Percutaneous transforaminal endoscopic discectomy ameliorates postoperative reactive pain in patients with lumbar disc herniation

Background: Approximately one-third patients with lumbar disc herniation (LDH) who accepted traditional discectomy presented with reactive pain few days after operation, and this reactive pain affected short-term clinical outcomes and postoperative early functional exercise. Recent studies demonstrated that this reactive pain may be ascribed to the increased release of inammatory mediators caused by surgical trauma. Percutaneous transforaminal endoscopic discectomy (PTED), one of the minimal invasive spinal surgical techniques, was demonstrated to be obviously associated with less soft tissue trauma. The aim of this study is to investigate the postoperative reactive pain in LDH patients undergoing PTED compared with open discectomy.

interlaminar approach has obtained satisfactory results [5,6]. However, approximately one-third patients who accepted traditional discectomy presented with reactive pain few days after operation [7]. Reactive pain is de ned as the patients with LDH presented with the initial pain relief after surgery followed by the recurrence of similar or more severe pain at the primary site or other sites in lower limbs [7]. Although it will gradually ease and disappear approximately 2 weeks after it appears [7,8], reactive pain may affect short-term clinical outcomes and postoperative early functional exercise. The true mechanism of this reactive pain is unclear, and recent studies demonstrated that increased release of in ammatory mediators caused by surgical trauma may be one of the possible reasons for this reactive pain [7,8].
Percutaneous transforaminal endoscopic discectomy (PTED), one of the minimal invasive spinal surgical techniques, provides a bene cial alternative to conventional surgical approaches to treat LDH [9,10].
Previous studies have demonstrated that PTED is obviously associated with less soft tissue trauma, preservation of dorsal musculature, shorter hospitalization times, reduced perioperative morbidity, and earlier return to work [9,10]. However, fewer studies involving the impact of PTED on the postoperative reactive pain in patients with LDH have been conducted, although this type of study may guide clinicians to explore better treatment that allow better prognoses in patients with LDH.
The aim of this study was to investigate the incidence of the postoperative reactive pain in LDH patients undergoing PTED compared with those undergoing traditional discectomy, and the potential possibilities of reactive pain after discectomy were also analyzed in this study.

Methods:
Subjects: A total of 72 patients with unilateral lumbosacral radiculopathy caused by single-level LDH were included in this study. In the present study, forty-one patients with LDH underwent PTED, and the other 31 patients underwent traditional discectomy described by Caspar with or without laminotomy (Table 1) [5]. All patients were recruited in SongJiang district central Hospital from December 2017 to March 2019. The study protocol was approved by Human Ethics Committees (Songjiang district central hospital, Shanghai, China). All subjects gave informed consent.
The inclusion criteria for patients with LDH includes [11,12] (1) low back discomfort with referral of pain or paresthesias into a single lower limb following an L4/L5/S1 distribution pattern; (2) lumbosacral magnetic resonance imaging (MRI) or computer tomography (CT) that demonstrated unilateral L4/L5/S1 nerve root compression by herniated disc at the L3/4, L4/L5 or L5/S1 level; (3) conventional electrophysiologic studies including normal sensory nerve conduction studies and a needle EMG revealing the presence of disease only on the involved side of abnormal spontaneous activity and/or changes in motor unit action potential in muscles that were innervated by the involved L4/L5/S1 root. (4) Surgical ndings of unilateral compressed herniated discs at the L4/L5/S1 root on the involved side. The exclusion criteria for patients with LDH includes previous spinal surgery, polyneuropathies, plexopathies, focal neuropathies, muscle disorders, cauda equina syndrome, scoliosis, spondylolisthesis, vertebral fractures, and other spinal pathologies.

Surgical procedures:
Open discectomy All patients underwent open discectomy performed by the same spine surgeon experienced in this technique. After the general anesthesia, the patient is placed in a knee-chest position, and intervertebral segment to treat is located by a positioning needle under the C-arm uoroscopy. After performing a paramedian 3-to 4-cm skin incision, a unilateral interlaminar approach is used, and the superior facet is partially removed if needed to provide a good view of the involved nerve root. A small annular incision is performed to remove the herniated disc part before smoothly extracting the mobile disc fragments. The intervertebral space is cleaned by suction without any excessive curettage. Afterwards, the canal is inspected to ensure that there is no more detached disc fragment and that the nerve root is freely mobile after decompression.
Percutaneous transforaminal endoscopic discectomy: All patients underwent PTED performed by the same spine surgeon experienced in this technique. The PTED procedure was performed in the prone position using C-arm uoroscopy under general anesthesia, and the positioning needle trajectory was planned on the preoperative MRI/CT to target the intervertebral foramen. The needle was introduced 10-13 cm lateral to the midline, with the transit corridor in Kambin's triangle, and C-arm uoroscopy was used during needle introduction to validate correct positioning. Then, Sequential reamers (joimax, Irvine, California, USA) were used to enlarge the neural foramen by removing the ventral aspect of the superior facet. The cannula and endoscope were then introduced, and herniated disc material was removed using endoscopic forceps under cold saline irrigation.
Postoperative Management: A drainage tube was placed for 72 hours. Antibiotics were given at postoperative 48 hours to prevent infection, and both hormone and non-steroidal anti-in ammatory drugs were not used in all patients in this study after operation. After one day of bed rest, the patients were allowed to walk with the protection of a waist brace. Lower extremity activities, including the straight-leg raising test, were encouraged. When the patients presented with postoperative reactive pain, the non-steroidal anti-in ammatory drugs were used until the Visual Analog Scale (VAS) are lower than 3.

Assessment of pain:
Lower limb pain in all patients with LDH were measured by VAS scales before and 1 day after operation, and the VAS scales was further evaluated in the patients with reactive pain. VAS is a continuous scale composed anchored by a score of zero, indicated no pain, and a score of 10, represented the worst pain.

Assessment of venous blood and drainage uid samples:
Venous blood samples were obtained before surgery and on the rst, third, and sixth days after operation, and the wound drainage uid was collected from rst to third day after operation. The blood samples were collected and immediately centrifuged at 3000rpm for 10min, and they were then stored at -20°C until assayed. The drainage uid samples were collected and immediately centrifuged at 1500rpm for the rst 15min and 3000rpm for the second 15min, and they were then stored at -80°C until assayed. For the blood samples, white blood cell (WBC) count, interleukin-6 (IL-6), C-reactive protein (CRP) and creatine kinase (CK) were measured. In the drainage uid samples, both interleukin (IL)-1β and IL-6 were measured. To determine the white blood cell (WBC) count, samples were collected in EDTA tubes and analyzed consecutively. Both IL-1β and IL-6 were analyzed by the enzyme-linked immunosorbent assay (ELISA) according to the protocol provided by the manufacturer (R&D Systems, Inc., USA).

Statistical methods:
The measurements were analyzed using SPSS version 18.0 (IBM, USA). Measurements between the cases in two patient groups were compared by the independent t-tests, and the same statistical method was also used to analyze the measurements between the cases with or without reactive pain in both patient groups. The frequencies of postoperative reactive pain between two patient groups were compared by chi-square tests. The correlations between both duration and extent of reactive pain and in ammation related markers in both blood and drainage uid samples were analyzed by Pearson correlation coe cient analysis. In all instances, a P-value < 0.05 was considered signi cant.

Results:
There was no statistical difference in either age or disease duration between patients who accepted PTED or open discectomy (Table 1, P > 0.05), and both VAS scales and all measurements of blood samples were similar between these two patient groups before operation (Fig 1 and 2, P > 0.05).
Compared with the patients accepting open discectomy, those undergoing PTED showed obviously less intraoperative bleeding and drainage (postoperative rst and second days) (Fig 1, P < 0.05). In contrast, there was no difference of operative time and drainage (postoperative third day) between these two patient groups (Fig 1, P > 0.05), and all patients with LDH in both treatment groups presented with similar immediate pain relief after operation (PTED group: 5.3 ± 1.4 vs. 1.6 ± 1.0; Open discectomy group: 5.1 ± 1.1 vs. 1.6 ± 1.2; P < 0.05).
Obviously lower CK and IL-6 in the blood samples were observed in the patients undergoing PTED than those in the patients accepting open discectomy in all postoperative assessments (Fig 2, P < 0.05), and the patients undergoing PTED also presented with signi cantly lower IL-6 and IL-1β in the drainage uid samples compared to those undergoing open discectomy (Fig 3, P < 0.05). Furthermore, similar measurements of both WBC and CRP were observed in both patient groups in all postoperative assessments (Fig 2, P > 0.05).
Importantly, signi cantly greater number of the patients who accepted open discectomy presented with postoperative reactive pain compared to the patients undergoing PTED (13/31, 41.9% vs. 7/41, 17.0%; P < 0.05), and duration of the reactive pain is mildly longer in the open discectomy group than that in the PTED group (Table 2, P < 0.05). Furthermore, both ve patients undergoing open discectomy (5/13, 38.5%) and 2 patients undergoing PTED (4/7, 57.1%) presented with reactive pain at the primary site, and the range of postoperative reactive pain was signi cantly wider than the preoperative pain in the other patients in this study. In addition, in both treatment groups, the patients with reactive pain presented with increased IL-6 and IL-1β in the drainage uid samples, as well as the increased IL-6 in the venous blood samples, compared with those without reactive pain ( Table 2, P < 0.05), and there is correlation between the IL-6 and IL-1β in drainage uid at the postoperative third day and the duration and extent of the reactive pain in both patient groups (PTED: R IL-6 and VAS = 0.81, R IL-6 and duration = 0.79, R IL-1β and duration = 0.81; Open discectomy: R IL-1β and VAS = 0.58, R IL-1β and duration = 0.80; P < 0.05).

Discussion:
The results of this study demonstrated a signi cant difference in the incidence of reactive pain between the patients who accepted PTED or open discectomy, and an obvious correlation between the reactive pain and surgical local in ammatory substances accumulation was also identi ed in this study.
Consistent with previous studies [9,10,13], both less intraoperative bleeding and postoperative drainage, as well as lower CK, were observed in patients undergoing PTED compared to those undergoing open discectomy, suggesting less surgical trauma in PTED patient group. Previous studies demonstrated that nerve root edema caused by intraoperative traction injury may be possible reason for postoperative lower limb pain [14,15]. However, some patients in this study showed obviously more extensive coverage of reactive pain than those supplied by intraoperative decompressed nerve root. Furthermore, recently published studies demonstrated that postoperative reactive pain even may occur at the other sites, not the preoperative involved site, in lower limbs [7,8]. These results collectively argued against the intraoperative over traction of nerve root is the main cause for the postoperative reactive pain.
These are increasing evidences that in ammatory stimulation presented with greater correlation with the radicular pain compared to the mechanical stimulation [1,2,[16][17][18]. Although in ammatory substances in the blood sample are similar between two patient groups in this study, the patients undergoing PTED presented with obviously fewer in ammatory substances in the drainage uid than those in the open discectomy patient group. These ndings suggested that postoperative reactive pain may be mainly ascribed to the stimulation of local in ammatory substance accumulation rather than systemic in ammatory response caused by surgical trauma, which was further supported by signi cant correlation between the in ammatory markers in drainage uid and both the duration and extent of the reactive pain in both patient groups in this study. Therefore, di culty in aggregating of in ammatory substances around the nerve roots after operation may be the main reason for the low incidence of reactive pain after PTED.
According to the previous studies [17,18], there are abundant in ammatory substances in the nucleus pulposus of lumbar intervertebral disc. When the herniated nucleus pulposus is removed, the surrounding annulus tissue around the nucleus will also be destroyed. As a result, the in ammatory mediators of the nucleus pulposus are released and gather around the nerve roots. Different from the open discectomy, PTED is performed under the water boundary during the operation [9,19,20], which may effectively prevent the aggregation of local in ammatory substances thorough continuous irrigation. Furthermore, previous studies demonstrated that in ammatory substances may also be released by the locally damaged tissue around the surgical site [21,22], that may also stimulate the nerve roots and cause reactive pain. Therefore, less in ammatory exudation at the surgical site caused by smaller surgical wounds in PTED may be another reason for reduced aggregation of local in ammatory substances around nerve roots.
When reviewing these ndings, one of the limitations is that in ammatory substances in the drainage uid can only indirectly re ect the local in ammation. Furthermore, another clinical limitation of this study is low sample size. Therefore, more signi cant results might be achieved in future study with establishment of both more suitable marker and an increased number of cases.

Conclusion
The results of the current study support the view that local in ammatory substance accumulation is a potential cause for postoperative reactive pain in patients with LDH. Therefore, perioperative management in patients with LDH should account for local in ammatory response. Importantly, differences in postoperative results between the PTED and open discectomy patient groups suggested that PTED may effectively reduce the local in ammatory substances at the surgical site, reduce the risk of postoperative reactive pain and improve patients' perioperative satisfaction.    In ammation related markers in the blood sample in both patient groups before and after operation. The gure shows that obviously higher CK (C) and IL-6 (D), as well as similar measurements of both WBC (A) and CRP (B), were observed in the patients undergoing open discectomy compared to the patients accepting PTED in all postoperative assessments. PTED: Percutaneous transforaminal endoscopic discectomy; WBC: White blood cell count, CRP: C-reactive protein; CK: Creatine kinase; IL-6: Interleukin-6. *P < 0.05, **P < 0.01, and ***P < 0.001.