5% 5 mg (5 mg/1 ml; Bupivacaine hydrochloride), triamcinolone acetonide 40 mg (40 mg/1 ml; E.I.P.I.C.O Pharmaceuticals), DEX (Precedex, Hospira, Inc.) at a dose of 0.5 mcg/kg, and 2 ml sterile saline.
Treatment protocol
Before the intervention, a thorough clinical examination and radiological assessment were performed to verify the level and site of injection. A preliminary 22-gauge IV cannula was inserted. Basic monitoring equipment were set up, including a 5-lead ECG, a pulse oximeter, and a noninvasive blood pressure monitor. The patient was positioned prone with a pillow under both iliac crests to counteract lumbar lordosis. Fluoroscopic lumbar levelling was then performed. The skin was cleaned three times with 10% povidone-iodine (10% Iodine Clean, Egypt Pharmaceuticals), followed by the application of a sterile drape. Lidocaine 60 mg (3 ml) was administered to induce local anesthesia. Fluoroscopy was oriented in two planes to monitor the trajectory of the needle toward the neural foramen. Initially, an anteroposterior orientation with a 15° tilt toward the affected side was used, followed by an oblique window of 20-30° to visualize the needle tip. The tip of a 3.5-inch, 22-gauge spinal needle (Becton) was directed to the 6 o'clock position beneath the neck of the Scotty dog, targeting the pars interarticularis via the subpedicular approach. The optimal position was identified as the posterior one-third of the foramen, avoiding the feeding posterior spinal artery. A 2 ml injection of radio-opaque dye (Omnipaque 300-Iohexol, GE Healthcare) was administered, with negative aspiration of blood verified through anteroposterior and lateral views [14]. Subsequently, medications were administered. After the procedure, the patient was transferred to the intermediate care unit for 3 h of observation, including monitoring of vital signs and checking for complaints. Sensory and motor examinations were conducted hourly to ensure that no neural injuries occured.
Statistical analysis
No previous studies have compared the efficacy of HA or DEX in FBSS; however, a pilot study was performed on 20 consenting candidates (10 in each group). To achieve the primary goal of reducing the VAS score by at least 25%, 94 patients were needed to reach 85% study power at a 5% significance level, as calculated using the G Power 3.1.9.2 software. To account for possible dropouts, we recruited 100 participants, with three additional cases for each group. We tested the data distribution for normality using the Shapiro-Wilk test. Data are presented as numbers (percentages) or medians (interquartile ranges), as appropriate. The chi-square test was used for categorical data. Differences between groups were assessed using an independent t-test for normally distributed continuous data and the Mann-Whitney U test for non-normally distributed continuous data. Intragroup comparisons at different follow-up times were compared to baseline values using the Kruskal-Wallis test. All statistical tests were two-tailed, with the significance level set at P < 0.05. Statistical analysis was performed using IBM SPSS Statistics for Windows version 22.
RESULTS
The study included 115 patients who were assessed for eligibility. Based on the exclusion criteria, nine cases were excluded because they did not fit the research design, and six patients refused to participate (Fig. 1).
Table 1 shows no significant differences between the studied groups in terms of demographic data, American Society of Anesthesiologists class, level of disc prolapse, and radiculopathy site. All enrolled patients underwent open spinal lumbar laminectomy with or without spine fixation.
The post-injection pain scores (VAS) presented in Table 2 were statistically significant when compared with the pre-injection values in both groups at all time points (P = 0.001). However, a statistically significant difference was observed between the two groups at 6 months post-intervention (P = 0.003). The median percentage decrease in VAS scores in the post-injection period (Table 3) was statistically significant in the two groups at 6 months (P = 0.027) and was more remarkable in the DEX group (80%) than in the HA group (65%). Data at 1 week, 1 month, and 3 months were comparable between the two groups.
The data reported in Table 4 regarding the reduction in the degree of functional disability were in favor of the DEX group, compared with the HA group, at all follow-ups, with a statistically significant difference between the two studied groups (P = 0.03, 0.02, 0.001, and 0.001, respectively). In each group, a significant difference was observed between the baseline value and the values at the 1-week, 1-month, 3-month, and 6-month follow-up after the intervention (P = 0.001 in the DEX group at all intervals; however, P = 0.001, 0.003, 0.003, and 0.003, respectively, in the HA group).
The median percentage decrease in the MODI was statistically significant in the DEX group at all follow-ups, compared with that in the HA group (P = 0.003, 0.004, 0.001, and 0.001 at 1 week, 1 month, 3 months, and 6 months, respectively) (Table 5).
Table 6 presents data on complications encountered throughout the procedure. Bradyarrhythmias were reported once in the HA group and three times in the DEX group, and vomiting occurred twice in both groups. All side effects were transient and managed successfully.
Table 7 presents MRI spine neuroimaging, revealing that dural scarring was the predominant finding, with 50 cases in the HA group and 49 cases in the DEX group. Recurrent disc prolapse was observed in 31 candidates in the HA group and in 29 candidates in the DEX group. Remnants of the lumbar disc were observed in three patients in the HA group and in one patient in the DEX group.
Fig. 2 shows the mean ibuprofen consumption before and after the intervention. The data obtained from both groups were comparable, except after 6 months, when the DEX group showed significantly lower consumption values than those of the HA group.
Case demonstration
Transforaminal approach for L3-L4, L4-L5, and L5-S1 epidural injection. The needle tip was placed under the pedicle (at 6 o’clock) with negative aspiration after dye injection. The course of the dye clearly denotes the course of the nerve.
A 40-year-old woman with laminectomy at L5-S1 with recurrent pain in the right leg. Epidural injection of HA was administered. The pain relapsed 3 months after the injection (Fig. 3).
DISCUSSION
In the current study, we compared the efficacy of DEX and HA when added to lumbar epidural particulate steroids in patients with FBSS. This study focused on pain, disability scores, and analgesic consumption. Our results showed that both adjuvants yielded favorable outcomes for the reduction of pain intensity and disability scores throughout the follow-up period. However, the DEX group showed statistically significant improvement in pain intensity at 6 months, suggesting potential superiority over the HA group in terms of long-term pain management. Regarding the MODI, both groups showed significant reduction in post-injection disability scores compared with pre-intervention values. Moreover, DEX had a greater effect on post-injection disability scores than HA throughout the follow-up period, highlighting its efficacy in improving functional outcomes. Non-steroidal anti-inflammatory drug consumption significantly decreased in both groups compared to pre-intervention values. Additionally, the significant reduction in analgesic consumption at 6 months in the DEX group further supports the benefits of DEX in reducing long-term reliance on analgesics.
The complex pathophysiology of FBSS, involving factors such as epidural scarring and disc reherniation, underscores the multifaceted nature of this condition. The emphasis on patient psychosocial factors and the accompanying cognitive dysfunction aligns with a holistic approach to managing FBSS [15]. Chronic pain associated with FBSS is aversive and associated with stress-related disorders (anxiety, mood swings, and cognitive dysfunction) due to dysfunction of the noradrenergic locus coeruleus pathway. Patient psychosocial factors are strongly associated with the development of FBSS. Cognitive behavioral therapy or other psychiatric therapies can lead to better outcomes in patients with FBSS [16]. Therefore, strategies are needed to counteract these factors.
Surgical trauma is associated with wound healing via the recruitment of neutrophils and fibroblasts, which secrete fibrin threads and deposit collagen. Furthermore, extravasation of nucleus pulposus into the epidural space aggravates scar tissue formation. Moreover, understanding the mechanisms underlying surgical trauma-induced scarring and the absence of effective treatments for this issue highlights the continuing challenges in managing FBSS [17].
The rationale for choosing transforaminal epidural injections over interlaminar epidural injections is well-established and reflects careful consideration of anatomical and procedural challenges. Interlaminar epidural injections can be complex and risky, particularly because of the distorted anatomy from previous damage and the potential for neuraxial bleeding, especially when a 17-gauge Tuohy needle is used [18]. In contrast, the transforaminal approach is more target-selective and requires a smaller volume of medication to reach the dorsal root ganglion at the desired level. This method also ensures that the drug is delivered to the ventral epidural sac, where excessive scarring often occurs, whereas the interlaminar approach primarily accesses the dorsal epidural sac, which is less affected by pathologies. In addition, caudal epidural injections require larger volumes and lack precision in targeting the specific pathological site. Mechanical factors, such as dural adhesions, may also obstruct the injectate's path to the desired nerve root because of secondary spinal canal stenosis [19]. Overall, the transforaminal approach is preferred for epidural injections because the needle is positioned close to the compressed neural tissue. It is considered the safest and most effective method with minimal risk of inadvertent dural puncture, making it the preferred choice for post-surgery syndrome epidural injections [20].
The unique aspects of the current study notably distinguish it in the field of FBSS management. First, the choice to use the transforaminal epidural approach exclusively as the therapeutic intervention for patients with FBSS sets it apart from previous studies. This unified approach ensured unbiased feedback. Second, the follow-up period of 6 months exceeded the typical duration observed in most contemporary clinical trials, which often have follow-up periods of only 1-3 months. This extended follow-up period allowed for a more comprehensive evaluation of the treatment efficacy and long-term outcomes, providing valuable insights into the sustained effects of the interventions. For example, a randomized controlled trial by Poupak et al. [21] on the use of HA in transforaminal epidural injections with particulate steroids in patients with FBSS had a follow-up period of only 4 weeks. Overall, this study significantly contributes to FBSS management by introducing new treatment methodologies, extending the follow-up duration, and implementing rigorous practices to minimize bias.
Ensuring the safety of neuraxially injected drugs is crucial when selecting specific adjuvants for particulate epidural steroids. Here, we conducted a thorough review of the safety profiles of HA and DEX. Both substances are ethically approved and widely accepted by pain management specialists for the treatment of chronic low back pain. Alpha-2 receptor agonists, such as clonidine and DEX, are highly regarded in the management of chronic neuropathic pain that requires neuraxial injection. DEX, in particular, has been extensively studied in clinical trials involving human populations. For instance, Farnad et al. [22] compared the clinical effects of DEX (50 µg) combined with 0.2% ropivacaine (4 ml) against particulate steroid (triamcinolone 20 mg) combined with 0.2% ropivacaine (4 ml). The combination of DEX and ropivacaine significantly reduced both pain and disability scores. HA is commonly used in neuroplasty to break down hyaluronic acid and assist in overcoming interstitial barriers. Its effectiveness persists when injected neuraxially in combination with other drugs, enabling enhanced diffusion of the accompanying medications [23].
Regarding dose adjustment, 1,500 IU of HA is used to provide maximum therapeutic efficacy. With respect to the DEX group, we injected a weight-based dose (0.5 µg/kg) rather than a fixed one to ensure compliance with patient demographics.
The immediate question that arose for us was “Why did DEX exhibit a greater impact than HA and through what mechanism?” This prompted us to search for answers to the question. We believe that HA, through its effect on the perineural matrix, can disrupt excess collagen bundles, whereas DEX. acts in two different ways: first, by alpha-2 agonistic action, and second, by improving patient cognitive function and psychosocial state through its sympatholytic effect on the locus coeruleus, which is the source for noradrenergic pathways from the medulla oblongata to the spinal cord. The noradrenergic pathway is involved in alertness, psychological balance, and sleep. Chronic pain often coincides with cognitive dysfunction, abnormal sleep rhythms, and anxiety [16]. Chronic pain is thought to affect 20-30% of the adult population in Europe and the United States [24], more than half of whom display comorbid depression and anxiety psychological imbalance. This indicates that the noradrenergic pathway, chronic pain, and psychosocial cognitive dysfunction are vicious cycles that should be interrupted to improve chronic neuropathy [25].
Yang et al. [26] examined the effects of DEX on postoperative cognitive dysfunction and psychosocial dissociation. The analysis found that even at low doses of 0.5-1 µg/kg, DEX prevented postoperative cognitive decline and improve Mini Mental State Examination scores across 26 randomized controlled trials.
Our findings align with those of Eskandr and Maseeh [27], who conducted a clinical trial comparing two groups. The DEX group received DEX (0.5 µg/kg), bupivacaine (0.5 mg), and betamethasone (14 mg), adjusted to a total volume of 20 ml with sterile saline. The control group received only bupivacaine and betamethasone in the same total volume. They used the interlaminar epidural approach to treat FBSS. The study reported a significant reduction in VAS scores up to 3 months post-intervention, with the median and range of VAS scores in the DEX group being 2-6 compared with 3-7 in the control group (P = 0.03). Additionally, the DEX group had significantly lower ibuprofen consumption (1,020 ± 260.66 mg) compared to the control group (1,290 ± 322.38 mg), with a P value of 0.002 at 3 months. The Oswestry Disability Index also significantly improved in the DEX group.
However, the study had several limitations. First, the interlaminar lumbar epidural approach is not ideal for FBSS because of extensive fibrosis, which complicates needle passage and increases the risk of bleeding. Moreover, injecting 20 ml into the epidural space may be excessive, increasing the risk of complications. In addition, the follow-up period was limited to 3 months, which is relatively short.
The rationale for using HA in epidural injections for FBSS is based on the ability of HA to disrupt epidural adhesions. HA breaks down hyaluronic acid and proteoglycans, primarily chondroitin-4 and chondroitin-6 sulfates. By disrupting the proteoglycan ground substance, HA facilitates the diffusion of injected substances and potentially remodels the extracellular matrix in ventral and dorsal epidural adhesions [28].
Rahimzadeh et al. [21] investigated the therapeutic effects of HA in FBSS by comparing transforaminal epidural injections of either HA (1,500 IU) or normal saline with particulate steroids. They observed that HA significantly improved both the quality and duration of pain relief in patients with FBSS 4 weeks after the procedure. This aligns with our findings of reduced analgesic consumption post-intervention. However, the study did not assess disability using the MODI but relied on subjective patient satisfaction scores instead. The limitations of the study include the relatively small sample size and short follow-up period.
Yousef et al. [29] conducted a prospective, randomized, double-blind study comparing 40 ml caudal injections of local anesthetics, steroids, and 3% saline with and without HA in patients with FBSS. Significant relief was observed only in the group that received HA after one year of treatment.
Another relevant study by Geurts et al. [30] examined the effect of adding HA to a fluoroscopically guided caudal epidural injection of 30 ml of hypertonic saline (3%), 10 ml of bupivacaine (0.25%), and 80 mg of methylprednisolone. They reported that adding HA to this combination helped manage intractable pain in patients with FBSS for up to one year. The strengths of this study include the long follow-up period and measurement of lumbar spine range of motion using long-arm goniometry. However, issues such as the use of a caudal approach for epidural injection in FBSS remain debatable. Additionally, the lack of a pre-injection radio-opaque dye to monitor drug distribution and the potential influence of various opioids (tramadol and morphine) during or after the procedure may have affected the results.
Geurts et al. [30] reported that mechanical adhesiolysis via epiduroscopy, combined with targeted injections of HA and steroids, led to a significant reduction in chronic radicular pain.
Complications, such as emesis and bradycardia, during the procedure were statistically insignificant in both groups. In the HA group, these issues may be attributed to potential allergic reactions, whereas in the DEX group, they may be related to the sympatholytic effects of the drug.
In conclusion, both drugs significantly improved pain and disability scores compared with pre-injection values. However, the DEX group showed more significant pain and disability score reduction than the HA group at all follow-ups.
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