Analgesic Effect of Peripheral Dexmedetomidine
Condition: Third Molar Extraction
Study type: Interventional
Phase: Phase 3

Summary: 
      Dexmedetomidine is an alpha 2-adrenoreceptor agonist, which provides sedation, analgesia and
      anxiolysis in clinical practice (Cortinez et al., 2004,Hall et al., 2000). Three types of
      alpha 2-adrenergic receptor subtypes are found in the human body and they have been
      designated alpha 2A, alpha 2B and alpha 2C. The alpha 2A subtype is most likely responsible
      for the analgesic properties of dexmedetomidine in both peripheral and central sites (Kingery
      et al., 2000, Smith et al., 2001). Activation of central alpha 2-adrenoreceptors in the locus
      ceruleus (Correa-Sales et al., 1992) and the dorsal horn of the spinal cord (Gaumann et al.,
      1992b) are responsible for both analgesic and sedative effects. Dexmedetomidine has a very
      high alpha 2 to alpha 1 selectivity, 1620 to 1, or approximately 8 times that of clonidine.
      It is also 4 to 6 times more potent than clonidine by weight (Bhana et al., 2000).

      Although dexmedetomidine produces dose dependent sedation upon intravenous administration,
      its the analgesic effect is of dexmedetomidine is more variable and controversial. In an
      ischaemic pain model in healthy volunteers, a single bolus of dexmedetomidine produced a 50%
      reduction in pain scores when compared to placebo (Jaakola et al., 1991). In another
      volunteer study using the cold pressor test, dexmedetomidine 1 µg/kg over 10 minutes followed
      by an infusion of 0.2 to 0.6 µg/kg/hour reduced pain by approximately 30% (Hall et al.,
      2000). However, when administered as a target controlled infusion at concentrations ranging
      from 0.09 to 1.23 ng/mL, dexmedetomidine had no analgesic effect in human volunteers
      subjected to heat and electrical pain, although sedation was produced (Memis et al., 2004).

      Clonidine and dexmedetomidine are two common alpha 2 agonists used clinically. Although
      clonidine former has been used successfully in regional analgesia and anesthesia (Gabriel et
      al., 2001)., There are only very few studies evaluating the peripheral analgesic effects of
      dexmedetomidine. Since acute postoperative dental pain is a common analgesia model (Cooper,
      1991; US Food and Drug Administration 1992), the investigators conducted this study, aiming
      to assess the postoperative analgesic efficacy of peripheral dexmedetomidine after bilateral
      third molar surgery under general anaesthesia. The analgesic effects were compared up to the
      72nd hour postoperatively in order to evaluate any potential preventive analgesic effect.
    

Detailed description: 
      The study protocol was approved by our local Institutional Review Board and written consent
      was obtained from all the participants. Eligibility for recruitment included American Society
      of Anesthesiologists (ASA) physical status I and II, age between 18 and 50 years of age with
      4 bilateral impacted third molar teeth scheduled for extraction under general anaesthesia.
      Exclusion criteria included clinical history or electrocardiographic evidence of heart block,
      ischaemic heart disease, asthma, sleep apnoea syndrome, impaired liver or renal function,
      alcohol consumption in excess of 28 units per week, pregnancy, patient refusal, known
      psychiatric illness, chronic sedative or analgesic use, and regular use of or known allergy
      to dexmedetomidine, paracetamol or dextropropoxypheneopioids. Patients with preoperative
      inflammation at the site of surgery were also excluded.

      After obtaining written, informed consent, patients were randomly allocated to receive
      1)Preoperative IV dexmedetomidine 1mcg/kg and normal saline infiltrated to wound at the end
      of surgery; 2) Preoperative normal saline IV infusion and dexmedetomidine 1mcg/kg infiltrated
      to wound or 3) Preoperative IV normal saline infusion and normal saline infiltrated to wound
      at the end of surgery. A computer generated random sequence was used for drug allocation and
      this was prepared by a statistician who was unaware of the clinical nature of the study. The
      patients were assessed by the list anaesthetist the day before surgery. They were fasted for
      at least 6 hours and did not receive any premedication before arrival at the operation
      theatre. Patients were educated on the use of the Numerical Rating Scale (NRS) for pain
      assessment, where zero corresponds to no pain and 10 represents the worst pain imaginable.

      A P-deletion test was performed in the ward preoperatively. The P-deletionThis test consists
      of 58 lines of closely typed text containing between 74 to 97 occurrences of the letter "p".
      The patients are instructed to cross out every letter "p" they can find as quickly as
      possible, reading from left to right down the page. The number deleted in 180 seconds and the
      number of errors counts. This test assesses speed, accuracy, concentration, mental activity,
      hand-eye coordination and vigilance. It was firstly described by Dixon and colleagues who
      found it to be an accurate test for psychomotor recovery from anesthesia and sedation (Dixon
      et al., 1973).

      On arrival at the operating theatre, a 20-gauge intravenous cannula was inserted in the
      dorsum of each patient's left hand. Either dexmedetomidine 1 µg/kg (Group D) diluted to 4ml
      with normal saline or the same volume of 0.9% saline alone (Group P) was prepared by another
      anaesthetist who did not participate in patient management or data collection. Both
      preparations were clear solutions, therefore patients, medical, nursing staff, and data
      collectors were all blinded to the allocated drug. Heart rate, blood pressure, respiratory
      rate and oxygen saturation were recorded (S/5 Anesthesia Monitor, Datex-Ohmeda, WI, USA)
      before general anaesthesia and thereafter at five-minute intervals from the time of
      commencing surgery until discharge from the recovery room.

      Induction and maintenance of anaesthesia were done according to a standard protocol.
      Anaesthesia was induced with propofol titration of 2 to 3 mg/kg, fentanyl 1 µg/kg and muscle
      relaxation was achieved with rocuronium 1 mg/kg. The trachea was intubated via the nasal
      route. General anaesthesia was maintained with a mixture of air, oxygen and sevoflurane at 1
      to 1.5 MAC. Before the start of the surgical procedures, regional anaesthesia were performed
      by infiltrating 2.7 mL of 2% lignocaine with 1 in 80,000 adrenaline around the base of the
      gum of each third molar by the same team of dental surgeons. Sevoflurane was stopped when the
      last suture had been inserted. andVolume of 1 ml of either dexmedetomidine (Group D, totally
      dexmedetomidine 1 µg/kg for 4 surgical sites) or saline (Group P) was infiltrated to the
      submucosa of each surgical site. Neuromuscular block was antagonized with neostigmine 50
      µg/kg and atropine 20 µg/kg, and followed by extubation after recovery of consciousness. The
      patients were then monitored in the recovery room for at least 30 minutes. Resting pain
      scores, blood pressure, heart rate, oxygen saturation and the Ramsay sedation score (RSS)
      (appendix 1) were assessed and recorded every 5 minutes. Intravenous ketorolac or morphine
      would be administered upon patients' request. Patients were transferred back to the general
      ward when fully consciousness with normal physiological parameters.

      The P-deletion test was repeated hourly from the first postoperative hour in the general ward
      until the performance reached the same level as that before surgery. Blood pressure, heart
      rate, oxygen saturation, and RSS were monitored hourly for 4 hours. NRS pain scores were
      charted hourly for 6 hours then 4-hourly thereafter. Patients were prescribed two analgesic
      tablets, each containing paracetamol 320 mg and dextropropoxyphene 32.5 mg (Dolpocetmol®,
      Synco Limited, Hong Kong, China), on an as required basis to a maximum of four times daily.
      The patients were explained told that the pain medications prescribed could be taken if the
      postoperative NRS pain score was more than 3.

      Final hospital discharge was at the discretion of the attending dental surgeon. The oral
      analgesic medication described above was prescribed for three days postoperatively and
      patients were given aA diary was given to our patients. diary to record NRS pain scores at
      rest and upon mouth opening, analgesic consumption and side effects were self recorded by
      each patient up to the 72nd hour postoperatively. Global pain satisfaction using NRS (zero
      being least satisfied and 10 being most satisfied) was recorded on postoperative day 3.

      By considering a difference of 2 units in NRS pain scores to be clinically significant, and
      an estimated standard deviation of 2.5 units among patients, we calculated that a sample size
      of 30 per group would give an 80% power of the test at the 5% level of significance. In order
      to account for possible dropouts due to protocol violation or missing data, 35 patients were
      recruited in each group. Statistical analysis was performed using SPSS 14.0 for Windows (SPSS
      Inc., IL, USA). NRS pain scores, analgesic consumption, NRS global pain satisfaction and the
      difference in pre- and post-operative P-deletion scores were compared using the Mann-Whitney
      U test. Perioperative vital signs and NRS pain scores up to the 72nd postoperative 72nd hour
      were plotted graphically using GraphPad Prism 4.03 (GraphPad Software Inc., CA, USA) and the
      mean area under the curve AUC were compared between groups using the Mann Whitney U test. All
      categorical data were analyzed using χ2 test. Time to first analgesic use was compared using
      the log-rank test in Kaplan-Meier survival analysis. The incidence of side effects was
      analyzed by χ2 test or Fisher's exact test as appropriate.
    

Intervention name(s): local dexmedetomidine; Peripheral normal saline; IV dexmedetomidine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Preoperative normal saline infusion and 1mcg/kg dexmedetomidine infiltrated locally to wound at the end of operation.; Same volume of normal saline as dexmedetomidine is infiltrated and IV infusion.; IV dexmedetomidine 1mcg/kg peroperative and normal saline infiltrated to wound at the end of operation
Other intervention name(s): Precedex
Intervention MeSH terms: Dexmedetomidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Analgesia; Dental pain; Dexmedetomidine; Pain; Peripheral effects