Analgesic Differences in Males and Females After Third Molar Surgery: A Subgroup Analysis of the OARS Randomized Clinical Trial
Janine Fredericks-Younger, Tracy Andrews, Shou-En Lu, Pamela B. Matheson, Patricia Greenberg, Vincent B. Ziccardi, Brent B. Ward, Gary Warburton, Michael Miloro, Hans Malmstrom, Paul J. Desjardins, Cecile A. Feldman
TL;DR
This study examines how pain relief and treatment satisfaction differ between males and females after wisdom tooth surgery.
Contribution
The study provides a gender-specific analysis of nonopioid versus opioid pain management effectiveness after third molar surgery.
Findings
Nonopioids showed noninferior pain relief compared to opioids in both males and females.
Patient satisfaction was comparable between nonopioid and opioid treatments in both genders.
Abstract
This prespecified subgroup analysis of a randomized clinical trial investigates noninferiority for pain relief, treatment effects, and patient satisfaction for nonopioids vs opioids in male and female patients after impacted mandibular third molar extraction.
Genes, proteins, chemicals, diseases, species, mutations and cell lines named across the full text — each resolved to its canonical identifier and authoritative record.
| Characteristic | Patients, No. (%) (N = 1815) | |||
|---|---|---|---|---|
| Female | Male | |||
| Nonopioid (n = 457/909 [50.3%]) | Opioid (n = 453/906 [49.7%) | Nonopioid (n = 452/909 [50.0%]) | Opioid (n = 453/906 [50.0%]) | |
|
| ||||
| Current age, mean (SD), y | 25.45 (5.81) | 25.70 (6.19) | 25.71 (6.13) | 25.93 (6.81) |
| Race and ethnicity | ||||
| Hispanic | 153 (33.5) | 132 (29.1) | 102 (22.6) | 125 (27.6) |
| Non-Hispanic Asian | 75 (16.4) | 89 (19.6) | 104 (23.0) | 89 (19.6) |
| Non-Hispanic Black | 64 (14.0) | 58 (12.8) | 77 (17.0) | 73 (16.1) |
| Non-Hispanic White | 138 (30.2) | 149 (32.9) | 141 (31.2) | 133 (29.4) |
| Other | 15 (3.3) | 12 (2.6) | 17 (3.8) | 18 (4.0) |
| Do not want to report | 12 (2.6) | 13 (2.9) | 11 (2.4) | 15 (3.3) |
| Education | ||||
| Some high school | 19 (4.2) | 26 (5.7) | 23 (5.1) | 31 (6.8) |
| High school graduate | 245 (53.6) | 254 (56.1) | 241 (53.3) | 252 (55.6) |
| Associate’s degree | 61 (13.3) | 55 (12.1) | 43 (9.5) | 34 (7.5) |
| College graduate | 95 (20.8) | 83 (18.3) | 90 (19.9) | 89 (19.6) |
| Master’s degree | 23 (5.0) | 20 (4.4) | 34 (7.5) | 27 (6.0) |
| Doctoral degree | 6 (1.3) | 8 (1.8) | 15 (3.3) | 15 (3.3) |
| Do not want to report | 8 (1.8) | 7 (1.5) | 6 (1.3) | 5 (1.1) |
| Smoking | ||||
| Do not smoke | 408 (89.3) | 402 (88.7) | 390 (86.3) | 396 (87.4) |
| Smoke <1 pack/d | 46 (10.1) | 48 (10.6) | 50 (11.1) | 50 (11.0) |
| Smoke 1 pack/d | 3 (0.7) | 3 (0.7) | 10 (2.2) | 5 (1.1) |
| Smoke >1 pack/d | 0 (0) | 0 (0) | 2 (0.4) | 2 (0.4) |
| Preoperative pain levels | ||||
| Pain rating, mean (SD) | ||||
| Composite pain experience | 1.22 (2.18) | 0.88 (1.74) | 1.21 (2.14) | 1.08 (2.17) |
| Worst pain | 1.77 (2.92) | 1.35 (2.56) | 1.70 (2.85) | 1.54 (2.85) |
| Average pain | 1.32 (2.41) | 0.93 (1.85) | 1.32 (2.38) | 1.12 (2.30) |
| Least pain | 0.79 (1.83) | 0.49 (1.26) | 0.82 (1.91) | 0.75 (1.90) |
| Pain now | 0.99 (2.17) | 0.75 (1.83) | 0.98 (2.09) | 0.89 (2.08) |
| Pain tolerance | 5.56 (2.43) | 6.29 (2.04) | 5.69 (2.29) | 6.04 (2.27) |
| Preoperative swelling | ||||
| None | 376 (82.3) | 356 (78.6) | 399 (88.3) | 389 (85.9) |
| Mild | 63 (13.8) | 78 (17.2) | 40 (8.8) | 47 (10.4) |
| Moderate | 14 (3.1) | 15 (3.3) | 11 (2.4) | 11 (2.4) |
| Severe | 4 (0.9) | 4 (0.9) | 2 (0.4) | 6 (1.3) |
|
| ||||
| Surgical treatment duration | ||||
| Time, mean (SD), min | 36.98 (19.21) | 40.23 (19.99) | 37.35 (19.85) | 41.31 (20.27) |
| Teeth extracted, mean (SD), No. | ||||
| Maxillary third molars | 1.09 (0.90) | 1.09 (0.90) | 1.13 (0.91) | 1.09 (0.90) |
| Mandibular third molars | 1.67 (0.47) | 1.66 (0.48) | 1.64 (0.48) | 1.65 (0.48) |
| Total third molars | 2.76 (1.17) | 2.74 (1.18) | 2.77 (1.21) | 2.74 (1.21) |
| Full bony impacted third molars | 0.95 (1.26) | 0.97 (1.20) | 1.00 (1.25) | 0.95 (1.19) |
| Full bony impacted mandibular third molars | 0.66 (0.85) | 0.71 (0.85) | 0.72 (0.84) | 0.70 (0.84) |
| Anesthesia or analgesia used during surgery | ||||
| Local only | 196 (42.89) | 199 (43.93) | 239 (52.88) | 243 (53.64) |
| Other (oral, conscious sedation, or nitrous oxide) | 75 (16.41) | 77 (17.00) | 60 (13.27) | 58 (12.80) |
| General anesthesia | 186 (40.70) | 177 (39.07) | 153 (33.85) | 152 (33.55) |
| Other pharmaceutical used | ||||
| Antibiotic | 84 (18.4) | 93 (20.5) | 67 (14.8) | 66 (14.6) |
| Anti-inflammatory agent | 154 (33.7) | 139 (30.7) | 129 (28.5) | 132 (29.1) |
| Marcaine | 42 (9.2) | 38 (8.4) | 31 (6.9) | 25 (5.5) |
| Most difficult surgical technique used | ||||
| Forceps only | 30 (6.6) | 32 (7.1) | 28 (6.2) | 14 (3.1) |
| Osteotomy | 86 (18.8) | 87 (19.2) | 69 (15.3) | 60 (13.2) |
| Osteotomy with sectioning | 341 (74.6) | 334 (73.7) | 355 (78.5) | 379 (83.7) |
| Outcome | Female | Male | ||||||
|---|---|---|---|---|---|---|---|---|
| Nonopioid | Opioid | Nonopioid vs opioid comparison | Nonopioid | Opioid | Nonopioid vs opioid comparison | |||
| Mean difference (99.375% CI | Mean difference (99.375% CI | |||||||
| Pain ratings, mean (95% CI) | ||||||||
| Composite | ||||||||
| First day and night (day of surgery) | 3.84 (3.56 to 4.12) | 4.46 (4.18 to 4.74) | −0.63 (−1.04 to −0.21) | <.001 | 3.24 (2.96 to 3.52) | 3.99 (3.70 to 4.28) | −0.75 (−1.17 to −0.33) | <.001 |
| Second day and night | 3.32 (3.04 to 3.60) | 3.60 (3.32 to 3.88) | −0.28 (−0.70 to 0.14) | <.001 | 2.63 (2.35 to 2.92) | 2.89 (2.60 to 3.18) | −0.26 (−0.68 to 0.17) | <.001 |
| Third day and night | 3.10 (2.83 to 3.38) | 3.18 (2.90 to 3.46) | −0.08 (−0.49 to 0.34) | <.001 | 2.39 (2.11 to 2.67) | 2.47 (2.18 to 2.76) | −0.08 (−0.51 to 0.34) | <.001 |
| Entire postoperative period | 2.83 (2.55 to 3.10) | 2.98 (2.70 to 3.26) | −0.15 (−0.52 to 0.21) | <.001 | 2.24 (1.96 to 2.52) | 2.37 (2.09 to 2.66) | −0.13 (−0.50 to 0.24) | <.001 |
| Satisfaction, No. (%) | ||||||||
| Very satisfied and satisfied | 375 (82.78) | 339 (76.18) | OR (97.5% CI) = 1.51 (1.04 to 2.20) | .01 | 389 (87.81) | 364 (81.61) | OR (97.5% CI) = 1.59 (1.04 to 2.44) | .01 |
| Neither satisfied nor dissatisfied, dissatisfied, and very dissatisfied | 82 (17.9) | 113 (25.0) | NA | NA | 64 (14.1) | 89 (19.6) | NA | NA |
| Sleep interference, mean (95% CI) | ||||||||
| Overall sleep quality | ||||||||
| First day (day of surgery) | 4.14 (3.79 to 4.49) | 4.44 (4.10 to 4.79) | −0.30 (−0.82 to 0.21) | .34 | 3.88 (3.53 to 4.23) | 4.19 (3.83 to 4.56) | −0.32 (−0.84 to 0.21) | .32 |
| Second day | 3.96 (3.62 to 4.31) | 4.00 (3.65 to 4.35) | −0.03 (−0.55 to 0.48) | .99 | 3.69 (3.34 to 4.04) | 3.68 (3.32 to 4.04) | 0.01 (−0.51 to 0.53) | .99 |
| Third day | 3.85 (3.50 to 4.19) | 3.61 (3.26 to 3.95) | 0.24 (−0.28 to 0.76) | .70 | 3.14 (2.78 to 3.49) | 3.43 (3.07 to 3.79) | −0.29 (−0.82 to 0.23) | .41 |
| Entire postoperative period | 3.59 (3.27 to 3.92) | 3.58 (3.26 to 3.91) | 0.01 (−0.39 to 0.41) | .99 | 3.16 (2.83 to 3.48) | 3.26 (2.93 to 3.60) | −0.11 (−0.51 to 0.30) | .99 |
| Pain interference ratingsd | ||||||||
| Composite | ||||||||
| First day (day of surgery) | 2.75 (2.58 to 2.93) | 3.10 (2.92 to 3.27) | −0.34 (−0.56 to −0.13) | <.001 | 2.49 (2.31 to 2.66) | 2.98 (2.80 to 3.16) | −0.50 (−0.72 to −0.28) | <.001 |
| Second day | 2.24 (2.06 to 2.41) | 2.46 (2.28 to 2.63) | −0.22 (−0.44 to −0.00) | .01 | 1.97 (1.80 to 2.15) | 2.22 (2.04 to 2.40) | −0.24 (−0.46 to −0.02) | .005 |
| Third day | 2.16 (1.99 to 2.34) | 2.26 (2.08 to 2.43) | −0.09 (−0.31 to 0.12) | .85 | 1.88 (1.71 to 2.06) | 2.04 (1.86 to 2.22) | −0.15 (−0.37 to 0.07) | .17 |
| Entire postoperative period | 2.07 (1.95 to 2.19) | 2.19 (2.07 to 2.31) | −0.12 (−0.28 to 0.04) | .14 | 1.87 (1.75 to 2.00) | 2.02 (1.89 to 2.14) | −0.14 (−0.31 to 0.02) | .05 |
| Safety measures | ||||||||
| Postoperative rescue opioid prescribed, patients, No. (%) | 16 (3.52) | 29 (6.50) | OR (97.5% CI) = 0.50 (0.24 to 1.04) | .04 | 10 (2.25) | 25 (5.63) | OR (97.5% CI) = 0.39 (0.16 to 0.94) | .02 |
| No. of rescue pills prescribed, mean (95% CI) | 9.75 (6.78 to12.72) | 8.73 (5.84 to 11.63) | 1.02 (−1.18 to 3.21) | .29 | 10.09 (7.09 to 13.10) | 9.50 (6.70 to 12.30) | 0.59 (−1.95 to 3.14) | .59 |
| No. of nonopioid or opioid tablets returned, mean (95% CI) | 7.24 (5.52 to 8.96) | 8.91 (7.19 to 10.62) | −1.66 (−2.59 to −0.74) | <.001 | 6.80 (5.07 to 8.54) | 7.93 (6.20 to 9.67) | −1.13 (−2.06 to −0.20) | .007 |
| Patients with AEs requiring clinic visit, No. (%) | 20 (4.38) | 19 (4.19) | OR (97.5% CI) = 1.10 (0.52 to 2.31) | .77 | 18 (3.98) | 19 (4.19) | OR (97.5% CI) = 0.98 (0.46 to 2.09) | .95 |
| Severity of AEs, mean (95% CI) | ||||||||
| Requiring clinic visit | 1.27 (1.23 to 1.32) | 1.34 (1.30 to 1.39) | −0.07 (−0.12 to −0.02) | .002 | 1.22 (1.17 to 1.27) | 1.27 (1.23 to 1.32) | −0.06 (−0.11 to −0.00) | .02 |
| Reported in eDiary | 1.78 (1.22 to 2.34) | 1.87 (1.32 to 2.41) | −0.09 (−0.61 to 0.44) | .71 | 1.35 (0.83 to 1.88) | 1.87 (1.28 to 2.45) | −0.51 (−1.05 to 0.03) | .03 |
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Taxonomy
TopicsDental Radiography and Imaging · Opioid Use Disorder Treatment · Dental Anxiety and Anesthesia Techniques
Introduction
Sex differences in pain are shaped by a range of biological, psychological, and social factors,^1^ with evidence that women often report greater postsurgical pain^2,3^ and lower pain thresholds and tolerance.^4^ To explore potential variation in pain experience and treatment response, the Opioid Analgesic Reduction Study (OARS)^5,6^ incorporated sex stratification. A prespecified subgroup analysis was conducted to evaluate noninferiority of nonopioids for pain and examined treatment effects on satisfaction and other secondary outcomes between nonopioid and opioid groups within male and female participants separately.
Methods
Rutgers University Institutional Review Board approved the OARS randomized clinical trial, which includes this subgroup analysis, which is reported following the CONSORT reporting guideline. Participants provided written informed consent. OARS, a multisite, noninferiority trial, compared analgesic effectiveness of a nonopioid combination (ibuprofen 400 mg and acetaminophen 500 mg) with an opioid (hydrocodone 5 mg and acetaminophen 300 mg) for postoperative pain management after impacted mandibular third molar extraction (eMethods in Supplement 1; study protocol in Supplement 2).^5^ Healthy adult participants were randomized by sex and site to receive blinded study analgesic and completed twice-daily electronic diaries postoperatively (eFigure in Supplement 1). A follow-up visit included a clinical exam and survey. Primary outcomes were pain experience and medication satisfaction. Secondary outcomes included sleep quality, pain interference, rescue medication, and adverse events. The noninferiority margin for pain experience was 1.0 points in an 11-point numeric rating scale. Superiority was assessed after establishing noninferiority. Conventional (not noninferiority) testing was used for all other outcomes. Analyses were performed using SAS version 9.4 (SAS Institute). For each outcome, statistical significance was defined by α = .025 (2-sided) for each sex after Bonferroni adjustment to control the overall α of .05, with further adjustments to control for multiple comparisons as appropriate.
Results
Among 1815 participants (mean [SD] age, 25.7 [6.2] years; 50.1% female; 15.0% Asian, 28.2% Black, 30.9% Hispanic, and 19.7% White), 909 received a nonopioid combination and 906 received an opioid. Sex distribution and baseline and surgical characteristics were comparable across groups (Table 1).
Nonopioids provided superior pain relief on day 1 for females (mean difference, −0.63; 99.375% CI, −1.04 to −0.21) and males (mean difference, −0.75; 99.375% CI, −1.17 to −0.33). On days 2 and 3 and over the postoperative period, nonopioids were noninferior, with all CIs within the noninferiority margin (d = 1). Patient satisfaction was higher in the nonopioid group; 82.8% of females and 87.8% of males reported being extremely satisfied or satisfied compared with 76.2% and 81.6%, respectively, in the opioid group (females: odds ratio [OR], 1.51; 97.5% CI, 1.04 to 2.20; males: OR, 1.59; 97.5% CI, 1.04 to 2.44) (Table 2).
There were no significant differences in sleep quality across groups. However, participants not receiving opioids experienced less pain interference on days 1 and 2. The need for rescue medication was lower in the nonopioid group for males but not significantly different for females. Adverse events requiring emergency visits were less severe (0-3 scale where 0 = none and 3 = severe) in the nonopioid group for both sexes, and electronic diary–reported adverse events were milder in males not receiving opioids (Table 2).
Discussion
In the overall OARS cohort in this prespecified subgroup analysis of a randomized clinical trial, nonopioid therapy provided superior pain control compared with opioid therapy during the first and second day-night periods after surgery. Thereafter, noninferiority was observed during the third day-night period and across the full 7-day postoperative interval. In subgroup analysis by sex, superiority was retained for the first day-night, while noninferiority was consistently observed for the second and third day-night periods and the entire 7-day follow-up.
These results support the overall OARS conclusion that nonopioid therapy was at least as effective as and often superior to opioid therapy for postoperative pain management. The consistency of treatment effects across male and female participants supports the robustness of the trial’s findings, underscoring the clinical utility of nonopioids as first-line therapy.
A key limitation of this analysis is that it focused on treatment effects within sex subgroups without examining sex-based differences between treatment groups. Nonetheless, the alignment of subgroup and overall results provides strong confirmatory evidence for the main trial conclusions.
The reference list from the paper itself. Each links out to its DOI / PubMed record.
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