Prospective randomized controlled study on improving sleep quality and impact of zolpidem after total hip arthroplasty

Patients with osteoarthritis commonly complain of sleep disturbance that may be due to pain and may also contribute to pain. Osteoarthritic (OA) hip pain is commonly alleviated by total hip arthroplasty (THA) [1]. The goals of total hip arthroplasty (THA) include relieving pain and improving physical function [2, 3].

A successful THA depends on multiple factors, such as patient and prosthesis selection, surgical technique, pain management, and functional exercise [4]. Generally, we can evaluate, qualitatively and quantitatively, how much patients benefit from THA by using Epworth Sleepiness Score (ESS), Pittsburgh Sleep Quality Index (PSQI), Hip disability and Osteoarthritis Outcome Score (HOOS), and visual analog scale (VAS) questionnaire to cover pain relief, functional recovery, and improvement in quality of life.

Zolpidem is short for zolpidem tartrate tablets (STILNOX, Sanofi-Synthelabo, Ltd, France) is a new generation of non-benzodiazepine drugs, which can effectively improve the quality of postoperative sleep in patients undergoing hip and knee arthroplasty and improve the proportion of postoperative fast eye movement and slow-wave sleep but do not change the sleep structure [5, 6]. Zolpidem is a proven safe and effective drug and is used for transient occasional insomnia and chronic insomnia and for repairing disrupted sleep [7]. It helps patients fall asleep quickly and wake up without movement disorders [4].

The prospective randomized, double-blind, controlled, and single-center study is a branch project of the Public Welfare Industry Research Project “Evaluation of the Safety and Effectiveness of Joint Replacement” (No. 201302007) hosted by the Department of Joint Surgery. At the same time, the China Clinical Trial Registration Center carries out prospective registration (registration number ChiCTR-IOR-16007861). The study was conducted in patients waiting for first-line primary unilateral total hip arthroplasty (THA) in the Joint Surgery Department, West China Hospital, Sichuan, between September 2015 and December 2016. The study was approved by the Medical Ethics Committee of West China Hospital of Sichuan University. Prior to the study, the informed consent from patients and/or their relatives were taken from those who were willing to participate.

The study was conducted by a team consisting of a professor, an attending doctor, and a postgraduate student. All staffs in this study were blinded to the study.

A total of 179 participants were eligible; eight patients withdrew as they were no longer interested in the study. Five patients had incomplete perioperative functional activity and pain score data. Three patients were reluctant to take sleep after surgery, and three patients had postoperative poor quality of sleep so they were excluded for the trial. Consequently, 160 participants aged between 26 and 83 years (mean, 66.06 years; standard deviation (SD), ± 8.44) were included, of whom 82% were women and 12% were men. The participants were then randomly allocated into two groups using the Random Number Generator which randomly assigned information into a sealed opaque envelope; the subjects were then randomly allocated into two groups using the Random Number Generator which randomly assigned information into a sealed opaque envelope. Three groups were involved in the current study: researchers, investigators, and outcome evaluators. The study was designed in such a way that each group was blinded to the other group’s assignment. The researchers did not participate in the distribution of the sub-group information into patients’ research kit. Investigators who did not participate in the outcome evaluation issue medication orders (medications or non-medications) and document medication adherence. Drugs were loaded into the opaque no description package. Outcome evaluators did not know random information and grouping information, mainly by senior physicians involved in clinical research to complete. The two groups are termed blank control group and treatment group. The treatment group received either zolpidem or placebo (control group) preoperatively 2–5 days postoperatively.

From September 2015 to December 2016, 160 patients completed the data collection of research-related indicators. The baseline information of the patients in the trial which are shown in Table 1 indicated there was no significant difference in age, body weight, height, and BMI in the control group and treatment group (zolpidem 10 mg) whereas statistically significant difference was noted in hospitalization time in the two groups. The treatment group patients were hospitalized for the shortest time and had the fastest time to go to ground for the first time and walk independently for the shortest time (Table 2).

The statistically significant difference was noted in VAS between two groups (Fig. 1) with patients in the treatment group had a relatively lower score as compared to the control group during postoperative days 1, 3, and 5.

The preoperative QoR-40 score in two groups was not statistically significant during pre-operation while the scores were statistically significant during discharge, 3 weeks and 3 months after surgery. The QoR-40 scores of patients in the treatment group were higher than the control group (Fig. 2).

Table 3 summarizes a significant difference in the five dimensions of HOOS in the control group and treatment group pre- and postoperatively. The treatment group showed relatively lower mean value with statistically significant result (P value is < 0.05) compared to the control group.

PSQI between two groups during the preoperative period in seven dimensions showed no significant difference while the scores were lower postoperatively in the treatment group. The statistically significant result was observed in all dimensions 3 weeks after surgery. Similarly, sleep quality, sleep latency, and sleep duration also showed significant results for 6 weeks postoperatively (Table 4).

No significant difference was seen in the Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rate Scale for Depression (HAM-D) scores between the two groups prior to the operation (Fig. 3). The HAM-A and HAM-D scores were significantly lower in the treatment group in days 1, 3, and 5 after the operation as compared to those in the blank control group, indicating the result statistically significant (Figs. 4 and 5).

Modern total hip arthroplasty (THA) has tremendously ameliorated the prognosis for patients with end-stage hip disease [9], and it is the most effective surgical modality for the treatment of hip degenerative or rheumatoid arthritis disease that is refractory to conservative treatment to minimize hip pain and improve patient quality of life [10]. According to statistics, the USA has annually more than one million joint replacements, with the accelerated aging and the growth of its demand day by day. With the gradual maturity and wide application of total hip arthroplasty, patients and doctors are increasingly demanding perioperative management and experience. Therefore, efficient and planned perioperative multi-modal management and perioperative management for rapid recovery are necessary. However, the study reported that the majority of patients undergoing major orthopedic surgery experienced severe deterioration of their sleep quality, seriously affecting perioperative functional exercise and rapid recovery and reducing perioperative [11, 12]. Researchers have speculated that sleep disturbance in older populations may, in part, be secondary to chronic medical conditions such as osteoarthritis (OA) [13, 14], and pain directly leads to sleep disruption or even deprivation and, in turn, poor-quality sleep aggravates pain sensation. There seems to be a vicious circle: pain—poor-quality sleep, intensified pain—even poorer-quality sleep [4].

Studies have shown that nocturnal pain directly causes sleep disorders, even sleep deprivation, which in turn can lead to pain sensitivity, low-quality sleep, worse pain, and worse cycle of lower quality sleep, which can greatly affect early rehabilitation of patients [15].

Other studies have shown postoperative pain is the most common cause of sleep quality in patients at night, often causing nighttime wakefulness, nightmares, or even unable to sleep [16].

Low-quality sleep can affect subjective experience and satisfaction of patients, prolong hospitalization, and increase the financial burden on the patients’ families, which runs counter to the concept of accelerated rehabilitation of the hip and knee [12, 17]. Still further, persistent postoperative low-quality sleep can lead to reduced pain thresholds and increased nighttime pain, which in turn can further affect nighttime sleep quality.

At the same time, postoperative sleep disorders in patients with total hip arthroplasty reduce postoperative pain tolerance and increased sense of pain experience, thereby increasing postoperative pain in patients.

Cremeans-Smith et al. prospectively enrolled 110 patients undergoing total hip and knee arthroplasty to assess the relationship between postoperative sleep disorders and pain and found that improving perioperative sleep quality can reduce postoperative pain and increase patient satisfaction and recovery [12]. Likewise, Sleep time, while improving the quality of sleep, can reduce hospital stays, speed early recovery, and improve patient satisfaction [18].

At present, the research on the relationship between perioperative rapid rehabilitation and quality of sleep is relatively lacking. Numerous studies have monitored the sleep of patients awaiting THA or have measured whether sleep disturbance diminishes after surgery. This study found significant improvements in this sleep measure at all post-surgery measurement points. Therefore, it led to believe that sleep quality is one of the important factors influencing THA’s results. Improved sleep quality at the early stage after THA may provide additional pain relief with the current analgesic protocol. This result is consistent with the previous study carried by Gong et al. [4].

At the present stage, the evidence of the lower level of evidence-based medicine cannot guide the improvement of clinical sleep and achieve the goal of rapid rehabilitation.

Therefore, multimodal sleep management with non-benzodiazepines in combination with psychological interventions can improve perioperative sleep quality and promote accelerated recovery in patients undergoing total hip arthroplasty.

Miller et al., 50 cases of patients after total hip or knee arthroplasty, with body motion recorder to detect perioperative sleep quality and analysis of postoperative quality of sleep and pain, found that effective postoperative analgesia can improve postoperative sleep quality and increase overall sleep time, while improving quality of sleep can reduce hospital stays, speed early recovery, and improve patient satisfaction [18].

After investigating postoperative orthopedic surgery pain in six medical centers in four countries, the report showed 81% of orthopedic patients undergoing severe night pain [19].

Robert and others prospectively enrolled 68 patients undergoing arthroscopic surgery to study the relationship between sleep quality and pain, fatigue index, and analgesic drug use, and found that postoperative quality of sleep and fatigue index is an important factor affecting postoperative pain and early rehabilitation of patients. Poor quality of sleep increases daytime fatigue in patients [4].

The present study found that patients’ nocturnal quality of sleep was positively correlated with daytime sleepiness index and fatigue index and that zolpidem 10 mg reduced the degree of daytime fatigue and somnolence by improving sleep quality indicating zolpidem is an effective drug in improving postoperative sleep quality in patients undergoing total hip arthroplasty. Valente et al. found that proper and short-term application of zolpidem has been proved to be safe and non-addictive [7].

Zolpidem quickly induces the patient to quickly fall asleep. In the current study, patients are asked to take medication half an hour before falling asleep. They were also asked to take the inevitable activities under the supervision of nurses after administering the medication to avoid the risk of falls. The current study showed the intervention of zolpidem had significantly reduced the hospital stay to 6 days which lowered the financial burden of a patient. The previous findings by Zhang et al. showed the mean hospital stay for patients who underwent unilateral THA was 17 days [20].

At the same time, through the PSQI of the patients after 3 weeks and 3 months of sleep quality, zolpidem 10 mg group patients with the fastest recovery of sleep quality. Similarly, the present study carried by Gong et al found that zolpidem can significantly improve postoperative pain, sleep quality, and joint activity and confirmed a positive correlation between activity and sleep quality [4]. Other studies showed zolpidem improves nighttime sleep quality and reduces daytime fatigue index [5]. The study showed medication with zolpidem postoperatively had a promising result and future studies should be directed at the long-term efficacy and safety of zolpidem for patients undergoing THA.

The study also confirmed that patients with postoperative sleep quality and joint mobility were positively correlated.

Studies have shown that anxiety and pain are independent risk factors for postoperative sleep quality, and conversely, low-quality sleep increases the postoperative anxiety and depression in patients [21, 22]. Unfamiliar environment and ward accommodation, postoperative rehabilitation exercises and rehabilitation anxiety, and a series of other factors lead to preoperative and postoperative anxiety. This study found that 10 mg zolpidem significantly improved anxiety and depression during hospitalization.

Sleep quality is impaired both before and after THA surgery to varying degrees. Relieving pain from osteoarthritis as a result of THA improves sleep quality which in turn contribute to the improved quality of life and day-to-day functioning seen after THA.

Short-term application of zolpidem can effectively improve the quality of perioperative sleep in patients undergoing THA under rapid rehabilitation management. It reduces perioperative nighttime, walking, rest, and pain, effective in alleviating pain resulting less doses of opioids during the perioperative period.

It is also effective in improving perioperative muscle strength and hip joint activity resulting in increased perioperative satisfaction and recovery confidence promoting patients to exercise in the morning and walk independently which in turn contribute in rapid recovery.

Zolpidem can relieve pain and increase early range of motion and muscle strength. It reduces perioperative anxiety and depressions and improves perioperative experience and satisfaction, thereby significantly reducing the hospital stay and medical costs and promotes rapid recovery and quality of life.