The effect of human assumed central sensitization on transforaminal epidural steroid injection in chronic lumbar radiculopathy: An observational study

Abstract

BACKGROUND:

Human assumed central sensitization (HACS) is a potential pathophysiological mechanism underlying a group of musculoskeletal disorders. HACS may negatively influence the outcomes of surgical or interventional procedures.

OBJECTIVE:

The present study aimed to investigate the impact of HACS on treatment outcomes of transforaminal epidural steroid injection (TFESI).

METHODS:

Patients who received fluoroscopy-guided single-level lumbosacral TFESI between January 2020 and January 2021 were included in the study. The patients were divided into two groups with respect to the existence of HACS. Patients were assessed before the procedure, at the third week, and at the third month after the procedure. The presence of HACS was investigated by central sensitization inventory (CSI). The Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI) were used for patient assessment.

RESULTS:

A total of 65 patients were included in the study. Thirty-one of the patients had HACS. There was no difference between the groups in terms of demographic data. Significant improvement in NRS was found at 3^rd week and 3^rd month compared to the baseline. BDI and ODI scores were also significantly reduced at the end of 3 months ( $p<$ 0.001). NRS scores at all time points were significantly lower in patients without HACS ( $p<$ 0.05).

CONCLUSION:

The presence of HACS has a negative effect on pain scores, disability, and mental state in patients undergoing TFESI.

Keywords

Lumbar disc herniation epidural injections central sensitization central sensitization inventory

1. Introduction

Lumbosacral radiculopathy (sciatica) is commonly caused by lumbosacral disc herniation. L5 and S1 are the most frequently affected nerve roots. Clinical manifestations include pain radiating down the leg, paresthesia, and motor impairment, which may lead to social and economic burden [1]. Sciatica symptoms occur through the interaction of compression-related, inflammatory, and immunological mechanisms. Epidural steroid injections are assumed to decrease inflammation around the affected nerve root, resulting in pain reduction and functional improvement. Through caudal, interlaminar, and transforaminal routes, steroids can be delivered to the epidural space, but the transforaminal route provides deposition of medication in close proximity to the site of pathology [2, 3].

Although it is not possible to directly evaluate central sensitization in humans, the term human assumed central sensitization (HACS) has been used [4]. The HACS is defined as the sensitivity of neurons to normal or subthreshold stimulation [5]. It is a potential pathophysiological mechanism underlying a group of musculoskeletal disorders associated with chronic pain [6, 7, 8]. It has been shown that the presence of HACS may have a negative effect on the clinical picture in some musculoskeletal diseases and also have a negative effect on spinal procedures [4, 8, 9, 10]. In particular, it is stated that the pain threshold of the patients decreases, causing them to experience more pain. Studies show that nerve fibers do not work properly and respond to even light touch as pain, possibly due to peripheral or central sensitization [4, 11]. Alternatively, central sensitization inventory (CSI) is a simple, low cost, and easily applicable tool to detect HACS, which has been increasingly used in clinical research [12]. HACS may negatively influence the outcomes of surgical or interventional procedures [10, 13]. However, the effect of HACS on the treatment outcomes of transforaminal epidural steroid injection (TFESI) is not established. We think that HACS diseases will negatively affect TFESI treatment. Therefore, the present study aimed to investigate the impact of HACS on the treatment outcomes of TFESI.

2. Materials and methods

2.1 Design and study population

Sixty-nine patients who underwent fluoroscopy-guided TFESI between January 2020 and January 2021 for unilateral lumbosacral radicular pain were included. The study was approved by the Sisli Hamidiye Etfal Training and Research Hospital Ethics Committee on 31 December 2019 (number 1361). Inclusion criteria were: 1) aged between 18–65 years, 2) having unilateral extremity pain (with or without axial back pain), for at least 3 months, and 3) having radiologically confirmed paracentral disc herniation compatible with clinical examination findings. Patients with systemic inflammatory disease, mental disorder, bleeding diathesis, malignancy, allergy to the contrast dye, lumbar spinal stenosis, surgical history, or epidural steroid injection (ESI) history in the last three months were excluded from the study. ESI were scheduled for patients who could not adequately relieve after conservative treatment (post-treatment NRS $>$ 4). The demographic data of the patients and their ongoing medical treatments were noted. The injection level and the grade of nerve root compression were also noted. According to the CSI, the patients were divided into a HACS group and a non-HACS group.

Table 1
Human assumed central sensitization according to sociodemograpic and clinical characteristics of patients

	Total cohort	Human assumed central sensitization		$P$ value
		No (34)	Yes (31)
Age (years)	39.93 (10.06)	40.85 (9.84)	38.93 (10.36)	0.448^*
BMI (kg/m²)	26.86 (1.73)	26.78 (1.85)	26.95 (1.48)	0.703^*
Symptom duration (month)	12.10 (2.29)	12.08 (2.16)	12.12 (2.47)	0.944^*
Sex (%)				0.180^‡
Male	35 (53.8)	21 (61.8)	14 (45.1)
Female	30 (46.2)	13 (38.2)	17 (54.9)
Nerve root copmression				0.732^‡
Grade 1	16 (24.6)	7 (20.5)	9 (29.0)
Grade 2	40 (61.5)	22 (64.7)	18 (58.0)
Grade 3	9 (13.9)	5 (14.8)	4 (13.0)
Medical treatment				0.834^‡
NSAİD	26 (40.0)	12 (35.2)	14 (45.2)
Weak opioid $+$ paracetamol	13 (20.0)	7 (20.5)	6 (19.3)
Gabapentinoids	13 (20.0)	8 (23.5)	5 (16.1)
Antidepressants	13 (20.0)	7 (20.5)	6 (19.3)

Data presented as mean (standard deviation), $n$ (%), NSAİD: Non-steroidal anti-inflammatory drugs. BMI: body mass index. ^*Independent-Samples $T$ test, ^‡Chi-Square test.

2.2 Measures

The Oswestry Disability Index (ODI) and Beck Depression Inventory (BDI) were used for functional status and depression level, respectively. The Numerical Rating Scale (NRS) was used to assess pain intensity. The patients were evaluated before the procedure, at three weeks, and three months after the procedure. The presence of HACS was checked with the CSI. The total scores of the scale range between 0–100, and patients with 40 points and above are considered to have symptoms of HACS [14]. The CSI has been shown to be valid and reliable in Turkish [15]. It has been shown to be valid for musculoskeletal system diseases in Turkish patients [16]. The BDI is a 21-item scale with scores of 0 to 3 for each question, where high scores correspond with severe depression [17]. The ODI is a 10-item scale that evaluates activities such as sleep, walking, and social and sexual life. Each question is scored between 0–5, and a low score indicates better functional status [18]. The severity of nerve root compression was assessed using magnetic resonance imaging (MRI) scans. Axial magnetic resonance images showing examples of varying degrees of nerve root compression as seen and interpreted in relevant study [19]. The subpedicular approach was chosen for TFESIs, and the procedures were carried out by a pain physician with at least 10 years of experience in fluoroscopy-guided interventions.

2.3 Statistical analysis

SPSS 22.0 software (IBM Corp., Armonk, NY, USA) was used for the statistics. Continuous variables are expressed as mean or median. Categorical variables were defined as number and frequency. The Shapiro-Wilk test was used to determine the normal distribution of the data. The Mann-Whitney $U$ test was used to compare non-normally distributed data, and the independent $t$ -test was used to compare normally distributed data. A chi-square test was used for categorical variables. The changes over time with treatment for non-normally distributed data were determined by Friedman test and by repeated measures ANOVA test for normally distributed data. Paired Sample $T$ -test and Wilcoxon tests were performed for pairwise comparisons with a Bonferroni correction for multiple comparisons. Statistical significance was accepted at the $P$ value $<$ 0.017 for Bonferroni correction. A $p$ value $<$ 0.05 was considered statistically significant with a 95% confidence interval.

3. Results

Table 2
Pre- and post-procedural NRS, ODI and BDI scores of patients

	NRS	ODI	BDI
	Median (IQR)	Median (IQR)	Median (IQR)
Pre	8 (5–10)	42 (20–64)	21 (10–29)
3. week	3 (0–7)
3. months	3 (0–9)	26 (14–50)	13 (4–29)
$P$ value	$<$ 0.001^*	$<$ 0.001^‡	0.001^‡
Pre vs. 3. week	$<$ 0.001
Pre vs. 3 months	$<$ 0.001

NRS: numeric rating scale, ODI: oswestry disability index, BDI: beck depression inventory. ^*Repeated Measure ANOVA, ^‡Paired-Samples $T$ test.

Four patients were lost during the follow-up period, and a total of 65 patients were included in the final analysis. The mean age of the patients was 39.93 $\pm$ 10.06, and the mean BMI was 26.86 $\pm$ 1.73. Of the patients, 31 were found to have HACS. CSI scores were 58.6 $\pm$ 11.8 and 28.4 $\pm$ 8.59 in the HACS and non-HACS groups, respectively. The mean duration of symptoms was 12.10 (7–17) months. Among all patients, 35 were male (53.8%). However, 54.9% [17] of the patients were female among those with HACS. There was no difference between patients with HACS and patients without HACS in terms of demographic data and the grade of nerve root compression. The mean ages of the both groups were 40.85 $\pm$ 9.84 and 38.93 $\pm$ 10.36, respectively, and no significant difference was detected. Additionally, symptom duration was found to be 12.08 $\pm$ 2.16 and 12.12 $\pm$ 2.47, respectively, and there was no significant difference between the groups. The most frequently used medication by the patients was non-steroidal anti-inflammatory drugs, and no significant difference was found between the medications used between the two groups (Table 1). Significant improvement in NRS was found at 3^rd week and 3^rd month compared to the baseline. BDI and ODI scores were also significantly reduced at the end of 3 months ( $p<$ 0.001) (Table 2). NRS scores at all time points were significantly lower in patients without HACS ( $p<$ 0.05) (Table 3). Similarly, 3^rd month ODI and BDI scores were significantly higher in patients with HACS (Table 4).

Table 3

NRS scores changes according to human assumed central sensitization

	Human assumed central sensitization		$P$ value
	Yes	No
NRS-neck/shoulder	Median (IQR)	Median (IQR)
Pre	8 (6–10)	7 (5–9)	0.034^*
3 week	3 (1–7)	2.5 (0–6)	$<$ 0.015^*
3 months	5 (1–9)	2.5 (0–6)	$<$ 0.001^*
$P$ value	$<$ 0.001^‡	$<$ 0.001^‡
Pre vs. 3 week	$<$ 0.001^†	$<$ 0.001^†
Pre vs. 3 months	$<$ 0.001^†	$<$ 0.001^†

NRS: Numeric Rating Scale; ^*Mann-Whitney $U$ test, ^‡ Friedman Test, ^†Wilcoxon sign test.

Table 4

ODI and BDI scores according to human assumed central sensitization

	Human assumed central sensitization		$P$ value
	Yes	No
ODI	Median (IQR)	Median (IQR)
Pre	46 (20–64)	38 (20–60)	0.040^*
3 months	30 (14–50)	24 (16–50)	0.027^*
BDI
Pre	24 (20–29)	18 (10–25)	0.001^*
3 months	19 (10–29)	9 (4–22)	0.001^*

^*Mann-Whitney $U$ test.

4. Discussion

There is no gold standard to estimate the presence of central sensitization in humans and there is also no clear definition, method or guideline applicable to diagnose central sensitization in humans. CSI and QST may help in determination [4]. HACS is a manifestation of enhanced plasticity of the somatosensory nervous system in response to inflammation or nerve injury. It is characterized by increased membrane excitability and synaptic action, as well as decreased function of inhibitory systems. The effect of HACS is to engage previously subthreshold synaptic inputs into nociceptive neurons and generate an exacerbated action potential output. That is, a state of facilitation, reinforcement, and augmentation. HACS is the cause of temporal, spatial, and threshold changes in pain sensitivity in acute and chronic clinical pain settings and is an example of the central nervous system’s contribution to the generation of pain hypersensitivity. Some changes in the properties of neurons in the central nervous system occur, and the presence of noxious peripheral stimuli is no longer necessary for pain as in acute nociceptive pain. Inputs that evoke harmless sensations and normal inputs appear as pain sensations due to pain hypersensitivity [20, 21]. It is not possible to demonstrate this effect directly in humans. Some methods are thought to assist in the clinical diagnosis of HACS. The presence of HACS may be evaluated with the CSI [4]. In our study, we aimed to show the negative effect of high HACS scores on the response to TFESI in patients with single-level nerve root compression at L4, L5, or S1 due to a paracentral disc herniation. A statistically significant decrease in NRS scores was observed at 3 weeks and 3 months after TFESI for both groups; however, a significant decrease in ODI and BDI scores was shown only at 3^rd month follow-up. NRS, ODI, and BDI scores, which were statistically significantly higher in the HACS group compared to the non-HACS group before TFESI, were also significantly higher after the treatment.

Based on results of previous high-quality systematic reviews, the evidence is Level I for epidural steroid injections with strong recommendation for long-term effectiveness [22]. Epidural steroid injection reduces cytokines and chemokines, inhibits neuroglial activation, and exerts anti-inflammatory effects by inhibiting nociceptive C-fiber transmission and ectopic neuronal discharge [23]. In our study, significant improvements were found in pain, disability, and depression scores 3 months after the treatment, supporting the previous reports inquiring about the treatment success of lumbar TFESI.

Previous studies have shown that patients with HACS have higher pain scores before and after various treatments [10, 24, 25]. According to Neblett et al. [26], the baseline CSI scores of the patients were highly correlated with previous diagnoses of central sensitization, HACS-related symptoms, and patient-reported clinically relevant psychosocial variables. All psychosocial variables, as well as CSI scores, improved significantly after the functional restoration program treatment [26]. They were used in CSI part B, but part B was not used in our study since it is difficult to measure and evaluate [27] and we think there is a deficiency in terms of HACS-related diseases. In the study by Ohashi et al. [9], it was observed that patients with hip osteoarthritis presenting high initial CSI scores also had high pain scores after the surgery. Similarly, we found that NRS scores were significantly higher in the HACS group compared to the non-HACS group before TFESI, and these scores remained significantly higher at the 3rd week and 3rd month follow-up after the treatment. Chronic painful stimuli cause synaptic plasticity in the central pain pathways, leading to central sensitization, which is an increased neuronal response. Studies show that neuroinflammation in the peripheral and central nervous systems (CNS) is also effective in central sensitization. Neuroinflammation induces the release of proinflammatory cytokines and chemokines, resulting in the activation of glial cells such as microglia and astrocytes in the spinal cord and brain. Central cytokines and chemokines are potent neuromodulators responsible for CNS-related hyperalgesia and allodynia. Briefly, mosaic alteration of membrane excitability, decreased inhibitory transmitters, and increased synaptic efficacy leads to the transition of acute to chronic pain [28, 29, 30]. The intensity of these structural alterations might be associated with severe pain presented in the HACS group.

CSI also increased disability in patients. Previously, the CSI showed a weak-to-moderate correlation with the ODI for lumbar spinal diseases [25]. In another study, CSI was moderately correlated with Neck Disability Index (NDI) [31]. In the current study, there was a significant decrease in ODI scores in both groups at 3 months after TFESI. The initial and post-treatment ODI scores were significantly higher in the HACS patients. Since the pain was severe in the HACS group, decreased mobility, functional limitations, and increased disability may occur in a manner to reduce the pain felt or as a natural consequence of the pain.

BDI scores were significantly poorer before and after TFESI in the HACS group. Symptoms of anxiety and depression are thought to be potential risk factors for negative outcomes in patients undergoing treatment [32]. These results suggest that the psychological state of patients with HACS is impaired, and this deterioration might be related to disability and pain, or vice versa. However, it would not be right to make a definitive decision about the mental status of patients based only on one questionnaire. This situation only gives us a clue about the mental state [33].

The small number of patients and short follow-up period can be considered the most important limitations of the study. Our primary aim was the presence of central sensitivity and since part B is difficult to measure and evaluate [27], we did not use it. Therefore, additional diseases that may occur with HACS may affect the treatment response. Another limitation is that the patients’ analgesics were not evaluated in detail. Furthermore, QST, which is believed to be the most sensitive technique for the evaluation of central sensitization, was not used in our study because of its impracticality. Ultimately, the main strengths of this study are its prospective design, homogeneous patient population, and, to our knowledge, being the first study to investigate the effects of HACS on the treatment success of lumbar TFESI.

5. Conclusion

The presence of HACS has a negative effect on pain scores, disability, and mental state in patients undergoing TFESI. In this respect, the presence of HACS should not be ignored while planning the treatment of patients who will receive lumbar TFESI injections.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Informed consent

Informed consent was obtained from all subjects prior to enrollment.

Ethical approval

The study was approved by the Sisli Hamidiye Etfal Training and Research Hospital Ethics Committee on 31 December, 2019 (number 1361).

Author contributions

Conceptualization: TS, RS, ECÖ; Data collection and analysis: TS, RS, MS; Writing-original draft: TS, RS, ECÖ, MS; Writing-review and editing: RS, ECÖ. All authors read and approved the final manuscript.

Footnotes

Acknowledgments

The authors have no acknowledgments.

Conflict of interest

The authors declare that they have no potential conflicts of interest regarding the investigation, authorship, and/or publication of this article.

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The effect of human assumed central sensitization on transforaminal epidural steroid injection in chronic lumbar radiculopathy: An observational study

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

2.1 Design and study population

Table 1 Human assumed central sensitization according to sociodemograpic and clinical characteristics of patients

2.3 Statistical analysis

3. Results

Table 2 Pre- and post-procedural NRS, ODI and BDI scores of patients

5. Conclusion

Funding

Informed consent

Ethical approval

Author contributions

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Human assumed central sensitization according to sociodemograpic and clinical characteristics of patients

Table 2
Pre- and post-procedural NRS, ODI and BDI scores of patients