Comparison of two combinations of opioid and non-opioid analgesics for acute periradicular abscess: a randomized clinical trial

Abstract Acute periradicular abscess is a condition characterized by the formation and propagation of pus in the periapical tissues and generally associated with debilitating pain. Objective: The aim of this study was to compare the overall analgesic effectiveness of two combinations of opioid and non-opioid analgesics for acute periradicular abscess. Material and Methods: This study included 26 patients who sought emergency care in a Brazilian dental school. The patients were randomly divided into two groups: Co/Ac - oral prescription of codeine (30 mg) plus acetaminophen (500 mg), every 4 h, for 3 days or Tr/Ac - oral prescription of tramadol hydrochloride (37.5 mg) plus acetaminophen (500 mg) on the same schedule. Two factors were evaluated: (1) pain scores recorded by the patients in a pain diary 6, 12, 24, 48, and 72 h after treatment, using the Visual Analogue Scale; and (2) the occurrence of adverse effects. Results: In both groups, there was a reduction in pain scores over time. For the Co/Ac group, there was a significant reduction in the scores 12, 24, 48, and 72 hours after treatment (P<0.05). In the Tr/Ac group, the scores significantly decreased over time from time point 6 h (P<0.05). Comparing the pain at each time point, the groups were not significantly different (P>0.05), i.e., both treatments were effective in controlling pain caused by APA; however, the combination of Tr/Ac caused more adverse reactions as two patients had to stop using the medication. Conclusion: This study suggests that, considering both analgesic efficacy and safety, the combination of codeine and acetaminophen is more effective to control moderate to severe pain from acute periradicular abscesses.

In the treatment of APA, besides the local clinical approach, which relies on surgical access and/or root canal debridement and provide pus drainage, a systemic medication oncoming that involves the use of analgesics and antibiotics is also considered.
Antibiotics can be prescribed as a complementary measure especially for abscesses associated with systemic involvement, including fever, malaise and lymphadenopathy; disseminating infections resulting in cellulitis, progressive diffuse swelling, and/or trismus; and abscesses in medically compromised patients at increased risk of a secondary infection following bacteremia 1,24,26 . In APA cases, analgesia becomes challenging because the immunological mechanisms of pain have already been triggered. It is generally accepted the use of non-steroidal anti-Ahmad, et al. 2 (1997) found that therapeutic doses of NSAIDs were more effective than the combination of acetaminophen (600-650 mg) and codeine (60 mg) in the treatment of pain caused by the extraction of third molars. However, for pain management of infectious diseases, the use of NSAIDs may mask clinical signs of infection 1 . Therefore, in the presence of infection and pain with moderate to severe intensity, the combined use of oral opioids (such as codeine or tramadol) and non-opioids (such as acetaminophen or aspirin) is considered more appropriate 13 , even though there is a clear lack of clinical evidence to support using these drug combinations in pain controlling, especially in APA cases.
Codeine/acetaminophen is the most frequently for the management of moderate-to-severe acute pain 28 . However, the tramadol/acetaminophen combination has also been proposed as an alternative to control acute pain 22 . The use of tramadol has been proven effective in treating some cases of acute in the treatment of acute pain of dental origin are not well characterized. Because APA is an infectious process of dental origin that might spawn a severe debilitating pain experience to the patient, it seems relevant to compare the overall effectiveness of the two combinations of opioid/non-opioid medications, as indicated by the analgesic effect and the incidence of difference in analgesic effectiveness is present when combining these two opioids (codeine or tramadol) with acetaminophen (non-opioid) to manage pain in patients with APA.

Randomization and blinding procedures
The random allocation sequence was performed using random table numbers generated at randomizer. org. A pharmacist encapsulated the drugs in identical capsules, and packaged in white bottles numbered 1 to 26. Information on drug administration was described on the label. An assistant who was blinded to the aim and the protocol of the study generated the numbers using a spreadsheet program (Microsoft Excel).

Outcomes
The primary outcome was the pain scores. They appointment. Secondary outcomes included frequency of additional medication use and adverse reactions reported by patients. All information was registered in the pain diary by the patient.
The Number Needed to Harm (NNH), i.e., the number of patients receiving Tr/Ac treatment to cause one additional patient to be harmed, compared with patients who received Co/Ac treatment was also calculated.

Statistical methods
The analyses were performed on an intention-to- Twenty-six patients met the inclusion criteria and agreed to participate in the clinical trial. Out of these 26 patients, three from the Co/Ac group and one from the Tr/Ac group did not return the pain diary and were excluded from the study. Two patients from the Tr/Ac group showed worsening clinical status, sought care elsewhere and also did not return the pain diary. Two patients from the Tr/Ac group dropped out of treatment due to the occurrence of adverse reactions that impaired their daily activities and were excluded from analysis of pain scores, but not from analysis of adverse effects ( Table 2). The number of patients in each group, taking into account dropouts and exclusions, is shown in Figure 1.
In both groups, pain scores decreased over time.   Table 2 -Median and 25 th /75 th percentiles of pain scores (mm) before (initial) and after administration of codeine and acetaminophen combination (Co/Ac) and tramadol and acetaminophen combination (Tr/Ac) A significantly higher pain relief provided by hydrocodone/acetaminophen was observed compared to codeine/acetaminophen (30 mg/300 mg) 10 , whereas a similar effect was found when compared to tramadol/ acetaminophen (75 mg/650 mg) 11 .
The frequency of additional drug use was also not a discriminating factor among groups. In both groups, four patients (40%) took additional acetaminophen. did not tolerate the side effects and two (20%) sought of drugs tested. Therefore, considering overall safety, the Co/Ac combination could be taken as superior to Tr/Ac group, which partially reject the originally set of both associations may be different and future studies must assess this outcome. However, because in this study the sample size calculation was not performed for this outcome (i.e. safety), the result can be a real difference between treatments or a statistic type II error (beta).
Opioid analgesics are useful agents for treating

Conclusions
The present randomized clinical trial indicated that Tr/Ac and Co/Ac treatment presented similar analgesic Ac, resulting in a greater frequency of abandoning treatment due to ineffectiveness or intolerance to adverse effects.