Evaluation of the Analgesic Efficacy and Safety of Ibuprofen Arginine and Tramadol Hydrochloride in Postoperative Dental Pain Management

The primary objective of this clinical trial is to evaluate the **analgesic efficacy** of an oral combination of ibuprofen (arginine) and tramadol HCl, administered every 6 hours, in patients experiencing moderate to severe pain following dental extraction of third molars. The study aims to determine if this combination provides superior pain relief, as measured by the difference in the Sum of Pain Intensity Differences (SPID) over 0-12 hours, compared to its individual active components administered as monotherapy and to placebo. This is clinically relevant as it may offer a more effective pain management strategy for patients undergoing dental surgery.

Secondary objectives include:

• Describing and comparing analgesic efficacy parameters such as the Visual Analogue Pain Scale (VAS) score, differences in pain intensity from baseline, Area Under the Curve of pain intensity differences over 12 hours, and the Sum of Pain Intensity Differences at 6 hours (SPID0-6h).
• Evaluating the time to first pain relief, the percentage of patients responding to each treatment, the demand for rescue medication, and the time until administration of rescue medication.
• Assessing the safety and tolerability of each study treatment.

The clinical trial involves participants experiencing **moderate to severe somatic pain** following dental extraction of third molars. The study population includes both male and female subjects aged 18 years and older, with a **body mass index** ranging from 18.5 to less than 35 kg/m². Participants are required to have undergone surgical extraction of at least two third molars, with at least one being a lower impacted molar necessitating bone removal. The trial does not include a vulnerable population. Participants must refrain from using analgesics other than those specified in the study protocol from 24 hours before surgery until 48 hours after the study medication ends. The sponsor has not provided the total number of participants involved in the trial. The selection criteria ensure that participants are capable of providing informed consent and are willing to adhere to all study procedures and visits. The trial aims to evaluate the efficacy of a combination of ibuprofen (arginine) and tramadol HCl in achieving superior pain relief compared to monotherapy and placebo.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, and active-treatment study to evaluate the analgesic efficacy and safety of an oral combination of **ibuprofen (arginine)** and **tramadol hydrochloride**. The trial targets patients experiencing moderate to severe pain following dental surgery, specifically the extraction of third molars. The primary objective is to determine if the combination therapy provides superior pain relief compared to its individual components and placebo, as measured by the Sum of the Pain Intensity Differences (SPID) over 12 hours using the Visual Analogue Scale (VAS).

The trial is expected to span from January 10, 2022, to March 31, 2025. Participants will be involved for a maximum of 48 hours post-surgery, with the treatment period lasting up to 2 days. The study includes several key visits: an initial screening visit to confirm eligibility, a baseline visit for randomization, and follow-up visits to assess pain intensity and any adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Inclusion criteria require participants to be at least 18 years old, with a body mass index between 18.5 and 35 kg/m², and scheduled for surgical extraction of at least two third molars. Participants must agree to refrain from using analgesics outside of the study protocol and achieve a pain score of at least 55 mm on the VAS within three hours post-surgery. Conditions for early termination include non-compliance with study procedures or the occurrence of significant adverse events.

Secondary endpoints include various measures of pain intensity and relief, such as the Area Under the Curve of pain intensity differences, patient responder rates, and the time to first pain relief. The trial will also monitor the use of rescue medication, vital signs, laboratory abnormalities, and any adverse events. The study aims to provide comprehensive data on the efficacy and safety of the combination therapy in managing post-surgical pain.

The clinical trial involves the administration of **Ibuprofen (arginine)/Tramadol HCl 400/37.5 mg granules for oral solution** as the experimental treatment. This pharmaceutical form is a granule intended for oral solution, produced by FARMALIDER S.A. The active substances in this formulation are **tramadol hydrochloride** and **ibuprofen**. The maximum daily dose is 1750 mg, with a total maximum dose of 3500 mg over a treatment period of up to 2 days. The medication is administered orally every 6 hours to patients experiencing moderate to severe pain following dental surgery.

As a comparator treatment, **Espididol 400 mg granulado para solución oral sabor menta** is used. This product, manufactured by ZAMBON, S.A.U., is an oral solution containing **ibuprofen arginine** as the active substance. The maximum daily dose is 1600 mg, with a total maximum dose of 3200 mg over a 2-day treatment period. The administration route is oral, and the dosing schedule is consistent with the experimental treatment.

Another comparator treatment in the study is **Adolonta 100 mg/ml solución oral**, produced by GRÜNENTHAL PHARMA S.A. This oral drops solution contains **tramadol hydrochloride** as the active ingredient. The maximum daily dose is 200 mg, with a total maximum dose of 400 mg over a 2-day treatment period. The administration is oral, and the dosing frequency aligns with the other treatments in the trial.

The study also includes a placebo group, utilizing **PL 1 Granules for oral solution** and **PL 2 Oral solution**. These placebo treatments do not contain active substances and are used to maintain the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the active treatments.

The efficacy of the clinical trial will be assessed by evaluating the analgesic effect of a combination of **ibuprofen (arginine)** and **tramadol HCl** administered orally to patients experiencing moderate to severe pain following dental surgery. The primary endpoint for efficacy evaluation is the Sum of the Pain Intensity Differences (SPID) from the start of administration until 12 hours post-administration, measured using the Visual Analogue Scale (VAS). Secondary endpoints include pain intensity and pain intensity difference at scheduled assessment times up to 48 hours, the Area Under the Curve of pain intensity differences during the first 12 hours, and the SPID at 6 hours from the start of administration. Additional secondary endpoints involve patient responder rate, time to first pain relief, proportion of patients using rescue medication, total use of rescue medication, time to first rescue administration, vital signs, laboratory abnormalities, and adverse events.