The analgesic effect of Preemptive multimodal analgesia in Direct Anterior Approach total hip arthroplasty：a randomized double-blind trial

doi:10.21203/rs.3.rs-3987823/v1

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The analgesic effect of Preemptive multimodal analgesia in Direct Anterior Approach total hip arthroplasty：a randomized double-blind trial

https://doi.org/10.21203/rs.3.rs-3987823/v1

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Background: The purpose of this experiment was to investigate the effect of PMA protocol (pericapsular nerve group (PENG), oxycodone and parecoxib) postoperative pain in direct anterior approach total hip arthroplasty (DAA-THA) patients with consistent preoperative pain thresholds .

Objectives:To explore effective preemptive multimodal analgesic protocols to meet the needs of enhanced recovery after surgery (ERAS) in joint surgery.

Study Design:This study was a prospective, single-center, randomized, double-blind trial with four groups.

Setting:In the Changzhou Second People's Hospital a single institution.

Methods: We recruited 160 patients with consistent preoperative pain thresholds to enter the final study analysis, and according to the criteria were randomly divided into four groups: the placebo group (n = 38), parecoxib group (n = 39), oxycodone group (n = 43), and combination group (n = 40). According to the corresponding PMA protocol, all groups were given advanced analgesic drugs at 30 min before surgery and PENG after 30 min. The main result of the pain VAS scores at rest and during exercise, and secondary results postoperative inflammation index( erythrocyte sedimentation rate and C-reactive protein ), 5-hydroxytryptamine(5-HT) ,postoperative rescue opioids medicine (total volume and time), first walking time, postoperative adverse effects, postoperative delirium occur and length of stay (LOS) after DAA-THA .

Results: The postoperative VAS scores in the combined group were significantly lower than those in the other three groups. The VAS scores between during exercise and at rest were significant differences in the four groups Within 48 hours after surgery (P < 0.05). The combination group had the lowest cumulative opioids dose and the first rescue analgesic is longer within 48 hours after surgery (P < 0.05). The inflammation indexes and 5-HT changes within 48 hours after surgery, the first walking time and the postoperative LOS of the combination group had significantly improved compared with the other three groups (P < 0.05). The postoperative adverse effects were no significantly difference in the four groups within postoperative 48 hours.

Conclusions: The PMA regimen of oxycodone associate with parecoxib and assist PENG was effectively improved perioperative pain (acute), reduced the cumulative dose of postoperative opioids and promoted patient recovery after DAA-THA.

PMA

DAA-THA

post-operative pain

ERAS

PENG

oxycodone

parecoxib

With the change of population aging, bone and joint diseases are increasing with each passing year. The number of patients undergoing THA is rising, in order to improve the surgical treatment effect and accelerate the postoperative recovery, surgeons have explored a new protocol that DAA-THA. In recent years ,studies have shown that DAA-THA is significant improvements in quality of life outcomes, therefore, which is being accepted by more surgeons[1]. After the ERAS concept was proposed, the researchers found that the total joint replacement patients’ LOS and postoperative complications were decreased[2, 3]. The ERAS concept is gradually being adopted by the clinicians. Therefore, the present experiment is considered that combining ERAS and DAA-THA may further improve the therapeutic efficacy. Postoperative pain was evident in patients undergoing hip arthroplasty, the application of postoperative opioids is more and more common, recent years found that opioids have abuse, more side effects and higher medical costs, the reduction of postoperative opioids requirements is being considered. To reduce postoperative opioids requirements, speed recovery and reduce complications, many protocols in total hip arthroplasty (THA) used multimodal analgesia (MMA) and preemptive analgesia[4–6]. As the researchers explore the analgesic mechanism, recently, exploring effective PMA has a high interest.

MMA concept is acting the different pharmacologic mechanisms or pain conduction pathways to provide analgesia ,the administration using two or more drugs or two or more techniques[7]. The purpose of MMA is to target all pathways involved in the pain response, to reduce the opioid medication use and side effects. The concept of preemptive analgesia was presented by Crile at the previous century on the basis of clinical observations[8]. Preemptive analgesia mechanism is proposed by Woolf, which define is as before nociceptive stimulus arises giving an analgesic intervention to prevent the pain sensitization, and this protocol has been proved that is more effective than the same intervention given after the surgery[9, 10]. By exploring the relationship between preemptive analgesia and surgical pain, found that patients were given preemptive analgesia protocol can decrease the release of inflammatory factors (cytokines and prostaglandins), prevent incisional inflammatory injuries. So preemptive analgesia was thought can decrease the incidence of postoperative hyperalgesia[10]. Multimodal preemptive analgesia (MPA) is the combination of MMA and preemptive analgesia concept .PMA protocol was introduced in the total joint arthroplasty, and widely adopted in conjunction with evolving regional anesthesia techniques. Relevant studies show that the postoperative analgesic of using multimodal advanced analgesia before total joint replacement surgery has positive effects in decreasing the use of opioid medicines, decreasing postoperative pain and facilitating postoperative recovery[11]. The early study of preemptive analgesia and MMA focusing on patients’ who undergoing the same type of surgery postoperative pain response, but different populations with preoperative pain response before surgery is abhorrent and unbeknown[12]. The individualized pain treatment plan is designed to make a plan according to the patient's own situation, it can better conform with ERAS concept, so this study tried to measure patients with preoperative pain threshold and screen classify subjects .

Previous studies have shown that PENG can effectively relieve postoperative pain in patients and has no effect on muscle strength, but it has little effect on the lateral femoral cutaneous nerve and sciatic nerve[13, 14]. Oxycodone preemptive analgesic is inconsistent in postoperative analgesic efficacy, total joint surgery patients experienced more postoperative pain, consumed more opioid medicines, and affected postoperative recovery, but in terms of other surgical types ,the postoperative analgesic effect was remarkable[15, 16]. Whether consideration is related to inconsistent preoperative pain response. Parecoxib preemptive analgesia study showed that nonsteroidal anti-inflammatory drugs (NSAIDs) drugs have significant effects in inhibiting the postoperative inflammatory response, but its postoperative analgesia time is short, mostly within 24H after surgery[17, 18]. At present, the postoperative analgesic effects of preemptive analgesia with parecoxib is still controversial for the postoperative acute pain in the aftermath of 24 hours after surgery[19]. Similar studies are not in the application of oxycodone combined with parecoxib and assisted peripheral nerve block for multimodal preemptive analgesia protocol. Thus, the purpose of this experiment was to evaluate the effect of PMA regimen of oxycodone (1kg mg^− 1) associate with parecoxib (40mg) and assisted PENG on postoperative analgesic effect in patients with consistent preoperative pain thresholds.

2.1 Study Ethical Approval

The randomized A prospective, single-center, double-blind trial. Patients undergoing DAA-THA in the Changzhou Second People's Hospital a single institution between June 2022 and May 2023. Its aim is to compared oxycodone (1kg mg^− 1) combined with parecoxib (40mg) and assisted PENG PMA in DAA-THA postoperative analgesic effect. The study was approved by the Medical Ethics Committee of The Changzhou Second People's Hospital (15/04/2022, [2022] YLJSA008) .All patients in the trail written informed content and registered at clinicaltrials.gov (05/23/2023, ChiCTR2300071934).

2.2 Participants, Study Design, and Randomization

The researchers screened patients with DAA-THA and informed patients the study experiment. All included subjects provided with informed consent and signed during the preoperative visit. Preoperative screens included completion of the preoperative pain threshold determination and opioids and NSAIDs use. Inclusion criteria were patients who met the diagnostic criteria for hip fracture and femoral head necrosis require total hip replacement surgery, Age 19–90 year, ASA grade I-III, BMI18.5-30Kg cm^− 2, no use opioids treatment and NSAIDs treatment before surgery, voluntary participation in the trial and provide the informed consent. Exclusion criteria were patients with severe disease (cardiopulmonary disease, severe brain, liver, kidney and other serious systemic diseases) (ASA > III) who required postoperative transfer to intensive care unit (ICU) for further treatment after surgery, combined with fractures in other sites, a history of chronic opioids abuse, allergy to experimental drugs and metabolites.

This study was a prospective, single-center, randomized, double-blind trial with four groups. Before the operation, patients who accord the inclusion criteria were randomized by the operating room nurse prior to surgery by the complete randomization method were divided into four groups and numbered: the placebo group (A), parecoxib group (B), oxycodone group (C), and combination group (D). The allocation ratio was set at 1:1:1:1. The patients and the anesthesiologist did not know the grouping and medication status. On the day of surgery, the anesthetic nurse opened the envelope and prepare the corresponding dose of the drugs to the anesthesiologist. After each administration of the medicine, closely monitored for patients’ drug adverse effects. Until after end of data analysis, the randomization envelope was preserved by the nurse to secure the blinding for all study participants and patients.

2.3 Outcome Variables

Primary outcome was VAS scores during exercise and at rest at post-anesthesia care unit (PACU), 3, 6, 12, 24 and 48 hours after surgery.(0: no pain, 10: the worst possible pain).

Secondary outcomes were included : (1) Changes in pain within 48 hours after surgery; (2) At before and after surgery 24 hours measured with 5-hydroxytryptamine (5-HT) ,C-reactive protein (CRP, mg L^− 1) and erythrocyte sedimentation rate (ESR, mm h^− 1) to evaluate pain and inflammatory responses; (3)The intraoperative total amount of sufentanil (ug) and the postoperative remedial analgesic opioids dosages and time(converted to morphine equivalent) ; (4) The postoperative complications ,the post-operative nausea and vomiting (PONV), urinary retention, deep vein thrombosis (DVT), postoperative delirium and sedation; (5) The other indexes included the postoperative length of stay (LOS), time of muscle strength recovery, the first ambulation session and correlation analysis among the indicators.

2.4 Preoperative pain thresholds Status

Using a nerve stimulator for plexus anesthesia (Simplex HNS-12) (Registration certificate number: National equipment registration 20153211252) to measure patient pain threshold. Stimulation pulse current: 0-5.0mA (within the range of 5 mA), SENSe sense stimulation mode frequency: 3 HZ. Measuring method: selecting the patients affected arm, chest wall and hip to measure the pain perception threshold. After the local application of alcohol for disinfection, the electrodes were fixed, the pain threshold detection frequency was 3 HZ, stimulation intensity (1–5) starts at 1, increase of 0.25 mA for every 2s, until the patient tilled the test site had electric current stimulates pain production, the stimulation intensity is the pain threshold at the site. Finally, the average of the pain threshold of the three sites was taken as the final pain threshold of the patient. Pain threshold determination in this experiment was performed preoperatively.

2.5 Study drug and Perioperative Protocol

Patients open peripheral veins of upper limbs by an operating room nurse 30min before the start of surgery. After the anesthesia nurse opened the coded envelope, according to the patient's weight to extract the corresponding experimental drugs, and the anesthesiologist unknowingly injected them to the patient. All patients were given PENG at 30min after drug injection, followed by general anesthesia. Earlier research showed that oxycodone (1mg Kg^− 1) and parecoxib (40mg) sodium as a single preoperative dose administered was no safety problems[15, 20–22]. All patients who received the DAA-THA were given general anesthesia by senior anesthesiologists and were performed by the senior doctors in the same group, the anesthesiologists and doctors with more than ten years of experience. After entering the operating room and routine monitoring. Oxygen was supplied via a face mask at a rate of 4–6 l min^− 1. The anesthesia induction: intravenous injection (I.V.) administered dexmedetomidine, remazolam, etomidate fat emulsion and sufentanil and rocuronium bromide. Tracheal intubation was performed after the patient had had muscle relaxation. The anesthesia maintained: the respiratory management by mechanical ventilation, and the parameter setting with a tidal volume (TV) and frequency to maintaining the end-tidal carbon dioxide (PETCO₂) between 35 and 45 mmHg. Anesthetic with a propofol and sevoflurane. After the start of the operation, according to the patient's blood pressure to add the amount of sufentanil and according to the metabolic time of muscle relaxants to given intermittently in muscle relaxants. According to common clinical doses to use hemodynamic medication: ephedrine Injection, metaraminol Bitartrate Injection, landfill hydrochloride for Injection. When the start of subcutaneous and skin closure, the sevoflurane was stopped, the time approximately 30min earlier than the discontinuation of propofol. After surgery with acetaminophen 400 mg every 6 h. After the surgery, if the patients had VAS score > 4, 0.1g Tramadol was given as remedial analgesia or equivalent doses of other opioids.

2.6 Statistical Analysis

Sample size was calculated based on data from previous studies[12]. By calculation, 24 patients for each group and 96 patients for four groups. Considering the follow-up rate loss of 20%, therefore, we at least needed to recruit 116 patients in the final data analysis. Data analysis using SPSS 25.0 statistical software (version 25.0; IBM, USA) and plotted using the original software.

The primary outcome was the pain VAS scores during exercise and at rest within postoperative 48 hours, by using the chi-square test to analyze and to see if there were differences. Patients lost to follow-up after surgery were excluded. All analyses were performed using SPSS Statistics version 25.0. The two-sided P < 0.05 was defined as statistical significance. Categorical data expressed as numbers (percentages), and using chi-square (x²) or Fisher tests to analyze. Continuous quantitative data were distributed to use t-test and described as mean and standard deviation (x ± s). Multiple comparisons between the groups were used Bonferroni. The P-values were considered as statistically significant if P-value < 0.05 in the primary outcome.

In the study, June 2022 and May 2023, a total of 172 patients were enrolled, stopped the surgery 4 patients, the preoperative VAS score was too high 2 patients. Consequently, 166 patients were included in the study. The preoperative pain threshold was determined, 1 patient in A group and 2 patients in B group were too low, so to be exclude. Postoperative follow-up loss 3 patients in D group to be excluded. Consequently, 160 patients were included in final analysis. (Fig. 1.)

3.1. Patient Clinical Characteristics.

There was no significant different in the general data among the four groups (Table 1).

Table 1

Patient Clinical Characteristics
Characteristic	Group A	Group B	Group C	Group D	P-value
	(N = 38)	(N = 39)	(N = 43)	(N = 40)
Age (y)	68.9 ± 11.5	73.9 ± 13.1	68.6 ± 10.7	69.4 ± 10.8	0.171
sex (M/F)	22/16	17/22	21/22	14/26	0.227
ASA (I/II/III)	5/30/3	3/31/5	4/34/5	4/32/4	0.981
BMI (Kg/m²)	23.7 ± 2.5	22.5 ± 3.0	23.1 ± 2.5	25.3 ± 2.8	1.439
Surgery Side (right/left)	21/17	20/19	27/16	30/10	0.143
Pain threshold (mA)	3.61 ± 0.23	3.66 ± 0.17	3.58 ± 0.23	3.55 ± 0.24	0.593
VAS pain score (before surgery)
rest	2.29 ± 0.65	2.26 ± 0.64	2.37 ± 0.62	2.45 ± 0.82	0.593
act	5.50 ± 0.83	5.56 ± 0.79	5.70 ± 0.77	5.55 ± 0.99	0.746
Preoperative Diagnosis (FNF/OHFN)	20/18	27/12	25/18	28/12	0.303
Time of surgery (min)	122.1 ± 21.4	113.7 ± 14.5	114.4 ± 22.3	116.0 ± 19.3	0.227
ASA, American Society of Anesthesiologists; FNF, Femoral Neck Fracture; ONFH, osteonecrosis of femoral head.

3.2. The VAS Scores and The use of Opioids .

The VAS scores as shown in Table 2 and Fig. 2, in the four groups were evidently difference (P < 0.05) upon movement and at rest. The combination group (D Group) VAS scores were lower than the other three groups at postoperative PACU ,6, 12, 24 and 48 hours (Table 2)(Fig. 2(a)(b)). Meanwhile, the study observed that the VAS scores in the four groups showed a downward trend upon movement over time within postoperative 48 hours (P < 0.05), only the parecoxib group (B Group) from 12 to 24 hours after surgery had a small rise (Fig. 2(a)(b)). The postoperative opioid cumulative dose in the combination group (D Group) (7.00 ± 14.71 mg) was significantly less than the other three groups within postoperative 48 hours (P < 0.05) (Table 2). The survival analysis chart showed that the proportion of patients in the combination group who did not receive rescue analgesia in a short postoperative period was high, therefore, time of the first rescue analgesic in the combined group was significantly later than the other three groups (P < 0.001)(Fig. 3).

Table 2

Postoperative VAS pain scores and the cumulative dose of opioids.
	Group A (n = 38)	Group B (n = 39)	Group C (n = 43)	Group D (n = 40)	F/X2	P-value
VAS pain score (act)
PACU	2.45 ± 0.602	2.26 ± 0.498	2.19 ± 0.450	2.13 ± 0.404	3.15	0.027
3H	2.74 ± 0.489	2.77 ± 0.742	2.79 ± 0.638	2.55 ± 0.504	1.205	0.31
6H	3.37 ± 0.819	3.10 ± 0.680	3.12 ± 0.586	2.7 ± 0.564	6.75	< 0.001
12H	3.58 ± 1.154	3.72 ± 1.538	3.05 ± 1.112	2.75 ± 0.707	6.03	0.001
24H	3.32 ± 1.042	3.08 ± 0.929	2.91 ± 1.019	2.68 ± 1.047	2.86	0.042
48H	2.76 ± 0.714	2.56 ± 0.641	2.35 ± 0.573	2.28 ± 0.506	5.13	0.002
VAS pain score (rest)
PACU	1.37 ± 0.489	1.26 ± 0.442	1.14 ± 0.351	1.1 ± 0.304	3.60	0.015
3H	1.55 ± 0.504	1.54 ± 0.505	1.58 ± 0.499	1.40 ± 0.496	1.05	0.372
6 H	2.00 ± 0.329	1.87 ± 0.469	1.93 ± 0.402	1.6 ± 0.496	6.60	< 0.001
12 H	2.16 ± 0.945	2.46 ± 1.166	1.98 ± 0.963	1.69 ± 0.591	5.82	0.001
24 H	2.03 ± 0.854	2.00 ± 0.761	1.65 ± 0.752	1.58 ± 0.844	3.35	0.021
48 H	1.55 ± 0.602	1.46 ± 0.555	1.33 ± 0.566	1.2 ± 0.464	3.12	0.028
Opioids cumulative dose
Operative (ug)	36.32 ± 5.54	35.13 ± 4.79	37.09 ± 5.145	34.75 ± 4.66	1.88	0.135
Postoperative (mg)	24.21 ± 25.11	16.41 ± 19.93	12.56 ± 19.53	7 ± 14.71	5.06	0.002
Data expressed as Mean ± Standard deviation.
H: hours;ACU, post-anesthesia care unit; Operative, Operative sufentanil; Postoperative, postoperative Tramadol within 48H converted to morphine equivalent^[23].

3.3 CRP, ESR, 5-HT

Before surgery, there was no significant difference in CRP values (P > 0.05) (Table 3).Postoperatively, there were statistical differences between the four groups, and in the combination group (D Group), the magnitude of the increase in CRP level was obviously lower than in the placebo group (A Group) and oxycodone group (C Group) at 24 hours after surgery (P_AD=0.002, P_CD=0.013, < 0.05) (Table 3) .Among the four groups, the preoperative ESR level (P = 0.256) and within postoperative 24 hours ESR level (P = 0.067) was no significant difference (Table 3). The difference in 5-HT between patients before and after surgery was statistically different between the four groups, and the within-group comparison showed that the parecoxib group and the combined group were significantly increased compared with the placebo group(P_AC=0.006, P_AD=0.002, P < 0.05) (Table 3).

Table 3

Preoperative and Postoperative CRP, ESR and 5-HT
	Group A (n = 38)	Group B (n = 39)	Group C (n = 43)	Group D (n = 40)	F/X2	P-value
CRP
before	14.96 ± 15.24	22.81 ± 30.32	20.68 ± 19.15	24.75 ± 32.3	1.085	0.357
after	39.28 ± 19.86^	32.97 ± 19.48	36.02 ± 22.45^	25.69 ± 10.99#*	3.828	0.011
ESR
before	27.16 ± 16.33	32.39 ± 19.69	30.41 ± 23.94	37.18 ± 27.90	1.365	0.256
after	13.63 ± 14.78	22.44 ± 21.37	22.02 ± 17.07	17.00 ± 13.67	2.436	0.067
5-HT
difference	45.71 ± 35.25&^	68.98 ± 36.65#	61.22 ± 37.45	71.07 ± 36.19#	3.843	0.011
#, indicates a significant difference compared with the A group (P < 0.05); &, indicates a significant difference compared with the B group (P < 0.05); *, indicates a significant difference compared with the C group (P < 0.05); ^, indicates a significant difference compared with the D group (P < 0.05).

3.4 Postoperative Recovery Indication

Compared with the other three groups, the postoperative time of first walking and LOS were significantly improved in the combined group (P < 0.05) (Table 4). The first walking time was evidently shorter in the combination group (D Group) than in placebo and parecoxib two groups (A and B) after surgery (P_AD=0.03, P_BD=0.009, < 0.05) (Table 3), however, the time of recovery of myodynamia was longer than the other three groups (P < 0.05). The placebo group (A Group) was shorter than the other three groups. The LOS was obviously shorter in the combined group (D Group) (7.85 ± 1.61) than in other three groups (P < 0.001), and all three groups (B, C and D groups) with preemptive analgesia medicine were shorter than the placebo group (A Group) in LOS (P_AB=0.004, P_AC=0.000, P_AD=0.000, < 0.05) (Table 4).

Table 4

Postoperative Recovery Indication
	Group A (n = 38)	Group B (n = 39)	Group C (n = 43)	Group D(n = 40)	F/X²	P-value
Extubation time(min)	39.34 ± 10.08	40.26 ± 7.43	40.58 ± 5.59	40.38 ± 4.30	0.23	0.874
delayed emergence(Yes/No)	4/34	2/37	2/41	1/39	2.41	0.493
Recovery of Myodynamia(H)	2.69 ± 0.58*^	2.81 ± 0.65	3.03 ± 0.67#	3.07 ± 0.73#	2.99	0.033
First walking time(H)	22.86 ± 9.69^	23.83 ± 14.32^	21.78 ± 6.98	18.21 ± 3.49#&	2.70	0.048
length of stay (LOS) (D)	9.95 ± 2.69&*^	8.33 ± 1.40#	8.35 ± 1.85#	7.85 ± 1.61#	1.02	P < 0.001
Data expressed as Mean ± Standard deviation. LOD, length of stay; Recovery of myodynamia, Patient muscle strength recovered to grade 3.
#, indicates a significant difference compared with the A group (P < 0.05); &, indicates a significant difference compared with the B group (P < 0.05); *, indicates a significant difference compared with the C group (P < 0.05); ^, indicates a significant difference compared with the D group (P < 0.05).

3.5 Postoperative Complications

As shown in Table 5, the incidence of postoperative complications were no significant differences in the four groups (Table 5).

Table 5

Incidence of postoperative complications.
	Group A (n = 38)	Group B (n = 39)	Group C (n = 43)	Group D (n = 40)	X²	P-value
PONV	5(13.2%)	5(12.8%)	5(11.6%)	5(12.5%)	0.49	0.997
Sedation	3(7.9%)	1(2.6%)	4(9.3%)	3(7.5%)	1.908	0.592
Dizziness	2(5.3%)	2(5.1%)	2(4.7%)	2(5%)	0.018	0.999
Urinary retention	2(5.3%)	2(5.1%)	2(4.7%)	1(2.5%)	0.521	0.914
DVT	2(5.3%)	1(2.6%)	1(2.3%)	1(2.5%)	0.676	0.879
Sedation: use the sedation scored to evaluate (< 2 = no, ≥ 2 = have). PONV: Postoperative nauseaand vomiting; DVT: Deep vein thrombosis.

To prevent the moderate or even severe postoperative pain ,the combined application of multiple perioperative analgesic methods may improve the postoperative acute pain in patients with THA .In some study also shown the THA postoperative moderate to severe postoperative pain with large individual differences[24]. So, effective perioperative pain management is necessary to operation and ERAS smoothly implement. Preemptive analgesia and MMA are important methods of perioperative pain management, and can further improve THA patients’ postoperative pain[25]. In order to further explore a more comprehensive perioperative analgesia program ,MPA is gradually stepping into the view of doctors[26]. However, the optimal analgesia regimen about MPA for improve the DAA-THA patients' postoperative pain is still controversial.

The study found that the VAS scores in the combination group (D Group) at rest and act were low compared to other three groups within postoperative 48 hours, and different from the other three groups, the changes in the VAS scores did not fluctuate greatly, which indicated that the combination regimen of the analgesic effect was relatively stable and durable, and this trend was not observed in the other groups. The study also found that the VAS scores during exercise were higher than at rest. The results of the present experiment are in agreement with these results[27–29]. Therefore, we believe that PMA with oxycodone and parecoxib assist PENG may have a better practical application in DAA-THA than using single agent. DAA-THA patients should get out of bed early to enhance recovery after surgery, the analgesia program may be having a positive effect in exercise as soon as possible after DAA-THA.

In recent years, analgesia plan after THA mainly involves various opioid drugs, such as tramadol, fentanyl, sufentanil and morphine and so on. Opioids drugs mainly exert pharmacological effects on the central and peripheral pain centers, and achieve the analgesic effect by inhibiting the production, amplification and transmission of pain factors^{[30, 31]}.However, with the massive use of opioids, researchers gradually found out opioid drugs have many bad effects, such as PNOV, drug dependence and abuse ,urinary retention, excessive sedation, and respiratory depression ,while also increasing LOS and medical costs[31]. The DAA-THA patients were mostly elderly patients, older people have a slow metabolism and a poor tolerance to drugs. And study have found that the incidence of opioids adverse effects was evidently higher in elderly patients[32]. The goal of PMA is to improve postoperative pain and reduce the amount of opioids to improve accelerate pati[3].In the combination group, the cumulative dose of opioids was converted to morphine reduction equivalents within postoperative 48 hours were significantly lower than in the other three groups. These may indicate that a synergistic effect of oxycodone combined with parecoxib PMA regimen to prolong postoperative analgesia, reduce the postoperative opioids cumulative dose and had no effect on the postoperative adverse effects.

The purpose of preemptive analgesia is to prevent hyperalgesia by reducing the central and peripheral pain sensitization, by increasing the pain threshold of patients[33]. However, just using a sort of drug or a kind technology is difficult to achieve. In the combination group, the rising range of postoperative CRP level at postoperative 24 hours was evidently lower than in the other three groups, and had magnitude of the change before and after surgery was smaller than that in the other three groups. Although the ESR level at 24 hours after surgery in the combination group was not evidently different compared with the other three groups, the combination group ESR decrease was greatest before and after surgery than the other three groups. Multiple studies were found by the same findings, in the preemptive analgesia with NSAIDs, which the postoperative CRP level was significantly lower than in the placebo group, this may indicate that a positive effect of NSAIDs in controlling inflammatory levels in the body[34]. The outcome may suggest that lower levels of inflammatory factors may be related to both peripheral and central pain sensitivity, and think about the PMA regimen of oxycodone combined with parecoxib may have a positive action to control inflammatory reaction. However, because the relation of the inflammatory reactions and pain sensitization mechanisms involves multiple factors, this still requires further investigation.

5-HT plays a crucial role in the regulation of centrally and peripherally pain [35] .This study found that the decrease in 5-HT before and after surgery in the combined group was greater than that in the other three groups. This result is consistent with the Yanjun Gao el at. experimental results[36]. This experiment from the difference, 5-HT changes were also evident in the parecoxib group. The study outcome may suggest that the reason combination group postoperative VAS scores during exercise was low because of using two kinds of drugs in patient preoperative have an action of the 5-HT receptor’ agonist and antagonist. However, since the current study of pain mechanism in 5-HT is mostly in the animal experimental stage, the inhibitory and productive pain mechanisms involve multiple factors, so further research in clinical trials.

During the hospital stay, in the combination group, the patients postoperative the first walking time and LOS increased o obviously shorter compared with the other groups. However, the time of Recovery of myodynamia the placebo group was shorter than the experimental groups. On the one hand, considering whether PMA drugs exert synergistic effects with nerve blocking drugs that affect the recovery of muscle strength. On the other hand, considering whether it is related to the amount of intraoperative opioid use.

Limitations of this study. Firstly, the limit is the timing of postoperative VAS pain scores, we cannot determine the possibility that the control of the postoperative acute pain after 48 hours will translate into long-term chronic pain. Second, our estimation of sample size methods may not be accurate. This experiment was a single-center test with a limited sample size. Thirdly, We cannot exclude whether postoperative analgesia with tramadol has an effect on the postoperative analgesic effect, postoperative inflammation index, postoperative complications and postoperative recovery. However, to include subjects into receiving an inferior treatment (without good analgesic effect) is not ethically acceptable. Last, in terms of postoperative complications, most of our subjects were Chinese, and individuals varied between populations from different countries.

The PMA regimen of oxycodone associate with parecoxib and assist PENG was effectively improved perioperative pain (acute), reduced the cumulative dose of postoperative opioids and promoted patient recovery after DAA-THA.

6.Ethical Statement

The study was approved by the Medical Ethics Committee of The Changzhou Second People's Hospital (04/15/2022, [2022] YLJSA008). All patients in the trail written informed content and registered at clinicaltrials.gov (05/30/2023, ChiCTR2300071934).

7.Availability of data and material

The datasets used or analysed during the current study are available from Shiyuan Qi by the email on reasonable request.

8.Competing interests

There are no conflicts of interest.

9.Funding

There is no funding.

10.Authors' contributions

Shiyuan Qi:Study design;Data collection;Wrote the paper;Revised and finally confirmed the manuscript.

Zirui Zhao: Data collation and chart beautification.

Huifang Yun:Revised and finally confirmed the manuscript.

Ziwei Xu:Data collection.

Xiaotong Chen:Data collection.

11.Acknowledgments

Thanks to the research department that participated in the trial (Anesthesiology Department and Joint Surgery Department of Changzhou Second People's Hospital).

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No competing interests reported.

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The analgesic effect of Preemptive multimodal analgesia in Direct Anterior Approach total hip arthroplasty：a randomized double-blind trial

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Abstract

Figures

1. Introduction

2. Methods

2.1 Study Ethical Approval

2.2 Participants, Study Design, and Randomization

2.3 Outcome Variables

2.4 Preoperative pain thresholds Status

2.5 Study drug and Perioperative Protocol

2.6 Statistical Analysis

3. Results

3.1. Patient Clinical Characteristics.

3.2. The VAS Scores and The use of Opioids .

3.3 CRP, ESR, 5-HT

3.4 Postoperative Recovery Indication

3.5 Postoperative Complications

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

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