| Objective: Postoperative pain is a kind of acute pain.Effective controlling of postoperative pain can reduce the complications of patients,help patients to recover quickly and improve the clinical outcomes after surgery.Postoperative analgesia should be adequate and with fewer side effects.Opioids,Dezocine and NSAIDs all have both advantages and disadvantages.So now the main postoperative pain treatment measures is combined analgesia: using a combination of different mechanisms of analgesic drugs,or different measures of analgesia,in order to get stronger analgesic efficacy and less side effects.Dezocine is a mixed opioid receptor partial agonist/antagonist.It is similiar to pentazocine in structure with shorter onset time and similar to morphine in analgesic efficacy with lower incidence of addiction and fewer adverse reactions.Dezocine has already been approved by SFDA and therefore,it is gaining popularity in China as an alternative medication for perioperative pain management.It has potentials in reducing the amount of pure opioid receptor agonist needed.However when used alone,its analgesic effect is limited by ceiling effect.Naloxone as a pure opioid receptor antagonist was to reduce the adverse reactions caused by opioids,such as respiratory depression,nausea,vomiting and opioid drug toxicity.However,naloxone also attenuates the analgesic effect of the opioids at the same time.Previous in vitro experiments reported that ultra-low dose naloxone(<1g/kg)when combined with opioid drugs,could reduce the side effects of opioid drugs without affecting their analgesic effects.However,there has been no research investigating whether ultra-low dose of naloxone could also mitigate the side effects of dezocine without affecting its analgesic efficacy.Methods: In animal experiment,we first established rat model of postoperative incision pain(Brennan’s method)in 24 male SD rats.After surgery rats were randomly divided into 4 groups receiving ultra-low dose naloxone(1ng/kg),dezocine(1mg/kg),dezocine(1mg/kg)+ naloxone(1ng/kg)and saline(same volume)respectively via the tail vein.PWT(paw withdrawal mechaical threshold)and PWL(paw withdrawal thermal latency)were measured before surgery(T0)and 2 h after surgery(T1)in ipsilateral side of hind paw.PWT were also measured 1day after surgery(T2),3 days after surgery(T3),5days after surgery(T4)and 7days after surgery(T5)respectively to evaluate time-course effects of different treatments on the recovery of postoperative pain.In this part of animal study,we aim to evaluate the effects of ultra-low dose naloxone on the analgesic efficacy of dezocine.In our first clinical study,sixty patients undergoing hepatobiliary surgeries were given dezocine(25mg)+ flurbiprofen axetil(250mg)for postoperative analgesia.They were randomly divided into 3 groups(n=20 per group)receiving different doses of naloxone: 0 μg.kg-1.h-1,0.05 μg.kg-1.h-1 or 0.1 μg.kg-1.h-1.We recorded NRS scores in both resting state and deep breathing state,FPS-R scores,sedation scores and adverse reactions of each patient at 2h,4h,8h,24 h,44h after surgeries to evaluate the analgesia effects and safety of different combinations.In this part of study,we aim to evaluate the dose-effects of naloxone on the analgesic efficacy of dezocine.In the second part of our clinical research,we recruited patients that have gone through hepatobiliary surgeries.44 patients were randomly divided into 2 groups(n=22 per group)receiving different combinations of analgesia drugs for postoperative analgesia management: dezocine(25mg)+ flurbiprofen axetil(250mg)+ naloxone(0.1μg.kg-1.h-1),or dezocine(25mg)+ sufentanil(1.5μg.kg-1)+ naloxone(0.1μg.kg-1.h-1.Again,we recorded NRS scores in both resting state and deep breathing state,FPS-R scores,sedation scores and adverse reactions of each patient at 2h,4h,8h,24 h,44h after surgeries to evaluate the analgesia effects and safety of different combinations.In this part of study,we aim to evaluate different combinations on the analgesic drugs for hepatobiliary surgeries.Results: Our results are as follows:1.The effects of ultra-low-dose naloxone on dezocine in incision pain rats.The preoperative baseline mechanical test showed that PWT values on ipsilateral side of hind paws across all experimental rats were comparable(P > 0.05).These rats were randomly divided into 4 groups receiving different treatments(N: naloxone NS: normal saline D+N: dezocine+ naloxone D: dezocine).2h after the incision,PWT values of all groups dropped significantly compared preoperative baseline(P < 0.01).Though no difference between group N with group NS were detected,PWT values of group D and group D+N were significantly higher than those of group NS and group N(P < 0.01),with an even higher PWT values in group D+N when dezocine was combined with the ultra-low dose of naloxone(D+N vs.D,P<0.01).The preoperative baseline thermal test showed that PWL values on ipsilateral side of hind paws across all experimental rats were comparable(P > 0.05).2h after the incision,PWL values of all groups decreased significantly than preoperative baseline(P < 0.01).Though no differences were observed between group N with group NS were detected,the PWL values of group D and group D+N were significantly higher than those of group NS and group N(P < 0.01),with an even higher PWL values in group D+N when dezocine was combined with the ultra-low dose of naloxone(D+N vs.D,P < 0.05).Ipsilateral post-incision PWT values at 1d,3d,5d and 7d had no statistical significance across the four groups(P>0.05).Within each group,PWT values on the ipsilateral side were significantly lowered on 1d,and 3d after surgeries compared with baseline(P<0.01)while resumed to baseline level after 5 days(5d vs.BL,7d vs.BL,P >0.05).2.The effects of ultra-low-dose naloxone with different concentrations on the analgesic efficacy of dezocine.The NRS scores of patients in the resting state was significantly lower in group DFN1(dezocine 25 mg + flurbiprofen axetil 250 mg + naloxone 0.05μg.kg-1.h-1)than in group DF(dezocine 25 mg + flurbiprofen axetil 250mg)at 2h,24 h,and 44 h after surgeries(P < 0.05).The NRS scores of patients in the deep breathing state was significantly lower in group DFN1 than in group DF at 24 h and 44 h after surgeries(P < 0.05).The FPS-R scores of patients in the resting state were significantly lower in group DFN1 than in group DF at 2h,8h,and 24 h after surgeries(P < 0.01).No significant differences were detected in sedation scores and the incidence of adverse reactions such as nausea,vomiting,chills and dizziness between two groups(P > 0.05).There was no significant differences about NRS scores both in resting state and deep breathing state,FPS-R scores in resting state,sedation scores and the incidence of adverse reactions such as vomiting,chills and dizziness between group DFN2(dezocine 25 mg + flurbiprofen axetil 250 mg + naloxone 0.1μg.kg-1.h-1)and group DF(P > 0.05),but the incidence of nausea in group DFN2 was significantly lower than in group DF(P < 0.05).The FPS-R scores in resting state at 24 h after surgeries were significantly lower in group DFN1 than in group DFN2(P < 0.05).No significant differences were observed at other time points(P > 0.05).There was no significant difference in NRS scores of resting state and deep breathing state,sedation scores or the incidence of adverse reactions between group DFN2 and group DFN1(P > 0.05).3.Better combination of analgesia drugs for hepatobiliary surgeriesThe NRS scores of patients in the resting state and FPS-R scores at 24 h and 44 h after surgeries were significantly lower in group DSN(dezocine 25 mg + sufentanil 1.5μg.kg-1+ naloxone 0.1μg.kg-1.h-1)than in group DFN(dezocine 25 mg + flurbiprofen axetil 250 mg + naloxone 0.1μg.kg-1.h-1)(P < 0.05).No significant differences were observed at other time points(P > 0.05).There were no significant differences in NRS scores of the deep breathing state,sedation scores and the incidence of adverse reactions between group DSN and group DFN(P > 0.05).Conclusion: Our study have found that though ultra-low dose of naloxone has no analgesic effect when used alone,it can enhance the analgesic efficacy of dezocine(a mixed opioid receptor partial agonist/antagonist)and can even reduce the side effects depending on the concentration used.Naloxone(0.05μg.kg-1.h-1)enhanced the anagesic effects of dezocine plus flurbiprofen when used for patients undergone hepatobiliary surgeries without affecting the incidence of adverse reactions.When dezocine plus flurbiprofen was combined with a higher dose naloxone(0.1μg.kg-1.h-1),the incidence of nausea was decreased without affecting their analgesic effects.Ultra-low dose of naloxone plus dezocine can provide better analgesic effect when combined with sufentanil than flurbiprofen.The underlying mechanism is not clear and needs further study. |
PDF Full Text Request