Interaction Of Morphine And Ketamine For Analgesia In Patients With Moderate To Severe Acute Pain

BACKGROUND:Both ketamine（KTM）and morphine（Morp）have obvious analgesic effects,but the combination of low doses of ketamine and morphine optimum dose is still not clear.The study included moderate to severe acute pain patients observed different doses of ketamine and（or）morphine analgesic effect of active pain on the limbs,to understand the analgesic effect of the combination therapy to explore the 50%effective dose(ED₅₀)of ketamine and morphine analgesia,and to explore the interaction between the two drugs.METHODS:This study is divided into two parts:The First Part:Ninety-six patients with moderate to severe pain（NRS scores 5-10）aged 18-65 years and ASA I-II were included and divided into 8 groups with 12patients in each group.Each group received a single intravenous infusion ketamine0.04 mg/kg（KTM 1）,ketamine 0.08 mg/kg（KTM 2）,ketamine 0.15 mg/kg（KTM 3）,ketamine 0.30 mg/kg（KTM 4）,Morphine 0.05 mg/kg（Morp 1）,morphine 0.08mg/kg（Morp 2）,morphine 0.13 mg/kg（Morp 3）,and morphine 0.20 mg/kg（Morp 4）.The values of NRS（numerical rating scale）were calculated before administration（T0）,1 min（T 1）,5 min（T 2）,10 min（T 3）,20 min（T 4）,and 30 min（T 5）rating pain by numerical rating scale（NRS）,observe and record the relevant adverse reactions,such as respiratory depression,loss of consciousness,hallucinations and so on.Integrate pain scores at each time point,establish the time-dependence graph and use the area under curve（AUC）as a measure of the analgesic effect of the drug.The ratio of area above curve（AAC）to total area,which is analgesic effect of drug remission,and then establish their own dose-effect curve to calculate the ED50 of KTM and Morp.The Second Part:48 patients aged 18-65 years and ASA I-II limb fractures were divided into 4 groups（moderate and severe pain NRS scores）,and 12 patients were randomly assigned to each group.According to the concentration of KTMED50 and MorpED50,according to the pharmacological inhibition of pain after the combination of the theory of 10%,20%,40%,80%of the dose grouping,mixing 1:1 KTM&Morp:ED50add*1/10（K&M 1）,ED50add*2/10（K&M 2）,ED50add*4/10（K&M 3）,ED50add*_8/10（K&M 4）.The pain were also scored and observed for related related adverse reactions and recorded.The dose-response curve of KTM&Morp was established and the actual combination drug ED50,ED50comb,was calculated.Isobolographic analysis was used to compare the size of ED_50add and ED_50comb to explore the pharmacodynamic relationship between KTM and Morp.RESULTS:1.Controlled limb pain in patients with limb fractures,in the individual drug groups:KTM 1,KTM 2,KTM 3,KTM 4,Morp 1,Morp 2,Morp 3 and Morp4%AAC effective（100%）medians correspond to 38.2%,46.1%,86.2%,100%,19.9%,37.1%,74.9%and 94.8%.In the combination group,the median of%AAC effective（100%）for K&M l,K&M 2,K&M 3 and K&M 4%is 24.8%,39.3%,70.2%and 93.0%respectively.2.The ED₅₀ of ketamine alone was 0.098 mg/kg（95%CI0.081 to 0.120 mg/kg）for fracture patients,and the ED95（95%effective dose,ED95）was calculated to be 0.190 mg/kg.The ED50 of morphine alone was used for fracture patients is 0.110 mg/kg（95%CI 0.095 to 0.127 mg/kg）,and the ED₉₅ of morphine is0.215 mg/kg.3.the pharmacodynamic relationship between KTM and Morp was synergistic effects obtained by isobolographic analysis.Low-dose ketamine in combination with morphine can reduce 40%of morphine use,reduce drug-related adverse reactions,and enhance the analgesic effect.CONCLUSION:1.The ED₅₀ for single-intravenous infusion of ketamine for moderate-severe pain was 0.098 mg/kg,and ED₉₅ was 0.190 mg/kg.2.The ED₅₀ for moderate-to-severe pain control was 0.110 mg/kg for a single intravenous infusion of morphine,and ED95 was 0.215 mg/kg.3.Ketamine and morphine are synergistic effects.