The Application Of Drug Combination For Pain Treatment

Part I Therapeutic effect of dezocine on morphine tolerance and involvement of opioid receptors expression in a bone cancer pain rat modelObjective The combination of morphine with opioid receptor agonists-antagonists is commonly used in clinical practice, but there is still large controversy over the effect. We aimed to investigate the analgesic efficacy and tolerance of dezocine in combination with morphine for rats with bone cancer pain.Methods A bone cancer pain model was made by inoculation of Walker 256 cells into the intramedullary space of rat tibia. Model rats were selected and randomly divided into six groups (n= 8 for each) based on different drug administrations. Morphine and/or dezocine or saline were subcutaneously given twice daily (at 7:30 am and 7:30 pm, respectively) for seven consecutive days:group M (mophine 10 mg/kg), group D1 (dezocine 10 mg/kg), group D2 (dezocine 1 mg/kg), group MD1 (morphine 10 mg/kg+dezocine 10 mg/kg), group MD2(morphine 10 mg+dezocine 1 mg) and group control (isotonic saline 1 mL). All rats underwent thermal pain threshold measurement 30min after drug adminstration at 7:30 pm by an experimenter who was blinded to animal grouping every day. To clarify the mechanisms underlying these distinct analgesic profiles, RT-PCR and western blot analysis examined the expression of opioid receptors’mRNA and protein levels in Periaqueductal gray and dorsal horn of lumbosacral spinal cord.Results1.The analgesic effect was significantly decrease after 4 days drug administration in group M. There were no obvious analgesic decrease in other groups.2.During the first four days, the pain threshold of rats in group M was significantly higher than those in group D1, D2 and group MD1 while no significant difference with that in group MD2 after drugs administration. Since day 5, the thermal pain threshold of group MD2 was significantly higher than that in goup M.3.The expression of opioid receptors’ mRNA and protein levels in periaqueductal gray and dorsal horn of lumbosacral spinal cord showed different changes in groups, including:1) Downregulated of μ-opioid receptors’(MOR) mRNA and protein, downregulated of delta-opioid receptors’(DOR) protein in periaqueductal gray, uprugulated of MOR’s, kappa-opioid receptors’(KOR) and DOR’s protein in dorsal horn of lumbosacral spinal cord of group M.2) The mRNA and protein of MOR were both upregulated in periaqueductal gray of group MD2.3) The mRNA and protein of KOR were both downregulated of in periaqueductal gray and dorsal horn of lumbosacral spinal cord of group MD2 compared with morphine alone.Conclusions Morphine could lead to obvious tolerance in the treatment of bone cancer pain in rats and dezocine alone would not lead to significant tolerance. Low-dose dezocine could prevent morphine tolerance and would not decrease the ananlgesic effect of morphine. Changes of opioid receptors in periaqueductal gray and dorsal horn of lumbosacral spinal cord may be one of the machanisms.Part II The effect of dezocine in combination with morphine for postoperative analgesia of thoracotomyAbstractObjective:When morphine and dezocine are mixed together, the clinical interactions with analgesic effects and adverse events remain unknown. We aimed to investigate the efficacy of low-dose dezocine in combination with morphine for postoperative pain.Method This was a prospective, randomized, double-blinded clinical trial. One hundred patients undergoing thoracotomy were randomized into five groups to investigate the analgesic efficacy of different doses of dezocine in combination with morphine:morphine group(Group M); dezocine group 1 (group D1); dezocine group 2(group D2); dezocine+morphine group 1 (Group MD1); dezocine+morphine group 2 (Group MD2).Anesthesia induction:sulfentanil 0.2 u g·kg-1, propofol 1.5 mg·kg-1, rocronium0.6 mg·kg-1, intravenous injection. Anesthesia maintance:sulfentanil and sevoflurane were titrated to autonomic responses according to hemodynamics and BIS. The inspired sevoflurane concentration were control between 1.5-2.0%. Before the end of surgery,0.25mg palonosetron was given intravenously.Postoperative analgesia pump was used for 48h as the analgesic after surgery. The morphine group (Group M) received morphine alone for postoperative analgesia(morphine 0.5mg·kg-1·d-1); the dezocine group (Group D) received dezocine alone for postoperative analgesia(dezocine 0.5 mg·kg-1·d-1); the morphine +dezocine groups (Group MDs) received morphine combined with dezocine at different doses(Group MD1, morphine 0.25 mg·kg-1·d-1 +dezocine 0.25 mg·kg-1·d-1; Group MD2:morphine 0.5 mg·kg-1·d-1+dezocine 0.3 mg·kg-1·d-1; Group MD3:morphine 0.5 mg·kg-1·d-1+dezocine O1lmg·kg-1·d-1). Total volume of the analgesia pump was 100ml with a continuous rate of 2ml/h. If verbal rating score(VRS,1-10) was greater than 3, rescue morphine was initially titrated 3mg each time by follow-up doctors who blinded to group assignments until VRS<3. Rescue morphine consumption, VRS and adverse events were evaluated throughout a 48h postoperative period.Results Cumulative rescue morphine requirements were (1) statistically higher in Group M than in Group MD3 at 48 h after surgery and (2) statistically higher in Group D than Group M、MD1、MD2、MD3 at 24h and 48 h after surgery. Postoperative VRS for evaluating pain were similar among the five groups. The incidence of postoperative pruritus was statistically higher in Group M than in Group MD1、MD2、MD3 and D. The incidence of dizziness was significantly higher in Group MD2 than Group M. The incidences of nausea and vomiting were no significant differences among groups.Conclusions Compared with morphine alone, low-dose of dezocine combined with morphine may enhance postoperative analgesia after thoractomy while may lower the incidence of postoperative pruritus at the sametime.