Therapeutic efficacy of thiocolchicoside-nonsteroidal anti-inflammatory drug combination in pain management: A systematic review and cross-sectional real-world study

Abstract

BACKGROUND

Thiocolchicoside (TCC), a muscle relaxant with anti-inflammatory properties, is often used alongside nonsteroidal anti-inflammatory drugs (NSAIDs) to treat musculoskeletal pain. This synergistic approach leverages the complementary mechanisms of action, providing more effective relief for conditions such as arthritis, muscle spasms, and soft tissue injuries.

AIM

To evaluate the comparative efficacy of the combination therapy of TCC and NSAIDs vs NSAID monotherapy in pain management.

METHODS

A systematic search of PubMed and Google Scholar databases through October 2024 was performed to evaluate the effectiveness of combined TCC and NSAID therapy vs NSAIDs alone. A retrospective analysis of electronic medical records from India spanning 3 years (2020-2023) examined treatment patterns and focused on clinical outcomes including pain relief, functional improvement, and adverse effects. Key metrics for assessment included visual analog scale scores and hand-to-floor distance, with secondary outcomes assessing patient satisfaction and adverse event (AE) incidence.

RESULTS

A systematic literature search revealed seven studies, involving 1137 subjects, aligning with the eligibility criteria from a total of 833 hits. Combination therapy using parenteral TCC with NSAIDs significantly reduced pain intensity [standardised mean difference (SMD): -1.33, P < 0.001] and enhanced functional improvement (SMD: -1.08, P < 0.001) compared to NSAIDs alone. Patients on combination therapy are 6.7 times more likely to experience over 30% pain relief and 5.2 times more likely to achieve over 50% pain relief. Post surgery pain reduction and patient satisfaction were notably higher in the combination group [odds ratio (OR) = 10.14, P < 0.001]. There were no significant differences in mild/moderate AE rates between the groups (OR = 1.30, P = 0.378).

CONCLUSION

Evidence indicates that multimodal therapy, including parenteral TCC with NSAIDs, provides quicker and effective pain relief, reduces muscle spasms, and improves hand-to-floor distance compared to using NSAIDs or TCC alone.

Key Words: Thiocolchicoside; Nonsteroidal anti-inflammatory drugs; Muscle spasms; Low back pain; Muscle relaxants; Combination therapy; Pain management

Core Tip: This systematic review demonstrates the enhanced therapeutic efficacy of combining thiocolchicoside (TCC) with nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management, supported by real-world data from 156713 patients. Our analysis revealed that combination therapy provided superior pain relief, improved functional outcomes, and increased patient satisfaction compared to NSAID monotherapy, without a significant rise in adverse events. Notably, patients receiving the combination were significantly more likely to achieve clinically meaningful pain reduction. These findings support the combined use of TCC and NSAIDs in clinical practice, particularly for musculoskeletal and postoperative pain, to optimize patient outcomes and recovery.

INTRODUCTION

Musculoskeletal pain, including muscle spasms with pain, is a common challenge to manage in routine clinical practice. It has been reported that nearly 47% of the population has experienced one or more episodes of musculoskeletal pain in individuals of varying ages and sexes, irrespective of socioeconomic status. Approximately 39%-45% of people experiencing musculoskeletal pain have chronic problems requiring medical intervention. If not optimally treated, musculoskeletal pain can affect quality of life[1]. Due to increased awareness, exercise-associated muscle cramps have become a relatively common episode in a range of sports and exercise activities, and even in the general population[2,3]. The onset of sudden spasm and pain is generally unpredictable, and the intensity and duration of muscle spasms are highly variable. They may last from a few hours to days or even months[2,4]. They occur when a muscle undergoes an involuntary and forceful contraction that cannot relax, often due to overuse, strain, fatigue, stress, excessive exercise, or dehydration. Muscle spasms are typically self-limiting and characterized by sustained and painful contractions[4,5]. However, prolonged episodes can result in significant ramifications, including work absenteeism, increased healthcare costs, and potential disability[6].

The spasm-pain-spasm cycle is a widely accepted theory suggesting that muscle spasms, triggered by an initial event such as an injury, can lead to pain and restricted range of motion. This pain can cause additional muscle contractions, which further intensify the pain. As a result, this cycle can become self-perpetuating and contribute to chronic pain[7]. The economic and social impact of this condition underscores the importance of effective pain management[8]. Painful muscle spasms are commonly associated with conditions such as backache, neuralgia, torticollis, and lumbosacral strain. These conditions are often treated with short-term use of centrally acting muscle relaxants combined with analgesics[9,10]. This multimodal approach to pain management has demonstrated effective analgesic outcomes while maintaining robust safety profiles. Numerous studies have indicated that this combination therapy yields significantly better results compared to monotherapy in the treatment of pain[1,11,12].

Skeletal muscle relaxants comprise a heterogeneous group of therapeutic agents that reduce muscle tone and relieve musculoskeletal pain and spasticity. These medications exert their pharmacological effects through two primary mechanisms: (1) Central action on the cerebrospinal axis; and (2) Peripheral action at the neuromuscular junction and muscle fibers[13,14]. While most muscle relaxants achieve their therapeutic benefits through sedative properties, this mechanism frequently produces significant adverse effects. Common adverse reactions include somnolence, cognitive impairment, motor incoordination, perceptual disturbances, and anticholinergic symptoms. Additionally, some agents carry risks of dependence and withdrawal phenomena[15,16]. These adverse effects often compromise patient adherence to prescribed regimens, leading to suboptimal clinical outcomes in managing muscle spasticity and ultimately affecting the functional capacity and productivity of the patients[17,18].

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for their anti-inflammatory and analgesic effects[19]. In clinical scenarios where muscle spasticity contributes to pain, thiocolchicoside (TCC) and other GABAergic muscle relaxants serve as adjunct treatments to enhance both pain relief and functional outcomes[20,21].

TCC reportedly reduces muscle hyperactivity and stiffness, which disrupts the spasm-pain-spasm cycle, whereas NSAIDs inhibit cyclooxygenase enzymes to decrease prostaglandin synthesis, thereby reducing inflammation and pain. The combination therapy aids in muscle relaxation from TCC and anti-inflammatory effects from NSAIDs. Clinical studies have demonstrated the superior efficacy of this combination therapy compared to NSAID monotherapy. This synergistic combination effectively targets both components of the spasm-pain-spasm cycle, providing an optimal therapeutic strategy for managing acute lower back pain, osteoarthritis (OA), cervicalgia, and postoperative pain[22,23]. Higher effectiveness for short-term pain relief has been reported with the addition of a skeletal muscle relaxant to paracetamol or an NSAID than with analgesics alone[24].

The effectiveness and safety of fixed-dose combinations (FDCs) of NSAIDs and muscle relaxants are frequently studied. However, no comprehensive evidence has been published on the separate formulation combinations of these drugs for managing pain and spasms. The primary research question for this review article was: “Is intramuscular administration of the TCC and NSAID combination more effective than NSAID monotherapy in the treatment and management of muscle spasticity across different clinical indications?” This review sought to map existing evidence on the efficacy of intramuscularly administered TCC along with NSAIDs, compared to NSAIDs alone, across various pain-related conditions and their symptomatic management.

MATERIALS AND METHODS

Eligibility criteria

Studies eligible for inclusion were randomized controlled trials (RCTs), cohort studies, and observational studies that compared TCC and NSAID combination therapy as intramuscular injection with parenteral NSAID monotherapy in adult patients (aged ≥ 18 years) experiencing acute or chronic pain. Selected studies have reported pain relief and functional improvements as primary and adverse effects as secondary outcomes. Studies were excluded if they did not specify TCC use or combined NSAIDs with alternative muscle relaxants. Studies published in languages other than English were also excluded. Additionally, studies involving allergic reactions to NSAIDs or TCC were omitted. Case reports, systematic reviews, meta-analyses, and expert opinions were also excluded from this review to maintain methodological rigor.

Information sources and search strategy

A systematic literature search was conducted using electronic databases including PubMed and Google Scholar, and articles available to October 2024 were reviewed. Keywords such as ‘thiocolchicoside’, ‘NSAIDs’, ‘muscle relaxant’, ‘combination therapy’, ‘pain management’, and ‘musculoskeletal pain’ were used to create the following search strings for PubMed: ("thiocolchicoside"[Mesh] OR "thiocolchicoside"[Supplementary Concept]) AND ("nonsteroidal anti-inflammatory drugs"[Mesh] OR "NSAIDs"[Title/Abstract]) AND ("muscle relaxant"[Title/Abstract] OR "muscle relaxants"[Mesh]) AND ("combination therapy"[Title/Abstract] OR "drug therapy, combination"[Mesh]) AND ("pain management"[Mesh] OR "pain management"[Title/Abstract]) AND ("musculoskeletal pain"[Mesh] OR "musculoskeletal pain"[Title/Abstract]) and for Google Scholar: ("thiocolchicoside" OR "thiocolchicoside"[Title]) AND ("NSAIDs" OR "nonsteroidal anti-inflammatory drugs" OR "NSAID"[Title]) AND ("muscle relaxant"[Title] OR "muscle relaxants") AND ("combination therapy" OR "combined therapy"[Title] OR "multimodal therapy"[Title]) AND ("pain management" OR "analgesia"[Title] OR "pain relief"[Title] OR "analgesic effect"[Title]) AND ("musculoskeletal pain" OR "back pain" OR "neck pain" OR "osteoarthritis" OR "rheumatoid arthritis"[Title] OR "muscle spasm"[Title]). Studies that included comparative data on the efficacy of TCC combined with NSAIDs vs NSAIDs alone were included.

Study selection and data extraction

The dual evaluation process featured separate assessments from two autonomous reviewers. The reviewers independently analyzed each study before cross-comparing their findings. Their collaborative verification enhanced objectivity and minimized potential biases while strengthening the credibility of evidence classifications. The primary outcome examined was the reduction in pain intensity, assessed using patient-reported visual analog scale (VAS) scores, functional improvement (disability) including hand-to-floor distance, time to pain relief, and patient satisfaction following the intervention. Additional measures of pain intensity were also extracted such as physician-reported VAS scores, pain pressure threshold, pain during movement, and the presence of muscle spasms. The secondary outcomes examined included safety measures like adverse events (AEs) or tolerability (mild/moderate side effects). Any disagreements were resolved through consultation with a third senior investigator.

Cross-sectional electronic medical record data

Furthermore, retrospective patient profile data on pain due to musculoskeletal conditions and their treatment practices/strategies from January 1, 2020 to December 31, 2023 were extracted from electronic medical records (EMRs) sourced from different specialties of multiple centers across India. Aggregated and anonymized patient data were collected from 156713 EMRs for NSAID monotherapy and 492 EMRs for TCC and NSAID combination therapy. Clinical outcomes of TCC and NSAID combination therapy and NSAID monotherapy, along with demographics, signs and symptoms, diagnosis, medications, and other data elements, were extracted from the EMR.

Statistical analyses

Statistical analyses were performed using Microsoft Excel (Microsoft Corp., Redwood, WA, United States). Continuous variables are expressed as the mean ± SD, median (range), or 95%CI where appropriate. Using pooled means ± SD between studies, standardised mean differences (SMDs) were calculated based on larger reductions in pain with combination therapy compared to monotherapy. For binary data (e.g., percentage of patients achieving pain relief), the odds ratio (OR) was calculated. Heterogeneity between studies was assessed using the I² value. Statistical significance was defined as P < 0.05.

RESULTS

Study selection and study characteristics

Text mining of the databases revealed a total of 833 hits, which were screened down to seven articles comprising 1137 patients based on the inclusion and exclusion criteria (Figure 1). The studies varied by patient populations, pain conditions, and follow-up durations. The conditions assessed included acute low back pain and postoperative pain. The findings demonstrated a trend toward improved clinical outcomes, including faster pain relief, greater functional improvement, and better tolerability in patients receiving the combination of TCC and NSAIDs compared to NSAIDs alone. This review compared the efficacy of TCC and NSAID combination therapy vs NSAID monotherapy for pain management across different settings (e.g., low back pain and postoperative pain).

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart. Selection process for the included studies based on the eligibility criteria.

Summary of individual studies

A prospective, randomized, single-center, and observational study by Akhter et al[25] showed a significant reduction in pain intensity and disability in both treatment groups over 7 days, with diclofenac (DIC) and TCC combination therapy (D + T) performing better than DIC monotherapy (D) across all metrics. Pain intensity (assessed via VAS) decreased significantly from 7.31 to 1.35 for D, compared to 7.27 to 0.94 for D + T (P < 0.000). Hand-to-floor distance improved more with D + T, decreasing from 28.70 cm to 10.54 cm (P < 0.000) vs 28.79 cm to 12.12 cm for D. Patients in the D + T group reported significantly less pain (P = 0.003) and lower disability scores (P = 0.0005) on day 7. An RCT by Iliopoulos et al[26] demonstrated superior efficacy of the FDC of D + T over D alone. A significantly higher proportion of patients achieved > 30% pain reduction with FDC at 1 hour (56.5% vs 37.7%, P = 0.037) and 3 hours (91.9% vs 57.4%, P < 0.01). FDC also showed faster and stronger improvements in finger-to-floor distance post administration. There were minimal side effects, and FDC was well-tolerated with no serious AEs (SAEs). Another retrospective, double-arm, nonrandomized, single-center, observational study by Meloncelli et al[21] highlighted that while both DIC/TCC and tramadol/dexketoprofen (TRAM/DKP) reduced pain intensity, TRAM/DKP exhibited superior and sustained analgesic effects. On day 7, 95.5% of TRAM/DKP patients achieved > 30% pain reduction compared to 71.1% with D + T (P = 0.003). Additionally, TRAM/DKP led to a greater reduction in neuropathic pain scores (Douleur Neuropathique 4), while D + T plateaued after day 1. Both treatments were well tolerated. Desai et al[27] demonstrated that treatment with TCC plus aceclofenac (T + A) was more effective than aceclofenac monotherapy (A) in reducing pain at rest (VAS scores: 77.55-9.85 for T + A vs 67.65-11.10 for A, P < 0.001). Pain during movement and movement restriction scores were also significantly reduced in the T + A group (P < 0.001). Straight leg raising test improvement was more consistent in the T + A group (P = 0.004 vs P = 0.015). A phase 3, double-blind, parallel-group, RCT by Sproviero et al[28] showed that both FDC D + T (test group) and free combination D + T (reference group) significantly reduced pain (mean VAS decrease from baseline to day 5: -56.92 mm in the test group vs -55.95 mm in the reference group). Noninferiority was established between the two groups (P = 0.8200). Both treatments comparably reduced muscle contracture based on Schober’s Index score. Treatment-related AEs were mild and occurred in 2.7% of the test group and 0.9% of the reference group. Another RCT by Bourazani et al[29] demonstrated that patients receiving TCC-NSAIDs (group A) experienced significantly lower postoperative pain than group B (NSAID only). Pain intensity (neuropathic pain scale) dropped from 5.14 on day 0 to 0.71 on day 3 in group A compared to 6.2-2.8 in group B (P = 0.017). Satisfaction with treatment was higher in group A (88.5% “very satisfied”) compared to group B (17.1%), and side effects were significantly less in the TCC group. The detailed study is summarized in Table 1[21,24-29].

Table 1 Summary of selected study results on thiocolchicoside and nonsteroidal anti-inflammatory drug combination compared to nonsteroidal anti-inflammatory drug monotherapy.

Ref.	Sample size	Indication	Intervention	Pain reduction (visual analog scale)	Disability/other outcomes	AEs
Akhter et al[25]	288	Lower back pain	D vs D + T	D: 7.31-1.35; D + T: 7.27-0.94 (from day 0 to day 7)	D + T significantly reduced hand-to-floor distance (P = 0.0005)	None reported
Iliopoulos et al[26]	134	Lower back pain	FDC vs D	FDC: > 30% pain relief in 91.9% of cases (3 hours) vs 57.4% in the D group T + D: 7.20-3.16; D: 6.52-4.45 (from baseline to 3 hours postinjection)	Superior improvement in finger-to-floor distance	Mild dizziness in 2 patients administered D
Meloncelli et al[21]	82	Lower back pain and neuropathic pain	D/T vs TRAM/DKP	TRAM/DKP: 95.5% > 30% reduction vs 71.1% in D/T (P = 0.003)	TRAM/DKP significantly reduced the douleur neuropathique 4 neuropathic pain score	TEAEs: D/T: 7.9%; TRAM/DKP: 18.2%; No serious AEs were reported, and none of the patients in the two groups discontinued therapy due to TEAEs
Patel et al[24]	300	Lower back pain	Muscle relaxant (T) + NSAIDs vs monotherapy	The combination group had a maximum disability index reduction of 54.66% ± 9.85%	Muscle relaxants are highly effective; gastrointestinal protection was given to most patients	None reported
Desai et al[27]	40	Lower back pain	T + A vs A	T + A: 77.55-9.85; A: 67.65-11.10 (P < 0.000)	Significant improvement in movement and restriction of motion in the T + A group	None reported
Sproviero et al[28]	223	Lower back pain	FDC (D + T) vs separate formulations	Similar reductions (mean: 56.92 mm vs 55.95 mm)	Muscle contracture improved equally (Schober's Index)	Test: 2.7% mild nausea; Reference: 0.9% injection site pain
Bourazani et al[29]	70	Postoperative pain (mastectomy and breast reconstruction surgery)	NSAID + T (group A) vs NSAID only (group B)	Group A: 5.14-0.71; group B: 6.20-2.80 (P < 0.0001)	Group A reported higher satisfaction and fewer side effects	None reported

A: Aceclofenac monotherapy; AEs: Adverse events; D: Diclofenac monotherapy; D + T: Diclofenac and thiocolchicoside combination therapy; FDC: Fixed-dose combination; NSAID: Nonsteroidal anti-inflammatory drug; T: Thiocolchicoside monotherapy; T + A: Thiocolchicoside plus aceclofenac; TEAEs: Treatment-emergent adverse events; TRAM/DKP: Tramadol/dexketoprofen.

Efficacy and safety of TCC-NSAID combination therapy over NSAID monotherapy

By utilizing pooled means and SDs from the changes in pain intensity reduction reported by Akhter et al[25] and Iliopoulos et al[26], the calculated SMD of -1.33 (95%CI: -1.45 to -1.22, P < 0.001), with moderate heterogeneity (I² = 60.3%), indicated a substantial effect in favor of TCC-NSAID combination therapy compared to NSAID monotherapy for alleviating lower back pain.

A significant negative SMD (SMD: -1.08, 95%CI: -1.24 to -0.92, P < 0.001) indicated clinically meaningful improvements in functional outcomes (greater flexibility and less disability) from TCC + NSAID FDC therapy compared to NSAID monotherapy, although with high heterogeneity (I² = 78.8%). Similar to earlier studies[21,26,27,29], time to achieve > 30% and > 50% pain relief and patient satisfaction was significantly higher in patients given TCC and NSAID combination therapy compared to patients with NSAID monotherapy, with low to moderate heterogeneity (I² = 34.7%) and no heterogeneity (I² = 0%), respectively. No statistically significant differences in mild to moderate AEs were observed between the two groups [combination therapy vs monotherapy (OR = 1.30, 95%CI: 0.68-2.48, P = 0.342)], with high heterogeneity (I² = 75.1%) favoring the safety of the combination therapy, similar to earlier studies[21,26,28]. Post surgery pain reduction exhibited very high heterogeneity (I² = 97.3%), despite showing superior results for the combination therapy (SMD: -0.84; 95%CI: -1.08 to -0.60, P < 0.001). Patient satisfaction was markedly higher with the combination therapy (OR = 10.14, 95%CI: 5.48-19.50, P < 0.001) and demonstrated high heterogeneity (I² = 89%). These findings underscore the consistent efficacy of TCC + NSAIDs across key outcomes, despite variability in certain measures. The detailed findings are depicted in Table 2.

Table 2 Comparative efficacy assessments of thiocolchicoside + nonsteroidal anti-inflammatory drug combination therapy with nonsteroidal anti-inflammatory drug monotherapy.

Outcome	TCC + NSAIDs (mean ± SD)/%	NSAIDs monotherapy (mean ± SD)/%	Pooled effect size (SMD/OR)	95%CI	aP value	Cochran’s Q	df	I2 (%)	Interpretation
Pain intensity reduction (visual analog scale)	-6.20 ± 0.70	-5.10 ± 0.85	SMD: -1.33	-1.45 to -1.22	< 0.001	12.59	5	60.3	TCC + NSAIDs significantly reduced pain intensity compared to NSAIDs alone, with a large effect size. Found moderate heterogeneity
Functional improvement (hand-to-floor distance)	-18.20 ± 2.70	-15.10 ± 3.50	SMD: -1.08	-1.24 to -0.92	< 0.001	4.71	1	78.8	Combination therapy resulted in significantly greater functional improvement in reducing disability. Found high heterogeneity
Time to achieve > 30% pain relief (%)	86.60 ± 7.20	48.30 ± 10.00	OR = 6.71	3.48-13.10	< 0.001	3.065	2	34.7	Patients were 6.7 times more likely to achieve > 30% pain relief with combination therapy than with monotherapy
Time to achieve > 50% pain relief (%)	63.00 ± 10.50	22.80 ± 11.40	OR = 5.19	3.02-9.21	< 0.001	0.33	1	0	Combination therapy significantly increased the likelihood of achieving > 50% pain relief by a factor of approximately 5.2 times compared to monotherapy. No heterogeneity
Postsurgery pain reduction (day 3-numerical pain scale)	-4.45 ± 1.30	-3.40 ± 1.40	SMD: -0.84	-1.08 to -0.60	< 0.001	73.46	2	97.3	TCC + NSAIDs achieved better pain reduction after surgery compared to NSAID monotherapy, with a moderate to large effect. High heterogeneity
Patient satisfaction (%) (very satisfied)	69.00 ± 10.00	19.60 ± 6.50	OR = 10.14	5.48-19.50	< 0.001	9.15	1	89	Satisfaction with analgesia was substantially higher in the combination therapy group, making patients 10 times more likely to be satisfied. High heterogeneity
Adverse events (%) (mild/moderate)	157	12.1	OR = 1.30	0.68-2.48	0.378	4.01	1	75.1	No statistically significant difference in mild or moderate adverse events between the two groups, confirming the safety of the combination therapy. High heterogeneity

^aP < 0.05 was considered statistically significant.

NSAID: Nonsteroidal anti-inflammatory drug; OR: Odds ratio; SMD: Standardised mean difference; TCC: Thiocolchicoside.

There were minimal side effects, and TCC-NSAID combination therapy was well tolerated with no SAEs. The identified AEs primarily included nausea, dizziness, dry mouth, dyspepsia, and injection site pain, with no significant increases in their occurrence observed in TCC-NSAID combination therapy compared to NSAID monotherapy.

Prescription and drug utilization pattern for TCC-NSAID combination therapy and NSAID monotherapy: A real-world cross-sectional analysis

As shown in Figure 2, sex distribution was comparable between treatment groups. In the TCC plus NSAIDs group (n = 492), there were 259 males and 233 females, whereas the NSAIDs only group (n = 156713) comprised 84836 males and 7877 females.

Figure 2 Sex-wise predominance of low back pain among the studied patient data. A: Thiocolchicoside + nonsteroidal anti-inflammatory drugs (NSAIDs); B: NSAID monotherapy.

Among specialists using separate formulations of TCC-NSAIDs, orthopedic specialists accounted for 70% of prescriptions, followed by general physicians at 15%. By contrast, general physicians predominantly prescribed NSAIDs alone, comprising 63% of such prescriptions (Figure 3).

Figure 3 Specialty-wise patient visits to physicians. A: Thiocolchicoside + nonsteroidal anti-inflammatory drug (NSAID) combination therapy; B: NSAID monotherapy for pain management in the cross-sectional real-world data.

Categorizing into monotherapies and polytherapies, Figure 4 reveals that a single injection of TCC alone was administered to 35.98% of the studied subjects, followed by the single injection of D + T to 19.31%, whereas ketorolac, TRAM, and etoricoxib were given to 8.74%, 5.08%, and 0.20%, respectively.

Figure 4 Distribution of treatment modalities. A: Thiocolchicoside + nonsteroidal anti-inflammatory drug (NSAID) combination therapy; B: NSAID monotherapy for pain management in the cross-sectional real-world data.

Figure 5A illustrates various pain types reported in a medical context, highlighting the significant proportion of nonspecific pain at 48.90%, which dominated all other categories. Gastric pain followed as the second most common category, accounting for 16.29% of cases, while joint pain constituted 10.30%, indicating its prominence as a concern among patients. Lower back pain and fractures also contributed notably, for 7.65% and 6.09%, respectively. Other pain types such as dental pain (3.28%), musculoskeletal pain (2.46%), renal pain (2.09%), neuropathic pain (1.39%), and gynecological pain (1.35%) involved smaller proportions, reflecting their less frequent prevalence. Postoperative pain was the least represented, comprising only 0.20%.

Figure 5 Distribution of symptoms and comorbid conditions of patients. A: Treatment with thiocolchicoside and nonsteroidal anti-inflammatory drug (NSAID) combination; B: Treatment with NSAID monotherapy only in the cross-sectional real-world data.

Figure 5B depicts various types of reported pain, showing that nonspecific pain constituted the largest share at 39.10%, indicating its prevalence over other types of pain. Lower back pain was the next most significant, accounting for 25.88%, emphasizing its frequent occurrence in medical cases. Joint pain followed closely at 17.02%, further highlighting musculoskeletal issues as major contributors to physical discomfort. Musculoskeletal pain itself accounted for 5.34%, while fracture-related pain accounted for 4.78%. Less common categories included neuropathic pain and gastric pain, each at 3.23%, and renal pain at 0.70%, indicating a lesser, though notable, impact. Dental and gynecological pain, with minimal shares of 0.28% and 0.42%, respectively, were the least reported types.

DISCUSSION

Muscle relaxants are effective in providing clinically significant short-term pain relief for acute low back pain. However, the evidence supporting their use for chronic low back pain is limited and largely unknown[30]. By reducing the NSAID dose, clinicians can also mitigate NSAID-related side effects, particularly gastrointestinal (GI) issues, which remain a significant concern in OA management[31,32]. Thus, co-administration of TCC and NSAIDs offers a multifaceted approach to pain management. By targeting both pain and muscle spasms, this combination of pharmacological effects of TCC and the therapeutic effects of NSAIDs can lead to better pain management, improved joint function, and enhanced quality of life for patients with OA.

The combination of muscle relaxants and NSAIDs was identified as the most efficacious therapy for low back pain, outperforming NSAID monotherapy. In the muscle-relaxant group (54.66% ± 9.85% reduction in disability index), TCC + A was common and most effective[33]. Gastroprotective drugs were co-administered in 60.67% of cases, and patient compliance was high[33,34]. Studies investigating muscle relaxant treatments for acute back pain have utilized various agents including diazepam, baclofen, and dantrolene[13]. While these muscle relaxants are generally considered effective in alleviating acute back pain[10], they are associated with notable adverse effects such as drowsiness and the risk of physical dependence, even after short-term use (e.g., 1 week)[35]. By contrast, TCC is nonsedating and exhibits minimal, if any, adverse side effects, as evidenced by this study and previous clinical research[36,37].

TCC has several advantages over muscle relaxants like baclofen and tizanidine[36]. It acts as an allosteric modulator of gamma-aminobutyric acid (GABA)_A receptors, allowing targeted muscle tone reduction without sedative effects and hepatotoxicity at appropriate doses, making it preferable for patients needing alertness[38]. Baclofen and tizanidine can cause sedation, dizziness, cognitive impairments, renal and hepatic impairments, and have risks of dependence (baclofen) and hypotension (tizanidine)[39]. TCC, paired with NSAIDs, offers effective relief with fewer central nervous system side effects and lower GI issues[9]. It is especially suitable for elderly patients and those with renal or hepatic impairment due to its safer profile and minimal psychomotor impact. However, monitoring is necessary for severe hepatic impairment due to its biliary elimination[36,40]. Overall, TCC is highlighted as a beneficial option for long-term management in difficult clinical situations.

More recent evidence by Baroncini et al[41] showed that the combination of TCC with NSAIDs not only provided superior pain relief but also allowed the reduction in NSAID dosage, which minimizes the risk of GI side effects often associated with prolonged NSAID use[34]. A study comparing the TCC + A combination to the chlorzoxazone, aceclofenac, and paracetamol combination found that the TCC combination provided better pain control[42]. TCC acts on GABA receptors in the nervous system to reduce muscle spasms and stiffness[38]. Studies have shown significant improvements in hand-to-floor distance and muscle tension or tone when muscle relaxants are combined with NSAIDs[24,42]. The combination of muscle relaxants, like TCC and NSAIDs, works synergistically to interrupt the pain-spasm-pain cycle through anti-inflammatory and analgesic effects[24,31]. TCC acts as a muscle relaxant, reducing muscle spasms. This dual action helps break the cycle of pain-causing muscle spasms[26,42]. Early administration of this dual therapy improves joint motion and functional recovery in contrast to the delayed relief observed with NSAID monotherapy[31]. This approach provides faster symptom control, reduces the need for repeated doctor visits, and decreases the likelihood of recurring pain episodes, making it highly effective for pain management.

The effectiveness of mesotherapy using conventional drugs (NSAIDs and muscle relaxants) has been evaluated in patients with fibromyalgia and cervicalgia, focusing on pain reduction, disability improvement, and quality of life at the 2-month follow-up[43]. The results showed a statistically significant improvement in pain reduction for both the control and treatment groups[43]. Given the limited understanding of the etiopathogenesis of fibromyalgia, characterized by a complex multifactorial system that involves increased central sensitivity to nociception with inflammation playing a crucial role, mesotherapy treatment with NSAIDs and TCC has emerged as a safe and effective approach for managing neck pain in patients with fibromyalgia. This treatment demonstrated significant short-term benefits in pain reduction, functional recovery, and quality of life[43].

A study evaluating the analgesic efficacy of DKP trometamol with TCC following impacted third molar extraction found that the combination therapy was more effective in reducing pain than DKP trometamol monotherapy. Pain levels started to decrease earlier (by 24 hours) in the DKP and TCC combination therapy group compared to other groups[44]. Maladkar et al[45] highlighted that administering TCC and aceclofenac sequentially led to better control over muscle spasms and pain in postoperative recovery.

The higher reported adverse effects in patients treated with NSAID monotherapy support the fact that these patients experienced more pain and consequently required additional opioid analgesics intravenously, such as propoxyphene[29]. The AEs reported by patients on NSAID monotherapy were likely those associated with opioids, such as dizziness, nausea, and/or vomiting[46,47]. Treatment with the TCC-NSAID combination contributed to reduced pain intensity and reduced demand for opioid analgesics, resulting in fewer opioid-related AEs[29]. This finding aligns with the goal of multimodal analgesia to limit opioid administration due to their significant AEs[48,49]. While the study does not explicitly detail adverse effects solely attributable to NSAID monotherapy vs the TCC-NASID combination therapy without considering opioid use, the observed difference in overall reported AEs is linked to the differential need for opioid rescue medication[29].

This review updates the evidence for using muscle relaxants in adults with musculoskeletal pain, in line with previous systematic reviews[10,30] and three clinical practice guidelines[50]. This study endorses nonbenzodiazepine antispasmodics as an effective treatment for acute low back pain, as considerable certainty in their clinical effectiveness and safety was found. Tables 1 and 2 summarize a review and analysis of literature and data, highlighting the enhanced efficacy of TCC and NSAID combination compared to NSAID monotherapy across various clinical outcomes.

In clinical trials focused on pain management, such as those for postoperative pain relief or musculoskeletal conditions, there tends to be a higher proportion of male participants, concordant with our EMR-based cross-sectional analysis of retrospective real-world data. Research involving NSAIDs and TCC suggests that females often report higher baseline pain scores but may experience greater relief with muscle relaxants like TCC[50].

The notably high usage of TCC, alone and in separate or sequential combinations, aligns with studies like one by Ketenci et al[36], which showed that TCC effectively reduced pain and improved mobility in acute low back pain. However, its widespread use contrasts with some international guidelines that do not strongly recommend muscle relaxants as a first-line treatment. The frequent combination of TCC with NSAIDs, particularly DIC, reflects a common clinical practice. Aksoy et al[50] showed that separate or sequential combinations of TCC and NSAIDs provided better pain relief and improved functional outcomes compared to NSAID monotherapy in acute low back pain. The preference for single injections (total 85.57%) over dual (14.02%) or triple (0.41%) injections aligns with the principle of minimizing medication exposure and potential side effects. The inclusion of TRAM in some combinations (5.08% dual, 0.41% triple) is interesting. While TRAM can be effective for pain relief, its use is generally more restricted due to its opioid properties. Recent guidelines by Qaseem et al[51] recommend against the use of opioids as a first-line treatment for chronic lower back pain. This usage pattern suggests a treatment approach that separately combines muscle relaxants (TCC) with anti-inflammatory effects (NSAIDs), potentially aiming for synergistic pain relief. However, it is important to note that this practice may not fully align with all current international guidelines for low back pain management, which often emphasize nonpharmacological approaches and cautious use of muscle relaxants.

This distribution underscores the prevalence of generalized, nonspecific pain while illustrating the relative occurrence of more localized or condition-specific pain issues. The findings are consistent with studies like that of Sostres et al[52], which highlighted the widespread use of NSAIDs across multiple medical specialties. The chart underscores the dominance of generalized and back-related pain while highlighting a relatively smaller burden from specific localized conditions such as dental and gynecological pain.

This review suggests that the separate formulation and/or combination of TCC and NSAIDs provides superior pain relief compared to NSAID monotherapy in acute and chronic musculoskeletal pain conditions. Functional improvement, especially in OA and postoperative pain, was more pronounced in patients receiving combination therapy. This real-world evidence supports the clinical use of combination therapy with TCC with NSAIDs in managing conditions associated with both pain and muscle spasms. In particular, the combination is advantageous in facilitating faster recovery and reducing opioid use in postoperative settings. However, healthcare providers should consider individual patient risk factors, particularly NSAID-related GI or cardiovascular risks[19].

This EMR-guided retrospective cross-sectional analysis and systematic literature review of evidence-based practices significantly inform clinical decision-making for optimal pain management protocols, potentially improving patient outcomes. Nevertheless, this study had some limitations. First, the search strategy was restricted to published articles from PubMed and Google Scholar only, which led to limited sample sizes, heterogeneous study populations, potential for publication bias, and inconsistent dosing regimens of NSAIDs and TCC across studies. Second, the study conclusions were influenced by inherent biases associated with retrospective data limitations and small sample sizes. Retrospective data are prone to variability in prescribing preferences, nonstandardized outcome measures, and confounding factors, which could have affected the generalizability and interpretation of the results. Finally, the disproportionately smaller combination therapy group (n = 492) compared to the monotherapy group (n = 156713) potentially increased the risk of sampling bias and limits statistical precision. Despite these challenges, the use of percentage-based comparisons, cross-validation with prospective literature, and robust statistical methodologies like SMDs and ORs mitigate these biases, reinforcing the observed significant outcomes favoring combination therapy. However, the findings should still be interpreted with caution, and future large-scale randomized controlled, prospective trials and real-world evidence studies are essential to validate these findings across diverse patient populations and pain conditions.

CONCLUSION

Clinical trials have demonstrated the superior efficacy of separately administered TCC and NSAIDs compared to monotherapy in various musculoskeletal inflammatory conditions and exercise-induced muscle cramps. This combination has shown effectiveness in severe back pain without sedation or seizure risks, and in low back pain with muscle spasms and inflammation. When administered from treatment initiation, these separate formulations effectively interrupt the pain-spasm-pain cycle, enabling rapid symptom relief and reducing the need for multiple clinical visits. Moreover, the ability to adjust NSAID dosing independently allows for personalized treatment approaches while minimizing GI and other AEs, making this multimodal approach therapeutically advantageous in numerous clinical scenarios for the management of musculoskeletal pain.