Preemptive Epidural Analgesia for Postoperative Pain Relief Revisited: Comparison of Combination of Buprenorphine and Neostigmine with Combination of Buprenorphine and Ketamine in Lower Abdominal Surgeries, A Double-blind Randomized Trial.

CONTEXT: Postoperative pain relief provides subjective comfort to patient in addition to blunting of autonomic and somatic reflex responses to pain, subsequently enhancing restoration of function by allowing the patient to breathe, cough, and move easily. AIMS: The aim is to evaluate and compare the effects of neostigmine + buprenorphine and ketamine + buprenorphine for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under general anesthesia (GA). SETTINGS AND
DESIGN: A double-blind randomized trial. SUBJECTS AND METHODS: A total of 60 American Society of Anesthesiologists physical status Classes I and II patients undergoing abdominal surgeries under GA were taken up for the study. They were randomly allocated into two groups, Group A and Group B of thirty patients each. Preemptive epidural analgesia for postoperative pain relief was provided by a combination of neostigmine 1 μg/kg + buprenorphine 2 μg/kg in Group A patients and ketamine 1 mg/kg + buprenorphine 2 μg/kg in Group B patients after induction of GA but before surgical incision. Postoperatively, vital parameters, pain score, requirement of top up doses, and side effects in the two groups were observed and recorded at 2, 4, 6, 10, 18, and 22 h. STATISTICAL ANALYSIS USED: Mean values within each of the Group A and Group B were compared using one-way analysis of variance (one-way ANOVA). Mean values between Group A and Group B were compared using double analysis of variance (two-way ANOVA).
RESULTS: Group A patients had a significant analgesia (visual analog scale [VAS] pain scores reduced significantly from 54.6 ± 6.3 at 2 h to 8.1 ± 8.9 at 22 h postoperatively). Group B patients had significant analgesia too (VAS pain scores reduced significantly from 36 ± 12.5 at 2 h to 5.3 ± 10.9 at 22 h postoperatively). There was however no significant difference between the two groups with respect to the degree of postoperative analgesia on comparison of VAS scores, effect on vital parameters, and incidence of side effects.
CONCLUSIONS: Either of the two combinations, neostigmine 1 μg/kg + buprenorphine μg/kg or ketamine 1 mg/kg + buprenorphine 2 μg/kg can be safely used for preemptive epidural analgesia for postoperative pain relief in patients undergoing abdominal surgeries under GA.

INTRODUCTION

Postoperative pain should be managed early and aggressively, because severe pain not only induces a delay in discharge and poorer patient satisfaction but also can create a hyperalgesic condition known as persistent postoperative pain.[1]

The main-stay of treatment has been the administration of exogenous opioids. However, pain is not always fully relieved by such agents and the ever-increasing doses of opioids are clearly not without their adverse effects.[2]

Opioids act mainly on presynaptic receptors and decrease neurotransmitter release. Buprenorphine an opioid agonist-antagonist has been found to provide excellent analgesia in low dosage with fewer side effects than morphine similarly administered.

Peripheral tissue injury provokes both peripheral and central sensitization. Peripheral sensitization is a reduction in the threshold of nociceptor afferent peripheral terminals and central sensitization is an activity-dependent increase in the excitability of neurons.[3] N-methyl-D-aspartate antagonist ketamine has the potential not to abolish pain but to prevent or block central hypersensitive states.

There have been anecdotal case reports of analgesia following spinal anticholinesterase by 1940s. Epidural neostigmine may be evaluated in proportionally higher doses and represents an alternative as it seems devoid of important side-effects. It provides analgesia by inhibiting the breakdown of acetylcholine, an endogenous spinal neurotransmitter.[45]

The efficacy of the combination of epidural ketamine and morphine for preemptive analgesia in postoperative period has been established.[6] Keeping in mind, the “choice of treatment modality,” “risk of side effects,” “degree of surveillance,” and “cost effectiveness,” this study was designed to evaluate the effect of combination of neostigmine and buprenorphine and combination of ketamine and buprenorphine in preemptive epidural analgesia in abdominal surgeries and compares the two combinations in terms of efficacy of postoperative pain relief and adverse effects.

SUBJECTS AND METHODS

Approval from the hospital ethical committee was obtained. A total of sixty patients of either sex in the age group of 30–60, in good physical status (American Society of Anesthesiologists [ASA] Class I or II) scheduled for abdominal surgeries under general anesthesia (GA) were selected for the study. They were randomly allocated into two groups, Group A and Group B of thirty patients each. Patients with neurological deficits, neuromuscular disorders, bleeding disorders, and those with obvious spinal deformity were excluded from the study. At preoperative visit, the patients were familiarized with the visual analog scale (VAS) and explained the pain assessment procedure. All patients were given tablet diazepam (5 mg) at night before the day of surgery and 2 h before surgery. In the operating room, baseline parameters were recorded, intravenous line was secured. Injection fentanyl (μg/kg) was given intravenously as a premedication before induction of anesthesia. Standard anesthesia technique was followed. Patients were induced with injection propofol 1% (2 mg/kg). Intubation was carried out by endotracheal tube of appropriate size after relaxation with injection vecuronium 0.1 mg/kg. Maintenance of anesthesia was carried out by oxygen, nitrous oxide (33.3% and 66.7%, respectively) and halothane (0.4%–0.6%) on controlled ventilation using a closed circuit with circle absorber. Muscle relaxation was maintained by injection vecuronium in incremental doses intraoperatively.

Once under GA, the patients were positioned in left lateral position with the spine flexed. Under strict asepsis, the intervertebral spaces between L2-3 and L3-4 were identified. A 18 gauge Tuhoy needle was introduced in the epidural space through the midline of interspaces. In Group A patients, preemptive analgesia is given by a bolus dose of injection neostigmine (1 μg/kg) + injection buprenorphine (2 μg/kg) and in Group B patients, injection ketamine (1 mg/kg) + injection buprenorphine (2 μg/kg) diluted in normal saline up to 10 ml were injected into the epidural space through the Tuhoy's needle. A graduated catheter size 20 gauge was passed in the epidural space through the needle and secured to the back after taking out the Tuohy needle. Patients were placed back in supine position and surgery allowed to proceed. Toward the end of surgery, effect of relaxant was reversed with injection neostigmine and injection glycopyrrolate in standard doses.

The following parameters were monitored in the postoperative period: heart rate (bpm), blood pressure (BP) (mmHg), respiration (/min), drowsiness, nausea, vomiting, pruritus, urinary retention, respiratory depression, pain score, and top up dose. The above parameters were assessed postoperatively, two hourly for first 6 h and then four hourly in a 24 h assessment period.

The severity of pain was assessed using a VAS in the postoperative period. The scale had markings from 0 to 100 with 0 depicting no pain and 100 the worst imaginable pain. Epidural top up was given when the level of pain score rose above 40. The epidural top up was carried out with injection buprenorphine (2 μg/kg) and the study was terminated in those patients.

RESULTS

Sixty patients in good physical status (ASA Class I or II) undergoing lower abdominal surgery were selected for the study. Mean age of the patient was 46.1 years and 48.2 years in Group A and Group B, respectively and mean weight was 59.7 kg and 58.8 kg in Group A and Group B, respectively. They were comparable in age, weight, and physical status. The standard protocol of anesthesia was followed in both the groups. Group A comprising thirty patients received preemptive analgesia with epidural buprenorphine (2 μg/kg) and neostigmine (1 μg/kg), whereas Group B comprising thirty patients received preemptive analgesia with buprenorphine (2 μg/kg) and ketamine (1 mg/kg).

Two patients from Group A had to be withdrawn from the study after 4 h and 18 h, respectively after surgery because of severe pain while one patient was withdrawn from Group B after 4 h postoperatively because she developed hallucination.

Demographic and operative data of the two groups are shown in Table 1.

Table 1

Demographic data and operative data

Patient demographic data and anesthesia time were not statistically different between the Groups A and B (age 46.1 ± 9.2 and 48.2 ± 6.1 years, weight 59.7 ± 7.3 kg and 58.8 ± 6.9 kg, height 151.2 ± 4.7 and 150.6 ± 5.0 cm, anesthesia time 109.8 ± 9.3 and 109.4 ± 8.8 min, surgical duration 90.7 ± 10.5 and 89.4 ± 8.3, respectively).

Preemptive analgesia was given to each patient after induction of general anesthesia but before surgical incision. Post-operative vital parameters, pain score, requirement of top-up doses, and side effects of each patient in the two groups were observed and recorded at 2, 4, 6, 10, 18, and 22 h.

Vital parameters recorded in the two groups are shown in Table 2.

Table 2

Vital parameters at different time interval

Table 2 show mean heart rates in Group A patients at 2, 4, 6, 10, 14, 18, and 22 h respectively postoperatively. The recordings were within normal limits and were statistically significant.

Table 2 show the mean heart rates recorded in Group B patients at 2, 4, 6, 10, 14, 18, and 22 h respectively postoperatively. The recordings were within normal limits and did not differ statistically.

No significant difference was observed between the Groups A and B as regards to postoperative heart rate.

Table 2 show the mean respiratory rates noted in Group A patients at 2, 4, 6, 10, 14, 18, and 22 h respectively postoperatively. The values were within normal limits, and there was no significant difference statistically.

Similarly, Table 2 show the mean respiratory rates recorded in Group B patients at the given time intervals. The recordings did not differ statistically and were within normal limits.

No significant difference was observed between the Groups A and B with respect to postoperative respiratory rate. There was no incidence of respiratory depression in both the groups.

Table 2 show the mean systolic and diastolic BP recordings in Group A at 2, 4, 6, 10, 14, 18, and 22 h respectively postoperatively. The recordings did not differ significantly and were within normal limits.

Table 2 also show the mean systolic and diastolic BP recordings in Group B at 2, 4, 6, 10, 14, 18, and 22 h respectively. The values were within normal limits and no significant difference was noted.

No significant difference in BP recordings was observed between the Groups A and B at the given time intervals. There was no incidence of hypotension in the two groups.

VAS pain scores of the two groups are shown in Table 3.

Table 3

Visual analog scale pain scores

The pain scores recorded in Group A at the given time intervals were 39.6 ± 13.9, 37.9 ± 13.6, 35 ± 13.5, 25 ± 11.6, 16.1 ± 8.9, 14.2 ± 17.1 and 8.1 ± 8.9 respectively showing a progressive decrease in pain over the period of observation.

Only two cases (6.7%) in Group A required top up doses of epidural buprenorphine. Two cases were given top up doses at 4 h and 18 h respectively when they developed distressing pain (VAS pain score 60). Both cases were withdrawn from the study after they received the top up doses.

Similarly, the pain scores recorded in Group B patient showed a decrease in pain over the period of observation. The values recorded were 36 ± 12.5, 30 ± 12.6, 19.7 ± 12.4, 10.7 ± 10.6, 4.7 ± 8.8, 4 ± 7.1, 5.3 ± 10.9, respectively, at the given time intervals. None of the cases in Group B required top up dose of buprenorphine.

Although the study of VAS pain scores showed significant reduction of pain within each of the groups, there was no significant difference in pain scores between the two Groups A and B. The number of cases requiring top-up doses in Group A and B was too small (2 and 0, respectively) and hence, the requirement of top-up doses could not be compared.

The side effects of preemptive epidural analgesia in Group A are shown in Table 4a.

Table 4a

Incidence of side effects in Group A

The most common side effect observed in Group A was drowsiness (cumulative incidence 28.4%) followed by nausea (cumulating incidence 18.6%) and vomiting (cumulative incidence 3.9%). All thirty cases were noted to have drowsiness at 2 h and thereafter incidence at 4, 6, 10, 14, 18, 22 h was 66.7%, 20, 7%, 6.9%, 0%, 0%, and 0%, respectively. The incidence of nausea was greatest at 2 h (46.7%) and thereafter it decreased to 40%, 27.6%, and 13.8% at 4, 6, and 10 h, respectively. After this, none of the patients complained of nausea. The incidence of vomiting was also greatest at 2 h (13.3%) and decreased to 6.7%, 6.9% at 4, 6 h respectively and thereafter, it was 0%. None of the cases complained of pruritus and none of them developed respiratory depression or urinary retention.

Side effects of preemptive epidural analgesia in Group B are shown in Table 4b.

In Group B as well the most common side effect was drowsiness followed by nausea and vomiting with cumulative incidence of 28.3%, 15.6%, and 7.8%, respectively. All thirty cases were drowsy at 2 h and thereafter the incidence decreased to 66.7%, 20.7%, and 6.9% at 4, 6, and 10 h respectively. Fourteen hours onward none of the cases were drowsy. Incidence of nausea was greatest at 4 h (46.7%) while it was 40%, 13.8%, 0%, 6.9%, 0%, and 0% at 2, 6, 10, 14, 18, and 22 h, respectively. The incidence of vomiting was 6.7% at 2 h it increased to 20% at 4 h and thereafter it was 13.8% at 6 and 10 h. After that, there were no cases of vomiting. None of the cases complained of pruritus and none of them developed respiratory depression or urinary retention. One patient, that is, case no. 5 in this group developed hallucinations and was unable to quantify pain after 4 h and hence was withdrawn from the study at that stage.

Side effects in the two groups are compared in Table 4c.

Incidence of drowsiness in both Groups A and B was nearly same (28.4% vs. 28.3%). Incidence of vomiting was more in Group B but again, the difference between the two groups was not significant.

DISCUSSION

The current study evaluates and compares the effectiveness and safety of two combinations of synergistically acting preemptive epidural analgesia used to provide postoperative pain relief.

Sixty patients of ASA physical status Class I or II, undergoing abdominal surgeries were given preemptive analgesia epidurally with a combination of buprenorphine and neostigmine or a combination of buprenorphine and ketamine after general anesthesia but before incision. Their vital parameters, pain scores, requirement of top up analgesia doses and side effects were observed over a period of 24 h after surgery and then compared to find out the more effective and safer combination.

Each of the drugs, buprenorphine, ketamine, and neostigmine are known to affect the cardio-respiratory system individually. In the present study, the combination of buprenorphine and neostigmine had no significant effect on the postoperative heart rates, respiratory rates, and BP which remained within normal limits. Chung et al. evaluated the combination of intrathecal morphine and intrathecal neostigmine for postoperative analgesia and found that it did not produce significant difference with regard to BP and heart rate,[78] Nelson et al. studied a similar combination of intrathecal sufentanil and intrathecal neostigmine and reported that the patient hemodynamic variables were unaffected.[9]

Similarly, the present study showed no significant effect on postoperative heart rates, respiratory rates and BPs when the combination of buprenorphine and ketamine was used. This was substantiated by the study of Edwards et al. who used combination of intravenous morphine and ketamine for postoperative analgesia and reported no significant effect on postoperative heart rates, respiratory rates, and mean arterial pressure.[10]

In the present study when the two combinations were compared for their effect on postoperative vital parameters, no significant difference was found as can be expected from the results of the previous studies.[8910] Neostigmine and ketamine produce analgesia by different mechanisms. The present study revealed that the combination of buprenorphine and neostigmine produced significant analgesia over the period of observation since the VAS pain scores reduced significantly from 54.6 ± 6.3 at 2 h to 8.1 ± 8.9 at 22 h postoperatively. Likewise, Dirksen and Nijhuis also showed that intrathecal morphine and neostigmine provided intense analgesia.[11] Chung et al. also reported that the combination of intrathecal morphine and intrathecal neostigmine resulted in significantly lower VAS pain scores.[7] Lauretti et al. also reported that the combination of intrathecal morphine and intrathecal neostigmine resulted in better analgesia.[6] However, Naguib and Yaksh reported no synergy between intrathecal morphine and neostigmine.[12] Preoperative epidural coadministration of a low dose of ketamine with midazolam is more effective in relieving postoperative pain than using ketamine alone. In addition, epidural midazolam prolongs the elimination of ketamine.[1314]

Similarly the other combination in this study, that is, buprenorphine and ketamine provided significant postoperative analgesia by decreasing the VAS pain scores significantly from 36 ± 12.5 at 2 h to 5.3 ± 10.9 at 22 h, similar results were reported in a study by Choe et al. who used a combination of epidural morphine and ketamine.[5] Wong et al. also concluded that ketamine potentiates analgesic effect of morphine in postoperative epidural pain control.[15] Javery et al. concluded that intravenous patient-controlled analgesia (PCA) with ketamine in combination with morphine provided superior postsurgical pain relief.[16] Recent study by Tverskoy et al. with fentanyl and ketamine also confirmed this.[8] In contrast, similar studies by Edwards et al. and Ilkjaer et al. did not demonstrate significant postoperative analgesia.[1017] Epidurally administered neostigmine reduced the use of supplemental analgesia after ovariohysterectomy in dogs. However, analgesic effects were less pronounced than for epidurally administered morphine or morphine-neostigmine. Adding neostigmine to epidurally administered morphine did not potentiate opioid-induced analgesia.[18]

However, when the VAS pain scores of the two groups were compared, no significant difference was found in the present study suggesting that both the combinations produced a similar degree of postoperative analgesia.

In this study, only 2 out of 30 patients (6.7%) of Group A required top up doses at 4 h and 18 h respectively. Chung et al. have also reported that patients who received combination of intrathecal morphine and neostigmine had a significantly prolonged time to first PCA use and a significantly reduced 24 h PCA consumption.[7]

Among the patients receiving the combination of buprenorphine and ketamine in the present study, none of them required top up doses. Choe et al. in a similar study reported that 56.7% (17 out of 30) patients required supplemental analgesic injections.[5]

Since the number of cases receiving top up doses was too small (2 vs. 0) in the two groups, the requirement of top up doses could not be statistically compared between the two groups in this study.

This study revealed drowsiness (cumulative incidence 28.4%) to be the most common side effect with maximum incidence at 2 h after surgery followed by nausea and vomiting (cumulative incidence 18.6% and 3.9%, respectively) in the group receiving buprenorphine and neostigmine. None of the cases complained of pruritus and none of them developed respiratory depression or urinary retention postoperatively. Chung et al. have also reported that patients receiving intrathecal morphine and intrathecal neostigmine experienced less severe nausea, vomiting and had significantly lower incidence of pruritus and none of them developed respiratory depression.[7] Lauretti et al. also reported fewer side effects with the above combination.[6]

In the case of the group receiving the buprenorphine and ketamine combination, the most common side effect was again drowsiness (cumulative incidence 28.3% with maximum incidence at 2 h) followed by nausea and vomiting (cumulative incidence 15.6% and 7.8%, respectively). In this group too, none of the patients developed pruritus, respiratory depression, or urinary retention. However, one case had hallucinations Choe et al. in a similar study reported the incidence of complications such as nausea and vomiting, urinary retention, pruritus, somnolence, respiratory depression, and hallucination as 1, 5, 2, 4, 0, and 0, respectively.[5] Wong et al. also reported reduced incidence of side effects when combination of morphine and ketamine was used.[15] Javery et al. in their study reported fewer side effects when the combination of morphine and ketamine was used for intravenous PCA.[16]

In this study, drowsiness was the most common side effect in both the groups followed by nausea and vomiting. There were no cases of pruritus, respiratory depression or urinary retention. However, the present study did not reveal any significant difference between the two combinations with respect to the incidence of the side effects.

The present study revealed that both combinations (buprenorphine + neostigmine and buprenorphine + ketamine) when given epidurally as preemptive analgesia produced significant postoperative pain relief. There was no significant difference between the combinations with respect to their effect on cardiorespiratory system, postoperative analgesia or incidence of side effects. The requirement of top-up doses in both the groups could not be analyzed statistically because of the small number of cases requiring it.

CONCLUSION

Hence, it is reasonable to conclude that addition of neostigmine or ketamine to buprenorphine in preemptive epidural analgesia can significantly enhance the postoperative analgesia qualitatively with reasonable safety and economy. In addition, lack of clinically and statistically significant side effects makes the above two combination of drugs an important tool in the armamentarium of anesthesiologist in the field of postoperative analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 4b

Incidence of side effects in Group B

Table 4c

Side effects in Groups A and B