Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: Translating clinical research to dental practice

BackgroundEffective and safe drug therapy for the management of acute postoperative pain has relied on orally administered analgesics such as ibuprofen, naproxen and acetaminophen, or N-acetyl-p-aminophenol (APAP), as well as combination formulations containing opioids such as hydrocodone with APAP. The combination of ibuprofen and APAP has been advocated in the last few years as an alternative therapy for postoperative pain management. The authors conducted a critical analysis to evaluate the scientific evidence for using the ibuprofen-APAP combination and propose clinical treatment recommendations for its use in managing acute postoperative pain in dentistry.Types of Studies ReviewedThe authors used quantitative evidence-based reviews published by the Cochrane Collaboration to determine the relative analgesic efficacy and safety of combining ibuprofen and APAP. They found additional articles by searching the Ovid MEDLINE, PubMed and http://ClinicalTrials.gov databases.ConclusionsThe results of the quantitative systematic reviews indicated that the ibuprofen-APAP combination may be a more effective analgesic, with fewer untoward effects, than are many of the currently available opioid-containing formulations. In addition, the authors found several randomized controlled trials that also indicated that the ibuprofen-APAP combination provided greater pain relief than did ibuprofen or APAP alone after third-molar extractions. The adverse effects associated with the combination were similar to those of the individual component drugs.Practical ImplicationsCombining ibuprofen with APAP provides dentists with an additional therapeutic strategy for managing acute postoperative dental pain. This combination has been reported to provide greater analgesia without significantly increasing the adverse effects that often are associated with opioid-containing analgesic combinations. When making stepwise recommendations for the management of acute postoperative dental pain, dentists should consider including ibuprofen-APAP combination therapy.     

Effects of pre-emptive analgesia on efficacy of buccal infiltration during pulpotomy of mandibular primary molars: a double-blinded randomized controlled trial

Objective: To assess the effect of preoperative administration of ibuprofen and acetaminophen on the efficacy of buccal infiltration for pulp therapy in mandibular primary molars.

Materials and methods: A randomized controlled trial with an ID no. NCT03423329 in Clinical-Trials.gov was conducted in the outpatient clinic of Paediatric Dentistry Department at Ain Shams University. The study was designed with two test arms where either ibuprofen or acetaminophen was administered to children whereas in the control arm a multivitamin placebo was used. Children's self-reported pain responses were recorded using Wong–Baker FACES pain scale. For statistical analysis, Chi-square test or Fisher’s exact test was used to compare between the three groups whereas Friedman’s test was used to study changes within each group.

Results: In a sample of 60 children, a significant decrease in the mean pain rating scores was detected in all groups where success rates ranged from 40% with ibuprofen to 55% and 65% with acetaminophen and placebo, respectively. However, there was no statistically significant difference between the three groups regarding severity of pain during access cavity preparation.

Conclusions: Both analgesics have no clinical advantage over the placebo in increasing the efficacy of buccal infiltration during pulp therapy in mandibular primary molars.     

Hospitalization costs and resource allocation in cholecystectomy with use of intravenous versus oral acetaminophen

Objective: To evaluate intravenous (IV) acetaminophen (APAP) vs oral APAP use as adjunctive analgesics in cholecystectomy patients by comparing associated hospital length of stay (LOS), hospital costs, opioid use, and rates of nausea/vomiting, respiratory depression, and bowel obstruction.

Methods: We conducted a retrospective analysis of the Premier Database (January 2012 to September 2015) including cholecystectomy patients who received either IV APAP or oral APAP. Differences in LOS, hospitalization costs, mean daily morphine equivalent dose (MED), and potential opioid-related adverse events were estimated. Multivariable logistic regression was performed for the binary outcomes and instrumental variable regressions, using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for continuous outcomes. Models were adjusted for patient demographics, clinical risk factors, and hospital characteristics.

Results: Among 61,017 cholecystectomy patients, 31,133 (51%) received IV APAP. Subjects averaged 51 and 57 years of age, respectively, in the IV and oral APAP cohorts. In the adjusted models, IV APAP was associated with 0.42 days shorter LOS (95% CI?=?–0.58 to –0.27; p?p?p?=?.0005), and lower rates of respiratory depression (odds ratio [OR]?=?0.89, 95% CI?=?0.82–0.97; p?=?.006), and nausea and vomiting (OR?=?0.86, 95% CI?=?0.86–0.86; p?Conclusions: In patients having cholecystectomy, the addition of IV APAP to perioperative pain management is associated with shorter LOS, lower costs, reduced opioid use, and less frequent nausea/vomiting and respiratory depression compared to oral APAP. These findings should be confirmed in a prospective study comparing IV and oral APAP.     

HPLC测定感冒清胶囊中对乙酰氨基酚和盐酸吗啉胍的溶出度

目的 建立感冒清胶囊中对乙酰氨基酚和盐酸吗啉胍的溶出度测定方法。方法 采用桨法,以0.1 mol·L^-1的盐酸溶液为溶出介质,转速为50 r·min^-1,取样时间为30 min。高效液相色谱法采用 ZORBAX SB-C₁₈(150 mm×4.6 mm,5 μm)色谱柱,以乙腈-0.02 mol·L^-1庚烷磺酸钠溶液(15∶85)为流动相,检测波长为237 nm,流速为1.0 mL·min^-1,柱温为30 ℃。结果 对乙酰氨基酚在4.588×10^-2~0.458 8 μg内呈良好的线性关系(r=0.999 8),平均回收率为98.1%,RSD为1.06%(n=9);盐酸吗啉胍在4.654×10^-2~0.465 4 μg内呈良好的线性关系(r=0.999 6),平均回收率为97.9%,RSD为1.09%(n=9)。结论 该法简便、准确、可行,能准确测定感冒清胶囊中对乙酰氨基酚和盐酸吗啉胍的溶出度,专属性良好。     

感冒灵颗粒中对乙酰氨基酚在人体的代谢特征研究

目的研究感冒灵颗粒中对乙酰氨基酚(APAP)在人体的代谢特征。方法 12名健康志愿者单次口服感冒灵颗粒后,收集尿液,采用LC-MS/MS法测定尿液中4种代谢物(葡萄糖醛酸结合物、硫酸结合物、半胱氨酸结合物和乙酰半胱氨酸结合物)的浓度,与常规剂量比较代谢产物的排泄总量及排泄比例。结果单次口服感冒灵颗粒(含APAP 200 mg)后24 h内,4种代谢物总排泄量占给药剂量的(49.1±16.74)%,毒性代谢物排泄率与总代谢物排泄率的比值为(7.7±0.08)%,与常规剂量相比,4种代谢物总排泄率降低,毒性代谢物排泄率与总代谢物排泄率的比值不变。结论感冒灵颗粒中小剂量APAP毒性代谢途径比例未发生改变,而毒性代谢物绝对量呈非线性地显著降低。提示感冒灵颗粒组方可能具有较好的安全性。     

Efficacy and Safety of an Intravenous Acetaminophen/Ibuprofen Fixed-dose Combination After Bunionectomy: a Randomized,Double-blind,Factorial, Placebo-controlled Trial

PurposeMultimodal analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs is recommended for the treatment of postoperative pain. Although oral fixed-dose combinations (FDCs) are available, parenteral administration may be clinically justified. The goal of this study was to investigate the clinical efficacy and safety of an intravenous FDC of ibuprofen and acetaminophen after bunionectomy.MethodsThis study was a prospective, randomized, double-blind, multicenter, placebo-controlled factorial clinical trial conducted at 2 clinical research centers in the United States between November 2016 and June 2017. Eligible patients (male and female subjects, aged 18–65 years, reporting pain intensity levels ≥40 mm on a 100-mm visual analog scale (VAS) after distal, first metatarsal bunionectomy) were randomized (3:3:3:2) to receive the FDC (ibuprofen 300 mg + acetaminophen 1000 mg), ibuprofen 300 mg, acetaminophen 1000 mg, or placebo (vehicle), administered as 15-minute intravenous infusions every 6 hours for 48 hours. The primary efficacy end point was the time-adjusted sum of pain intensity differences from baseline over 48 hours (SPID₄₈). In addition to VAS pain intensity scores, pain relief scores, time to perceptible and meaningful pain relief, the use of rescue medication, and participant's global evaluations of the study drug were recorded. Adverse events occurring during the 48-hour treatment period were included in the safety analysis.FindingsA total of 276 participants were enrolled; most were female (82%), the mean age was 42.4 years, and the median baseline VAS was 67 mm, indicating moderate to severe pain. SPID₄₈ was significantly higher for the FDC (23.4 [2.5] mm) than for ibuprofen (9.5 [2.5] mm), acetaminophen (10.4 [2.5] mm), and placebo (−1.3 [3.1] mm; all, P < 0.001). The superior analgesic effect of the FDC was supported by a range of secondary end points, including reduced opioid usage rates (75% for FDC, 92% for ibuprofen, 93% for acetaminophen, and 96% for placebo; all, P < 0.005). The safety profile of the FDC was comparable to that of intravenous ibuprofen or acetaminophen alone. Three participants withdrew from the study due to adverse events: 2 in the ibuprofen group and 1 in the acetaminophen group.ImplicationsThe study found that repeated administration of an intravenous FDC of ibuprofen and acetaminophen provided statistically significant improvement in SPID₄₈ over comparable doses of either monotherapy without an increase in adverse events. ClinicalTrials.gov identifier: NCT02689063.     

Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448±48 µg/g to 82±2 µg/g (P<0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454±446 IU/liter and 2571±2944 IU/liter, respectively) compared to those without misoprostol treatment (1348±480 IU/liter and 6077±3025 IU/liter, respectively,P<0.01). TNBT staining showed a reduced area of damage from 28.6±22.3% to 7.3±8.9% (P<0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose. Late administration of misoprostol may also be beneficial and thus may be considered in treating patients with APAP toxicity.This study is supported by the Australian National Health and Medical Research Council Grant 91/0662.     

Cytoprotective effect of acetaminophen against taurocholate-induced damage to rat gastric monolayer cultures

Acetaminophen has recently been reported to protect against drug damage to gastric mucosa in vivo.The present study tested acetaminophen protection in cultured rat gastric mucous cells against sodium taurocholate-induced damage and assessed the role of endogenous prostaglandins. Cell damage was assessed by phase-contrast microscopy and quantitated by Chromium-51 release assay which positively correlated with the trypan blue dye exclusion test (r=0.98). The effect of acetaminophen on the production of PGE ₂ and 6-keto-prostaglandin F _1a (6KF) was also studied. Sodium taurocholate caused cell death in a dose-dependent manner as indicated by increased ⁵¹ Cr release. Preincubation with 5 mM acetaminophen significantly reduced ⁵¹ Cr release caused by 5 mM sodium taurocholate, producing a 40% increase in cell survival. This cytoprotection was not blocked by indomethacin. PGE ₂ and 6KF of the media did not change after preincubation with nondamaging concentrations of acetaminophen or taurocholate. These results indicate that: (1) acetaminophen exerts a direct protective effect on gastric mucous cells cultured in vitroindependent of indirect factors such as blood flow and (2) this protection is not associated with increased prostaglandin production.