Persistence of analgesic usage and opioid consumption in sarcopenic patients undergoing neuraxial anesthesia: a nationwide retrospective cohort study

Supplemental Digital Content is Available in the Text. Sarcopenia in patients undergoing surgery under neuraxial anesthesia increases the risk of chronic postsurgical pain and long-term analgesic use.


Introduction
Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength, which can have a negative impact on patients' quality of life, physical function, and overall health. 8The underlying causes of sarcopenia remain unclear, but contributing risk factors include unhealthy lifestyle habits, malnutrition, physical inactivity, and chronic illness. 7Sarcopenia can also affect the occurrence, progression, and prognosis of various diseases and increase the risk of falls, disability, hospitalization, and mortality. 21In addition, patients with sarcopenia are often older adults with limited physical function, which can increase their susceptibility to postoperative complications. 9Given these risks, it is crucial for surgeons and anesthesiologists to closely monitor and manage patients with sarcopenia during and after surgery to mitigate adverse outcomes.
Postsurgical pain is among the commonest adverse events after surgery.Chronic postsurgical pain (CPSP), which is triggered by surgery and lasts for more than 3 months, may occur if acute postoperative pain is not completely relieved. 15The pathogenesis of CPSP remains unclear.In addition to causing physical pain, CPSP can lead to multiple comorbidities, such as sleep disorders, pneumonia, immunosuppression, anxiety, and depression. 19Analgesics are often the first choice of treatment for CPSP.However, the long-term use of analgesics or opioids can cause stomach ulcers, liver damage, blood coagulation abnormalities, drug addiction, and cancer. 16,20,24Therefore, the prevention of CPSP and reduction of the long-term use of postoperative analgesic drugs are crucial goals.
The correlation between sarcopenia and long-term analgesic and opioid use after surgery under neuraxial anesthesia remains not fully understood, and studies with adequate sample sizes and clear definitions of sarcopenia are limited. 18Moreover, no study has investigated the incidence of CPSP and long-term analgesic use in patients with sarcopenia after surgery.Understanding the relationship between sarcopenia and long-term analgesic use is essential, particularly in the context of older patients, who are more vulnerable to sarcopenia.This knowledge is pivotal for tailoring effective pain management strategies while minimizing the potential risks associated with prolonged analgesic, including opioids, use.By investigating this connection, health care providers can achieve a delicate balance between pain relief, improved patient quality of life, and optimized resource allocation.Moreover, given the potential variations in long-term analgesic use between neuraxial and general anesthesia, 32 a comprehensive study using real-world data is imperative to explore this complex relationship.To bridge this knowledge gap, we conducted a comparative analysis using propensity score matching (PSM) to evaluate the influence of preoperative sarcopenia on long-term analgesic and opioid utilization in patients undergoing surgery under neuraxial anesthesia, ultimately shedding light on its impact on CPSP development.

Data source
Data from Taiwan's National Health Insurance Research Database (NHIRD) from January 1, 2016, to December 31, 2019, were used in this study.The follow-up period for patients extended until December 31, 2020.In addition, there was no loss to follow-up within the scope of our study.The Taiwan NHIRD provided comprehensive data until the end of 2020.The NHIRD includes registration and original claims data for all NHI beneficiaries, totaling approximately 27.38 million individuals.To ensure patient privacy, all NHIRD data are encrypted and contain comprehensive outpatient and inpatient claims information, including patient identification numbers, birth dates, sex, diagnostic codes based on the International Classification of Diseases (ICD-9-CM and ICD-10-CM), treatment information, medical costs, dates of hospital admission and discharge, and dates of death. 24,25atient identification numbers were used to link all data sets.

Ethics
Ethical approval for this study (Ethical Committee Tzu-Chi Medical Foundation) was provided by the Ethical Committee Tzu-Chi Medical Foundation, Taiwan (Chairperson Prof Chien-Hsing Wang), on 12 May 2021.The study protocols were reviewed and approved by the Institutional Review Board of Tzu-Chi Medical Foundation (IRB109-015-B).Patient consent was waived because data files are deidentified by scrambling the identification codes of both patients and medical facilities and sent to the National Health Research Institutes to form the original files of NHIRD.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This study used retrospective data from Taiwan's NHIRD, a comprehensive source of patient information.
Owing to its observational nature and reliance on existing data, preregistration was not pursued.

Design
This retrospective population-based case-control analysis focused on patients who underwent elective surgeries under neuraxial anesthesia between January 1, 2016, and December 31, 2019.This study aimed to explore the potential relationship between sarcopenia and long-term analgesic use after surgery.The surgeries included herniorrhaphy, hip and knee replacements, lower-limb open reduction internal fixation, and lowerlimb amputation, chosen for their suitability for neuraxial anesthesia.Patient eligibility for neuraxial anesthesia was determined based on a set of established criteria.These criteria encompassed factors such as the type of surgical procedure, patient suitability, informed consent, thorough preoperative assessments, careful monitoring during surgery, comprehensive documentation, and postoperative care.By adhering to these criteria, health care professionals ensured that neuraxial anesthesia was applied when most appropriate and beneficial, considering both patient safety and surgical efficacy.The anesthesia type was ascertained using the corresponding payment code in Taiwan's NHIRD. 32To eliminate the influence of underlying chronic pain and pain from other sources, patients who used analgesics, opioids, or nonopioids for more than 1 month before surgery were excluded.Patients with cancer that may have significantly affected their recovery from surgery or cancer-related pain were also excluded.Patients who passed away within 6 months of surgery were excluded, and the surgeries were performed until December 31, 2019, with follow-up until the end of 2020.The index date was the day of surgery.
In October 2016, the formal recognition of sarcopenia as a disease and its classification as M62.84 in ICD-10-CM was announced by the US Centers for Disease Control and Prevention. 1 The diagnosis of sarcopenia in our study adhered to the ICD-10-CM code, 25 which was established after 2016.We used a criterion of at least 2 claims for patients with a principal diagnosis of sarcopenia within the 12-month preoperative period to diagnose sarcopenia. 6The coding of sarcopenia in our study was based on a previous research investigation.The definition of sarcopenia was a skeletal muscle mass index (SMI) that was 2 or more standard deviations below the mean values of young individuals of the same sex.Computed tomography images provided the relevant measurements, and the SMI was calculated using the following formula: SMI 5 L3 skeletal muscle crosssectional area (cm 2 )/height 2 (m 2 ). 30Sarcopenia diagnoses made by orthopedic physicians, rehabilitation physicians, family medicine specialists, and geriatricians were included in the sarcopenia group.
The study size in our research was determined based on the retrospective available data within the Taiwan NHIRD over the specified timeframe, in accordance with our inclusion and exclusion criteria.We have included a flow diagram that illustrates the patient selection process, including the number of patients at each stage, which provides clarity regarding our study size determination (Supplemental Figure 1, http://links.lww.com/PR9/A217).

Covariates and propensity score matching
After adjustment for potential confounding factors, a multivariable logistic regression model was used to analyze the use of analgesics 3 or 6 months after surgery under neuraxial anesthesia, comparing patients with and without preoperative sarcopenia.To reduce potential bias when comparing analgesic use between sarcopenia and nonsarcopenia groups, we used PSM to match all patients based on age, sex, surgery type, medical center level, American Society of Anesthesiology (ASA)derived physical status, coexisting comorbidities, smoking status, alcohol-related diseases (ARDs), Charlson Comorbidity Index (CCI) score, and adapted Diabetes Complications Severity Index (aDCSI) score.We matched the cohorts using a 1:4 ratio and a caliper of 0.1, 2 and comorbidities were identified using ICD-9-CM and ICD-10-CM codes in the main diagnosis records of inpatients, or with at least 2 outpatient visits within 1 year.Comorbidities that occurred 1 year before the index date were considered.The hospital accreditation level was also taken into account.Medical centers were defined as facilities with 1000 to 2500 beds, providing tertiary medical services and conducting most staff training within the center, as well as having research facilities, in accordance with the Taiwan Joint Commission on Hospital Accreditation. 32Owing to the comprehensive nature of the covariates in the Taiwan National Health Insurance Research Database (NHIRD), the occurrence of missing data was minimal, with all covariates containing less than 1% missing data.Consequently, patients with missing data in any of these covariates were excluded from the analysis to ensure data completeness and accuracy.
In our PSM study, we used methods to examine subgroups and interactions, including stratifying the study population into distinct subgroups based on specific covariates of interest for subgroup analysis.Interaction terms were incorporated into our regression models to formally test interactions between treatment variables and key covariates.Sensitivity analyses using different PSM techniques and caliper widths were performed to assess the robustness of our findings. 10Forest plots were created to visually present effect sizes and confidence intervals for different subgroups.Formal interaction tests based on interaction terms were conducted to assess the statistical significance of treatment-covariate interactions. 34ppropriate continuous variables are presented as means 6 standard deviations.To minimize differences among participants, we used a PSM ratio of 1:4 for the preoperative sarcopenia and nonsarcopenia groups, which is commonly used to select controls with identical background covariates.To determine whether preoperative sarcopenia is an independent predictor of high rates of long-term analgesic use in surgical patients, a multivariable logistic regression model was used.Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by performing the multivariable logistic regression analysis.The analysis was conducted for all analgesics, including opioids.

Outcomes
As CPSP is pain that is specific to surgery and lasts for more than 3 months, 15 we defined the primary outcome as the combined rate of analgesic prescriptions given 3 and 6 months after surgery.To be classified as a long-term analgesic user, patients needed to receive one or more prescriptions for analgesics, which included acetaminophen, nonsteroidal anti-inflammatory drugs, phenytoin, carbamazepine, pregabalin, gabapentin, and opioids, from outpatient clinics at 3 months or later after surgery.Those who were prescribed opioids such as morphine, fentanyl, oxycodone, buprenorphine, hydromorphone, tramadol, codeine, and meperidine were classified as long-term opioid users. 32

Statistic
The descriptive findings pertaining to age, sex, surgery type, medical center level, ASA-derived physical status, coexisting comorbidities, smoking status, ARDs, CCI score, and aDCSI score were presented as absolute frequencies with percentages, while standardized differences were used to evaluate the baseline information between the 2 groups.The potential confounders linked to the occurrence of persistent analgesic use were considered as covariates in the predicted model to explore the association between the sarcopenia and nonsarcopenia groups that underwent elective surgery under neuraxial anesthesia.Despite applying PSM using SAS PROC PSM, the residual imbalance might still persist in a population due to a large sample size 33 ; hence, we used multivariable logistic regression with SAS PROC LOGISTIC to assess the probability of long-term analgesic use between the groups by estimating adjusted ORs (aORs) and 95% CIs.All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC).

Study cohort
This study analyzed data from 3805 surgical patients undergo neuraxial anesthesia, with 761 in the sarcopenia group and 3044 in the nonsarcopenia group.Table 1 presents their characteristics, including age, sex, surgery type, medical center level, ASA-derived physical status, coexisting comorbidities, smoking status, ARD, CCI score, and aDCSI score.After PSM, there were no significant differences in these characteristics between the groups.The 3month analgesic and opioid prescription rates were higher in the sarcopenia group compared with the nonsarcopenia group, with rates of 62.3% and 57.1% (P 5 0.009) and 2.9% and 0.8% (P 5 0.014), respectively.Similarly, the 6-month analgesic and opioid prescription rates were also higher in the sarcopenia group, with rates of 30.8% and 26.3% (P 5 0.013) and 1.7% and 0.3% (P 5 0.030), respectively (Table 1).

Analgesic prescription 3 months after surgery
To evaluate the rate of long-term analgesic use between sarcopenia and nonsarcopenia patients undergoing neuraxial anesthesia, we examined outpatient clinical records and postoperative analgesic usage for 6 months after surgery.The aORs and corresponding 95% CIs of 3-month analgesic and opioid use for the sarcopenia and nonsarcopenia groups undergoing elective surgery are presented in Tables 2 and 3.The rate of analgesic prescription was significantly higher in the sarcopenia group than in the nonsarcopenia group 3 months after surgery  2).

Opioid prescription 3 months after surgery
The rate of opioid prescriptions was notably greater in the sarcopenia group compared with the nonsarcopenia group (Table 1) at the 3-month follow-up after surgery, with an aOR of 1.11 (95% CI, 1.05-2.45),as presented in Table 3.After adjustment, the aORs (95% CI) of 3-month opioid use for the patients who underwent hip replacement and those who underwent knee replacement were 6.21 (2.48-11.89)and 4.55 (3.68-12.15)compared with those who underwent herniorrhaphy (Table 3).

Analgesic prescription 6 months after surgery
After the 6-month follow-up, the risk of receiving analgesic prescriptions was found to be significantly greater in the sarcopenia group compared with the nonsarcopenia group (aOR, 1.17; 95% CI, 1.07-1.42;Table 4).After adjustment for the aforementioned cofounding factors, the aORs (95% CI) of 6-month analgesic use in the patients who underwent hip replacement and those who underwent knee replacement were 3.83 (2.57-5.71)and 5.66 (4.32-7.41),respectively, compared with those who underwent herniorrhaphy (Table 4).

Discussion
Numerous challenges and severe surgical complications are experienced by many patients with sarcopenia. 14However, it remains uncertain whether preoperative sarcopenia is associated with CPSP and long-term analgesic use.This is, to our knowledge, the first and largest study that used a PSM method to compare the long-term postoperative analgesic use of patients with and without sarcopenia.This retrospective cohort study, based on real-world data, included 3805 surgical patients, with 761 diagnosed with sarcopenia and 3044 without.The analysis revealed significant differences in postoperative analgesic and opioid prescription rates between these 2 groups.Notably, at 3 months postsurgery, 62.3% of patients with sarcopenia received analgesics (2.9% opioids), whereas 57.1% of those without sarcopenia received analgesics (0.8% opioids).Similarly, at 6 months postsurgery, 30.8% of sarcopenic patients received analgesics (1.7% opioids), compared with 26.3% of nonsarcopenic patients receiving analgesics (0.3% opioids).Multivariable logistic regression analyses demonstrated that patients with sarcopenia undergoing neuraxial anesthesia surgery were significantly more likely to receive analgesic prescriptions at both 3 months (aOR 1.27; 95% CI 1.05-1.53)and 6 months (aOR 1.17; 95% CI 1.07-1.42)postoperatively, compared with those without sarcopenia.Moreover, sarcopenic patients exhibited significantly higher opioid prescription rates at 3 months (aOR 1.11; 95% CI 1.05-2.45)and 6 months (aOR 1.89; 95% CI 1.12-4.96)postsurgery.In addition, advanced age (above 50 years) and specific surgical procedures, such as hip and knee replacements, were associated with a higher likelihood of persistent analgesic and opioid consumption.These findings offer insights into postoperative pain management in the context of sarcopenia, emphasizing the importance of addressing chronic postsurgical pain and reducing long-term analgesic or opioid use, particularly among sarcopenic patients.Recognizing the impact of age and specific surgical procedures on postoperative pain management is vital for optimizing patient care and outcomes.This study adds valuable information to the existing literature, guiding future research and clinical practices. 16,20,24egarding frailty, we acknowledge its significant impact on postoperative outcomes, including pain experiences and analgesic usage.Regrettably, owing to the limitations of our data source, we were unable to directly conduct a comprehensive analysis of frailty.Nonetheless, we endeavored to mitigate this limitation by considering relevant covariates that might indirectly encompass aspects of frailty in our study.Specifically, we incorporated ASA scores and assessed various coexisting comorbidities, including conditions such as dysthymic disorder, peripheral vascular diseases, osteoporosis, gout, headache, diabetic neuropathy, rheumatoid arthritis, pressure ulcer, and alcohol-related diseases, along with the Charlson Comorbidity Index (CCI) score.These variables reflect patients' physical status and the presence of comorbid conditions, which can indirectly signify frailty. 23,29This approach facilitated the matching and control for potential confounding factors within our PSM analysis.While we could not directly measure frailty, these surrogate measures helped us indirectly address its influence in our study.
Analyzing the patterns of analgesic consumption at both the 3month and 6-month postsurgery intervals is a critical component of our research.Since analgesic usage is used as a surrogate measure for assessing CPSP, a thorough examination of the variations in analgesic consumption at 3 months between sarcopenia and nonsarcopenia patients, while informative, may not provide a complete picture. 15Therefore, a more rigorous approach entails investigating the distinctions in analgesic consumption at the 6-month postsurgery point.This scrutiny reinforces the presence of CPSP, particularly within the context of sarcopenic and nonsarcopenic patients.Our study consistently demonstrates that regardless of whether we evaluate analgesic consumption at 3 months or 6 months, a notably higher proportion of CPSP cases are observed among sarcopenic patients.This trend is particularly prominent within the subgroup of patients who were prescribed opioids.Importantly, it is essential to highlight that patients in our cohort did not use opioids before the surgery; opioid use only commenced postoperatively.The strict regulation and limited accessibility of opioids, which are typically not available from standard pharmacies, render their postoperative usage a robust indicator.Consequently, when we analyze opioid usage at both the 3month and 6-month marks, we can confidently assert that sarcopenic patients face a significantly increased risk of experiencing CPSP.Focusing on opioids at both time points enhances the robustness of CPSP as the primary outcome in our study.Sarcopenia, characterized by the age-related loss of muscle mass and function, is a complex condition influenced by a range of factors, including the natural process of aging, physical inactivity, inadequate nutrition, hormonal shifts, chronic illnesses, neurological disorders, medications, and genetic predispositions. 7,8,21It is essential for both researchers and clinicians to acknowledge and address these multifaceted causes when diagnosing and managing sarcopenia.9]21 In our study, we made a comprehensive effort to account for these potential confounding factors by using PSM.This approach allowed us to match patients based on a wide range of variables, including age, sex, type of surgery, the level of the medical center, ASA-derived physical status, and various coexisting comorbidities (such as dysthymic disorder, peripheral vascular diseases, osteoporosis, gout, headache, diabetic neuropathy, rheumatoid arthritis, pressure ulcer, and alcohol-related diseases).In addition, we considered smoking status, CCI score, and aDCSI score.These covariates encompass factors available in our NHIRD to minimize potential biases and enhance the accuracy of our results.However, it is crucial to acknowledge that certain factors, such as genetic predispositions, are beyond the scope of our data source.This limitation is transparently included in our study.While the causes of sarcopenia are indeed diverse, our research primarily concentrated on the impact of postoperative analgesic consumption, rather than providing an exhaustive exploration of the underlying causes of sarcopenia.Currently, the causal relationship between sarcopenia and CPSP remains unclear, as does the relevant mechanism of action.Our results indicate a higher probability of developing CPSP in patients with preoperative sarcopenia due to increased long-term analgesic use.Sarcopenia is a multifaceted syndrome with a complex pathogenesis. 14CPSP, a special type of chronic pain, also has a complex and unclear pathogenesis similar to sarcopenia, and the related research is still in the exploratory stage. 15,27Sarcopenia and CPSP share common mechanisms, such as an imbalance between the inflammatory response and oxidative stress. 3In addition, the ubiquitinated proteasome system plays a crucial role in muscle fiber degradation, and its overactivation can lead not only to sarcopenia but also to chronic pain. 22The same causative gene may also be responsible for both conditions.A UK Biobank cohort study reported that homozygous HFEC282Y was strongly associated with sarcopenia and chronic pain in older patients. 26Therefore, patients with sarcopenia might develop CPSP and thus require the long-term use of analgesics, especially opioids.
While there is currently a dearth of research exploring the potential correlation between sarcopenia and prolonged analgesic and opioid use, a plethora of studies have established a noteworthy relationship between sarcopenia and increased occurrence of unfavorable postoperative outcomes when compared with individuals who do not have sarcopenia. 9Our findings demonstrated that sarcopenia is an independent risk factor for 30-day and 90-day adverse postoperative outcomes, such as postoperative pneumonia, bleeding, septicemia, and mortality.Postoperative complications tend to prolong the duration of postoperative pain, leading to the prolonged use of analgesics after surgery. 11Therefore, this may be a reason for long-term analgesic use in patients with sarcopenia.
The number of studies on postoperative pain in older patients with sarcopenia is limited.Most of them have focused on acute postoperative pain, and whether sarcopenia affects acute postoperative pain in older patients remains inconclusive. 18Generally, older patients are less sensitive to pain than younger patients. 28owever, in this study, we found a significant increase in anesthetic techniques, including multimodal analgesia, minimally invasive surgery, and nerve block, might be associated with a reduction in acute postsurgical pain that contributes to CPSP. 27his study used data from the NHIRD, which reliably records the detailed medical information of NHI enrollees, and this database has been used in many high-quality studies. 24,25,32The present comparative study used a large PSM-based design to maintain balance among confounders of case and control groups, resulting in the absence of bias (Table 1).This study presents several noteworthy limitations that require careful consideration.First, while PSM was thoughtfully used to enhance the comparability of study groups, it remains susceptible to the influence of unmeasured confounding factors.Second, the study's exclusive inclusion of patients of Asian descent raises questions about the generalizability of its findings to populations of different ethnic backgrounds.However, it is important to note that previous reports have not shown significant variations in the occurrence of CPSP between Asian and non-Asian populations.Nonetheless, exercising caution is advisable when extending these findings beyond Asian cohorts.Third, the study's use of analgesic consumption as an indicator for Chronic Postsurgical Pain (CPSP) is influenced by limitations inherent in the Numeric Rating Scale (NRS).The NRS is prone to recall bias and is less effective in patients with lower educational backgrounds, as well as those facing communication challenges due to nonverbal or cognitive impairments.Moreover, it may not adequately capture the nuances of complex or chronic pain conditions. 12,17To address these constraints, the study chose analgesic consumption as a surrogate measure for CPSP, with the understanding that it may not encompass instances where patients endure pain without seeking medication.Nonetheless, it is essential to highlight that the study's meticulous inclusion and exclusion criteria are anticipated to mitigate the potential impact of this approach on the study's findings.Fourth, an acknowledged limitation is the study's inability to definitively establish a direct correlation between pain experienced at 3 or 6 months postsurgery and its direct relation to the surgical site.While concerns about potential complications and new hospitalizations, as raised by the reviewer, were not observed in the patient cohort, as the study explicitly excluded readmissions related to postoperative complications, it is important to recognize that using analgesic consumption as a surrogate parameter for CPSP represents an indirect approach and does not offer a direct assessment of pain.These limitations emphasize the need for caution when drawing definitive conclusions regarding the relationship between sarcopenia and CPSP based solely on analgesic consumption.Fifth, the lack of detailed information on certain variables such as lifestyle factors, nutrition, dietary data, laboratory results, and genetic predispositions within the NHIRD limits our ability to fully account for all potential confounding factors.Nevertheless, it is worth noting that previous studies have reported the accuracy and quality of data from NHIRD, which provides a level of confidence in the database's reliability. 4,5,13Finally, it is important to note that the research is limited to patients who underwent neuraxial anesthesia, and the findings may not be universally applicable to individuals receiving alternative anesthesia modalities.

Conclusion
Our study highlights sarcopenia as a distinctive risk factor for prolonged analgesic use after surgery with neuraxial anesthesia.Patients diagnosed with sarcopenia face an elevated risk of extended reliance on analgesics and opioids.These findings emphasize the clinical importance of identifying and addressing sarcopenia in surgical patients undergoing neuraxial anesthesia procedures, offering potential avenues to optimize postoperative pain management and improve patient outcomes.

Table 1
Demographic characteristics of patients receiving elective surgery under neuraxial anesthesia, grouped according to the presence of sarcopenia (after propensity score matching).

Table 1 (
continued)Demographic characteristics of patients receiving elective surgery under neuraxial anesthesia, grouped according to the presence of sarcopenia (after propensity score matching).

Table 2
Logistic regression model of analgesic prescription 3 months after surgery under neuraxial anesthesia.

Table 4
Logistic regression model of analgesic prescription 6 months after surgery under neuraxial anesthesia.