Real-world study on adverse events of central muscle relaxants in the treatment of cervicogenic headache based on the U.S. FAERS database

Real-world study on adverse events of central muscle relaxants in the treatment of cervicogenic headache based on the U.S. FAERS database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world study on adverse events of central muscle relaxants in the treatment of cervicogenic headache based on the U.S. FAERS database Jiaxi Zhang, Wenhui Liu, Chen Li, Ruitao Wang, Peng Mao, Bifa Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6492591/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Central muscle relaxants are widely used in the treatment of cervicogenic headache, which can inhibit the excessive excitation of the central nervous system, relieve neck muscle spasms, and thereby reduce pain and discomfort. However, there is still a lack of real-world studies on the safety of central muscle relaxants. Given the rising incidence of cervicogenic headache in recent years, it is imperative to gain a deeper understanding of the adverse events (AEs) associated with this class of drugs. Methods: The online platform Open Vigil 2.1 was used to query the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database for reports on common central muscle relaxants, baclofen and tizanidine. The query spanned from January 1, 2004, to August 31, 2024, and extracted all AEs across all age groups. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) was used to match relevant preferred terms (PTs) and system organ classes (SOCs). The proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) methodology were employed to compare the AEs of the two muscle relaxants. Results： There were 14,431 reports with baclofen as the primary suspected drug, with a roughly equal proportion of male and female patients. For tizanidine, there were 365 reports, with more female patients than male. For both drugs, the age group with the highest proportion of patients was 40-59 years old, and the country with the most reports was the United States. Nervous system disorders were the most common SOC category for AEs associated with both drugs. The three most frequently reported AEs for baclofen were withdrawal syndrome, hypersomnia, and pruritus, while the top three AEs for tizanidine were confusional state, dry mouth, and hypotension. Conclusion: The analysis indicates that AEs of both drugs are present in various systemic diseases including nervous system, psychiatric, cardiovascular, respiratory, urinary, and general disorders. However, the incidence and signal strength of these AEs vary depending on the specific drug discussed. In clinical practice, appropriate drugs should be selected based on the specific characteristics of individual patients, and AEs should be monitored. Central muscle relaxants Food and drug administration adverse event reporting system Real-world study Adverse events Pharmacovigilance Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Background Cervicogenic headache (CEH), referring to secondary headache caused by cervical spine lesions involving vertebrae, intervertebral discs, and soft tissues, typically manifests as unilateral neck dull pain or referred pain. It is often accompanied by neck stiffness, limited active and passive movement, and ipsilateral shoulder and upper limb pain. The pathophysiological mechanisms primarily involve abnormalities in cervical vertebral bodies, intervertebral discs, neuromuscular structures, leading to neck muscle spasms, nerve endings compression, and enhanced pain signal transmission. Recently, with the widespread use of electronic devices and sedentary lifestyles, the incidence of CEH has been on the rise. Global data reveals that CEH accounts for approximately 15% to 20% of all chronic headaches and 17.5% of severe headaches. Furthermore, CEH imposes a significant economic burden, with annual costs reaching billions of dollars due to medical expenses and productivity losses. Central muscle relaxants play a crucial role in treating CEH. The pathophysiology of CEH is closely related to continuous tension and spasms in neck muscles. Central muscle relaxants can alleviate neck muscle spasms, improve local blood circulation, and reduce pain and discomfort by inhibiting excessive excitation in the central nervous system, regulating neural reflex activities in the spinal cord and brainstem, and decreasing muscle tension[1]. These relaxants constitute a heterogeneous group of drugs, with Baclofen and Tizanidine being two commonly used agents for CEH treatment, each with distinct chemical structures and mechanisms of action. Baclofen, a γ-aminobutyric acid (GABA) B receptor agonist with a chemical structure of 4-amino-3-(4-chlorophenyl)butyric acid, activates GABA B receptor subunit 2 in the spinal cord. This activation inhibits the release of excitatory neurotransmitters, thereby reducing hyperactivity in spinal reflex arcs and alleviating muscle spasms and pain. Thus, it significantly relieves muscle tension and pain in CEH patients. Tizanidine, an α2-adrenergic receptor agonist, chemically structured as 5-chloro-4-(2-imidazolinyl)-2,1,3-benzothiadiazole, acts by activating α2 receptors in the central nervous system. It suppresses excitatory neurotransmission at the spinal level, reduces muscle spasms, and exerts analgesic effects. Additionally, Tizanidine improves local blood circulation, further relieving CEH symptoms. Previous studies investigating adverse events (AEs) associated with Tizanidine and Baclofen treatment for spasms have reported similar overall AE incidence rates for both drugs. Common AEs include dry mouth, drowsiness, and fatigue, with fatigue being more prominent in Baclofen-treated patients and dry mouth being the most frequent AE in Tizanidine-treated patients. Some patients also reported dizziness, headache, and abnormal liver function[2,3]. Lisa et al. [4]conducted a statistical analysis of AEs in adults over 50 years old treated with Baclofen and Tizanidine in the community, revealing that Baclofen's adverse reactions primarily affect the nervous and motor systems (movement disorders, encephalopathy or disorientation, and drowsiness), whereas Tizanidine's AEs mainly involve the cardiovascular system (hypotension and bradycardia). There are also reports suggesting that Baclofen may induce dural arteriovenous fistula (DAVF). Studies on special populations, such as elderly patients and those with renal insufficiency, have found that the use of muscle relaxants in chronic kidney disease and end-stage renal disease patients is associated with an increased risk of hospitalization due to neurological diseases. Additionally, the risk of falls after medication use is elevated in the elderly[5]. Another study examining Baclofen use in patients with varying renal function found that the drug's dosage should be adjusted proportionally based on renal function in cases of mild, moderate, or severe renal failure[6]. However, existing clinical trials assessing the safety of central muscle relaxants have limitations: most studies have small sample sizes, typically involving only tens to hundreds of patients, and short follow-up durations, often less than six months. This makes it difficult to comprehensively evaluate the long-term safety of these drugs. Furthermore, some trials have a relatively homogeneous study population, lacking quantitative analysis and comparison based on gender, age, country, and other demographic characteristics. Drug safety studies based on a larger range of real-world, up-to-date clinical data are becoming more and more important as drug research continues to deepen and indications and dosage forms expand. The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) is an authoritative drug safety database that collects real-time data on AEs and medication errors from multiple countries. It serves as a valuable source of real-world AE data, providing essential insights for monitoring drug safety and assessing risks. This study aims to conduct a pharmacovigilance analysis of AEs associated with commonly used central muscle relaxants, Baclofen and Tizanidine, using the FAERS database. The goal is to gain a deeper understanding of the safety profiles of these drugs and provide clinicians, patients, and regulatory authorities with valuable information to inform personalized treatment decisions. 2 Methods 2.1 Data Sources The data for this study were obtained from the publicly available FAERS database, which compiles spontaneous reports from healthcare professionals, patients, drug manufacturers, and other sources across different regions. These data provide a reflection of the true incidence of adverse events (AEs). This retrospective study used Open Vigil 2.1 to query the FAERS database and retrieve reports on the target drugs over the past 20 years, from January 1, 2004, to August 31, 2024, to better represent the real-world AE profile of these drugs. The target drugs were the central muscle relaxants "baclofen" and "tizanidine." Unlike previous studies that often focused on specific age groups, this study aimed to conduct a broad investigation of AEs associated with the use of central muscle relaxants across all age groups. We selected AE report cases where the target drugs were identified as the "primary suspects." Subsequently, we classified and described the AEs based on the preferred terms (PT) and system organ classes (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA version 27.0). As the data were sourced from a public database, ethical approval was not required. 2.2 Statistical Analysis The proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) are commonly used methods for detecting drug safety signals related to AEs. The PRR is used to estimate relative risk but can be susceptible to false-positive signals [8]. The ROR provides a stable estimate of ratios or risk ratios with less bias [3,10]. The BCPNN is a supervised learning method based on neural networks that utilizes known drug adverse reactions as a training set and maintains stability even with a small number of reports [9,11]. Therefore, we combined the ROR, PRR, and BCPNN methods to mine AE signals for the target drugs and calculated PRR and χ²values using a contingency table for measures of disproportionality. When all three methods yielded positive results, the criteria in Table 1 were considered met, and the signal was classified as a suspicious AE signal. Data statistical analysis and graphing were performed using Microsoft Office Excel 2021, R 4.3.1 software, and online platforms.(https://www.bioincloud.tech/,https://www.chiplot.online/,https://www.bioinformatics.com.cn) [7] Table1 . Formulas and signal detection criterias for reporting odds ratio (ROR), proportional reporting ratio (PRR) and bayesian confidence propagation neural network (BCPNN). Algorithms Equation Criteria ROR ROR=ad/bc lower limitof 95%CI>1,a≥3 95%CI=eIn(ROR)±1.96(1/a+1/b+1/c+1/d)^0.5 PRR PRR=a(c+d)/c/(a+b) PRR>2,χ²>4,a>3 χ²=[(ad-bc)^2](a+b+c+d)/[(a+b)(c+d)(a+c)(b+d)] BCPNN IC=log2a(a+b+c+d)(a+c)(a+b) IC025＞0 95%CI=E(IC)±2V(IC)^0.5 Fourfold table of disproportionality measures Target AE Other AE Total Target drugs a b a+b Other drugs c d c+d Total a+c b+d a+b+c+d ROR reporting odds ratio, CI confidence interval, PRR proportional reporting ratio, χ2 chi-squared, BCPNN bayesian confidence propagation neural network, IC information component, IC025 the lower limit of 95%CI, of the IC 3 Results 3.1 Demographic information on the AE reports Between January 1, 2004, and August 31, 2024, the US FAERS database received reports with baclofen as the primary suspected drug totaling 14,431 cases. Excluding unknown reports, the ratio of male to female patients was roughly equal (53.3% and 44.5%, respectively). The age group with the highest representation was 40-59 years old (5,369 cases, accounting for 37.2%). The country with the most reported cases was the United States (11,451 cases, 79.4%). The period with the highest number of reported cases was from 2014 to 2016 (3,855 cases, 26.7%). For tizanidine, the total number of reports with it as the primary suspected drug was 365 cases. Among these, the number of female patients (215 cases, 58.9%) was significantly higher than male patients (114 cases, 31.2%). The age distribution was concentrated in the 40-59 age group (160 cases, 43.8%). The country with the most reported cases was also the United States (201 cases, 55.0%). The most concentrated period for case reporting was from 2004 to 2006 (168 cases, 46.0%)(Figure 1). Excluding unknown reports, "pain" ranked second and third among the indications for the two drugs, respectively. (Details are provided in Table 2). Table 2 Signal detection results and grading for all positive adverse event signals of Tizanidine in the FAERS database PT n PRR x2 ROR(95%Cl) confusional state 8 56.797 76957.831 64.95 dry mouth 7 4.353 1382.477 4.50 hypotension 7 2.028 219.260 2.06 somnolence 7 18.815 6540.678 19.42 fall 6 10.262 3228.469 10.57 loss of consciousness 6 3.692 757.238 3.78 overdose 6 63.580 20984.099 65.60 amnesia 5 15.751 4091.724 16.13 asthenia 5 2.953 388.755 3.00 convulsion 5 3.454 488.513 3.51 dysarthria 5 5.092 854.128 5.18 muscle spasms 5 6.840 1240.185 6.96 pallor 5 7.155 1237.179 7.27 alanine aminotransferase increased 4 3.709 452.457 3.76 bradycardia 4 2.340 163.229 2.36 coma 4 2.575 203.730 2.60 drug interaction 4 4.198 507.525 4.25 feeling abnormal 4 2.405 170.438 2.43 hallucination 4 17.953 3074.433 18.23 insomnia 4 7.891 1153.595 8.00 agitation 3 3.077 270.595 3.11 aspartate aminotransferase increased 3 2.838 227.465 2.87 blood pressure decreased 3 2.537 178.233 2.56 blood pressure increased 3 4.213 431.954 4.26 depressed level of consciousness 3 3.838 361.926 3.88 drug effect decreased 3 3.385 286.820 3.42 heart rate increased 3 9.576 1278.145 9.70 irritability 3 14.844 1938.927 15.02 sleep disorder 3 179.888 19408.290 182.04 urinary tract infection 3 3.222 214.084 3.25 vision blurred 3 4.686 5.438 4.81 All positive adverse event signals of Tizanidine identified in the FAERS database using disproportionality analysis (PRR, ROR, BCPNN). Signal thresholds and grading criteria are applied as per standard definitions. 3.2 AE Signal Mining and Analysis of AE Signals at the PT Level In this study, three methods, ROR, PRR, and BCPNN, were used to analyze AE signals. After excluding cases with input errors, incomplete records, and signals related to product quality, usage issues, various injuries, poisoning, concomitant procedures, and drug indications, a total of 52 positive AE signals related to baclofen and 31 positive AE signals related to tizanidine were obtained. All AE signals are listed in Table 2 . Next, we analyzed all signals at the PT level, focusing on the top 30 most frequent and highest signal strength detections (Table 3, Figure 2) . Table 3 Top 30 adverse event signals of baclofen and tizanidine in the FAERS database (PRR, ROR, BCPNN) PT n PRR x2 ROR(95%Cl) drug withdrawl syndrome 1542 56.797 76957.831 64.95 somnolence 534 4.353 1382.477 4.50 pruritus 415 2.028 219.260 2.06 mental status changes 400 18.815 6540.678 19.42 coma 392 10.262 3228.469 10.57 confusional state 385 3.692 757.238 3.78 hypotonia 379 63.580 20984.099 65.60 unresponsive to stimuli 304 15.751 4091.724 16.13 tremor 300 2.953 388.755 3.00 hyperhidrosis 280 3.454 488.513 3.51 agitation 261 5.092 854.128 5.18 lethargy 251 6.840 1240.185 6.96 depressed level of consciousness 236 7.155 1237.179 7.27 seizure 229 3.709 452.457 3.76 hypoaesthesia 212 2.340 163.229 2.36 completed suicide 211 2.575 203.730 2.60 musculoskeletal stiffness 209 4.198 507.525 4.25 loss of consciousness 207 2.405 170.438 2.43 neurotoxicity 198 17.953 3074.433 18.23 delirium 194 7.891 1153.595 8.00 tachycardia 193 3.077 270.595 3.11 muscular weakness 191 2.838 227.465 2.87 hospitalisation 191 2.537 178.233 2.56 bradycardia 177 4.213 431.954 4.26 convulsion 173 3.838 361.926 3.88 respiratory failure 171 3.385 286.820 3.42 sedation 169 9.576 1278.145 9.70 respiratory depression 154 14.844 1938.927 15.02 cerebrospinal fluid leakage 144 179.888 19408.290 182.04 The thirty most prominent adverse event signals of baclofen and tizanidine identified in the FAERS database by disproportionality analysis (PRR, ROR, BCPNN), including preferred term (PT), case number, and main signal detection parameters. Among the selected AE signals related to baclofen, the top three reported signals were drug withdrawal syndrome, somnolence, and pruritus. The top three PRR values were intracranial hypotension, cerebrospinal fluid leakage, and hypotonia. For tizanidine-related AE signals, the top three reported signals were confusional state, dry mouth, and somnolence. The top three PRR values were pallor, dysarthria, and dry mouth. 3.3 SOC Stratified Analysis and the Relationship between Major AE Signal Detection and SOC In this study, MedDRA27.0 was used to categorize the AE signals of the 2 drugs according to the SOC involving organs and systems. Visual analysis was then performed to examine the PT signals and their corresponding SOCs.The results showed that Nervous system disorders was the category with the highest number of AE signals for both drugs in the FAERS database, followed by Psychiatric disorders.Subsequently, we focused on the signals in the top 30 most common AEs occurring in the drugs in terms of their ROR 95% confidence interval (CI) strengths, which were visualized and analyzed by forest and volcano plots (Figure 3). The strongest signal associated with baclofen (ROR = 320.60 (271.76 to 378.21)) was intracranial hypotension, which is categorized as a neurological disorder. In addition to oral administration, intrathecal injection is a common route of drug administration and is often used in the treatment of chronic intractable pain, but the risks associated with intrathecal pump placement need to be guarded against. intracranial hypotension and cerebrospinal fluid leakage, the top 2 AE signals in terms of PRR, are related to this, and although the incidence of intrathecal baclofen Although the incidence of intrathecal baclofen overdose is low, there have been case reports of patients with intrathecal baclofen pumps experiencing brainstem suppression during surgery, which may have been caused by baclofen overdose, and perioperative vigilance is needed to prevent the occurrence of this phenomenon. SOCs not included in the drug insert for baclofen include skin and subcutaneous tissue disorders. Clinical use of central muscle relaxants such as baclofen should still be closely monitored for adverse reactions in patients with associated systemic diseases. The strongest signal associated with tizanidine (ROR = 31.10 (12.64 to 76.53)) was pallor, with descriptions of “hypotension” and “anemia” adverse reactions in the tizanidine hydrochloride insert. The main adverse events for both drugs were related to nervous system disorders, psychiatric disorders, respiratory disorders, gastrointestinal disorders and several general disorders (Figure 4, Table 4). Table 4 Distribution of AE signals in each SOC SOCs Baclofen % Tizanidine % Nervous system disorders 3728 42.16% 35 25.36% Psychiatric disorders 1591 17.99% 25 18.12% General disorders and administration site conditions 1542 17.44% 16 11.59% Skin and subcutaneous tissue disorders 695 7.86% 0 0.00% Musculoskeletal and connective tissue disorders 400 4.52% 5 3.62% Cardiac disorders 370 4.18% 4 2.90% Respiratory, thoracic and mediastinal disorders 325 3.68% 0 0.00% Surgical and medical procedures 191 2.16% 0 0.00% Gastrointestinal disorders 0 0.00% 7 5.07% Infections and infestations 0 0.00% 3 2.17% Injury, poisoning and procedural complications 0 0.00% 12 8.70% Investigations 0 0.00% 16 11.59% 4. Discussion Based on the US FAERS database, this study systematically analyzed the characteristics and risk signals of adverse events (AEs) associated with commonly used central muscle relaxants, baclofen and tizanidine, in the treatment of pain-related diseases such as cervicogenic headache. Other central muscle relaxants like eperisone and cyclobenzaprine were not discussed in detail due to the limited number of AE reports in the database. This analysis provides crucial evidence for evaluating the safety of these drugs in real-world settings. 4.1 Key Findings Utilizing Open Vigil 2.1, we retrieved ADE reports for baclofen and tizanidine from the FAERS database, spanning from January 1, 2004, to August 31, 2024. Aside from reports with missing information, we found that both drugs were most commonly associated with AEs in patients aged 40-59, aligning with the peak age for cervical degenerative changes. The male-to-female ratio of AEs was roughly equal for baclofen, while tizanidine showed a higher proportion of female patients. The majority of AE reports for both drugs originated from the United States, likely due to the data source being the FAERS database. After analyzing AE signals using ROR, PRR, and BCPNN methods, and reviewing the selected signals, we identified 52 AE signals related to baclofen and 31 positive AE signals linked to tizanidine. These signals primarily involved neurological and psychiatric conditions. When compared to the adverse reactions listed in their respective product information, most AE signals were covered. However, it's noteworthy that skin and subcutaneous tissue disorders were not explicitly mentioned in baclofen's product information, despite itching and hyperhidrosis being among the top ten AE signals in our study. Sigg et al. also reported a clinical case of psoriasis induced by baclofen, suggesting a potential risk of other skin and subcutaneous tissue disorders associated with baclofen, which requires further clinical investigation. Clinicians should be aware of this risk during treatment. 4.2 Interaction of Disease, Central Muscle Relaxant Pharmacology, and AEs Central muscle relaxants are a heterogeneous group of drugs, each with unique mechanisms of action. Their common effect is to relieve muscle spasms caused by diseases of the spinal cord or brain, making them frequently used in the pharmacological treatment of various local pain syndromes, including cervicogenic headache. Taking baclofen and tizanidine as examples, the exact mechanism of action for baclofen remains unclear. It is currently believed that baclofen reduces the release of excitatory neurotransmitters from presynaptic neurons and stimulates inhibitory neuronal signals in postsynaptic neurons. By binding to GABA-β receptors, baclofen leads to potassium influx into neurons, resulting in neuronal membrane hyperpolarization and reduced calcium influx into presynaptic nerve terminals. This decreases the rate of presynaptic neurons reaching action potential threshold and reduces the action potential of postsynaptic motor neurons innervating muscle spindles. Additionally, baclofen may act on certain voltage-gated calcium channels. Besides its involvement in synaptic inhibition, baclofen may also be related to hippocampal long-term potentiation, slow-wave sleep, muscle relaxation, and anti-nociception. Renaud[12]found in animal experiments that baclofen also exhibits certain anti-inflammatory and neuroprotective effects. However, since GABA-B receptors are also widely present in other regions of the central nervous system, including the brainstem and cerebral cortex, they may inhibit the brainstem reticular activating system, leading to adverse reactions such as drowsiness and respiratory depression[13]. The identified AE signals, including hypoesthesia, disorientation, and dysarthria, may be partially associated with the central inhibitory effects of baclofen. Meanwhile, as GABA-β receptors also exist in the peripheral nervous system, the occurrence of itching symptoms after medication administration may be related, but further research is needed to support this association. The common adverse reactions listed in baclofen's product information primarily involve the nervous system (sedation, drowsiness, dizziness), gastrointestinal tract (nausea, digestive disorders, vomiting), and eyes (accommodation abnormalities, visual disturbances). These adverse reactions mostly occur during the initial stage of medication and are often temporary[5,6,15]. For patients with renal insufficiency, caution is advised due to the risk of nervous system problems, including toxic encephalopathy, caused by the accumulation of drug concentration in the body. Therefore, careful evaluation is recommended before using baclofen in patients with special conditions. The adverse reactions documented in tizanidine's product information mainly include nervous system effects (drowsiness, fatigue, dizziness), gastrointestinal issues (abdominal pain, diarrhea, indigestion), musculoskeletal system effects (muscle weakness, back pain), skin and accessory organ problems (rash, sweating, skin ulceration), and cardiovascular system effects (vasodilation, postural hypotension). Similar to baclofen, the severity of tizanidine's adverse reactions is dose-related and generally short-lived. However, in patients with special conditions such as advanced age or renal insufficiency, adverse reactions may manifest more severely. The U.S. FDA's black box warning for baclofen clearly states that sudden discontinuation of long-term baclofen use can cause withdrawal syndromes like hallucinations. Thus, unless severe adverse reactions occur, the drug should be gradually tapered off. The most frequently reported AE signal, "drug withdrawal syndrome," supports this point. This syndrome may be due to adaptive downregulation of GABA-β receptors after long-term baclofen use, leading to a sudden reduction in GABAergic inhibition and subsequent central overexcitation (such as anxiety, convulsions, hallucinations) upon drug withdrawal. Clinically, adverse reaction severity during baclofen use has been linked to the administered dose. Leung et al. [16]reported 23 clinical cases where seizures, decreased level of consciousness, delirium, and eight cases of arrhythmia and blood pressure fluctuations were observed[17]. They found that patients receiving 200 mg or more of baclofen had higher rates of ICU admission, mechanical ventilation, and prolonged hospital stays. Additionally, baclofen should not be combined with opioids, as it may cause symptoms like respiratory distress, compromising patient safety. The present study also found that respiratory diseases ranked high among the organ and system diseases involved in the major adverse effects of baclofen, and there are now clinical cases reporting an increased risk of respiratory depression with the use of baclofen in patients with CKD[18,19]. Tizanidine, an imidazoline derivative, acts as a fast-acting muscle relaxant primarily by binding to Alpha-2 adrenergic receptor sites. This binding reduces the release of excitatory amino acids like glutamate and aspartate, which cause neuronal discharge leading to muscle spasms. Tizanidine induces presynaptic inhibition of motor neurons to alleviate spasms. Its strongest effects have been demonstrated on polysynaptic pathways in the spinal cord. In animal models, tizanidine does not directly affect skeletal muscle fibers or neuromuscular junctions and has minimal impact on monosynaptic spinal reflexes. This mechanism explains the vasodilation and postural hypotension observed with tizanidine use. The anti-nociceptive and anti-convulsive activities of tizanidine may also be attributed to its agonist effect on Alpha-2 receptors. Additionally, tizanidine has some affinity for Alpha-1 receptors, explaining its mild and temporary effects on the cardiovascular system, including elevated blood pressure seen as an AE signal. Mahajan et al[20]. reported clinical cases of hypotension induced by tizanidine and cautioned about its synergistic effects with ACE inhibitors and ARBs in lowering blood pressure and heart rate. It's worth noting that tizanidine's mechanism of action does not directly explain its documented effects on cardiac electrophysiological activity, requiring further pharmacological research and clinical observation. Cervicogenic headache is currently believed to primarily involve referred pain from upper cervical joints, including surrounding intervertebral discs and soft tissue lesions. This process is often accompanied by nerve root irritation symptoms, as well as potential hyperalgesia or nociceptive sensitization. These conditions may increase the body's sensitivity to central muscle relaxants, enhancing inhibitory signal transmission and leading to excessive inhibition of central nervous system activity, manifesting as symptoms like drowsiness and altered consciousness[14]. Additionally, patients with advanced age or renal insufficiency may experience similar effects due to slowed drug metabolism. Some cervicogenic headache patients may develop insomnia due to headache and neck pain during the disease course. While the sedative effect may be perceived as improved sleep by some patients, they should be advised to avoid risky activities like driving during medication use. Elderly patients should also be cautious to prevent falls during daily care[2,5]. Due to central sensitization, patients may experience adaptive downregulation of GABA-β receptors upon drug withdrawal, putting them at risk of withdrawal syndromes caused by central nervous system overexcitation. Cervicogenic headache patients with a history of anxiety or depression may be more sensitive to the psychiatric side effects of central muscle relaxants. Therefore, it's essential to monitor for the emergence of corresponding adverse reactions during medication use and adjust dosing carefully under medical guidance. Since cervicogenic headache involves structural changes in the cervical vertebrae, which may cause autonomic nervous system dysfunction, there is a potential risk of increased sweating symptoms when using GABA-β receptor agonists like baclofen. In conclusion, further clinical research investigating adverse reactions associated with central muscle relaxants is currently a priority. Our study addresses existing gaps in the literature by analyzing AE signals at multiple levels. These findings can inform treatment choices and facilitate communication and clinical decision-making between patients and clinicians. Future research should delve deeper into the detailed mechanisms of central muscle relaxants in cervicogenic headache and other acute and chronic pain conditions. Additionally, efforts should be made to minimize potential side effects, address real-world adverse reactions, and develop new-generation drugs to optimize treatment strategies for muscle spasm-related pain syndromes. Although more mature neuromodulation techniques have been used in the treatment of cervicogenic headache, pharmacological treatment is still the first choice for patients with contraindications to treatment. 4.3 Limitations The limitations of this study stem from the characteristics of the data source, the FAERS, which is a self-reporting database in the United States. It has inherent limitations, such as incomplete reporting information and uncertainty regarding the causal relationship between reported events and medications. Additionally, issues like duplicate reporting and underreporting affect data quality, rendering it unsuitable for calculating the incidence of adverse events in the general population. Nonetheless, the results of this comprehensive data mining effort provide guidance for the safe and rational use of medications. It should be noted that all signal detection results merely indicate statistical associations. They cannot determine prevalence rates or confirm causal relationships. Therefore, future research should build upon the AE signals identified in this study and conduct further high-quality investigations to elucidate the prevalence of these AEs in real-world usage scenarios. Large-scale clinical studies are needed to establish whether there are clear causal relationships. 5 Conclusion This study utilized the FAERS database to explore potential adverse events (AEs) associated with commonly used central muscle relaxants, baclofen, and tizanidine. The findings indicate that both drugs are linked to AEs related to nervous system, psychiatric, cardiovascular, respiratory, urinary system disorders, as well as systemic diseases. The clinical implications of these findings merit further exploration. Simultaneously, there is a hope for the development of a new generation of central muscle relaxants with fewer adverse reactions and stronger selectivity for use by clinicians and patients in the future. Abbreviations CEH: Cervicogenic headache AEs: Adverse events FDA: Food and Drug Administration FAERS: U.S. Food and Drug Administration Adverse Event Reporting System MedDRA: Medical Dictionary for Regulatory Activities PRR: Proportional reporting ratio ROR: Reporting odds ratio BCPNN: Bayesian Confidence Propagation Neural Network Cl: confidence interval PT: Preferred terminology SOC: System organ classification GABA:γ-aminobutyric acid DAVF: dural arteriovenous fistula Declarations Ethical approval and consent to participate This study was based on the open-access data from [database name, e.g., The Cancer Genome Atlas (TCGA)], and all data were collected with informed consent and ethical approval by the original data providers. No additional ethical approval or informed consent was required for this secondary analysis. Consent for publication Not applicable. Availability of data and materials No datasets were generated or analysed during the current study. Competing interests The authors declare no competing interests. Funding National Key Research and Development Program of China (SQ2022YFC3600037), Capital Health Development Research Special Project (2022–1-4061) Authors' contributions In this study, JZ: Data curation, Funding acquisition, Project administration, Resources, Investigation, Supervision, Writing review & editing. WL: Data curation, Methodology, Software, Visualization, Writing-original draft, Writing – review &editing. RW: Conceptualization, Investigation, Visualization, Writing-original draft. CL: Formal analysis, Methodology, Visualization. BF and PM: Funding acquisition, Project administration, Resources, Supervision, Validation, Writing-original draft. Acknowledgements We sincerely thank the researchers, including clinicians, patients, and regulatory agencies, who contributed to the FAERS data. References Xiao H, Peng B, Ma K, Huang D, Liu X, Lu Y, Liu Q, Lu L, Liu J, Li Y, Song T, Tao W, Shen W, Yang X, Wang L, Zhang X, Zhuang Z, Liu H, Liu Y. The Chinese Association for the Study of Pain (CASP): Expert Consensus on the Cervicogenic Headache. Pain Res Manag. 2019 Apr 1;2019:9617280. doi: 10.1155/2019/9617280. PMID: 31065305; PMCID: PMC6466854. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004 Aug;28(2):140-75. doi: 10.1016/j.jpainsymman.2004.05.002. PMID: 15276195. Li D, Chai S, Wang H, Dong J, Qin C, Du D, Wang Y, Du Q, Liu S. Drug-induced QT prolongation and torsade de pointes: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System database. Front Pharmacol. 2023 Dec 21;14:1259611. doi: 10.3389/fphar.2023.1259611. PMID: 38186652; PMCID: PMC10771307. Liu H, Zou Y, Zhang Q, Zhao J, Wu J, Li X, Cheng Y, Wei H, Li H, Cao S. Pharmacovigilance insights into medication-induced risk of dural arteriovenous fistula. Int J Surg. 2025 Feb 1;111(2):1847-1859. doi: 10.1097/JS9.0000000000002214. PMID: 39764589. Killam-Worrall L, Brand R, Castro JR, Patel DS, Huynh K, Lindley B, Torres BP. Baclofen and Tizanidine Adverse Effects Observed Among Community-Dwelling Adults Above the Age of 50 Years: A Systematic Review. Ann Pharmacother. 2024 May;58(5):523-532. doi: 10.1177/10600280231193080. Epub 2023 Aug 17. PMID: 37589096. Vourc'h M, Dailly E, Hourmant Y, Bellouard R, Mahe PJ, Deslandes G, Grégoire M, Asehnoune K. Pharmacokinetics and toxicity of high-dose baclofen in ICU patients. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:450-456. doi: 10.1016/j.pnpbp.2019.02.016. Epub 2019 Feb 28. PMID: 30826461. Liu WH, Hu HM, Li C, Shi Q, Liu CH, Liu AX, Li YF, Zhang Y, Mao P, Fan BF. Real-world study of adverse events associated with triptan use in migraine treatment based on the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) database. J Headache Pain. 2024 Nov 25;25(1):206. doi: 10.1186/s10194-024-01913-0. PMID: 39587512; PMCID: PMC11587596. Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):483-6. doi: 10.1002/pds.677. PMID: 11828828. Noguchi Y, Tachi T, Teramachi H. Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source. Brief Bioinform. 2021 Nov 5;22(6):bbab347. doi: 10.1093/bib/bbab347. PMID: 34453158. Noguchi Y, Tachi T, Teramachi H. Comparison of Signal Detection Algorithms Based on Frequency Statistical Model for Drug-Drug Interaction Using Spontaneous Reporting Systems. Pharm Res. 2020 Apr 30;37(5):86. doi: 10.1007/s11095-020-02801-3. PMID: 32356247. Sharma P, Varghese Gupta S, Bhatt P, Kandukuru A, Cheng F, Upadhyay G, Sutariya V. Cardiovascular adverse events associated with triptans for treatment of migraine: a pharmacovigilance study of the FDA adverse event reporting system (FAERS). Can J Physiol Pharmacol. 2024 Dec 1;102(12):720-728. doi: 10.1139/cjpp-2024-0117. Epub 2024 Oct 22. PMID: 39435747. Alamri A, Mostofi A, Aziz T, Pereira E. Intrathecal baclofen overdose mimicking brainstem death during deep brain stimulation surgery for pain. Ann R Coll Surg Engl. 2022 Sep;104(8):e232-e235. doi: 10.1308/rcsann.2021.0341. Epub 2022 May 26. PMID: 35616338; PMCID: PMC9433185. de Beaurepaire R. A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder. Front Psychiatry. 2018 Oct 17;9:506. doi: 10.3389/fpsyt.2018.00506. PMID: 30459646; PMCID: PMC6232933. Antonaci F, Sjaastad O. Cervicogenic headache: a real headache. Curr Neurol Neurosci Rep. 2011 Apr;11(2):149-55. doi: 10.1007/s11910-010-0164-9. PMID: 21125430. Romito JW, Turner ER, Rosener JA, Coldiron L, Udipi A, Nohrn L, Tausiani J, Romito BT. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Med. 2021 Jun 3;9:20503121211022197. doi: 10.1177/20503121211022197. PMID: 34158937; PMCID: PMC8182184. Parker-Pitts CK, Weymouth CW, Frawley MT. Intrathecal Baclofen Overdose With Paradoxical Autonomic Features Mimicking Withdrawal. J Emerg Med. 2020 Apr;58(4):616-619. doi: 10.1016/j.jemermed.2019.12.031. Epub 2020 Mar 20. PMID: 32204996. Leung NY, Whyte IM, Isbister GK. Baclofen overdose: defining the spectrum of toxicity. Emerg Med Australas. 2006 Feb;18(1):77-82. doi: 10.1111/j.1742-6723.2006.00805.x. PMID: 16454779. Mitsuboshi S. Association Between Baclofen and Respiratory Depression in Patients With Chronic Kidney Disease. J Clin Pharmacol. 2021 Jun;61(6):836-837. doi: 10.1002/jcph.1843. Epub 2021 Mar 27. PMID: 33629349. Reade MC. Baclofen to Prevent Agitation Caused by Alcohol Withdrawal in the ICU. JAMA. 2021 Feb 23;325(8):727-729. doi: 10.1001/jama.2021.0597. PMID: 33620385. Sigg N, Delaunay J, Potey C, Drablier G. Baclofen-induced psoriasis. Ann Dermatol Venereol. 2022 Dec;149(4):291-293. doi: 10.1016/j.annder.2022.03.009. Epub 2022 May 25. PMID: 35643883. Mahajan R, Kalita J. Tizanidine Induced Hypotension: Report of a Case and Review of the Literature. Curr Drug Saf. 2024;19(2):313-316. doi: 10.2174/1574886318666230725113855. PMID: 37489780. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6492591","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463254457,"identity":"e3a943aa-dbe0-4f60-9c31-5ba55d4c75d7","order_by":0,"name":"Jiaxi Zhang","email":"","orcid":"","institution":"Beijing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiaxi","middleName":"","lastName":"Zhang","suffix":""},{"id":463254458,"identity":"c9d36db3-a3d6-4d43-9c58-83f05838f84f","order_by":1,"name":"Wenhui Liu","email":"","orcid":"","institution":"Beijing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wenhui","middleName":"","lastName":"Liu","suffix":""},{"id":463254460,"identity":"5099cf1c-0b28-4850-8ad4-172d07432347","order_by":2,"name":"Chen Li","email":"","orcid":"","institution":"Beijing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Li","suffix":""},{"id":463254463,"identity":"0b84c400-8ba7-4eab-a98f-75c9fdef72df","order_by":3,"name":"Ruitao Wang","email":"","orcid":"","institution":"Beijing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ruitao","middleName":"","lastName":"Wang","suffix":""},{"id":463254464,"identity":"65c053e7-f87b-4149-9184-752c3346db47","order_by":4,"name":"Peng Mao","email":"","orcid":"","institution":"Beijing University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Mao","suffix":""},{"id":463254465,"identity":"76f04124-70ae-4bb5-b4fd-6f3d1e2aa3dd","order_by":5,"name":"Bifa Fan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBAC9hmMDw58MLCRA7LZiNPCc4PZ8OCMgjRjmBYJYrQYH+b4cCixgXgt0s0MhxkMDqRvON787AHjDps6wlpkDjMcLjC4k7vhzDFzA8YzaYRtsZfIP3B4hsGz3A03EswkGNsOE+EwiWSGwzwGh9MN7j//BtTyn3gtCQY3eEC2HCBCC9AvB2cYpBnOPJNTJpHYlizZQFCLdDPzhw9/bOT5jh/fJvGxzY6foC1woHAASCQQrx4I5Ak6aBSMglEwCkYsAAAHxkFnqy+sCwAAAABJRU5ErkJggg==","orcid":"","institution":"China-Japan Friendship Hospital","correspondingAuthor":true,"prefix":"","firstName":"Bifa","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2025-04-21 05:23:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6492591/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6492591/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83648219,"identity":"c3d6634e-2073-4032-a4e4-055822439dc2","added_by":"auto","created_at":"2025-05-30 06:21:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":214936,"visible":true,"origin":"","legend":"\u003cp\u003eDemographic information reported by AE in FAERS. (A)Distribution of reported AE in last ten years. (B) Gender distribution of baclofen-related adverse events. (C) Gender distribution of tizanidine-related adverse events. (D) Distribution of AE outcomes related to two drugs.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6492591/v1/31793c1408c080e66b26e234.png"},{"id":83648220,"identity":"b028eee1-1d81-41f4-aba0-b8d154622400","added_by":"auto","created_at":"2025-05-30 06:21:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":371242,"visible":true,"origin":"","legend":"\u003cp\u003eThe names and numbers of the top 30 AE signals with the highest percentage of 2 drug signals detected in the FAERS database and SOCs related. (A) Top 30 AE signals of Baclofen and SOCs related. (B) Top 30 AE signals of Tizanidine and SOCs related. (C)The distribution of the top 30 AE signals and their three signal values with the highest frequency of occurrence of Baclofen. (D) The distribution of the top 30 AE signals and their three signal values with the highest frequency of occurrence of Tizanidine.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6492591/v1/2da2c8aca31660525be5acd3.png"},{"id":83648221,"identity":"d1a09b96-3fc7-46db-9f2e-413be10ada66","added_by":"auto","created_at":"2025-05-30 06:21:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":517489,"visible":true,"origin":"","legend":"\u003cp\u003eSignal detection results of AE reports and ROR (95%CI). (A)Forest plot for signal detection of baclofen-related adverse events. (B) Volcano plot for signal detection of baclofen-related adverse events. (C) Forest plot for signal detection of tizanidine-related adverse events. (D) Volcano plot for signal detection of tizanidine-related adverse events.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6492591/v1/c4c659483d60fb3f64d80800.png"},{"id":83648222,"identity":"d79633e2-01c0-4c9e-ab1c-6a92d14a3588","added_by":"auto","created_at":"2025-05-30 06:21:08","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":715246,"visible":true,"origin":"","legend":"\u003cp\u003ea. Network Venn diagram of PT positive signals of two central muscle relaxants in FAERS database.(A) Network Venn diagram of PT positive signals of two central muscle relaxants in FAERS database. (B) Distribution network plot of the top 30 AE signals in each SOC for tizanidine.The root node represents the drug name, with the inner ring indicating SOC and the outer ring indicating AE signal names. (C)Distribution network plot of the top 30 AE signals in each SOC for baclofen.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6492591/v1/f991ad9aca51482a38fec14e.png"},{"id":95560482,"identity":"ea7f608a-79e9-44ce-bd37-5ab14f1d3e18","added_by":"auto","created_at":"2025-11-10 15:23:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2566689,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6492591/v1/8a5e25a9-fe15-4308-91fb-3a702e250cb6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real-world study on adverse events of central muscle relaxants in the treatment of cervicogenic headache based on the U.S. FAERS database","fulltext":[{"header":"1 Background","content":"\u003cp\u003eCervicogenic headache (CEH), referring to secondary headache caused by cervical spine lesions involving vertebrae, intervertebral discs, and soft tissues, typically manifests as unilateral neck dull pain or referred pain. It is often accompanied by neck stiffness, limited active and passive movement, and ipsilateral shoulder and upper limb pain. The pathophysiological mechanisms primarily involve abnormalities in cervical vertebral bodies, intervertebral discs, neuromuscular structures, leading to neck muscle spasms, nerve endings compression, and enhanced pain signal transmission. Recently, with the widespread use of electronic devices and sedentary lifestyles, the incidence of CEH has been on the rise. Global data reveals that CEH accounts for approximately 15% to 20% of all chronic headaches and 17.5% of severe headaches. Furthermore, CEH imposes a significant economic burden, with annual costs reaching billions of dollars due to medical expenses and productivity losses.\u003c/p\u003e\n\u003cp\u003eCentral muscle relaxants play a crucial role in treating CEH. The pathophysiology of CEH is closely related to continuous tension and spasms in neck muscles. Central muscle relaxants can alleviate neck muscle spasms, improve local blood circulation, and reduce pain and discomfort by inhibiting excessive excitation in the central nervous system, regulating neural reflex activities in the spinal cord and brainstem, and decreasing muscle tension[1]. These relaxants constitute a heterogeneous group of drugs, with Baclofen and Tizanidine being two commonly used agents for CEH treatment, each with distinct chemical structures and mechanisms of action.\u003c/p\u003e\n\u003cp\u003eBaclofen, a\u0026nbsp;γ-aminobutyric acid (GABA) B receptor agonist with a chemical structure of 4-amino-3-(4-chlorophenyl)butyric acid, activates GABA B receptor subunit 2 in the spinal cord. This activation inhibits the release of excitatory neurotransmitters, thereby reducing hyperactivity in spinal reflex arcs and alleviating muscle spasms and pain. Thus, it significantly relieves muscle tension and pain in CEH patients.\u003c/p\u003e\n\u003cp\u003eTizanidine, an α2-adrenergic receptor agonist, chemically structured as 5-chloro-4-(2-imidazolinyl)-2,1,3-benzothiadiazole, acts by activating\u0026nbsp;α2 receptors in the central nervous system. It suppresses excitatory neurotransmission at the spinal level, reduces muscle spasms, and exerts analgesic effects. Additionally, Tizanidine improves local blood circulation, further relieving CEH symptoms.\u003c/p\u003e\n\u003cp\u003ePrevious studies investigating adverse events (AEs) associated with Tizanidine and Baclofen treatment for spasms have reported similar overall AE incidence rates for both drugs. Common AEs include dry mouth, drowsiness, and fatigue, with fatigue being more prominent in Baclofen-treated patients and dry mouth being the most frequent AE in Tizanidine-treated patients. Some patients also reported dizziness, headache, and abnormal liver function[2,3]. Lisa et al. [4]conducted a statistical analysis of AEs in adults over 50 years old treated with Baclofen and Tizanidine in the community, revealing that Baclofen's adverse reactions primarily affect the nervous and motor systems (movement disorders, encephalopathy or disorientation, and drowsiness), whereas Tizanidine's AEs mainly involve the cardiovascular system (hypotension and bradycardia). There are also reports suggesting that Baclofen may induce dural arteriovenous fistula (DAVF). Studies on special populations, such as elderly patients and those with renal insufficiency, have found that the use of muscle relaxants in chronic kidney disease and end-stage renal disease patients is associated with an increased risk of hospitalization due to neurological diseases. Additionally, the risk of falls after medication use is elevated in the elderly[5]. Another study examining Baclofen use in patients with varying renal function found that the drug's dosage should be adjusted proportionally based on renal function in cases of mild, moderate, or severe renal failure[6].\u003c/p\u003e\n\u003cp\u003eHowever, existing clinical trials assessing the safety of central muscle relaxants have limitations: most studies have small sample sizes, typically involving only tens to hundreds of patients, and short follow-up durations, often less than six months. This makes it difficult to comprehensively evaluate the long-term safety of these drugs. Furthermore, some trials have a relatively homogeneous study population, lacking quantitative analysis and comparison based on gender, age, country, and other demographic characteristics. Drug safety studies based on a larger range of real-world, up-to-date clinical data are becoming more and more important as drug research continues to deepen and indications and dosage forms expand.\u003c/p\u003e\n\u003cp\u003eThe U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) is an authoritative drug safety database that collects real-time data on AEs and medication errors from multiple countries. It serves as a valuable source of real-world AE data, providing essential insights for monitoring drug safety and assessing risks. This study aims to conduct a pharmacovigilance analysis of AEs associated with commonly used central muscle relaxants, Baclofen and Tizanidine, using the FAERS database. The goal is to gain a deeper understanding of the safety profiles of these drugs and provide clinicians, patients, and regulatory authorities with valuable information to inform personalized treatment decisions.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003ch2\u003e\u003cem\u003e2.1\u0026nbsp;\u003c/em\u003e\u003cem\u003eData Sources\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe data for this study were obtained from the publicly available FAERS database, which compiles spontaneous reports from healthcare professionals, patients, drug manufacturers, and other sources across different regions. These data provide a reflection of the true incidence of adverse events (AEs). This retrospective study used Open Vigil 2.1 to query the FAERS database and retrieve reports on the target drugs over the past 20 years, from January 1, 2004, to August 31, 2024, to better represent the real-world AE profile of these drugs. The target drugs were the central muscle relaxants \u0026quot;baclofen\u0026quot; and \u0026quot;tizanidine.\u0026quot; Unlike previous studies that often focused on specific age groups, this study aimed to conduct a broad investigation of AEs associated with the use of central muscle relaxants across all age groups. We selected AE report cases where the target drugs were identified as the \u0026quot;primary suspects.\u0026quot; Subsequently, we classified and described the AEs based on the preferred terms (PT) and system organ classes (SOC) from the Medical Dictionary for Regulatory Activities (MedDRA version 27.0). As the data were sourced from a public database, ethical approval was not required.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e2.2\u0026nbsp;\u003c/em\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eThe proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) are commonly used methods for detecting drug safety signals related to AEs. The PRR is used to estimate relative risk but can be susceptible to false-positive signals [8]. The ROR provides a stable estimate of ratios or risk ratios with less bias [3,10]. The BCPNN is a supervised learning method based on neural networks that utilizes known drug adverse reactions as a training set and maintains stability even with a small number of reports [9,11]. Therefore, we combined the ROR, PRR, and BCPNN methods to mine AE signals for the target drugs and calculated PRR and\u0026nbsp;\u0026chi;\u0026sup2;values using a contingency table for measures of disproportionality. When all three methods yielded positive results, the criteria in \u003cstrong\u003eTable 1\u003c/strong\u003e were considered met, and the signal was classified as a suspicious AE signal. Data statistical analysis and graphing were performed using Microsoft Office Excel 2021, R 4.3.1 software, and online platforms.(https://www.bioincloud.tech/,https://www.chiplot.online/,https://www.bioinformatics.com.cn) [7]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable1\u003c/strong\u003e. Formulas and signal detection criterias for reporting odds ratio (ROR), proportional reporting ratio (PRR) and bayesian confidence propagation neural network (BCPNN).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlgorithms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEquation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCriteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 105px;\"\u003e\n \u003cp\u003eROR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003eROR=ad/bc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003elower limitof 95%CI\u0026gt;1,a\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003e95%CI=eIn(ROR)\u0026plusmn;1.96(1/a+1/b+1/c+1/d)^0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 105px;\"\u003e\n \u003cp\u003ePRR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePRR=a(c+d)/c/(a+b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003ePRR\u0026gt;2,\u0026chi;\u0026sup2;\u0026gt;4,a\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003e\u0026chi;\u0026sup2;=[(ad-bc)^2](a+b+c+d)/[(a+b)(c+d)(a+c)(b+d)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 105px;\"\u003e\n \u003cp\u003eBCPNN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003eIC=log2a(a+b+c+d)(a+c)(a+b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eIC025＞0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 321px;\"\u003e\n \u003cp\u003e95%CI=E(IC)\u0026plusmn;2V(IC)^0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003eFourfold table of disproportionality measures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eTarget AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003eOther AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003eTarget drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003ea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003eb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003ea+b\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003eOther drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003ec\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003ed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003ec+d\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003ea+c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 140px;\"\u003e\n \u003cp\u003eb+d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003ea+b+c+d\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eROR reporting odds ratio, CI confidence interval, PRR proportional reporting ratio, \u0026chi;2 chi-squared, BCPNN bayesian confidence propagation neural network, IC information component, IC025 the lower limit of 95%CI, of the IC\u003c/p\u003e"},{"header":"3 Results","content":"\u003ch2\u003e\u003cem\u003e3.1\u0026nbsp;\u003c/em\u003e\u003cem\u003eDemographic information on the AE reports\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eBetween January 1, 2004, and August 31, 2024, the US FAERS database received reports with baclofen as the primary suspected drug totaling 14,431 cases. Excluding unknown reports, the ratio of male to female patients was roughly equal (53.3% and 44.5%, respectively). The age group with the highest representation was 40-59 years old (5,369 cases, accounting for 37.2%). The country with the most reported cases was the United States (11,451 cases, 79.4%). The period with the highest number of reported cases was from 2014 to 2016 (3,855 cases, 26.7%). For tizanidine, the total number of reports with it as the primary suspected drug was 365 cases. Among these, the number of female patients (215 cases, 58.9%) was significantly higher than male patients (114 cases, 31.2%). The age distribution was concentrated in the 40-59 age group (160 cases, 43.8%). The country with the most reported cases was also the United States (201 cases, 55.0%). The most concentrated period for case reporting was from 2004 to 2006 (168 cases, 46.0%)(Figure 1). Excluding unknown reports, \u0026quot;pain\u0026quot; ranked second and third among the indications for the two drugs, respectively. (Details are provided in Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Signal detection results and grading for all positive adverse event signals of Tizanidine in the FAERS database\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ex2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROR(95%Cl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003econfusional state\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e56.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e76957.831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e64.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003edry mouth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1382.477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e4.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003ehypotension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e219.260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003esomnolence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e18.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e6540.678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e19.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003efall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e10.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3228.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e10.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eloss of consciousness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e757.238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eoverdose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e63.580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e20984.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e65.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eamnesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e15.751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e4091.724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e16.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003easthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e388.755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003econvulsion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e488.513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003edysarthria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e5.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e854.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e5.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003emuscle spasms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e6.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1240.185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e6.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003epallor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e7.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1237.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e7.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003ealanine aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e452.457\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003ebradycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.340\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e163.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003ecoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.575\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e203.730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003edrug interaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4.198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e507.525\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e4.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003efeeling abnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e170.438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003ehallucination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e17.953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3074.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e18.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003einsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e7.891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1153.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e8.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eagitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e270.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003easpartate aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e227.465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eblood pressure decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e2.537\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e178.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eblood pressure increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4.213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e431.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e4.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003edepressed level of consciousness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e361.926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003edrug effect decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e286.820\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eheart rate increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e9.576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1278.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e9.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eirritability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e14.844\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e1938.927\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e15.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003esleep disorder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e179.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e19408.290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e182.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003eurinary tract infection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e3.222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e214.084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e3.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 190px;\"\u003e\n \u003cp\u003evision blurred\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e4.686\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e5.438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e4.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAll positive adverse event signals of Tizanidine identified in the FAERS database using disproportionality analysis (PRR, ROR, BCPNN). Signal thresholds and grading criteria are applied as per standard definitions.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e3.2 AE Signal Mining and Analysis of AE Signals at the PT Level\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eIn this study, three methods, ROR, PRR, and BCPNN, were used to analyze AE signals. After excluding cases with input errors, incomplete records, and signals related to product quality, usage issues, various injuries, poisoning, concomitant procedures, and drug indications, a total of 52 positive AE signals related to baclofen and 31 positive AE signals related to tizanidine were obtained. All AE signals are listed in \u003cstrong\u003eTable 2\u003c/strong\u003e. Next, we analyzed all signals at the PT level, focusing on the top 30 most frequent and highest signal strength detections\u003cstrong\u003e\u0026nbsp;(Table 3, Figure 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Top 30 adverse event signals of baclofen and tizanidine in the FAERS database (PRR, ROR, BCPNN)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ex2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROR(95%Cl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003edrug withdrawl syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e56.797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e76957.831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e64.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003esomnolence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e534\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e4.353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1382.477\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e4.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003epruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e415\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e219.260\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003emental status changes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e18.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e6540.678\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e19.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ecoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e10.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e3228.469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e10.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003econfusional state\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e757.238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ehypotonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e63.580\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e20984.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e65.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003eunresponsive to stimuli\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e304\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e15.751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e4091.724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e16.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003etremor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e388.755\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ehyperhidrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e488.513\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003eagitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e261\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e5.092\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e854.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e5.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003elethargy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e6.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1240.185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e6.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003edepressed level of consciousness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e7.155\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1237.179\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e7.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003eseizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e452.457\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ehypoaesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e212\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.340\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e163.229\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ecompleted suicide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e211\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.575\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e203.730\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003emusculoskeletal stiffness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e4.198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e507.525\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e4.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003eloss of consciousness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e207\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e170.438\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003eneurotoxicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e17.953\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e3074.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e18.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003edelirium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e7.891\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1153.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e8.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003etachycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e270.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003emuscular weakness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e227.465\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ehospitalisation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e2.537\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e178.233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ebradycardia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e4.213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e431.954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e4.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003econvulsion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e361.926\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003erespiratory failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e3.385\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e286.820\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e3.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003esedation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e169\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e9.576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1278.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e9.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003erespiratory depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e14.844\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e1938.927\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e15.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 240px;\"\u003e\n \u003cp\u003ecerebrospinal fluid leakage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e179.888\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e19408.290\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 93px;\"\u003e\n \u003cp\u003e182.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe thirty most prominent adverse event signals of baclofen and tizanidine identified in the FAERS database by disproportionality analysis (PRR, ROR, BCPNN), including preferred term (PT), case number, and main signal detection parameters.\u003c/p\u003e\n\u003cp\u003eAmong the selected AE signals related to baclofen, the top three reported signals were drug withdrawal syndrome, somnolence, and pruritus. The top three PRR values were intracranial hypotension, cerebrospinal fluid leakage, and hypotonia. For tizanidine-related AE signals, the top three reported signals were confusional state, dry mouth, and somnolence. The top three PRR values were pallor, dysarthria, and dry mouth.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e3.3 SOC Stratified Analysis and the Relationship between Major AE Signal Detection and SOC\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eIn this study, MedDRA27.0 was used to categorize the AE signals of the 2 drugs according to the SOC involving organs and systems. Visual analysis was then performed to examine the PT signals and their corresponding SOCs.The results showed that Nervous system disorders was the category with the highest number of AE signals for both drugs in the FAERS database, followed by Psychiatric disorders.Subsequently, we focused on the signals in the top 30 most common AEs occurring in the drugs in terms of their ROR 95% confidence interval (CI) strengths, which were visualized and analyzed by forest and volcano plots\u003cstrong\u003e\u0026nbsp;(Figure 3).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strongest signal associated with baclofen (ROR = 320.60 (271.76 to 378.21)) was intracranial hypotension, which is categorized as a neurological disorder. In addition to oral administration, intrathecal injection is a common route of drug administration and is often used in the treatment of chronic intractable pain, but the risks associated with intrathecal pump placement need to be guarded against. intracranial hypotension and cerebrospinal fluid leakage, the top 2 AE signals in terms of PRR, are related to this, and although the incidence of intrathecal baclofen Although the incidence of intrathecal baclofen overdose is low, there have been case reports of patients with intrathecal baclofen pumps experiencing brainstem suppression during surgery, which may have been caused by baclofen overdose, and perioperative vigilance is needed to prevent the occurrence of this phenomenon. SOCs not included in the drug insert for baclofen include skin and subcutaneous tissue disorders. Clinical use of central muscle relaxants such as baclofen should still be closely monitored for adverse reactions in patients with associated systemic diseases. The strongest signal associated with tizanidine (ROR = 31.10 (12.64 to 76.53)) was pallor, with descriptions of\u0026nbsp;\u0026ldquo;hypotension\u0026rdquo;\u0026nbsp;and\u0026nbsp;\u0026ldquo;anemia\u0026rdquo;\u0026nbsp;adverse reactions in the tizanidine hydrochloride insert. The main adverse events for both drugs were related to nervous system disorders, psychiatric disorders, respiratory disorders, gastrointestinal disorders and several general disorders \u003cstrong\u003e(Figure 4, Table 4).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u003c/strong\u003e\u0026nbsp; Distribution of AE signals in each SOC\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSOCs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaclofen\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTizanidine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eNervous system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e3728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e42.16%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e25.36%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003ePsychiatric disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1591\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e17.99%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e18.12%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e1542\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e17.44%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e11.59%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e695\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e7.86%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e4.52%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e3.62%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eCardiac disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e4.18%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e2.90%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e325\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e3.68%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eSurgical and medical procedures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e2.16%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eGastrointestinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e5.07%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eInfections and infestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e2.17%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e8.70%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eInvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 83px;\"\u003e\n \u003cp\u003e0.00%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 103px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e11.59%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eBased on the US FAERS database, this study systematically analyzed the characteristics and risk signals of adverse events (AEs) associated with commonly used central muscle relaxants, baclofen and tizanidine, in the treatment of pain-related diseases such as cervicogenic headache. Other central muscle relaxants like eperisone and cyclobenzaprine were not discussed in detail due to the limited number of AE reports in the database. This analysis provides crucial evidence for evaluating the safety of these drugs in real-world settings.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e4.1 Key Findings\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eUtilizing Open Vigil 2.1, we retrieved ADE reports for baclofen and tizanidine from the FAERS database, spanning from January 1, 2004, to August 31, 2024. Aside from reports with missing information, we found that both drugs were most commonly associated with AEs in patients aged 40-59, aligning with the peak age for cervical degenerative changes. The male-to-female ratio of AEs was roughly equal for baclofen, while tizanidine showed a higher proportion of female patients. The majority of AE reports for both drugs originated from the United States, likely due to the data source being the FAERS database.\u003c/p\u003e\n\u003cp\u003eAfter analyzing AE signals using ROR, PRR, and BCPNN methods, and reviewing the selected signals, we identified 52 AE signals related to baclofen and 31 positive AE signals linked to tizanidine. These signals primarily involved neurological and psychiatric conditions. When compared to the adverse reactions listed in their respective product information, most AE signals were covered. However, it's noteworthy that skin and subcutaneous tissue disorders were not explicitly mentioned in baclofen's product information, despite itching and hyperhidrosis being among the top ten AE signals in our study. Sigg et al. also reported a clinical case of psoriasis induced by baclofen, suggesting a potential risk of other skin and subcutaneous tissue disorders associated with baclofen, which requires further clinical investigation. Clinicians should be aware of this risk during treatment.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e4.2 Interaction of Disease, Central Muscle Relaxant Pharmacology, and AEs\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eCentral muscle relaxants are a heterogeneous group of drugs, each with unique mechanisms of action. Their common effect is to relieve muscle spasms caused by diseases of the spinal cord or brain, making them frequently used in the pharmacological treatment of various local pain syndromes, including cervicogenic headache. Taking baclofen and tizanidine as examples, the exact mechanism of action for baclofen remains unclear. It is currently believed that baclofen reduces the release of excitatory neurotransmitters from presynaptic neurons and stimulates inhibitory neuronal signals in postsynaptic neurons. By binding to GABA-β receptors, baclofen leads to potassium influx into neurons, resulting in neuronal membrane hyperpolarization and reduced calcium influx into presynaptic nerve terminals. This decreases the rate of presynaptic neurons reaching action potential threshold and reduces the action potential of postsynaptic motor neurons innervating muscle spindles. Additionally, baclofen may act on certain voltage-gated calcium channels. Besides its involvement in synaptic inhibition, baclofen may also be related to hippocampal long-term potentiation, slow-wave sleep, muscle relaxation, and anti-nociception. Renaud[12]found in animal experiments that baclofen also exhibits certain anti-inflammatory and neuroprotective effects. However, since GABA-B receptors are also widely present in other regions of the central nervous system, including the brainstem and cerebral cortex, they may inhibit the brainstem reticular activating system, leading to adverse reactions such as drowsiness and respiratory depression[13]. The identified AE signals, including hypoesthesia, disorientation, and dysarthria, may be partially associated with the central inhibitory effects of baclofen. Meanwhile, as GABA-β receptors also exist in the peripheral nervous system, the occurrence of itching symptoms after medication administration may be related, but further research is needed to support this association.\u003c/p\u003e\n\u003cp\u003eThe common adverse reactions listed in baclofen's product information primarily involve the nervous system (sedation, drowsiness, dizziness), gastrointestinal tract (nausea, digestive disorders, vomiting), and eyes (accommodation abnormalities, visual disturbances). These adverse reactions mostly occur during the initial stage of medication and are often temporary[5,6,15]. For patients with renal insufficiency, caution is advised due to the risk of nervous system problems, including toxic encephalopathy, caused by the accumulation of drug concentration in the body. Therefore, careful evaluation is recommended before using baclofen in patients with special conditions.\u003c/p\u003e\n\u003cp\u003eThe adverse reactions documented in tizanidine's product information mainly include nervous system effects (drowsiness, fatigue, dizziness), gastrointestinal issues (abdominal pain, diarrhea, indigestion), musculoskeletal system effects (muscle weakness, back pain), skin and accessory organ problems (rash, sweating, skin ulceration), and cardiovascular system effects (vasodilation, postural hypotension). Similar to baclofen, the severity of tizanidine's adverse reactions is dose-related and generally short-lived. However, in patients with special conditions such as advanced age or renal insufficiency, adverse reactions may manifest more severely.\u003c/p\u003e\n\u003cp\u003eThe U.S. FDA's black box warning for baclofen clearly states that sudden discontinuation of long-term baclofen use can cause withdrawal syndromes like hallucinations. Thus, unless severe adverse reactions occur, the drug should be gradually tapered off. The most frequently reported AE signal, \"drug withdrawal syndrome,\" supports this point. This syndrome may be due to adaptive downregulation of GABA-β receptors after long-term baclofen use, leading to a sudden reduction in GABAergic inhibition and subsequent central overexcitation (such as anxiety, convulsions, hallucinations) upon drug withdrawal. Clinically, adverse reaction severity during baclofen use has been linked to the administered dose. Leung et al. [16]reported 23 clinical cases where seizures, decreased level of consciousness, delirium, and eight cases of arrhythmia and blood pressure fluctuations were observed[17]. They found that patients receiving 200 mg or more of baclofen had higher rates of ICU admission, mechanical ventilation, and prolonged hospital stays. Additionally, baclofen should not be combined with opioids, as it may cause symptoms like respiratory distress, compromising patient safety. The present study also found that respiratory diseases ranked high among the organ and system diseases involved in the major adverse effects of baclofen, and there are now clinical cases reporting an increased risk of respiratory depression with the use of baclofen in patients with CKD[18,19].\u003c/p\u003e\n\u003cp\u003eTizanidine, an imidazoline derivative, acts as a fast-acting muscle relaxant primarily by binding to Alpha-2 adrenergic receptor sites. This binding reduces the release of excitatory amino acids like glutamate and aspartate, which cause neuronal discharge leading to muscle spasms. Tizanidine induces presynaptic inhibition of motor neurons to alleviate spasms. Its strongest effects have been demonstrated on polysynaptic pathways in the spinal cord. In animal models, tizanidine does not directly affect skeletal muscle fibers or neuromuscular junctions and has minimal impact on monosynaptic spinal reflexes. This mechanism explains the vasodilation and postural hypotension observed with tizanidine use. The anti-nociceptive and anti-convulsive activities of tizanidine may also be attributed to its agonist effect on Alpha-2 receptors. Additionally, tizanidine has some affinity for Alpha-1 receptors, explaining its mild and temporary effects on the cardiovascular system, including elevated blood pressure seen as an AE signal. Mahajan et al[20]. reported clinical cases of hypotension induced by tizanidine and cautioned about its synergistic effects with ACE inhibitors and ARBs in lowering blood pressure and heart rate. It's worth noting that tizanidine's mechanism of action does not directly explain its documented effects on cardiac electrophysiological activity, requiring further pharmacological research and clinical observation.\u003c/p\u003e\n\u003cp\u003eCervicogenic headache is currently believed to primarily involve referred pain from upper cervical joints, including surrounding intervertebral discs and soft tissue lesions. This process is often accompanied by nerve root irritation symptoms, as well as potential hyperalgesia or nociceptive sensitization. These conditions may increase the body's sensitivity to central muscle relaxants, enhancing inhibitory signal transmission and leading to excessive inhibition of central nervous system activity, manifesting as symptoms like drowsiness and altered consciousness[14]. Additionally, patients with advanced age or renal insufficiency may experience similar effects due to slowed drug metabolism. Some cervicogenic headache patients may develop insomnia due to headache and neck pain during the disease course. While the sedative effect may be perceived as improved sleep by some patients, they should be advised to avoid risky activities like driving during medication use. Elderly patients should also be cautious to prevent falls during daily care[2,5]. Due to central sensitization, patients may experience adaptive downregulation of GABA-β receptors upon drug withdrawal, putting them at risk of withdrawal syndromes caused by central nervous system overexcitation. Cervicogenic headache patients with a history of anxiety or depression may be more sensitive to the psychiatric side effects of central muscle relaxants. Therefore, it's essential to monitor for the emergence of corresponding adverse reactions during medication use and adjust dosing carefully under medical guidance. Since cervicogenic headache involves structural changes in the cervical vertebrae, which may cause autonomic nervous system dysfunction, there is a potential risk of increased sweating symptoms when using GABA-β receptor agonists like baclofen. In conclusion, further clinical research investigating adverse reactions associated with central muscle relaxants is currently a priority. Our study addresses existing gaps in the literature by analyzing AE signals at multiple levels. These findings can inform treatment choices and facilitate communication and clinical decision-making between patients and clinicians. Future research should delve deeper into the detailed mechanisms of central muscle relaxants in cervicogenic headache and other acute and chronic pain conditions. Additionally, efforts should be made to minimize potential side effects, address real-world adverse reactions, and develop new-generation drugs to optimize treatment strategies for muscle spasm-related pain syndromes. Although more mature neuromodulation techniques have been used in the treatment of cervicogenic headache, pharmacological treatment is still the first choice for patients with contraindications to treatment.\u003c/p\u003e\n\u003ch1\u003e\u003cem\u003e4.3\u0026nbsp;\u003c/em\u003e\u003cem\u003eLimitations\u003c/em\u003e\u003c/h1\u003e\n\u003cp\u003eThe limitations of this study stem from the characteristics of the data source, the FAERS, which is a self-reporting database in the United States. It has inherent limitations, such as incomplete reporting information and uncertainty regarding the causal relationship between reported events and medications. Additionally, issues like duplicate reporting and underreporting affect data quality, rendering it unsuitable for calculating the incidence of adverse events in the general population. Nonetheless, the results of this comprehensive data mining effort provide guidance for the safe and rational use of medications. It should be noted that all signal detection results merely indicate statistical associations. They cannot determine prevalence rates or confirm causal relationships. Therefore, future research should build upon the AE signals identified in this study and conduct further high-quality investigations to elucidate the prevalence of these AEs in real-world usage scenarios. Large-scale clinical studies are needed to establish whether there are clear causal relationships.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis study utilized the FAERS database to explore potential adverse events (AEs) associated with commonly used central muscle relaxants, baclofen, and tizanidine. The findings indicate that both drugs are linked to AEs related to nervous system, psychiatric, cardiovascular, respiratory, urinary system disorders, as well as systemic diseases. The clinical implications of these findings merit further exploration. Simultaneously, there is a hope for the development of a new generation of central muscle relaxants with fewer adverse reactions and stronger selectivity for use by clinicians and patients in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCEH: Cervicogenic headache\u003c/p\u003e\n\u003cp\u003eAEs: Adverse events\u003c/p\u003e\n\u003cp\u003eFDA: Food and Drug Administration\u003c/p\u003e\n\u003cp\u003eFAERS: U.S. Food and Drug Administration Adverse Event Reporting System\u003c/p\u003e\n\u003cp\u003eMedDRA: Medical Dictionary for Regulatory Activities\u003c/p\u003e\n\u003cp\u003ePRR: Proportional reporting ratio\u003c/p\u003e\n\u003cp\u003eROR: Reporting odds ratio\u003c/p\u003e\n\u003cp\u003eBCPNN: Bayesian Confidence Propagation Neural Network\u003c/p\u003e\n\u003cp\u003eCl: confidence interval\u003c/p\u003e\n\u003cp\u003ePT: Preferred terminology\u003c/p\u003e\n\u003cp\u003eSOC: System organ classification\u003c/p\u003e\n\u003cp\u003eGABA:\u0026gamma;-aminobutyric acid\u003c/p\u003e\n\u003cp\u003eDAVF: dural arteriovenous fistula\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was based on the open-access data from [database name, e.g., The Cancer Genome Atlas (TCGA)], and all data were collected with informed consent and ethical approval by the original data providers. No additional ethical approval or informed consent was required for this secondary analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNational Key Research and Development Program of China (SQ2022YFC3600037), Capital Health Development Research Special Project (2022\u0026ndash;1-4061)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, JZ: Data curation, Funding acquisition, Project administration, Resources, Investigation, Supervision, Writing review \u0026amp; editing. WL: Data curation, Methodology, Software, Visualization, Writing-original draft, Writing\u0026nbsp;\u0026ndash;\u0026nbsp;review \u0026amp;editing. RW: Conceptualization, Investigation, Visualization, Writing-original draft. CL: Formal analysis, Methodology, Visualization. BF and PM: Funding acquisition, Project administration, Resources, Supervision, Validation, Writing-original draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the researchers, including clinicians, patients, and regulatory agencies, who contributed to the FAERS data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXiao H, Peng B, Ma K, Huang D, Liu X, Lu Y, Liu Q, Lu L, Liu J, Li Y, Song T, Tao W, Shen W, Yang X, Wang L, Zhang X, Zhuang Z, Liu H, Liu Y. The Chinese Association for the Study of Pain (CASP): Expert Consensus on the Cervicogenic Headache. Pain Res Manag. 2019 Apr 1;2019:9617280. doi: 10.1155/2019/9617280. PMID: 31065305; PMCID: PMC6466854.\u003c/li\u003e\n\u003cli\u003eChou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004 Aug;28(2):140-75. doi: 10.1016/j.jpainsymman.2004.05.002. PMID: 15276195. Li D, Chai S, Wang H, Dong J, Qin C, Du D, Wang Y, Du Q, Liu S. Drug-induced QT prolongation and torsade de pointes: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System database. Front Pharmacol. 2023 Dec 21;14:1259611. doi: 10.3389/fphar.2023.1259611. PMID: 38186652; PMCID: PMC10771307.\u003c/li\u003e\n\u003cli\u003eLiu H, Zou Y, Zhang Q, Zhao J, Wu J, Li X, Cheng Y, Wei H, Li H, Cao S. Pharmacovigilance insights into medication-induced risk of dural arteriovenous fistula. Int J Surg. 2025 Feb 1;111(2):1847-1859. doi: 10.1097/JS9.0000000000002214. PMID: 39764589.\u003c/li\u003e\n\u003cli\u003eKillam-Worrall L, Brand R, Castro JR, Patel DS, Huynh K, Lindley B, Torres BP. Baclofen and Tizanidine Adverse Effects Observed Among Community-Dwelling Adults Above the Age of 50 Years: A Systematic Review. Ann Pharmacother. 2024 May;58(5):523-532. doi: 10.1177/10600280231193080. Epub 2023 Aug 17. PMID: 37589096.\u003c/li\u003e\n\u003cli\u003eVourc\u0026apos;h M, Dailly E, Hourmant Y, Bellouard R, Mahe PJ, Deslandes G, Gr\u0026eacute;goire M, Asehnoune K. Pharmacokinetics and toxicity of high-dose baclofen in ICU patients. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:450-456. doi: 10.1016/j.pnpbp.2019.02.016. Epub 2019 Feb 28. PMID: 30826461.\u003c/li\u003e\n\u003cli\u003eLiu WH, Hu HM, Li C, Shi Q, Liu CH, Liu AX, Li YF, Zhang Y, Mao P, Fan BF. Real-world study of adverse events associated with triptan use in migraine treatment based on the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) database. J Headache Pain. 2024 Nov 25;25(1):206. doi: 10.1186/s10194-024-01913-0. PMID: 39587512; PMCID: PMC11587596.\u003c/li\u003e\n\u003cli\u003eEvans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001 Oct-Nov;10(6):483-6. doi: 10.1002/pds.677. PMID: 11828828.\u003c/li\u003e\n\u003cli\u003eNoguchi Y, Tachi T, Teramachi H. Detection algorithms and attentive points of safety signal using spontaneous reporting systems as a clinical data source. Brief Bioinform. 2021 Nov 5;22(6):bbab347. doi: 10.1093/bib/bbab347. PMID: 34453158.\u003c/li\u003e\n\u003cli\u003eNoguchi Y, Tachi T, Teramachi H. Comparison of Signal Detection Algorithms Based on Frequency Statistical Model for Drug-Drug Interaction Using Spontaneous Reporting Systems. Pharm Res. 2020 Apr 30;37(5):86. doi: 10.1007/s11095-020-02801-3. PMID: 32356247.\u003c/li\u003e\n\u003cli\u003eSharma P, Varghese Gupta S, Bhatt P, Kandukuru A, Cheng F, Upadhyay G, Sutariya V. Cardiovascular adverse events associated with triptans for treatment of migraine: a pharmacovigilance study of the FDA adverse event reporting system (FAERS). Can J Physiol Pharmacol. 2024 Dec 1;102(12):720-728. doi: 10.1139/cjpp-2024-0117. Epub 2024 Oct 22. PMID: 39435747.\u003c/li\u003e\n\u003cli\u003eAlamri A, Mostofi A, Aziz T, Pereira E. Intrathecal baclofen overdose mimicking brainstem death during deep brain stimulation surgery for pain. Ann R Coll Surg Engl. 2022 Sep;104(8):e232-e235. doi: 10.1308/rcsann.2021.0341. Epub 2022 May 26. PMID: 35616338; PMCID: PMC9433185.\u003c/li\u003e\n\u003cli\u003ede Beaurepaire R. A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder. Front Psychiatry. 2018 Oct 17;9:506. doi: 10.3389/fpsyt.2018.00506. PMID: 30459646; PMCID: PMC6232933.\u003c/li\u003e\n\u003cli\u003eAntonaci F, Sjaastad O. Cervicogenic headache: a real headache. Curr Neurol Neurosci Rep. 2011 Apr;11(2):149-55. doi: 10.1007/s11910-010-0164-9. PMID: 21125430.\u003c/li\u003e\n\u003cli\u003eRomito JW, Turner ER, Rosener JA, Coldiron L, Udipi A, Nohrn L, Tausiani J, Romito BT. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Med. 2021 Jun 3;9:20503121211022197. doi: 10.1177/20503121211022197. PMID: 34158937; PMCID: PMC8182184.\u003c/li\u003e\n\u003cli\u003eParker-Pitts CK, Weymouth CW, Frawley MT. Intrathecal Baclofen Overdose With Paradoxical Autonomic Features Mimicking Withdrawal. J Emerg Med. 2020 Apr;58(4):616-619. doi: 10.1016/j.jemermed.2019.12.031. Epub 2020 Mar 20. PMID: 32204996.\u003c/li\u003e\n\u003cli\u003eLeung NY, Whyte IM, Isbister GK. Baclofen overdose: defining the spectrum of toxicity. Emerg Med Australas. 2006 Feb;18(1):77-82. doi: 10.1111/j.1742-6723.2006.00805.x. PMID: 16454779.\u003c/li\u003e\n\u003cli\u003eMitsuboshi S. Association Between Baclofen and Respiratory Depression in Patients With Chronic Kidney Disease. J Clin Pharmacol. 2021 Jun;61(6):836-837. doi: 10.1002/jcph.1843. Epub 2021 Mar 27. PMID: 33629349.\u003c/li\u003e\n\u003cli\u003eReade MC. Baclofen to Prevent Agitation Caused by Alcohol Withdrawal in the ICU. JAMA. 2021 Feb 23;325(8):727-729. doi: 10.1001/jama.2021.0597. PMID: 33620385.\u003c/li\u003e\n\u003cli\u003eSigg N, Delaunay J, Potey C, Drablier G. Baclofen-induced psoriasis. Ann Dermatol Venereol. 2022 Dec;149(4):291-293. doi: 10.1016/j.annder.2022.03.009. Epub 2022 May 25. PMID: 35643883.\u003c/li\u003e\n\u003cli\u003eMahajan R, Kalita J. Tizanidine Induced Hypotension: Report of a Case and Review of the Literature. Curr Drug Saf. 2024;19(2):313-316. doi: 10.2174/1574886318666230725113855. PMID: 37489780.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Central muscle relaxants, Food and drug administration adverse event reporting system, Real-world study, Adverse events, Pharmacovigilance","lastPublishedDoi":"10.21203/rs.3.rs-6492591/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6492591/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCentral muscle relaxants are widely used in the treatment of cervicogenic headache, which can inhibit the excessive excitation of the central nervous system, relieve neck muscle spasms, and thereby reduce pain and discomfort. However, there is still a lack of real-world studies on the safety of central muscle relaxants. Given the rising incidence of cervicogenic headache in recent years, it is imperative to gain a deeper understanding of the adverse events (AEs) associated with this class of drugs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The online platform Open Vigil 2.1 was used to query the U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database for reports on common central muscle relaxants, baclofen and tizanidine. The query spanned from January 1, 2004, to August 31, 2024, and extracted all AEs across all age groups. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) was used to match relevant preferred terms (PTs) and system organ classes (SOCs). The proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) methodology were employed to compare the AEs of the two muscle relaxants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults：\u003c/strong\u003eThere were 14,431 reports with baclofen as the primary suspected drug, with a roughly equal proportion of male and female patients. For tizanidine, there were 365 reports, with more female patients than male. For both drugs, the age group with the highest proportion of patients was 40-59 years old, and the country with the most reports was the United States. Nervous system disorders were the most common SOC category for AEs associated with both drugs. The three most frequently reported AEs for baclofen were withdrawal syndrome, hypersomnia, and pruritus, while the top three AEs for tizanidine were confusional state, dry mouth, and hypotension.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The analysis indicates that AEs of both drugs are present in various systemic diseases including nervous system, psychiatric, cardiovascular, respiratory, urinary, and general disorders. However, the incidence and signal strength of these AEs vary depending on the specific drug discussed. In clinical practice, appropriate drugs should be selected based on the specific characteristics of individual patients, and AEs should be monitored.\u003c/p\u003e","manuscriptTitle":"Real-world study on adverse events of central muscle relaxants in the treatment of cervicogenic headache based on the U.S. FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-30 06:21:03","doi":"10.21203/rs.3.rs-6492591/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2a958b4-ce4a-4f6d-bdaa-fcc9e99f48e3","owner":[],"postedDate":"May 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-10T15:23:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-30 06:21:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6492591","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6492591","identity":"rs-6492591","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}