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British Journal of Anaesthesia - current issue

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  1. Development and characterisation of novel fentanyl-delta opioid receptor antagonist based bivalent ligands
    Background

    Opioid tolerance is a limiting factor in chronic pain. Delta opioid peptide (DOP)() receptor antagonism has been shown to reduce tolerance. Here, the common clinical mu opioid peptide (MOP)(µ) receptor agonist fentanyl has been linked to the DOP antagonist Dmt-Tic (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydrisoquinoline-3-carboxylic acid) to create new bivalent compounds.

    Methods

    Binding affinities of bivalents(#9, #10, #11, #12 and #13) were measured in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, Kappa opioid peptide (KOP)() and nociceptin/orphanin FQ opioid peptide (NOP) receptors. Functional studies, measuring GTP[35S] or β-arrestin recruitment, were performed in membranes or whole cells respectively expressing MOP and DOP.

    Results

    The new bivalents bound to MOP (pKi : #9:7.31; #10:7.58; #11:7.91; #12:7.94; #13:8.03) and DOP (#9:8.03; #10:8.16; #11:8.17; #12:9.67; #13:9.71). In GTP[35S] functional assays, compounds #9(pEC50:6.74; intrinsic activity:0.05) #10(7.13;0.34) and #11(7.52;0.27) showed weak partial agonist activity at MOP. Compounds #12 and #13, with longer linkers, showed no functional activity at MOP. In antagonist assays at MOP, compounds #9 (pKb:6.87), #10(7.55) #11(7.81) #12(6.91) and #13(7.05) all reversed the effects of fentanyl. At DOP, all compounds showed antagonist affinity (#9:6.85; #10:8.06; #11:8.11; #12:9.42; #13:9.00), reversing the effects of DPDPE ([D-Pen2,5]enkephalin). In β-arrestin assays, compared with fentanyl (with response at maximum concentration (RMC):13.62), all compounds showed reduced ability to activate β-arrestin (#9 RMC:1.58; #10:2.72; #11:2.40; #12:1.29; #13:1.58). Compared with fentanyl, the intrinsic activity was: #9:0.12; #10:0.20; #11:0.18; #12:0.09 and #13:0.12.

    Conclusions

    The addition of a linker between fentanyl and Dmt-Tic did not alter the ability to bind to MOP and DOP, however a substantial loss in MOP functional activity was apparent. This highlights the difficulty in multifunctional opioid development.

  2. Postoperative pain after laparoscopic cholecystectomy is not reduced by intraoperative analgesia guided by analgesia nociception index (ANI(R)) monitoring: a randomized clinical trial
    Background

    Laparoscopic cholecystectomy frequently results in significant immediate postoperative pain. A new pain monitor, analgesic nociception index (ANI®), based on heart rate variability, has recently been approved for intraoperative nociception monitoring. We designed a single-blind, parallel-group, randomized control trial to test the hypothesis that protocol-driven intraoperative analgesia guided by ANI during laparoscopic cholecystectomy would improve titration of intraoperative analgesics leading to decreased postoperative pain.

    Methods

    One hundred and twenty consecutive adult participants presenting for elective laparoscopic cholecystectomy were recruited. Participants were randomly allocated by sealed envelope to receive intraoperative morphine either guided by ANI via a protocol (intervention group) or guided by the anaesthetist with ANI concealed (control group). All participants received paracetamol, parecoxib, fentanyl at induction, and local anaesthetic to port sites. The primary endpoint was the presence of moderate/severe pain (visual analogue scale ≥50 mm) at any of the four time points in the first postoperative hour. Secondary endpoints included postoperative rescue morphine.

    Results

    Sixty participants were randomized to each group, and all but one drop-out from the intervention group were analysed. The usage of ANI guidance did not result in a decrease in the rate of moderate/severe pain (50.8% vs 45.0%: difference of –5.8%, 95% confidence interval, –23.7% to 12.1%, P=0.58), or the use of postoperative rescue analgesia.

    Conclusions

    This randomized control trial of intraoperative ANI-guided morphine administration in elective laparoscopic cholecystectomy failed to show any advantage over the current standard of care, and demonstrated a high level of postoperative pain, despite the use of multimodal analgesia.

    Clinical trial registration

    ANZCTR Reference ACTRN12612000953831 (URL: http://www.anzctr.org.au/trial_view.aspx?ID=362949).

  3. Ambulatory Anesthesia, An Issue of Anesthesiology Clinics
  4. Essential Equations for Anaesthesia
  5. Oxford Textbook of Anaesthesia for the Elderly Patient
  6. Transcutaneous Electrical Nerve Stimulation (TENS). Research to support clinical practice
  7. PAIN Dynamics and Complexities
  8. Are the obese difficult to intubate?
  9. Perioperative management of severe anorexia nervosa
  10. Robotic assistance with needle guidance
  11. Need for development of face-to-face orotracheal intubation using direct (Macintosh) laryngoscopy
  12. Difficult decisions
  13. Do not resuscitate and the intensive care unit: time to talk
  14. Chlorhexidine allergy: sources of exposure in the health-care setting
  15. Usefulness of ultrasound in percutaneous tracheotomy