Analgesic Preoperative/Postoperative Dexketoprofen Trometamol in Third Molar Surgery
Condition: Postoperative Pain
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of the present investigation is to evaluate the effectiveness of the preoperative
      administration of Dexketoprofen Trometamol, employing the third molar surgery model, when
      compared to postoperative administration of the same drug. It was hypothesized that
      preoperative oral Dexketoprofen trometamol will reduce the intensity of pain by 30% after 8
      hours of the surgery, when compared with post-operative administration.
    

Detailed description: 
      MODEL OF SURGICAL REMOVAL OF TOOTH IMPACTION. The model of Dental Impaction Pain Model (DIPM)
      is the most utilized of all the acute pain models. Its popularity is due to a
      well-established, well-validated, and extensively used postsurgery pain model in assessing
      the efficacy of analgesics on inflammatory pain.

      The surgical procedure is very standardized and surgery require either minimal or nothing use
      of CNS depressant anesthetics. The methodology is similar to other models of acute pain;
      however, the DIPM is much more versatile than most other models. The model can be easily
      adapted to carry out studies of multiple-dose, pharmacokinetics / pharmacodynamics,
      preventive interventions and analgesic efficacy

      The impacted lower third molar extraction involves the manipulation of hard and soft tissue,
      making the patient undergoes a series of effects which include acute pain, inflammation and
      trismus in the immediate postoperative period and goes from 24 to 72 postoperative hours. The
      pain associated with the surgical removal of a third molar is moderate to severe, increasing
      with greater intensity during the first 24 hours after surgery with spikes of pain between
      the first six to eight hours when using a conventional local anesthetic.

      In this context, the control of pain and inflammation post-surgical associated with third
      molar removal has been very varied; highlighting the use of anti-inflammatory pain relievers
      non (NSAIDs) and some opioids.

      PAIN. Pain is defined as the perception of a potentially injurious stimulus; which jointly to
      several not pleasurable experiences (sensory, emotional and cognitive), same that are caused
      by tissue damage (actual, potential or described in terms of such damage) and manifested by
      certain reactions physiological, autonomic and behavioral. Pain is typically classified as
      either acute or chronic.

      Acute pain: is of sudden onset and is usually the result of a clearly defined cause such as
      an injury. The acute pain includes the estimated time as necessary so that the tissues heal,
      as described by John Bonica in 1953, usually in the span of a month, according to the
      Committee of taxonomy of the pains of IASP, the length limit for a sharp pain is three
      months, however should be noted that there are authors who continue classifying pain acute
      with a duration of up to 6 months.

      Chronic pain: is defined as pain that lasts more than 12 weeks, or the one that according to
      the characteristics of their origin, exceeds time which could usually be defined a similar
      pain. It is accompanied by psychological commitment to important behavior disorders that can
      lead to depressive states; depending on the individual baseline emotional.

      Although it can also be classified according to their structure (somatic or visceral) origin
      and physiological mechanism (nociceptive or neuropathic).

      The scheme to perceive pain needs: a) a peripheral structure that acts as a receiver; b) a
      synapse in the spinal cord, c) pathways from spinal cord to superiority centers and d)
      descending pathways from the superiority center to the marrow, which act as mainly inhibitory
      mechanisms but also facilitated by change of neurotransmitters .

      The study of the neurophysiology of pain has been an important advance in the knowledge of
      the mechanism of the painful stimulus in the perioperative period describing a dynamic system
      where multiple input have a place nociceptive, which conditions the first stage of peripheral
      awareness that amplifies transmission of stimulation to condition a second tier of central
      sensitization to keep in time.

      MEASUREMENT OF PAIN. Clinicians and researchers have recognized that pain is a
      multidimensional experience, which includes a number of qualities or measurable elements as
      intensity, involvement, sensory quality, quality spatial (location), temporary quality, and
      the impact on daily activities. While the focus on the measurement of pain remain in the
      intensity, there has been an increase in the interest of measure other elements of pain.

      PAIN INTENSITY SCALES. The domain of pain used in clinical studies and research is the
      intensity of the pain. The three scales used to measure the intensity of pain are: a) visual
      analog (VAS scale), b) the scale of numeric value (NRS) and c) the verbal value (VRS).

      STRATEGIES IN THE MANAGEMENT OF DENTAL PAIN.

      In dental practice pain of moderate to severe intensity conditions are usually treated with
      Nonstereoidal anti-inflammatory (NSAIDs) drug, although there are other different types of
      drugs used for this purpose that are described below:

        -  NASAIDs are a class of drugs that provides analgesic and antipyretic effects. Since they
           have a mechanism of action in common based on the inhibition of cyclooxygenase (COX)
           enzyme responsible for the biosynthesis of prostaglandins and general of Eicosanoids.
           Unfortunately, prostaglandins mediate other physiological functions that cause
           undesirables adverse effects.

        -  New inhibitors of COX show great power and analgesic effectiveness and are better at
           reducing the incidence of adverse effects compared to the classic AINE´S.

      DEXKETOPROFEN TROMETAMOL. Dexketoprofen is a new anti-inflammatory drug non-steroidal (NSAID)
      belonging to the family of the arylpropionic acid derivatives. Dexketoprofen is the
      enantiomer S (+) of the composite ketoprofen, a drug with analgesic effects and
      anti-inflammatory clearly documented.

      Dexketoprofen has been developed (dexketoprofen trometamol) tromethamine salt as a
      formulation with a higher than the free acid aqueous solubility. Pharmacokinetic studies
      performed in healthy individuals showed that oral administration of dexketoprofen trometamol
      presented a kinetic favorable profile for use in acute pain compared to the formulation of
      free acid or racemic ketoprofen.

      Dexketoprofen trometamol, is one of the most powerful inhibitors of prostaglandin synthesis
      "in vitro". 12.5-25 mg orally is given with a quickly absorbed on an empty stomach, which has
      a strong binding to albumin and inactive metabolites after glucuronization renal excretion.
      It is well accumulate in synovial fluid and its analgesic potency is comparable to 50 mg of
      ketoprofen or diclofenac and more than 600 mg of ibuprofen, so its main indication is acute
      postoperative pain.

      The production of a unique isomer of ketoprofen formulation simplifies the pharmacokinetics
      of the drug and allows a reduction of 50% in the dose. This can reduce adverse effects to
      reduce the metabolic and renal work, rapid absorption appears to offer some protection
      against gastrointestinal complications as a method to avoid gastrointestinal toxicity
      different of the selectivity of COX presents a good profile of security and reported adverse
      effects are similar to placebo in these studies, the uniqueness of the therapeutic profile of
      the DKP.TRIS could be the result of a combination of factors which include the higher power
      as it is given only the active molecule, inhibition of COX two isoenzymes, rapid absorption
      from the gastrointestinal tract and high capacity to enter the CNS.

      PREVENTIVE ANALGESIA. Preventive analgesia (PA) is an antinociceptive treatment which
      prevents the establishment of the altered processing of the sensory input, that amplifies and
      chronic postoperative pain. The PA concept was formulated by Crile at the beginning of the
      century on the basis of clinical observations. There are two terms in English which refer to
      the same concept: preemptive analgesia, which consists of a treatment that is given before
      the surgical incision and maintained for intervention to avoid an altered sensory processing
      that amplifies and chronic postoperative pain. Is usually to compare the same way and the
      same drug management before and after the incision; and preventive analgesia consists of a
      longer lasting analgesic effect which that would theoretically be expected after
      administration of a certain drug on the basis of its pharmacological properties.

      In oral surgery, primary hyperalgesia is the awareness of the receivers of the mucosa and the
      periosteum by a range of mediators of inflammation such as prostaglandins. Secondary
      hyperalgesia is central sensitization of neurons in the nucleus trigeminal and spinal supra
      structures. Secondary hyperalgesia can be observed over the time, while the primary
      hyperalgesia is provable within a few hours after the injury; Prostaglandins are synthesized
      quickly after damage to the tissue and appear in significant concentrations 1 hour after
      trauma.

      The concept of preventive analgesia is based on the prior administration to the surgical
      incision of a painkiller to dampen or prevent phenomena of hypersensitisation central in
      order to reduce the consumption of analgesics in the postoperative period.

      WORK PLAN. Using a format in which specify the inclusion and exclusion criteria, the
      selection of the patients will be held, during this visit will also fill the form of
      demographic data, status of the patient, current condition, medical history, physical
      examination, x-ray and diagnostic studies. See annex 3.

      Then patients will be randomized distributed in two groups of participants, group 1 and 2:

      Experimental drugs. The randomized patient is determined to a group according with the
      administration of the drug in two groups.

      GROUP 1 Oral administration of dexketoprofen Trometamol 25 mg, 30 minutes before the
      beginning of surgery and administered immediately at the end of the same placebo.

      GROUP 2 The placebo is oral administered 30 minutes before the beginning of surgery and
      administered immediately at the end of the same dexketoprofen Trometamol 25 mg.

      Surgical procedure. All surgeries will be performed by the same surgeon, to achieve a local
      anesthetic effect, a previous asepsis and antisepsis of the area will be necessary. The lower
      alveolar nerve with reinforcement of the lingual nerve and long buccal nerve using 2
      cartridges of lidocaine with epinephrine 2% with a concentration of 1:100 ml.

      Once the anaesthetic effect is present, surgery can be performed, a flap of total thickness
      of mucoperiosteal will be made, using a triangular incision design liberating the tissue at
      the level of the second mandibular molar, subsequently the third molar extraction will be
      performed. Finally the reposition of the flap and suturing will be made using black silk
      suture (3-0).

      In all cases the duration of the surgery procedure will be registered in every step. see
      annex 4.

      Measurement of the variables. Intensity of pain. For both groups, a measure will be performed
      between the distance in mm from point 0 to the point that the patient indicates; with the
      understanding that the point represents the intensity of the pain using the NRS, values were
      registered in the NRS scale of each patient. This procedure will beginning after the second
      intake of the drug or placebo (basal), after 8 hours (8-NRS), 24 hours, 48 hours and 72 hours
      post operatory.

      Time to remedication. The time in minutes that the patient request remedication with
      dexketoprofen, registering again the intensity of pain will be registered.

      Total of tablets consumed. The number of tablets consumed in the 72 hrs of the postoperative
      will be recorded. The dosage of dexketoprofen 25mg will be standardized for every 8 hours,
      and not to exceed 75mg every 24 hours until the patient deems necessary.

      The antibiotic used in the clinical trial will be:

      Clindamycin 300 mg every 8 hrs for 5 days. After 7 days of postoperative evolution, the
      patient will return to the clinic for removal of stitches, evaluating the operative area and
      general health condition, with this step, the attention will be concluded for the surgical
      procedure and the medical discharge will be indicated.
    

Intervention name(s): Dexketoprofen trometamol; Preoperative control
Intervention type(s): Drug; Drug
Intervention description(s): White round pill containing 25mg of Dexketoprofen will be administered either prior/after to third molar surgery.; white round pill containing 25mg of placebo will be administered prior/after to third molar surgery. The placebo pill is identical to active dexketoprofen, in size and color
Other intervention name(s): Enantyum; Miracox; Placebo
Intervention MeSH terms: Dexketoprofen trometamol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Postoperative pain; Dexketoprofen trometamol; third molar surgery