Effect of NSAIDs, melatonin, vitamin D and vitamin B12 chronotherapy on postoperative recovery after third molar surgical extraction: A pilot randomized crossover placebo-controlled trial

Jun 2, 2026Oral and maxillofacial surgery

Timing of NSAIDs, melatonin, vitamin D, and vitamin B12 use may affect recovery after wisdom tooth surgery

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Abstract

Chronotherapy was associated with higher postoperative pain and increased swelling compared to ibuprofen.

Postoperative pain scores increased by an average of 0.94 points (p < 0.001) in females using chronotherapy.
Females experienced greater facial swelling but less restriction in mouth opening compared to males.
Males showed similar pain levels to the control but had a shorter time to pain cessation with chronotherapy.
Exploratory analyses indicated increased levels of certain inflammatory mediators in males receiving chronotherapy, while females had limited changes.
No overall improvement in postoperative outcomes was observed with the replacement of nighttime ibuprofen.

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PURPOSE: This pilot study aimed to evaluate whether replacing nighttime ibuprofen with melatonin, vitamin D, and vitamin B12 (chronotherapy) improves postoperative recovery after third molars extraction, and to explore sex-dependent responses.

METHODS: A double-blind, randomized, two-period pilot crossover trial was conducted with 12 healthy adults undergoing bilateral mandibular third molars extraction. In the control period, participants received ibuprofen 400 mg three times daily. In the chronotherapy period, the nighttime ibuprofen dose was replaced with melatonin (10 mg), vitamin D (1000 IU), and vitamin B12 (1000 µg). Outcomes included pain intensity (Visual Analogue Scale [VAS]), facial swelling, trismus, rescue medication use, and inflammatory cytokines.

RESULTS: Overall, chronotherapy was associated with higher postoperative pain, increased vertical swelling, and reduced trismus compared with control. Significant treatment-by-sex interactions were observed. Female participants reported statistically higher, although clinically insignificant, postoperative pain scores with chronotherapy (mean VAS increase: +0.94 points, p < 0.001), along with greater swelling but less restriction in mouth opening. In contrast, males showed similar pain levels but a shorter time to pain cessation and reduced swelling with chronotherapy. Exploratory cytokine analyses suggested broader increases in pro- and anti-inflammatory mediators in males receiving chronotherapy (e.g., IL-10, IL-13), whereas females showed limited cytokine changes.

CONCLUSION: Replacing nighttime ibuprofen with the chronotherapy regimen did not appear to improve overall postoperative pain outcomes. However, chronotherapy may produce sex-dependent postoperative responses, with mixed recovery patterns in females and modest benefits in selected outcomes in males. Given the pilot nature of the study and limited sample size, these findings should be considered exploratory and hypothesis-generating.

CLINICAL TRIAL NUMBER: ClinicalTrials.gov (NCT07133360), retrospectively registered on 2025/06/20.

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Effect of NSAIDs, melatonin, vitamin D and vitamin B12 chronotherapy on postoperative recovery after third molar surgical extraction: A pilot randomized crossover placebo-controlled trial

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