The effect of preoperative tizanidine on postoperative pain and trismus following surgical removal of mandibular third molar: A randomized clinical trial

Abstract

Background:

Pain and trismus are common complications that significantly impair quality of life after mandibular third molar surgery. This study investigated the efficacy of only one preoperative dose of oral tizanidine, a centrally acting muscle relaxant having analgesic properties, in reducing these outcomes.

Methods:

Forty patients who needed surgical removal of bilateral impacted mandibular third molars were selected for a split-mouth, triple-blind, randomized clinical trial. Each patient was randomly assigned to receive 4 mg tizanidine or a placebo 1 h before surgery on one side. In the other surgery, the contralateral side was treated alternatively. The Visual Analog Scale (VAS) was used for pain assessment, and trismus was measured by maximum mouth opening (MMO) in millimeters at Days 1, 3, and 7 post-surgery. Paired t-test and repeated measures analysis of variance were used to analyze data.

Results:

Tizanidine group had significantly lower mean VAS pain scores compared to the placebo group on the first postoperative day (3.30 ± 0.87 vs 5.25 ± 1.02; p < 0.001). Both groups experienced a decrease in pain scores over time, though the differences in Days 3 and 7 did not reach statistical significance. Nonetheless, the tizanidine group had significantly greater MMO (less trismus) than the control group at all postoperative time points (p < 0.001 for all).

Conclusions:

A single dose of preoperative oral tizanidine provides a useful supplementary tool to diminish immediate postoperative pain and relieve trismus after surgical removal of mandibular third molars. Tizanidine can be included as an adjunct in multimodal techniques to improve patient comfort and recovery following oral surgeries.

Keywords

Tizanidine third molar surgery wisdom tooth postoperative pain trismus randomized clinical trial muscle relaxants

Introduction

Wisdom teeth are present in 90% of the population, and their impaction has a 33% prevalence.¹ Pain and trismus are two of the most common complications after wisdom tooth surgery.^2–5 Given the negative impact of these complications on wound healing, quality of life, mouth opening and closing, and patient motivation for future dental visits, their control is of particular importance.^6–10 So far, depending on the time of intervention, various methods have been introduced to control these complications.^11–13 Preoperative methods include the use of various anesthetics and analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, alone and in combination, and corticosteroids such as dexamethasone, submucosally and in combination with anesthetics.^14–16 Various wound closure techniques with and without drains are also helpful during surgery.^17,18 Paracetamol and ibuprofen can be used postoperatively to reduce pain, chlorhexidine mouthwash to reduce the risk of alveolar osteitis, and corticosteroids and antibiotics in specific cases.^19–22 However, recently, new methods such as lingual flap design, photo-biomodulation, piezo-surgery, and intramuscular injection of dexamethasone, low-level laser therapy, low-intensity pulsed ultrasound, and intra-sacral injection of ketamine and tramadol have also been introduced.^23–29

Despite the widespread use of NSAIDs for pain control in dentistry, there are concerns about their side effects, which mainly involve the gastrointestinal tract, kidneys, and respiratory tract.³⁰ Complications include gastric ulcers, gastrointestinal bleeding, and renal failure.^31,32 Also, since NSAIDs are less effective in reducing swelling and trismus than corticosteroids, and NSAIDs have a relatively greater loss of function, researchers have tested various substances in combination with NSAIDs to control problems after wisdom tooth surgery and found that the combination of ibuprofen 400 mg and oxycodone 5 mg was most effective in controlling these problems.^33–36 However, due to the problems caused by the side effects of this combination, the combination of ibuprofen 200 mg and caffeine 100 or 200 mg seemed more reasonable.^30,37–39

Trismus following mandibular third molar surgery is primarily attributed to postoperative inflammation and reflex spasm of the masticatory muscles, particularly the medial pterygoid muscle, which limits mandibular excursion.^40,41 Muscle spasm not only contributes directly to restricted mouth opening but also amplifies nociceptive input, thereby exacerbating postoperative pain. Therefore, targeting muscle hyperactivity represents a logical therapeutic strategy for improving both pain control and mandibular function after oral surgical procedures.^42,43

Tizanidine is a centrally acting α2-adrenergic receptor agonist that exerts its muscle relaxant effects by inhibiting excitatory intraneuronal transmission in the spinal cord.^44,45 By suppressing the release of excitatory neurotransmitters such as glutamate and substance P, tizanidine reduces muscle tone, attenuates reflex muscle spasm, and modulates central nociceptive pathways.⁴⁶ In addition to its antispastic effects, tizanidine possesses analgesic and anxiolytic properties, which may further contribute to postoperative comfort. Unlike clonidine, tizanidine demonstrates a more favorable cardiovascular safety profile, with a lower incidence of hypotension and bradycardia, making it a potentially suitable adjunct in outpatient oral surgery settings.^47,48

The null hypothesis was that preoperative administration of Tizanidine would have no effect on postoperative pain intensity or trismus following mandibular third molar surgery.

Despite the established role of centrally acting muscle relaxants in orthopedic and neurosurgical settings, their preemptive use in oral and maxillofacial surgery remains underexplored. This study addresses this clinical gap by evaluating whether a single preoperative dose of oral tizanidine can effectively reduce postoperative pain and trismus following mandibular third molar surgery.

Material and methods

Study design

In this 12-month, randomized triple-blind split-mouth trial, we assessed whether oral tizanidine alleviates pain and trismus after third molar surgery. The study was conducted between September 2023 and August 2024 at Shahid Beheshti University of Medical Sciences, School of Dentistry, under standardized clinical and ethical conditions. This was designed as a superiority trial to determine whether preoperative tizanidine is superior to placebo in reducing postoperative pain and trismus following mandibular third molar surgery.

Patient selection and eligibility criteria

The study enrolled patients aged 17–45 years who required bilateral extraction of partially erupted mandibular wisdom teeth with mesio-angular impaction. Written informed consent was obtained from all participants aged 18 years and older. For participants under 18 years of age, written informed consent was obtained from their parents or legally authorized representatives, with additional assent obtained from the minor participants themselves, in accordance with Iranian ethical guidelines and the Declaration of Helsinki. Impaction difficulty was assessed using the Pell and Gregory classification system, incorporating angulation, depth of impaction, and ramus relationship to ensure comparable surgical difficulty between both sides.⁴⁹ Inclusion criteria required almost symmetrical anatomical positioning and the absence of inferior alveolar nerve proximity on panoramic radiology that would necessitate cone beam computed tomography. Exclusion criteria included the use of other analgesics, systemic disorders such as coagulopathy, signs of acute infection or pericoronitis, weeks, and lack of willingness or ability to complete the study protocol and follow-up assessments. Additional exclusion criteria included pregnancy or lactation, known hepatic impairment, cardiovascular disease, hypersensitivity to α2-adrenergic agonists, and current use of centrally acting muscle relaxants or sedative medications.

Intervention protocol and randomization

Eligible patients underwent two separate surgeries for their lower third molars. One side was randomly assigned to the tizanidine group and the other to the placebo group using a block randomization method and sealed opaque envelopes to ensure allocation concealment. One hour before the surgery, the tizanidine group received a single 4 mg oral dose of tizanidine, while the placebo group received an identical placebo. The 4 mg dose of Tizanidine was selected based on previous clinical studies demonstrating effective muscle relaxation with minimal sedative and cardiovascular adverse effects. One hour before the surgery, the tizanidine group received a single 4 mg oral dose of tizanidine. The placebo group received an identical oral placebo formulation. Blinding was maintained for the patient, surgeon, and outcome assessor, and only the third-party administrator of the preoperative medication was aware of the allocation.

To minimize potential carryover effects between surgeries, a washout interval of 4 weeks was maintained between the two surgical procedures for each patient. This interval was selected to ensure complete resolution of postoperative inflammation and restoration of baseline mandibular function before the second surgery. In the event of a medical emergency requiring unblinding, the treatment allocation could be disclosed by the independent third party responsible for randomization.

Surgical procedure standardization

All surgeries were performed under the same anesthetic and surgical protocol by a single experienced oral and maxillofacial surgeon under standardized local anesthesia using inferior alveolar, lingual, and long buccal nerve blocks with 2% lidocaine containing 1:80,000 epinephrine. The type of flap, suturing technique, and postoperative instructions were consistent across all cases.

Evaluation of postoperative pain and trismus

Postoperative pain was assessed using the Visual Analog Scale (VAS) on postoperative Days 1, 3, and 7. All patients received a standardized postoperative medication regimen consisting of amoxicillin 500 mg and metronidazole 500 mg as antibiotic therapy, along with acetaminophen administered every 8 h for pain control. Acetaminophen was selected to avoid the confounding anti‑inflammatory effects of NSAIDs. No rescue analgesics were permitted during the first 24 h postoperatively. Pain intensity was evaluated 8 h after the administration of postoperative drugs in the anti-inflammatory effects of NSAIDs. No rescue analgesics were permitted during the first 24 h postoperatively. Pain intensity was evaluated 8 h after administration of postoperative medications in all participants. Trismus was assessed by measuring the maximum mouth opening (MMO) in millimeters at the same time points. Baseline MMO was measured immediately before each surgical procedure, and postoperative MMO values were compared with the corresponding baseline measurement for each surgery.⁵⁰

Study outcomes

The primary outcome was postoperative pain intensity based on VAS scores. The secondary outcome was the degree of trismus as indicated by the reduction in MMO. These outcomes were chosen to directly reflect the common complications of third molar surgery that tizanidine might influence through its muscle relaxant and analgesic effects.

Sample size determination

First, the sample size was calculated with the help of G*Power software (ver. 3.1.9.7 for comparison with other previous studies in the field). This was a sample size calculation involving the primary outcome (VAS pain intensity on postoperative days) as a continuous variable, treated analytically with a paired t-test attributable to the split-mouth study design.

We established a statistical power (1-β) of 95% and a one-sided alpha (α) level of 0.05 to ensure confidence in the results. Given that we assumed a standardized effect size (Cohen’s d) of 0.5 (i.e., clinically “large” effect), this sample size was determined to be sufficient for detecting a significant difference between tizanidine and placebo sides.

From these inputs, the analysis suggested 34 patients needed to be recruited to reach study completion. Accounting for roughly 15% dropout during the follow-up period, the initial recruitment target was adjusted upwards. Therefore, the final target sample size was projected to be:

Initial Target Sample Size = Required Completers / (1 − Dropout Rate)

Initial Target Sample Size = 34 / (1 − 0.15) = 34/ 0.85 ≈ 39.9

A rounded-up number was set at 40 as the recruitment target, which would allow sufficient statistical strength for the final analysis.

The assumed effect size, alpha level, and power parameters were selected based on previous clinical trials evaluating postoperative pain outcomes following third molar surgery.⁵¹

Data collection and analysis

Clinical examinations and standardized questionnaires were used to collect data. Measurements were obtained at baseline and on postoperative Days 1, 3, and 7. Data were analyzed using SPSS version 23. Paired comparisons between intervention and control groups were performed using paired t‑tests, and repeated‑measures analysis of variance (ANOVA) was used to assess changes over time. Normality was evaluated using the Shapiro–Wilk test, and sphericity was assessed using Mauchly’s test. When violations of sphericity were detected, Greenhouse–Geisser corrections were applied. Statistical significance was set at p < 0.05. This randomized clinical trial was conducted and reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines (Figure 1).⁵²

Figure 1.

CONSORT flow diagram.

Results

Postoperative pain

A total of 40 patients (20 males and 20 females) participated in the study, with a mean age of 27.4 ± 6.1 years. All participants met the inclusion criteria and completed the follow-up assessments without any dropouts.

The comparison of pain levels between the intervention (tizanidine) and control groups revealed statistically significant differences on the first postoperative day. The mean VAS score was significantly lower in the tizanidine group (3.30 ± 0.87) compared to the control group (5.25 ± 1.02) (p < 0.001). Although pain scores decreased over time in both groups, the differences on Days 3 and 7 were not statistically significant (p = 0.216 and p = 0.114, respectively) (Table 1 and Figure 2).

Table 1.

Comparison of postoperative pain (VAS Score).

Time (day)	Tizanidine group (Mean ± SD)	Control group (Mean ± SD)	p value
1	3.30 ± 0.87	5.25 ± 1.02	<0.001
3	1.30 ± 0.80	1.70 ± 1.17	0.216
7	0.35 ± 0.59	0.65 ± 0.59	0.114

VAS: Visual Analog Scale.

Figure 2.

Mean VAS pain scores on days 1, 3, and 7 after surgery in the tizanidine (black line) and control group (blue line).

Multivariate analysis using repeated measures ANOVA confirmed a significant main effect for tizanidine (β = −1.51, p < 0.001), indicating that on average, patients in the tizanidine group reported 1.51 units less pain than those in the control group across all time points. A significant time effect was also observed (β = −0.98, p < 0.001), showing that pain decreased approximately 1 unit with each passing day. In addition, the interaction between time and treatment was significant (β = −0.28, p < 0.001), reflecting greater pain reduction over time in the tizanidine group (Table 2).

Table 2.

Multivariate analysis of pain levels.

Variable	β coefficient	Standard error	p value
Tizanidine	−1.51	0.28	<0.001
Time (days)	−0.98	0.04	<0.001
Tizanidine × time	−0.28	0.05	<0.001

Trismus (maximum mouth opening)

The analysis of MMO demonstrated significantly better outcomes in the tizanidine group across all postoperative time points. On day 1, the mean MMO was 33.60 ± 7.10 mm in the tizanidine group versus 22.95 ± 4.76 mm in the control group (p < 0.001). This trend persisted on Days 3 and 7, with all differences reaching statistical significance (Table 3 and Figure 3).

Table 3.

Comparison of maximum mouth opening (MMO).

Time (day)	Tizanidine group (Mean ± SD, mm)	Control Group (Mean ± SD, mm)	p Value
1	33.60 ± 7.10	22.95 ± 4.76	<0.001
3	36.15 ± 5.43	26.65 ± 4.39	<0.001
7	43.60 ± 2.92	40.05 ± 1.99	<0.001

Figure 3.

Mean maximum mouth opening on Days 1, 3, and 7 postoperatively in the tizanidine and control groups.

According to the repeated measures analysis, tizanidine significantly increased MMO on average by 9.98 mm across all postoperative assessments (β = 9.98, p < 0.001). A main effect of time was observed (β = 2.23, p < 0.001), indicating increased MMO over time in both groups. The interaction effect (β = −0.81, p = 0.036) further supported the greater recovery in mouth opening for the tizanidine group (Table 4).

Table 4.

Multivariate analysis of mouth opening.

Variable	β coefficient	Standard error	p Value
Tizanidine	9.98	2.02	<0.001
Time (days)	2.23	0.27	<0.001
Tizanidine × Time	−0.81	0.39	0.036

Discussion

The present study aimed to evaluate the effect of a single preoperative dose of 4 mg oral tizanidine on postoperative pain and trismus following mandibular third molar surgery using a randomized, triple-blind, split-mouth design. The results demonstrated that tizanidine significantly reduced pain intensity on the first postoperative day and improved mouth opening (trismus) at all measured time points, without the need for additional administration postoperatively. These findings underscore the potential of tizanidine as an effective adjunct in early postoperative management of pain and trismus.

The current results partially diverge from the findings reported by Kirmeier et al.,⁵³ who found no significant differences in pain and swelling between the tizanidine and control groups, although improved mouth opening was observed in the intervention group. The discrepancy may be attributed to differences in study design, particularly their lack of a split-mouth model, which in our study enhanced internal validity by controlling for interindividual variability. Additionally, their continued administration of tizanidine for 2 days may have introduced confounding interactions with concurrent anti-inflammatory and antibiotic medications.

Similarly, our findings contrast with those of Santos et al.,⁵⁴ who used cyclobenzaprine, another central muscle relaxant, and found no significant improvement in any of the three parameters studied (pain, swelling, and trismus). While both cyclobenzaprine and tizanidine share muscle-relaxant properties, tizanidine’s additional analgesic and anti-inflammatory effects via central α2-adrenergic receptor agonist, which inhibit substance P and glutamate release and thereby modulate nociceptive transmission, may explain the superior performance observed in our study. Furthermore, the triple-blind design and careful timing of drug administration in our protocol may have contributed to the greater efficacy observed.

In contrast, the results of Cigerim et al.,⁵⁵ who demonstrated enhanced pain control using thiocolchicoside in combination with dexketoprofen trometamol, align more closely with our findings. Their study, however, focused solely on pain, while ours extends to trismus, providing a more comprehensive view of postoperative complications. The combination of a centrally acting muscle relaxant with a nonsteroidal anti-inflammatory drug (NSAID) may provide synergistic effects, supporting the potential of combination therapies in oral surgery.

A study by Rao et al.,⁵⁶ which directly compared thiocholchicoside and tizanidine, found no significant difference between the two drugs in managing pain, swelling, and trismus. However, the absence of a split-mouth design and a smaller sample size may have limited their statistical power to detect subtle differences. Our study’s significant results, particularly in early postoperative pain and consistent improvements in trismus, reinforce the clinical relevance of tizanidine in this context.

The findings of the review by Sani et al.⁵⁷ supports the safety and efficacy of muscle relaxants such as tizanidine for acute postoperative pain relief, particularly as alternatives to opioids. Although their analysis was not limited to oral surgery, it strengthens the rationale for incorporating centrally acting muscle relaxants in pain management protocols, especially in light of growing concerns about opioid use.

Moreover, the results of Kasapoğlu et al.⁵⁸ further validate the benefits of combining muscle relaxants with NSAIDs for controlling postoperative complications. Their study reported significant reductions in pain and trismus, echoing our findings and emphasizing the importance of targeting both muscular and inflammatory pathways. Notably, their split-mouth design also supports the methodological strength of our approach.

Lastly, Dadmehr et al.⁵⁹ found that tizanidine effectively reduced pain following orthognathic surgery, which shares procedural and tissue-trauma similarities with third molar surgery. However, unlike our study, they did not assess trismus or other complications. Interestingly, their use of a single preoperative dose—similar to our protocol—provides further evidence of the acute efficacy of tizanidine when timed appropriately.

Overall, the current study contributes novel evidence that a single preoperative dose of tizanidine can significantly reduce early postoperative pain and consistently improve trismus in third molar surgery patients. The use of a randomized, split-mouth design ensures robust internal validity, while the triple-blinding minimizes bias. These results suggest that tizanidine may serve as a valuable adjunct in clinical protocols aimed at enhancing patient comfort and recovery.

This study has several limitations. Although postoperative swelling is a common sequela of third molar surgery and was discussed in the introduction, it was not quantitatively assessed in the present study. Trismus was evaluated independently using MMO measurements, which primarily reflect muscle spasm rather than facial edema. Second, we used only a single preoperative 4 mg dose of tizanidine in our protocol, so these results cannot be extrapolated to other dosing regimens, and future studies are needed to determine if a dose-response relationship exists. Finally, known adverse effects such as sedation or dizziness were not assessed in a structured manner, which would be important for overall risk-benefit evaluation. Future studies may consider evaluating its effects on postoperative swelling and in combination with NSAIDs to explore potential synergistic outcomes.

Conclusion

This study demonstrated that a single preoperative dose of 4 mg oral tizanidine significantly reduced postoperative pain on the first day and improved mouth opening at all evaluated time points following mandibular third molar surgery. These findings suggest that tizanidine, as a centrally acting muscle relaxant with additional analgesic properties, can be an effective adjunct in managing common postoperative complications such as pain and trismus. Given its generally accepted safety profile and ease of administration, tizanidine may offer a valuable alternative or complement to conventional analgesic regimens. Further studies with larger sample sizes and evaluation of additional outcomes, such as swelling and patient satisfaction, are warranted to confirm and expand upon these findings.

Supplemental Material

sj-docx-1-smo-10.1177_20503121261433738 – Supplemental material for The effect of preoperative tizanidine on postoperative pain and trismus following surgical removal of mandibular third molar: A randomized clinical trial

Supplemental material, sj-docx-1-smo-10.1177_20503121261433738 for The effect of preoperative tizanidine on postoperative pain and trismus following surgical removal of mandibular third molar: A randomized clinical trial by Mohsen Golkar, Fatemeh Latifi, Mostafa Alam, Amirmohammad Salamatmanesh and Farzan Zakermashhadi in SAGE Open Medicine

Footnotes

Acknowledgements

Special thanks to all fellow authors and participants who contributed to this work.

ORCID iD

Amirmohammad Salamatmanesh

Ethical considerations

Ethical approval and consent to participate: This study was conducted in accordance with the ethical standards of the institutional and national research committee and with the 1975 Helsinki Declaration, as revised in 2013. The study protocol was approved by the Professional Ethics Committee of Shahid Beheshti University of Medical Sciences (Ethical code: IR.SBMU.DRC.REC.1403.009). Written informed consent was obtained from all participants. The trial was prospectively registered in the Iranian Registry of Clinical Trials (IRCT No: IRCT20240805062664N1).

Author contributions

Mohsen Golkar and Farzan Zakermashhadi contributed to the conception and design of the study, the acquisition and analysis of data, the drafting and critical revision of the article, and the final approval of the manuscript. Amirmohammad Salamatmanesh participated in the conception and design, data analysis, drafting and critical revision, and final approval. Fatemeh Latifi and Mostafa Alam both contributed to the acquisition of data, the critical revision of the article, and the final approval of the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Data supporting the findings of this study are available from the corresponding author, but restrictions apply to the availability of these data, which were used under license for the current study, and are therefore not publicly available. However, the data is available in the form of an Excel file from the authors upon reasonable request.

Supplemental material

Supplemental material for this article is available online.

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