Probiotics for Improving Post-surgical Healing

Study Overview
=================
Brief Summary
-----------------
A randomized, double-blind, placebo-controlled clinical trial will be performed to assess the efficacy of a probiotic containing Lactobacillus reuteri in improving post-surgical wound healing after impacted tooth extractions. The Primary aim is to evaluate the efficacy of L. reuteri in improving post-extractive healing. The Secondary aim is to evaluate the efficacy of L. reuteri in association with an antibiotic therapy (amoxicillin) in reducing the incidence and severity of antibiotic-associated gastro-intestinal symptoms.

Detailed Description
-----------------
Probiotics are defined by the World Health Organization as live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Human microbiome is a complex system that contributes to maintaining a good health status in humans. Broad-spectrum antibiotic therapies act against pathogen bacteria but also affect the intestinal microbiome, leading to different side effects such as abdominal pain, gastric pain, nausea, vomit and diarrhea. The use of probiotics has been advocated as a possible means in reducing intensity and incidence of the symptoms related to antibiotic therapies. Some probiotics like Lactobacillus reuteri (L. reuteri) showed good anti-inflammatory properties and also antimicrobic action, assuming a possible role in wound healing processes. Few studies have been conducted on the use of L. reuteri in dentistry. Twetman et al. (2018) conducted a trial to assess the efficacy of L. reuteri in improving post-surgical healing in the oral cavity after a punch biopsy, showing promising results. The authors concluded that larger trials may be useful to better clarify the role of probiotics in oral wounds healing. The only data regarding the possible role of L. reuteri in post- extractive healing comes from a pilot study (Walivara at al. 2019) that showed a reduction of the perceived swelling and of the number of disturbed-sleep nights in patients who underwent impacted-tooth extraction and assumed L. reuteri. Authors concluded that larger trials with closer follow-up visits are required to fully understand the clinical correlation. The primary aim of the present research is to evaluate the efficacy of a probiotic containing L. reuteri in improving post-surgical healing following impacted tooth extractions and the secondary aim is to investigate its possible role in preventing or reducing gastro-intestinal side effects related to post-operative antibiotic therapy.A Randomized, double-blind, placebo-controlled clinical trial will be performed to evaluate the efficacy of L. reuteri in improving post-extractive healing. All patients who need impacted tooth extractions at University Hospital of Pisa (Operative Unit of Odontostomatology and Oral Surgery) will be considered eligible for the study. The number of patients to include is set to 160, divided in two experimental groups (80 patients per group). Patients who meet inclusion/exclusion criteria will be enrolled in this trial.

Official Title
-----------------
Efficacy of Probiotics in Improving Post-surgical Healing for Impacted Tooth Extractions

Conditions
-----------------
Probiotics, Tooth, Impacted, Wound Heal, Gastrointestinal Complication

Intervention / Treatment
-----------------
* Procedure: Impacted tooth extraction


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: need for impacted tooth extractions over age 18 ability to understand and to sign an informed consent form Exclusion Criteria: allergy to penicillin contraindications to oral surgery treatment with immunosuppressive agents or immunocompromised treatment with amino-bisphosphonate and anti-angiogenetic medications irradiation to head and neck area uncontrolled diabetes renal failure drug and alcohol addiction psychiatric disorders

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>All patients will undergo an impacted tooth extraction; patients allocated to group 1 will receive an antibiotic therapy with amoxicillin for 6 days (2 g/day) and a probiotic for 21 days (2 tablets/day). | Procedure: Impacted tooth extraction<br>* All patients will undergo a surgical tooth extraction<br>|
| Placebo Comparator: Group 2<br>All patients will undergo an impacted tooth extraction; patients allocated to group 1 will receive an antibiotic therapy with amoxicillin for 6 days (2 g/day) and a placebo of the probiotic for 21 days (2 tablets/day). | Procedure: Impacted tooth extraction<br>* All patients will undergo a surgical tooth extraction<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical wound healing | Clinical assessment of the characteristics of the surgical wound | 3 days after the surgery | 
| Surgical wound healing | Clinical assessment of the characteristics of the surgical wound | 7 days after the surgery | 
| Surgical wound healing | Clinical assessment of the characteristics of the surgical wound | 14 days after the surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of pain | presence of pain assessed by VAS (0-10) | 3 days after the surgery | 
| Presence of pain | presence of pain assessed by VAS (0-10) | 7 days after the surgery | 
| Presence of pain | presence of pain assessed by VAS (0-10) | 14 days after the surgery | 
| Abscess | presence of suppuration | 3 days after the surgery | 
| Abscess | presence of suppuration | 7 days after the surgery | 
| Abscess | presence of suppuration | 14 days after the surgery | 
| Edema | presence and evaluation of the post-operative edema (intra-oral and extra-oral) | 3 days after the surgery | 
| Edema | presence and evaluation of the post-operative edema (intra-oral and extra-oral) | 7 days after the surgery | 
| Edema | presence and evaluation of the post-operative edema (intra-oral and extra-oral) | 14 days after the surgery | 
| Fever | Body temperature > 37°C | 3 days after the surgery | 
| Fever | Body temperature > 37°C | 7 days after the surgery | 
| Fever | Body temperature > 37°C | 14 days after the surgery | 
| Alveolar osteitis | Presence of alveolar osteitis | 3 days after the surgery | 
| Alveolar osteitis | Presence of alveolar osteitis | 7 days after the surgery | 
| Alveolar osteitis | Presence of alveolar osteitis | 14 days after the surgery | 
| Trismus | reduction in mouth opening (measured in mm) | 3 days after the surgery | 
| Trismus | reduction in mouth opening (measured in mm) | 7 days after the surgery | 
| Trismus | reduction in mouth opening (measured in mm) | 14 days after the surgery | 
| Painkillers | Number of painkillers assumed in the first 7 days after the surgery | 7 days after the surgery | 
| bleeding on palpation | presence of bleeding on palpation | 3 days after the surgery | 
| bleeding on palpation | presence of bleeding on palpation | 7 days after the surgery | 
| bleeding on palpation | presence of bleeding on palpation | 14 days after the surgery | 
| Difficulty in chewing | Difficulty in chewing assessed by VAS (0-10) | 3 days after the surgery | 
| Difficulty in chewing | Difficulty in chewing assessed by VAS (0-10) | 7 days after the surgery | 
| Difficulty in chewing | Difficulty in chewing assessed by VAS (0-10) | 14 days after the surgery | 
| Difficulty in speaking | Difficulty in speaking assessed by VAS (0-10) | 3 days after the surgery | 
| Difficulty in speaking | Difficulty in speaking assessed by VAS (0-10) | 7 days after the surgery | 
| Difficulty in speaking | Difficulty in speaking assessed by VAS (0-10) | 14 days after the surgery | 
| Difficulty in performing oral hygiene | Difficulty in performing oral hygiene assessed by VAS (0-10) | 3 days after the surgery | 
| Difficulty in performing oral hygiene | Difficulty in performing oral hygiene assessed by VAS (0-10) | 7 days after the surgery | 
| Difficulty in performing oral hygiene | Difficulty in performing oral hygiene assessed by VAS (0-10) | 14 days after the surgery | 
| Daily routine alterations | days of stay off work | 3 days after the surgery | 
| Daily routine alterations | days of stay off work | 7 days after the surgery | 
| Daily routine alterations | days of stay off work | 14 days after the surgery | 
| Sensation of swelling | assessed by VAS (0-10) | 3 days after the surgery | 
| Sensation of swelling | assessed by VAS (0-10) | 7 days after the surgery | 
| Sensation of swelling | assessed by VAS (0-10) | 14 days after the surgery | 
| Number of disturbed-sleep nights following the extraction | Number of disturbed-sleep nights | 3 days after the surgery | 
| Number of disturbed-sleep nights following the extraction | Number of disturbed-sleep nights | 7 days after the surgery | 
| Number of disturbed-sleep nights following the extraction | Number of disturbed-sleep nights | 14 days after the surgery | 
| Abdominal pain | presence of Abdominal pain (questionnarie Y/N) | 3 days after the surgery | 
| Abdominal pain | presence of Abdominal pain (questionnarie Y/N) | 7 days after the surgery | 
| Abdominal pain | presence of Abdominal pain (questionnarie Y/N) | 14 days after the surgery | 
| Abdominal distension | presence of Abdominal pain (questionnarie Y/N) | 3 days after the surgery | 
| Abdominal distension | presence of Abdominal pain (questionnarie Y/N) | 7 days after the surgery | 
| Abdominal distension | presence of Abdominal pain (questionnarie Y/N) | 14 days after the surgery | 
| Alvus variation | presence of alvus variations (questionnarie Y/N) | 3 days after the surgery | 
| Alvus variation | presence of alvus variations (questionnarie Y/N) | 7 days after the surgery | 
| Alvus variation | presence of alvus variations (questionnarie Y/N) | 14 days after the surgery | 
| Nausea | presence of nausea (questionnarie Y/N) | 3 days after the surgery | 
| Nausea | presence of nausea (questionnarie Y/N) | 7 days after the surgery | 
| Nausea | presence of nausea (questionnarie Y/N) | 14 days after the surgery | 
| Vomit | presence of vomit (questionnarie Y/N) | 3 days after the surgery | 
| Vomit | presence of vomit (questionnarie Y/N) | 7 days after the surgery | 
| Vomit | presence of vomit (questionnarie Y/N) | 14 days after the surgery | 
| Acid reflux | presence of acid reflux (questionnarie Y/N) | 3 days after the surgery | 
| Acid reflux | presence of acid reflux (questionnarie Y/N) | 7 days after the surgery | 
| Acid reflux | presence of acid reflux (questionnarie Y/N) | 14 days after the surgery | 
| Gastric acidity | presence of gastric acidity (questionnarie Y/N) | 3 days after the surgery | 
| Gastric acidity | presence of gastric acidity (questionnarie Y/N) | 7 days after the surgery | 
| Gastric acidity | presence of gastric acidity (questionnarie Y/N) | 14 days after the surgery | 
| Gastric pain | presence of gastric pain (questionnarie Y/N) | 3 days after the surgery | 
| Gastric pain | presence of gastric pain (questionnarie Y/N) | 7 days after the surgery | 
| Gastric pain | presence of gastric pain (questionnarie Y/N) | 14 days after the surgery | 
| Loss of appetite | presence of loss of appetite (questionnarie Y/N) | 3 days after the surgery | 
| Loss of appetite | presence of loss of appetite (questionnarie Y/N) | 7 days after the surgery | 
| Loss of appetite | presence of loss of appetite (questionnarie Y/N) | 14 days after the surgery |