<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03789058</url>
  </required_header>
  <id_info>
    <org_study_id>20170307</org_study_id>
    <nct_id>NCT03789058</nct_id>
  </id_info>
  <brief_title>Efficacy of Ibuprofen Chronotherapy in Healing After Surgical Extraction of the Mandibular Third Molar</brief_title>
  <official_title>Efficacy of Non-Steroidal Anti-Inflammatory Drug (Ibuprofen) Chronotherapy in Healing After Surgical Extraction of the Mandibular Third Molar - A Randomized Clinical Trial Protocol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jordan University of Science and Technology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>McGill University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>InterPharma One LLC</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Jordan University of Science and Technology</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Clinical and preclinical studies have demonstrated encouraging results of non-steroidal&#xD;
      anti-inflammatory drug (NSAID) chronotherapy in the management and treatment of inflammatory&#xD;
      diseases such as rheumatoid arthritis. However, no previous clinical trials have addressed&#xD;
      how the timing of NSAID administration within the day affects pain and healing outcomes after&#xD;
      oral surgery that involves bone removal, such as surgical extraction of the third molars.&#xD;
      Methods to address our aim, Single-center double-blind randomized controlled trial study&#xD;
      design has been adopted. Patients who needed a lower third molar extraction and meet the&#xD;
      eligibility criteria will be recruited. Participants will be randomized into two groups.&#xD;
      Subjects in group one will be instructed to take an NSAID (ibuprofen 400 mg) at 7 AM and 12&#xD;
      PM combined with a placebo before bed between 8 and 10 PM for three days postoperatively.&#xD;
      Subjects in group 2 will be instructed to take an NSAID (ibuprofen 400 mg) between 7 AM, 12&#xD;
      PM and between 8 and 10 PM for three days postoperatively. The patients' self-reported pain&#xD;
      in the three days after surgery will be recorded as the primary outcome.&#xD;
&#xD;
      Additionally, healing indicators such as the maximum interincisal distance and measurements&#xD;
      of facial swelling will be recorded preoperatively and four days postoperatively. Each&#xD;
      participant's blood level of C-reactive protein will be recorded pre- and postoperatively as&#xD;
      an inflammatory marker.&#xD;
&#xD;
      Discussion:&#xD;
&#xD;
      The study will estimate the effect of using NSAID only in the morning following surgical&#xD;
      extraction of the third molar to decrease pain and improve postoperative healing and recovery&#xD;
      in comparison to the routine use of NSAIDs three times per day.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction and background:&#xD;
&#xD;
      The surgical extraction of wisdom teeth under local anesthesia is one of the most common oral&#xD;
      surgical procedures (1). Ten million third molars (wisdom teeth) are extracted from&#xD;
      approximately 5 million people in the United States of America each year at an annual cost of&#xD;
      over $3 billion. Additionally, more than 11 million patient-days of &quot;standard discomfort or&#xD;
      disability&quot; were reported due to surgical removal of wisdom teeth, with an average of 4.9&#xD;
      lost work days per procedure (2, 3). Most of wisdom teeth surgical extractions require bone&#xD;
      removal (4). Bone removal is associated with a broad range of postoperative discomfort and&#xD;
      complications (e.g., pain, swelling, bruising, and malaise). Most of these complications are&#xD;
      initiated by the inflammatory process from traumatic injury to the bone during the surgery.&#xD;
      Currently, postoperative pain management is limited to acetaminophen, opioids and NSAIDs (5,&#xD;
      6). However, these drugs are all problematics. Acetaminophen is not effective in managing&#xD;
      severe pain (6). Opioids and NSAID are effective in pain management, but opioids can cause&#xD;
      constipation and addiction (7, 8), While NSAIDs may delay bone healing (9, 10). Dentists and&#xD;
      maxillofacial surgeons all over the world prefer to prescribe NSAID after this type of&#xD;
      surgery (11). The mechanism of action of NSAIDs is the reversible inhibition of the enzyme&#xD;
      cyclooxygenase (COX), which is believed to be responsible for the synthesis of prostaglandins&#xD;
      (PGs) (10). Prostaglandins play a major role in inflammatory and nociceptive processes (12).&#xD;
      Two isoforms of COX, namely, COX-1 and COX-2, are responsible for the synthesis of PG from&#xD;
      arachidonic acid (AA). Both have essential roles in the inflammatory process after bone&#xD;
      surgery, but COX-1 is involved more in the integrity of the gastrointestinal tract and renal&#xD;
      tract tissue, while COX-2 is mainly involved in the inflammatory and healing process later&#xD;
      (13). NSAIDs are either nonselective (inhibiting both COX-1 and COX-2) or selective&#xD;
      (inhibiting COX-2 only). Ibuprofen is a peripherally acting analgesic with potent&#xD;
      anti-inflammatory action that works through reversible and balanced COX-1/ COX-2 inhibition,&#xD;
      which provides faster and more effective analgesia than many other NSAIDs without any&#xD;
      apparent increased safety risk (14). Ibuprofen is routinely used in the treatment of moderate&#xD;
      to severe acute pain in the general population, including dantal pain (15-17). Results from&#xD;
      Cochrane systematic reviews demonstrate that higher doses and frequencies of NSAID use are&#xD;
      associated with better pain control after dental (wisdom tooth extraction) and non-dental&#xD;
      surgeries (9, 18, 19). Increasing the dose and frequency of NSAIDs was associated with an&#xD;
      increased risk of adverse effects. Despite the promising results associated with the use of&#xD;
      different NSAIDs for pain control after wisdom tooth surgeries, patients still report pain&#xD;
      and other discomfort indicators such as swelling and trismus, especially during the first&#xD;
      three days after the procedure (20). These symptoms can affect patient's life, including&#xD;
      activities of daily living and even quality of life (3, 20-22). Animal studies suggest that&#xD;
      NSAID affect bone healing outcomes such as biomechanical measuments and number of bones with&#xD;
      non-unions (23-35). Some authors have even compared the effect of NSAIDs on fracture healing&#xD;
      with those of other pharmacological agents such as steroids (36, 37). Høgevold et al,&#xD;
      demonstrated that short-term administration of some anti-inflammatories, such as&#xD;
      indomethacin, inhibits fracture healing, while methylprednisolone does not (36).&#xD;
      Bhattacharyya et al. reported that patients receiving NSAIDs within 90 days after fracture&#xD;
      had a 3.7-fold risk of nonunion, while the risk for opioid users was 1.6-fold (38). Clinical&#xD;
      trials in humans pose some challenges, especially the need to control confounders such as&#xD;
      smoking, diabetes, obesity and other factors that are associated with the healing of&#xD;
      long-bone fractures (6, 39). Four retrospective studies suggested that patients using NSAIDs&#xD;
      after fracture had a higher incidence of non-union compared to those that did not use NSAIDs&#xD;
      (38, 40-42). All living organisms possess a circadian rhythm that anticipates the response to&#xD;
      changes during the 24-hour cycle (43). The circadian system in mammals is composed of a&#xD;
      central clock within the suprachiasmatic nuclei and a peripheral clock inside all cells. The&#xD;
      circadian clock is controlled through a feedback loop featuring a heterodimer of two core&#xD;
      clock gene products: circadian locomotor output cycles kaput (Clock) and brain and muscle&#xD;
      Arnt-like protein-1 (Bmal1). Clock and Bmal1 drive the expression of two inhibitors,&#xD;
      cryptochrome (Cry) and period (Per) (44). This molecular clock modulates the immune response&#xD;
      and bone healing process (44). The circadian rhythms in the expression of various cytokines&#xD;
      by immune cells are presented in Table S1. Macrophage activity, leukocyte recruitment, and&#xD;
      proinflammtory mediators such as interleukin-1β (IL-1β), IL-6, and IL-12 increased at the&#xD;
      beginning of the daily activity phase.&#xD;
&#xD;
      During the active phase, there are also increased levels of Toll-like receptors TLR9 and&#xD;
      TLR4, which upregulate the expression of CCL2, CXCL1, and CCL5, leading to leukocyte&#xD;
      recruitment and potential tissue damage at the injured site (43-46)(Fig.1.). On the other&#xD;
      hand, anti-inflammatory mediators and other growth and angiogenesis factors, such as vascular&#xD;
      endothelial growth factor (VEGF), peak during the resting phase (44, 47, 48) (Table S2.). The&#xD;
      24-hour circadian rhythm oscillation occur in bone tissue during growth (49), formation,&#xD;
      resorption (50, 51), and endochondral ossification during fracture bone healing (51).&#xD;
      Experimental studies in rodents and humans reveal that disruption of sleep and circadian&#xD;
      rhythm impair bone formation (52). All bone cells such as osteoblasts, osteoclasts, and&#xD;
      chondrocytes express clock genes that influence bone volume regulation, such as Per or Cry&#xD;
      (53, 54). The circadian clock also affects pain, with sensitivity peaking during the active&#xD;
      phase (55). Part of the pain response oscillation could be explained by changes in COX-1 and&#xD;
      COX-2 activity throughout the day (56), especially after an injury or insult (57). These&#xD;
      variations may contribute to the clinical evidence of circadian and circannual variations in&#xD;
      the pharmacokinetics effects of NSAID. Specifically, maximum absorption and effectiveness are&#xD;
      achieved when the drug is administered during the active phase (58-62). We performed&#xD;
      experimental studies to estimate the extent to which the timing of NSAID doses can affect&#xD;
      animal pain behaviour and recovery after bone fracture surgery. We used a validated model of&#xD;
      fracture healing in young female mice. The results showed that administration of NSAIDs&#xD;
      during the active phase after tibia fracture surgery, compared to administration during the&#xD;
      resting phase, significantly attenuated the pain response and improved the mechanical and&#xD;
      histomorphometric properties of the healing callus. Recent evidence suggests that the timing&#xD;
      of skin wounds or surgery affects healing and postoperative recovery after cardiovascular&#xD;
      surgeries (63, 64). The chronotherapeutic use of anti-inflammatory medications after oral&#xD;
      surgeries is of clinical importance, especially with increasing evidence regarding the&#xD;
      clinical efficacy of this approach in medicine. No clinical studies have investigated the&#xD;
      effectiveness of this approach after minor oral surgeries. Expected contribution and research&#xD;
      question The overarching aim of this study is to contribute evidence regarding the efficacy&#xD;
      of NSAID chronotherapy in patient recovery from wisdom tooth surgery. This is an important&#xD;
      aim considering that the outcomes of this investigation can be used for other medical&#xD;
      interventions involving bone healing. The research question is as follows: among patients&#xD;
      undergoing surgical extraction of wisdom teeth, to what extent does a morning doses of&#xD;
      ibuprofen 400 mg, in comparison to a routine dose schedule of three times per day, decrease&#xD;
      patients' pain and improve wound healing when taken for three days after surgery .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 19, 2018</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2021</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Parallel Assignment a single-center double-blind randomized controlled trial</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>The treatment regimens were masked for both participants and care provider (Clinical investigator)</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Pain Measurement</measure>
    <time_frame>four days measurement of VAS</time_frame>
    <description>Measuring of post operative pain severity according to Visual Analogue Scale healing indicators such as edema and mouth opening .</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammation Degree Measurement</measure>
    <time_frame>Pre-Op, 4th day after operation</time_frame>
    <description>Inflammation Degree by measuring C-reactive Protein (CRP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Facial Swelling and mouth opening measuring</measure>
    <time_frame>pre-op, 4th day post op.</time_frame>
    <description>Facial Swelling will be measured according to LASKIN method</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">70</enrollment>
  <condition>Operation Site Inflammation</condition>
  <condition>Pain, Postoperative</condition>
  <condition>Teeth, Impacted</condition>
  <arm_group>
    <arm_group_label>Surgical with conventional NSAID 3 times/day</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control group will have surgical intervention to remove wisdom tooth and receive conventional NSAID treatment three times per day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Surgical with conventional NSAID 2 times/days</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The experimental group will have surgival intervention to remove wisdom tooth and receive NSAID treatment only two times per day: once after breakfast and once after lunch, but not at night.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ibuprofen 400 mg</intervention_name>
    <description>Surgical removal of wisdom teethb with different regimen of Ibuprofen frequency ; three times versus two times .</description>
    <arm_group_label>Surgical with conventional NSAID 2 times/days</arm_group_label>
    <arm_group_label>Surgical with conventional NSAID 3 times/day</arm_group_label>
    <other_name>Advil</other_name>
    <other_name>Motrin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        (i) be aged between 18 and 35 years old&#xD;
&#xD;
        (ii) be healthy according to the American Society of Anesthesiologists (ASA) classification&#xD;
        (subject should not have an active infection, trismus, hyperthermia, or swelling before&#xD;
        surgery and must be able to maintain adequate oral hygiene)&#xD;
&#xD;
        (iii) have an adequate understanding of written and spoken English or Arabic to fill out a&#xD;
        questionnaire,&#xD;
&#xD;
        (iv) be capable of signing an informed consent form&#xD;
&#xD;
        (vi) third molar surgical extraction, the indicated teeth should be lower third molars and&#xD;
        partially or completely impacted&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        (i) have a history of systemic diseases (e.g., diabetes mellitus, hypertension, gastric&#xD;
        ulcer)&#xD;
&#xD;
        (ii) have a severe/serious illness that requires frequent hospitalization&#xD;
&#xD;
        (iii) are current smokers&#xD;
&#xD;
        (iv) are pregnant or breastfeeding&#xD;
&#xD;
        (v) are taking antinflammtory or analgesic drugs in the previous two weeks or are allergic&#xD;
        to NSAIDs&#xD;
&#xD;
        (vi) have impaired cognitive or motor function&#xD;
&#xD;
        (vii) are unable to return for evaluations/study recalls.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zaid Z Tamimi, HSD</last_name>
    <role>Principal Investigator</role>
    <affiliation>JUST</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zaid Z Tamimi, HSD</last_name>
    <phone>00962795036670</phone>
    <email>zztamimi@just.edu.jo</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ala M Abu Roqaa, M.SC.</last_name>
    <phone>00962795052394</phone>
    <email>director@interpharma-1.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Jordan University of Science and Technology</name>
      <address>
        <city>Irbid</city>
        <country>Jordan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zaid Z Tamimi, HSD</last_name>
      <phone>00962795036670</phone>
      <email>zztamimi@just.edu.jo</email>
    </contact>
    <contact_backup>
      <last_name>Ala M Abu Roqaa, M.SC.</last_name>
      <phone>00962795052394</phone>
      <email>director@interpharma-1.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Jordan</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 23, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <last_update_submitted>August 24, 2021</last_update_submitted>
  <last_update_submitted_qc>August 24, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tooth, Impacted</mesh_term>
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Pain, Postoperative</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ibuprofen</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>data will be provided upon request or required for publication .</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03789058
org study id: 20170307
nct id: NCT03789058
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Clinical and preclinical studies have demonstrated encouraging results of non-steroidal
      anti-inflammatory drug (NSAID) chronotherapy in the management and treatment of inflammatory
      diseases such as rheumatoid arthritis. However, no previous clinical trials have addressed
      how the timing of NSAID administration within the day affects pain and healing outcomes after
      oral surgery that involves bone removal, such as surgical extraction of the third molars.
      Methods to address our aim, Single-center double-blind randomized controlled trial study
      design has been adopted. Patients who needed a lower third molar extraction and meet the
      eligibility criteria will be recruited. Participants will be randomized into two groups.
      Subjects in group one will be instructed to take an NSAID (ibuprofen 400 mg) at 7 AM and 12
      PM combined with a placebo before bed between 8 and 10 PM for three days postoperatively.
      Subjects in group 2 will be instructed to take an NSAID (ibuprofen 400 mg) between 7 AM, 12
      PM and between 8 and 10 PM for three days postoperatively. The patients' self-reported pain
      in the three days after surgery will be recorded as the primary outcome.

      Additionally, healing indicators such as the maximum interincisal distance and measurements
      of facial swelling will be recorded preoperatively and four days postoperatively. Each
      participant's blood level of C-reactive protein will be recorded pre- and postoperatively as
      an inflammatory marker.

      Discussion:

      The study will estimate the effect of using NSAID only in the morning following surgical
      extraction of the third molar to decrease pain and improve postoperative healing and recovery
      in comparison to the routine use of NSAIDs three times per day.
Introduction and background:

      The surgical extraction of wisdom teeth under local anesthesia is one of the most common oral
      surgical procedures (1). Ten million third molars (wisdom teeth) are extracted from
      approximately 5 million people in the United States of America each year at an annual cost of
      over $3 billion. Additionally, more than 11 million patient-days of "standard discomfort or
      disability" were reported due to surgical removal of wisdom teeth, with an average of 4.9
      lost work days per procedure (2, 3). Most of wisdom teeth surgical extractions require bone
      removal (4). Bone removal is associated with a broad range of postoperative discomfort and
      complications (e.g., pain, swelling, bruising, and malaise). Most of these complications are
      initiated by the inflammatory process from traumatic injury to the bone during the surgery.
      Currently, postoperative pain management is limited to acetaminophen, opioids and NSAIDs (5,
      6). However, these drugs are all problematics. Acetaminophen is not effective in managing
      severe pain (6). Opioids and NSAID are effective in pain management, but opioids can cause
      constipation and addiction (7, 8), While NSAIDs may delay bone healing (9, 10). Dentists and
      maxillofacial surgeons all over the world prefer to prescribe NSAID after this type of
      surgery (11). The mechanism of action of NSAIDs is the reversible inhibition of the enzyme
      cyclooxygenase (COX), which is believed to be responsible for the synthesis of prostaglandins
      (PGs) (10). Prostaglandins play a major role in inflammatory and nociceptive processes (12).
      Two isoforms of COX, namely, COX-1 and COX-2, are responsible for the synthesis of PG from
      arachidonic acid (AA). Both have essential roles in the inflammatory process after bone
      surgery, but COX-1 is involved more in the integrity of the gastrointestinal tract and renal
      tract tissue, while COX-2 is mainly involved in the inflammatory and healing process later
      (13). NSAIDs are either nonselective (inhibiting both COX-1 and COX-2) or selective
      (inhibiting COX-2 only). Ibuprofen is a peripherally acting analgesic with potent
      anti-inflammatory action that works through reversible and balanced COX-1/ COX-2 inhibition,
      which provides faster and more effective analgesia than many other NSAIDs without any
      apparent increased safety risk (14). Ibuprofen is routinely used in the treatment of moderate
      to severe acute pain in the general population, including dantal pain (15-17). Results from
      Cochrane systematic reviews demonstrate that higher doses and frequencies of NSAID use are
      associated with better pain control after dental (wisdom tooth extraction) and non-dental
      surgeries (9, 18, 19). Increasing the dose and frequency of NSAIDs was associated with an
      increased risk of adverse effects. Despite the promising results associated with the use of
      different NSAIDs for pain control after wisdom tooth surgeries, patients still report pain
      and other discomfort indicators such as swelling and trismus, especially during the first
      three days after the procedure (20). These symptoms can affect patient's life, including
      activities of daily living and even quality of life (3, 20-22). Animal studies suggest that
      NSAID affect bone healing outcomes such as biomechanical measuments and number of bones with
      non-unions (23-35). Some authors have even compared the effect of NSAIDs on fracture healing
      with those of other pharmacological agents such as steroids (36, 37). Høgevold et al,
      demonstrated that short-term administration of some anti-inflammatories, such as
      indomethacin, inhibits fracture healing, while methylprednisolone does not (36).
      Bhattacharyya et al. reported that patients receiving NSAIDs within 90 days after fracture
      had a 3.7-fold risk of nonunion, while the risk for opioid users was 1.6-fold (38). Clinical
      trials in humans pose some challenges, especially the need to control confounders such as
      smoking, diabetes, obesity and other factors that are associated with the healing of
      long-bone fractures (6, 39). Four retrospective studies suggested that patients using NSAIDs
      after fracture had a higher incidence of non-union compared to those that did not use NSAIDs
      (38, 40-42). All living organisms possess a circadian rhythm that anticipates the response to
      changes during the 24-hour cycle (43). The circadian system in mammals is composed of a
      central clock within the suprachiasmatic nuclei and a peripheral clock inside all cells. The
      circadian clock is controlled through a feedback loop featuring a heterodimer of two core
      clock gene products: circadian locomotor output cycles kaput (Clock) and brain and muscle
      Arnt-like protein-1 (Bmal1). Clock and Bmal1 drive the expression of two inhibitors,
      cryptochrome (Cry) and period (Per) (44). This molecular clock modulates the immune response
      and bone healing process (44). The circadian rhythms in the expression of various cytokines
      by immune cells are presented in Table S1. Macrophage activity, leukocyte recruitment, and
      proinflammtory mediators such as interleukin-1β (IL-1β), IL-6, and IL-12 increased at the
      beginning of the daily activity phase.

      During the active phase, there are also increased levels of Toll-like receptors TLR9 and
      TLR4, which upregulate the expression of CCL2, CXCL1, and CCL5, leading to leukocyte
      recruitment and potential tissue damage at the injured site (43-46)(Fig.1.). On the other
      hand, anti-inflammatory mediators and other growth and angiogenesis factors, such as vascular
      endothelial growth factor (VEGF), peak during the resting phase (44, 47, 48) (Table S2.). The
      24-hour circadian rhythm oscillation occur in bone tissue during growth (49), formation,
      resorption (50, 51), and endochondral ossification during fracture bone healing (51).
      Experimental studies in rodents and humans reveal that disruption of sleep and circadian
      rhythm impair bone formation (52). All bone cells such as osteoblasts, osteoclasts, and
      chondrocytes express clock genes that influence bone volume regulation, such as Per or Cry
      (53, 54). The circadian clock also affects pain, with sensitivity peaking during the active
      phase (55). Part of the pain response oscillation could be explained by changes in COX-1 and
      COX-2 activity throughout the day (56), especially after an injury or insult (57). These
      variations may contribute to the clinical evidence of circadian and circannual variations in
      the pharmacokinetics effects of NSAID. Specifically, maximum absorption and effectiveness are
      achieved when the drug is administered during the active phase (58-62). We performed
      experimental studies to estimate the extent to which the timing of NSAID doses can affect
      animal pain behaviour and recovery after bone fracture surgery. We used a validated model of
      fracture healing in young female mice. The results showed that administration of NSAIDs
      during the active phase after tibia fracture surgery, compared to administration during the
      resting phase, significantly attenuated the pain response and improved the mechanical and
      histomorphometric properties of the healing callus. Recent evidence suggests that the timing
      of skin wounds or surgery affects healing and postoperative recovery after cardiovascular
      surgeries (63, 64). The chronotherapeutic use of anti-inflammatory medications after oral
      surgeries is of clinical importance, especially with increasing evidence regarding the
      clinical efficacy of this approach in medicine. No clinical studies have investigated the
      effectiveness of this approach after minor oral surgeries. Expected contribution and research
      question The overarching aim of this study is to contribute evidence regarding the efficacy
      of NSAID chronotherapy in patient recovery from wisdom tooth surgery. This is an important
      aim considering that the outcomes of this investigation can be used for other medical
      interventions involving bone healing. The research question is as follows: among patients
      undergoing surgical extraction of wisdom teeth, to what extent does a morning doses of
      ibuprofen 400 mg, in comparison to a routine dose schedule of three times per day, decrease
      patients' pain and improve wound healing when taken for three days after surgery .
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Parallel Assignment a single-center double-blind randomized controlled trial
primary purpose: Supportive Care
masking: Double (Participant, Care Provider)
masking description: The treatment regimens were masked for both participants and care provider (Clinical investigator)
measure: Pain Measurement
time frame: four days measurement of VAS
description: Measuring of post operative pain severity according to Visual Analogue Scale healing indicators such as edema and mouth opening .
measure: Inflammation Degree Measurement
time frame: Pre-Op, 4th day after operation
description: Inflammation Degree by measuring C-reactive Protein (CRP)
measure: Facial Swelling and mouth opening measuring
time frame: pre-op, 4th day post op.
description: Facial Swelling will be measured according to LASKIN method
arm group label: Surgical with conventional NSAID 3 times/day
arm group type: Active Comparator
description: Control group will have surgical intervention to remove wisdom tooth and receive conventional NSAID treatment three times per day
arm group label: Surgical with conventional NSAID 2 times/days
arm group type: Experimental
description: The experimental group will have surgival intervention to remove wisdom tooth and receive NSAID treatment only two times per day: once after breakfast and once after lunch, but not at night.
intervention type: Drug
intervention name: Ibuprofen 400 mg
description: Surgical removal of wisdom teethb with different regimen of Ibuprofen frequency ; three times versus two times .
arm group label: Surgical with conventional NSAID 2 times/days
arm group label: Surgical with conventional NSAID 3 times/day
other name: Advil
other name: Motrin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Zaid Z Tamimi, HSD
role: Principal Investigator
affiliation: JUST
last name: Zaid Z Tamimi, HSD
phone: 00962795036670
email: zztamimi@just.edu.jo
last name: Ala M Abu Roqaa, M.SC.
phone: 00962795052394
email: director@interpharma-1.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Jordan
responsible party type: Sponsor
mesh term: Tooth, Impacted
mesh term: Inflammation
mesh term: Pain, Postoperative
mesh term: Ibuprofen
sharing ipd: No
ipd description: data will be provided upon request or required for publication .