A Retrospective Analysis of the Effects of Different Analgesics on the Pain and Functional Recovery of Patients with Traumatic Thoracolumbar Fractures in the Peri-Treatment Period

Background: There are few literatures analyze the effects of traumatic thoracolumbar vertebral fractures on prognosis pain and functional recovery from the perspective of analgesics used in the perioperative period, and lack of clinical guidance on the application of analgesics for its surgery. Objective: To analyze the effects of peri-treatment analgesics on pain and recovery status of patients with thoracolumbar fractures combined with network pharmacology. Methods: 719 patients with thoracolumar fractures were collected and divided into acetaminophen dihydrocodeine group (n=476), celecoxib group (n=130) and etoricoxib group (n=113) according to the use of analgesics. The visual analogue scale (VAS) was used to measure the degree of pain the number of days of the use of three analgesics, the postoperative Oswestry dysfunction index (ODI) scores and some Japanese orthopedics Association score (JOA) were recorded. The targets of three analgesics were obtained by Drugbank, and the target of acute pain caused by fracture is obtained by Genecards, then Venn diagram of the intersection genes was drawn through Venn. Protein interaction mapping (PPI) was obtained by using STRING database, the functional enrichment analysis of Gene Ontology (GO) and the enrichment analysis of Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway were carried out based on Metascape database. Results: The codeine group was higher than celecoxib and etoricoxib groups in the number of days of preoperative and postoperative analgesic use, VAS score difference on the preoperative and postoperative, and postoperative ODI index (all P<0.01). There exist no statistically conspicuous differences among the three groups in basic characteristics, injury and intraoperative conditions, ODI score except ODI index, three JOA marks, and postoperative walking ability (P>0.05). Identify 3332 disease targets. PPI network analysis identi�ed OPRM1, OPRK1, TRPV1, PTGS1 and PTGS2 as the core targets for acetaminophen dihydrocodeine in the treatment. Conclusion: If multiple analgesic modes are adopted in the perioperative analgesic use, and the use of acetaminophen dihydrocodeine in combination with anti-inammatory analgesics, the duration of analgesic use is expected to be shortened as far as possible to reduce the pain degree in postoperative recovery, providing a reference for the optimal use of anesthetics for clinical traumatic thoracolumbar fractures.


Introduction
Traumatic thoracolumbar fracture is a serious spinal injury that can involve the middle column, resulting in spinal instability, deformity, and nerve function injury.An epidemiological study showed that thoracolumbar fractures accounted for about 80% of spinal injuries (56.09% of lumbar vertebrae, 23.77% of thoracic vertebrae), of which about 18% were burst fractures [1].The main causes of injuries are highenergy injuries, such as tra c injuries, sports injuries, falling from high altitudes, etc.According to the survey, more than 160,000 people in North America are hospitalized for traumatic thoracolumbar fractures every year [2], with the rapid development of transportation and construction industry in China in recent years, the incidence of thoracolumbar fractures is increasing day by day.Every year, tens of thousands of people in China are deeply affected by thoracolumbar fractures, which is not conducive to social and economic development and people's happiness.Among them, the effect of pain treatment is a key factor that affects patients' functional recovery and a happy life.Therefore, the choice of analgesics during the peri-treatment period is particularly important.
In fracture surgery, acetaminophen dihydrocodeine celecoxib and etoricoxib are commonly used in clinical analgesics.Acetaminophen dihydrocodeine is a compound preparation composed mainly of acetaminophen and dihydrocodeine tartaric acid.Dihydrocodeine is a weak agonist for opioid receptors, similar to morphine and codeine in structure, but about 2 times stronger than codeine in analgesic effect, and is not easy to addiction, because it has the advantages of quick analgesic effect, good effect and so on, it is widely used for all kinds of pain, especially in the acute pain caused by fractures.But the disadvantage of its poor anti-in ammatory effect is also obvious [3,4].Acetaminophen, which has analgesic and antipyretic effects, can selectively inhibit the biological production of prostaglandins in the central nervous system through the cyclooxygenase (COX) pathway.Meanwhile, its receptor selectivity for central COX-2 is 4.4 times that of COX-1.The results of Esmailian et al. illustrated that intravenous acetaminophen and morphine have the same therapeutic value in relieving fracture pain, and acetaminophen has a higher success rate of administration [5].
From the effects of the above-mentioned analgesics, it can be understood that different types of analgesics have different analgesic effects on trauma and different effects on patients' recovery.Therefore, this article will focus on analyzing the effects of peri-treatment analgesics on the pain and recovery status of patients with thoracolumbar fractures after surgery, as well as analyzing their analgesic mechanisms through network pharmacology.

Selection and grouping of patients
A total of 719 patients with thoracolumbar fractures from November 2009 to January 2019 were collected from the A liated Hospital of Zunyi Medical University in Guizhou Province.All the patients were treated for thoracolumbar fractures by the same medical group under general anesthesia and underwent posterior unilateral laminectomy with small fenestration and intrathoracic bone grafting.The speci c surgical methods include posterior pedicle screw distraction and reduction, unilateral spinal cord nerve decompression, and vertebral bone grafting and shaping.This study was approved by the Ethics Committee of the A liated Hospital of Zunyi Medical College (2015 Review No. ( 23)) Inclusion criteria: Patients with thoracolumbar fracture Tlics score > 4 (Table 1) [8], under general anesthesia, the posterior unilateral lamina interlamellar space with small fenestration was performed for vertebroplasty in vivo.Exclusion criteria: absence of preoperative statistics from the injured segment.
According to the analgesic drugs used during the perioperative period, the patients were divided into three groups: the acetaminophen dihydrocodeine group (n = 476), the celecoxib group (n = 130), and the etoricoxib group (n = 113).

Statistical methods
The above data are classi ed into quantitative data and counting data according to data characteristics.
Age, height, weight, BMI, injury after how long does it take to start the operation (d), preoperative Tlics score, operation time consuming (h), intraoperative blood loss (ml) and analgesic use preoperative postoperative VAS score, number of days and how long will it take to walk (d), each time walking distance (m), ODI score, ODI index as the quantitative data of single factor analysis of variance, and use it in positive results for multiple comparison, using Bonferroni or Tamhane results to mean ± standard deviation.Gender, age, body type, complications, occupation, altitude of long-term residence, cause of injury, number of injured segments, postoperative walking duration, walking distance and ODI index were grouped as counting data, and chi-square test was used to represent the results in the composition ratio of analgesics use.Rank sum test was used for Frankel classi cation, JOA lumbago, gait, and urine grade data.
In addition, through [25] to search for acetaminophen dihydrocodeine tablets (paracetamol and Dihydrocodeine (PD)), celecoxib and etoricoxib's drug target.Through [26] to retrieve the target of acute pain caused by fracture, use [27] to draw the Venn diagram of the intersection gene.According to the intersection gene information, use the [28] database to obtain the Protein interaction mapping (PPI) of the intersection gene, and use the Metascape database to obtain the GO and KEGG of the target gene.Use Cytoscape to make a disease drug function interaction map.The nal results are represented by Venn diagram, PPI, GO analysis, KEGG analysis, and disease drug function interaction diagram.

Basic characteristics of the patient
There exist no statistical differences in gender, age, BIM, body type, complications, occupational and altitude sex, age, BIM, body type, complications, occupation and altitude among the three groups (p > 0.05, Fig. 1).

Injury and condition assessment of the patient
There exist no statistically conspicuous differences among the three groups in the cause of injury, number of injured segments, time from injury to operation, preoperative Tlics score, Frankel classi cation, operation time and intraoperative blood loss (P > 0.05, Fig. 2).

The use time and pain assessment of analgesics in the peri-therapeutic period
There were statistically signi cant differences in the number of days of use of analgesics and pain related indicators among the three groups.The number of days of use of analgesics before and after operation in the codeine group was signi cantly higher than that in the celecoxib and etoricoxib groups (8.8 ± 0.98 vs 5.05 ± 0.37,8.8± 0.98 vs 5.60 ± 0.54, P < 0.01), and the celecoxib group was slightly lower than that in the etoricoxib group (5.05 ± 0.37 vs 5.60 ± 0.54, P < 0.01, Fig. 2K).
VAS score of the codeine group was obviously higher than that of the other groups (8.10 ± 0.33 vs 6.99 ± 0.09,8.10± 0.33 vs 7.12 ± 0.13, P < 0.01) one day before the operation, and there existed no statistical signi cance between the celecoxib and etoricoxib group (P > 0.05, Fig. 2L).
VAS scores of the codeine group at rest one month after surgery were higher than those of the celecoxib and etoricoxib group (1.64 ± 0.77 vs 1.12 ± 0.75,1.64± 0.77 vs 1.15 ± 0.72, P < 0.01), but there remained no statistical signi cance between the celecoxib and etoricoxib group (P > 0.05, Fig. 2M).
The difference of VAS scores before and after operation in the codeine group was greater than that in the celecoxib and etoricoxib group.(6.45 ± 0.87 vs 5.98 ± 0.75, 6.45 ± 0.87 vs 5.87 ± 0.73, P < 0.01), there was no obvious difference between celecoxib and etoricoxib group (P > 0.05, Fig. 2N)

Recovery after 1 year of follow-up
After the same surgery, the postoperative ODI score and JOA score, ODI personal life, extract, walk, sit, stand, sleep, sex, social life, the number of tourism, the ODI index section, ODI index grouping, JOA lumbocrural pain, gait, and postoperative bladder function and how long will it take to walk and postoperative walking distance there were no statistical signi cance (P > 0.05, Fig. 3B-J, Fig. 3L, Fig. 3M, Fig. 4).In terms of ODI-1 pain score, the codeine group was signi cantly higher than the other two groups (1.06 ± 0.47 vs 0.87 ± 0.59, 1.06 ± 0.47 vs 0.88 ± 0.58, P < 0.01), and the comparison between celecoxib and etoricoxib group was not signi cant (P > 0.05, Fig. 3A).
The ODI index of the codeine group was higher than that of the celecoxib group (14.44 ± 4.35 vs 13.35 ± 4.39, P < 0.01), and there existed no obvious differences among the three groups (P > 0.05, Fig. 3K).

Disease targets and drug targets and their Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) analyses
Through network pharmacology, we will further analyze the targets of the above-mentioned drugs in the treatment of acute pain, and explain the characteristics of the above-mentioned analgesics from the analgesic mechanism.3332 targets of acute pain caused by fracture were retrieved through Genecards, and 7 targets of acetaminophen and dihydrocodeine were obtained through Drugbank database, namely PTGES3, OPRD1, PTGS2, OPRK1, TRPV1, OPRM1, PTGS1; Celecoxib There are 5 targets, namely PDPK1, PTGS2, CDH11, CA2, CA3; 1 target of etoricoxib, namely PTGS2.According to the protein interaction map (PPI), OPRM1, OPRK1, TRPV1, PTGS1 and PTGS2 are directly related.Statistics show that acetaminophen and dihydrocodeine are mainly involved in neuropeptide binding, peroxidase activity, oxidoreductase activity, antioxidant activity, calcium channel activity, heme binding, calcium ion transmembrane transport protein activity, ion-gated channel activity and other biological processes.The main KEGG pathways are arachidonic acid metabolism, stimulation of interactions in nerve tissue, and serotonin-containing synapses.Celecoxib is mainly involved in biological processes such as carbon oxygen lyase activity, lyase activity, oxidoreductase activity, peroxidase activity, heme binding and tetrapyrrole binding.The main pathway of the drug KEGG is nitrogen metabolism.Etoricoxib is mainly involved in biological processes such as oxidoreductase activity, antioxidant activity, dioxygenase activity, heme binding and tetrapyrrole binding.The main pathways of KEGG related to the disease are VEGF, IL-17, NF-kappa B signaling pathway, tumor necrosis factor signaling pathway, and arachidonic acid metabolism.

Discussion
It can be seen from the results that acetaminophen dihydrocodeine have been used for a longer duration of time within the peri-treatment analgesia of traumatic thoracolumbar fractures, the preoperative pain level is higher, and the pain improvement is relatively more during postoperative recovery, but the overall VAS score was still high after the operation, and the pain index was still high one year after the operation, and the functional recovery was poor.In addition, the timeliness of acetaminophen and dihydrocodeine is relatively poor, and an attempt is made to increase the use time of analgesics to greatly reduce pain.
According to network pharmacology analysis, it is concluded that acetaminophen and dihydrocodeine mainly block central nerve pain by controlling calcium channels and so on.Celecoxib and etoricoxib play an analgesic effect mainly by controlling in ammation-related pathways and inhibiting the release of in ammatory factors.Therefore, it is believed that it may be the ability of celecoxib and etoricoxib to control in ammation, but not the ability of acetaminophen dihydrocodeine, that the clinical effect of postoperative pain and functional recovery in the acetaminophen dihydrocodeine group is worse than that in the other two groups.

Analysis and discussion of case results
This study found that acetaminophen dihydrocodeine may be used for a long time before surgery due to the lack of anti-in ammatory effects, which makes postoperative patients more painful.The pain caused by traumatic fracture is mainly caused by periosteum tear to the mechanical sensitive nerve bers that supply the bone, bleeding at the broken end of the fracture, hyperemia and edema of local soft tissue to stimulate peripheral nerves and in ammatory pain, etc [9].Acetaminophen dihydrocodeine is a compound preparation, acetaminophen has analgesic and antipyretic effects, but it is generally believed that it lacks anti-in ammatory effects [10].Dihydrocodeine is metabolized into dihydromorphine, and the drug targets TRPV1, OPRM1H and OPRD1 mainly inhibit the release of neurotransmitters by controlling the voltage-gated calcium channel activity to reduce calcium ion current and increase potassium ion conductivity, thereby blocking the delivery of pain [11].As an opioid alkaloid, acetaminophen dihydrocodeine, similar to morphine, mainly ACTS on the central nervous system.By binding to opioid receptors in the presynaptic membrane and postsynaptic membrane of pain-sensing nerve afferents, it inhibits the release of substance P and thus blocks pain signals from being sent into the brain.The drug is effective in reducing the pain of nerve damage caused by fractures, but is less effective in treating in ammation caused by trauma.The main target of celecoxib, PTGS2, prevents the production of in ammatory prostaglandins by inhibiting the expression of COX-2 in the peripheral and central regions, inhibits pain hypersensitivity and achieves dual anti-in ammatory and analgesic effects.Peripheral tissue injury inhibits the production of in ammatory factors, reduces COX-2 mediated in ammatory response in the central center, increases the pain threshold, and inhibits the production of pain sensation [12,13].Etoricoxib, also a COX-2 inhibitor drugs, has the same e cacy and safety as celecoxib, and the comparison of VAS scores of the two in the table showed no statistical difference.Therefore, acetaminophen double hydrogen codeine and celecoxib and relying on exam yesterday two non-steroidal anti-in ammatory drugs compared to its anti-in ammatory effect is poor, may result in traumatic thoracolumbar fractures especially after surgery incision healing process in the process of in ammation persists, so acetaminophen double hydrogen codeine in preoperative use of postoperative days were greater than the other two kinds of pain relievers.Our results suggest that clinical use of this drug should be cautious because its lack of anti-in ammatory effects can lead to persistent in ammation and increase the time of analgesic use.In clinical practice, it is not advisable to enhance the analgesic effect by increasing the duration of the usage of acetaminophen dihydrocodeine.Although it is not easy to become addicted to it, long-term use of analgesics may also cause patients to become addicted to it, and the drug has side effects on liver and kidney function.

Network pharmacology analysis of analgesia mechanism
In this paper, the network pharmacology analysis indicates that acetaminophen dihydrocodeine mainly blocks central nerve pain by controlling calcium channel and has no effect on fracture healing.Celecoxib and etoricoxib play an analgesic role by controlling in ammation-related pathways and inhibiting the release of in ammatory factors, and may have a positive effect on fracture healing.
In this study, all the three analgesics have PTGS2 common intersection targets with the acute pain caused by fracture, so PTGS2 is an important target for this acute pain.The PTGS2 protein, named peroxidase synthase 2 in prostaglandin, converts arachidonic acid into prostaglandin H2 (PGH2), which is an important step in the synthesis of prostaglandin.The double cyclooxygenase and peroxidase in the prostaglandins biosynthesis pathway are a kind of C20 lipoproteins mainly derived from arachidonic acid, which have a special role in in ammatory response [14][15][16].In addition, in the synthesis process, 2arachidonic acid glyceride is metabolized to produce PGH2 glyceride, which can lead to pain response [17].Cyclooxygenase activity oxidized arachidonic acid to intracorporate prostagtin G2 (PGG2), and peroxidase activity reduced PGG2 to intracorporate peroxidase PGH2 [18,19].The binding site of Non-Steroidal Antiin ammatory Drugs (NSAIDS) corresponds to the active site of cyclooxygenase.
GO enrichment analysis con rmed that acetaminophen dihydrocodine mainly regulates neuropeptide binding, peroxidase activity, redox enzyme activity, calcium channel activity, heme binding, calcium ion transmemmeteral transporter activity and other biological processes to block the transmission of pain signals in the central nervous system.CA2, which is essential for bone resorption and osteoclast differentiation at the celecoxib intersection target, is analgesic, anti-in ammatory and bene cial to fracture healing.Celecoxib and etoricoxib are mainly involved in biological processes such as redox activity, antioxidant activity, dioxidase activity, heme binding and tetrapyrrole binding.The main pathways of KEGG associated with the disease were VEGF, IL-17, NF-Kappa B, TNF signaling pathway, and arachidonic acid metabolism.VEGF signaling pathway is the upstream pathway of the MAPK signaling pathway, which controls its activation or not.MAPK signaling pathway plays a vital role in growth reproduction, cell differentiation, cell movement and other cell activities, and is one of the important pathways in the dynamic balance of bone development and bone metabolism, and is involved in the regulation of osteoblasts' metabolism and in ammatory response [20].The activation of MAPK signaling pathway can accelerate the maturation cycle of osteoblasts, stimulate the release of alkaline phosphatase, and accelerate the deposition of calcium, which is conducive to fracture healing [21].Moreover, the activation of VEGF signaling pathway is also conducive to the regeneration of blood vessels and the reconstruction of blood circulation in the fractured part [22].IL-17 signaling pathway is a pro-in ammatory pathway, which is related to various biological activities such as in ammatory development and immune response, and can induce the differentiation and maturation of pre-osteoblastic cells independent of GSK-3 cell/catenin activity [23].The NF-Kappa B signaling pathway regulates genes involved in immunity, in ammation, and cell survival [24].Therefore, it can be known that celecoxib and etoricoxib are mainly involved in cellular immune response, in ammatory response and bone cell metabolism to relieve the pain of traumatic fracture and achieve good postoperative fracture recovery with low pain degree.Hence, the results of network pharmacology analysis can explain the phenomenon that the therapeutic effect of acetaminophen dihydrocodeine in clinical retrospective analysis is better than celecoxib and etoricoxib.
This study retrospectively analyzed the effect of analgesics on postoperative recovery of 719 thoracolumbar fracture patients in the A liated Hospital of Zunyi Medical University in Guizhou Province from November 2009 to January 2019, and the analgesic mechanism was analyzed by combining network pharmacology.The results manifested that if the multi-unit analgesic mode is used during the use of analgesics in the peri-treatment period, and the use of acetaminophen dihydrocodeine in combination with anti-in ammatory analgesics, it is expected to shorten the use time of analgesics as much as possible to reduce postoperative.The degree of pain during recovery provides a reference for the high-quality use of anesthetics for clinical traumatic thoracolumbar fractures. Tables

Figure 2 Assessment
Figure 2

Table 1
Tlics standard scale FiguresFigure 1 Basic features of the patient A. Number of different genders; B. Percentage by sex; C. Age value; D. Number of age groups; E. Percentage of different age groups; F. Height value; G. Body weight; H. BMI value; I. Number of different body types; J. Percentage of different body types; K. Number of different occupations; L. Percentage of different occupations; M. Percentage of different comorbidities; N. Number