Evaluation of Systemic Nonsteroidal Anti-inflammatory Drugs on Orthodontic Tooth Movement Rate: A Clinical and Biomarker-Based Study

Abstract

Background:

Pain management is a critical component of orthodontic treatment, often necessitating pharmacological intervention. Nonsteroidal anti-inflammatory drugs are commonly prescribed; however, their mechanism of action involves the inhibition of cyclooxygenase enzymes and prostaglandins, which are essential mediators of bone remodeling.

Materials and Methods:

A randomized, double-blind clinical trial was conducted with 30 orthodontic patients requiring bilateral maxillary first premolar extractions and subsequent canine retraction. Patients were randomly allocated into two groups: Group A (Ibuprofen, 400 mg) and Group B (Paracetamol, 500 mg), taken thrice daily for 3 days following appliance activation. Canine retraction was performed using nickel–titanium coil springs (150 g force). The rate of tooth movement (mm/month) was measured over 3 months. Gingival crevicular fluid (GCF) samples were analyzed using Enzyme-Linked Immunosorbent Assay.

Results:

The mean cumulative tooth movement over 3 months was significantly lower in the Ibuprofen group (2.85 ± 0.32 mm) compared to the Paracetamol group (3.45 ± 0.41 mm; P < 0.01). Biochemical analysis revealed that Group A exhibited significantly reduced concentrations of Prostaglandin E2 (145.2 ± 22.1 pg/mL) compared to Group B (210.5 ± 35.4 pg/mL; P < 0.001) at the T1 interval. Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) levels followed a similar trend.

Conclusion:

Systemic administration of Ibuprofen significantly inhibits the rate of orthodontic tooth movement and suppresses key inflammatory biomarkers necessary for bone resorption. Paracetamol is the preferred analgesic for orthodontic patients as it provides pain relief without interfering with the biological mechanisms of tooth movement.

INTRODUCTION

Orthodontic tooth movement (OTM) is a biological process characterized by the remodeling of alveolar bone and periodontal ligament (PDL) in response to mechanical loading. This process is fundamentally inflammatory, relying on an “aseptic inflammation” cascade to facilitate bone resorption on the compression side and bone deposition on the tension side.[1] A crucial component of this cascade is the synthesis of prostaglandins (PGs), particularly Prostaglandin E2 (PGE2), which stimulates osteoclast differentiation and activity via the Receptor Activator of Nuclear Factor Kappa-B (RANK)/ Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)/ Osteoprotegerin (OPG) signaling pathway.[2]

Pain is a prevalent side effect of orthodontic force application, reported by up to 95% of patients, leading to a high demand for analgesics.[3] Nonsteroidal anti-inflammatory drugs (NSAIDs), such as Ibuprofen, are frequently used due to their efficacy in pain reduction. NSAIDs function by inhibiting cyclooxygenase (COX) enzymes, thereby blocking the conversion of arachidonic acid into PGs. While effective for analgesia, the suppression of PGs raises concerns regarding the inhibition of osteoclastic activity, which could theoretically decelerate the rate of OTM.[4]

Conversely, Paracetamol (acetaminophen) acts primarily through the central nervous system and has a weak peripheral anti-inflammatory effect, theoretically exerting minimal impact on alveolar bone remodeling.[5]

Therefore, this study aims to evaluate and compare the effects of short-term systemic administration of Ibuprofen and Paracetamol on the rate of OTM and Gingival crevicular fluid (GCF) levels of PGE2 and RANKL in patients undergoing orthodontic canine retraction.

MATERIALS AND METHODS

Study design and participants

This study was designed as a prospective, randomized, double-blind, parallel-arm clinical trial. The sample consisted of 30 patients (14 males, 16 females; mean age 20.5 ± 2.4 years) recruited from the Department of Orthodontics.

Inclusion and exclusion criteria

Inclusion criteria were: Permanent dentition, Class II malocclusion requiring maxillary first premolar extraction and canine retraction, good periodontal health (probing depth <3 mm), and no history of systemic diseases. Exclusion criteria included: Chronic use of anti-inflammatory or bisphosphonate medication, smoking, pregnancy, and previous orthodontic treatment.

Orthodontic procedure

Following maxillary first premolar extractions and a healing period of 4 weeks, leveling and aligning were completed using the McLaughlin–Bennett–Trevisi (MBT) 0.022-slot bracket system. Canine retraction was initiated on a 0.019 × 0.025-inch stainless steel wire. Retraction was achieved using nickel–titanium (NiTi) closed coil springs delivering a constant force of 150 g per side, calibrated with a force gauge.

Drug administration protocol

Participants were randomly assigned via a computer-generated sequence into two groups (n = 15 each):

• Group A (NSAID): Ibuprofen 400 mg.

• Group B (Control/Analgesic): Paracetamol 500 mg.

Medications were repackaged in identical unidentified capsules to ensure blinding. Patients were instructed to take one capsule every 8 hours for 3 days immediately following the monthly activation of the retraction spring. This protocol was repeated for 3 consecutive months (T1, T2, T3).

Data collection

1. Clinical Measurement: The distance between the distal wing of the canine bracket and the mesial wing of the second premolar bracket was measured using digital vernier calipers (accuracy 0.01 mm). Measurements were taken at baseline (T0) and at 4-week intervals (T1, T2, T3).

2. GCF Collection and Analysis: GCF was collected from the distal gingival crevice of the maxillary canines using periopaper strips inserted for 30 s. Samples were pooled and stored at −80°C. The concentrations of PGE2 and RANKL were quantified using commercially available Enzyme-Linked Immunosorbent Assay kits.

Statistical analysis

Data were analyzed using SPSS software (v25.0).

RESULTS

All 30 participants completed the study with no dropouts. Demographic analysis showed no significant differences in age or gender distribution between the two groups [Table 1], ensuring baseline comparability.

Table 1.

Baseline demographic characteristics

Variable	Group A (Ibuprofen)	Group B (Paracetamol)	P
n	15	15	-
Age (mean±SD)	20.1±2.2	20.9±2.5	0.36
Sex (M/F)	7/8	7/8	1.00

Clinical tooth movement

The cumulative OTM over the 3-month observation period is presented in Table 2. Group B (Paracetamol) demonstrated a consistently higher rate of space closure compared to Group A (Ibuprofen). The difference became statistically significant at Month 2 and Month 3. The total accumulated movement after 3 months was 2.85 mm for the Ibuprofen group versus 3.45 mm for the Paracetamol group (P < 0.01).

Table 2.

Comparison of cumulative tooth movement (mm) (mean±SD)

Time interval	Group A (Ibuprofen)	Group B (Paracetamol)	P
Month 1	0.92±0.15	1.05±0.18	0.052
Month 2	1.84±0.22	2.21±0.29	0.001*
Month 3 (total)	2.85±0.32	3.45±0.41	0.000*

*Statistically significant

Biomarker analysis

GCF analysis [Table 3] revealed that PGE2 levels were significantly suppressed in the Ibuprofen group compared to the Paracetamol group at the T1 interval (peak inflammation phase). Similarly, RANKL levels, which indicate osteoclast recruitment, were significantly lower in Group A.

Table 3.

GCF biomarker levels at T1 (mean±SD)

Biomarker	Group A (Ibuprofen)	Group B (Paracetamol)	P
PGE2 (pg/mL)	145.2±22.1	210.5±35.4	<0.001*
RANKL (pg/mL)	58.4±12.3	89.7±15.6	<0.001*

*Statistically significant. PGE2=prostaglandin E2

DISCUSSION

Orthodontic forces induce local hypoxia and fluid shifts, triggering the release of inflammatory mediators, specifically PGs synthesized via the COX pathway.[6] PGE2 is instrumental in upregulating RANKL expression on osteoblasts and PDL cells. RANKL subsequently binds to the RANK receptor on osteoclast precursors, leading to their differentiation and the bone resorption necessary for tooth movement.[7]

In the present study, Group A (Ibuprofen) showed a 17.4% reduction in total tooth movement compared to Group B over 3 months. This aligns with previous findings by Bartzela et al.,[4] who highlighted the inhibitory effects of NSAIDs on bone kinetics. The specific suppression of COX enzymes by Ibuprofen effectively “brakes” the remodeling process. In contrast, Paracetamol, acting primarily as a central analgesic with negligible peripheral COX inhibition, allowed for physiological levels of PGE2 to be maintained, as evidenced by the significantly higher GCF concentrations in Group B.

The reduced levels of RANKL in Group A further validate the mechanism: Without sufficient PGE2 stimulation, the RANKL/OPG ratio shifts to favor bone density maintenance rather than resorption.[8] This suggests that the analgesic choice in orthodontics is not merely a matter of pain control but has biomechanical implications. While potent NSAIDs may offer superior pain relief in some contexts, the trade-off is a statistically significant delay in treatment progress.

CONCLUSION

Systemic administration of Ibuprofen (400 mg) significantly reduces the rate of OTM compared to Paracetamol. Ibuprofen usage leads to a significant reduction in GCF levels of PGE2 and RANKL, disrupting the biochemical cascade required for osteoclastic bone resorption. Paracetamol is the recommended analgesic for orthodontic patients, as it provides pain relief without compromising the efficiency of tooth movement.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.