Comparative study between epidural morphine and bupivacaine with epidural clonidine and bupivacaine for postoperative pain relief in abdominal surgeries.

BACKGROUND: Many adjuvants are used to increase the efficacy of epidural local anesthetics for postoperative analgesia. AIMS: The aim was to compare the efficacy of epidural morphine (0.1 mg/kg) and clonidine (2 μg/kg) with bupivacaine (0.125%) for postoperative analgesia in abdominal surgeries. SETTINGS AND
DESIGN: Double-blind retrospective randomized study.
METHODOLOGY: All the patients (n = 60) varying from age group belonging to American Society of Anesthesiologists I-II were randomly allocated to receive epidural analgesia Group A - Morphine (0.1 mg/kg). + Bupivacaine (0.125%) (n = 30), Group B - Clonidine (2 μ/kg) + Bupivacaine (0.125%) (n = 30). We monitored vitals and requirement of inhalational gases intra-operatively, pain by visual analogue score (VAS) and vitals postoperatively. We used rescue analgesics (injection diclofenac 1 mg/kg intravenous) when VAS score > 5. Postoperatively, various parameters were monitored for first 2 h at intervals of 30 min and at 4, 8, 12, 16, and 24 hourly intervals after giving 1(st) dose. STATISTICAL ANALYSIS USED: Continuous data are analyzed by Student's t-test (paired 't'-test for intragroup variations and unpaired 't'-test for intergroup variations). Chi-square test was used for categorical data. A P ≤ 0.05 was considered to be statistically significant.
RESULTS: Mean duration of analgesia was 8.35 ± 0.42 h in Group A (morphine) and 7.45 ± 0.44 h in Group B (clonidine). This difference was statistically significant (P < 0.001), indicating a prolongation of analgesia in group morphine. There was no need of rescue analgesia in any subjects. Group A patients were hemodynamically stable and required less inhalation agents intra-operatively compared to group B patients.
CONCLUSIONS: Epidural morphine plus bupivacaine has a longer duration of analgesia and greater hemodynamic stability as compared to epidural clonidine plus bupivacaine for postoperative analgesia in abdominal surgeries.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Postoperative pain is currently a significant and ubiquitous problem. It is associated with a myriad of postoperative complications, which lead to delayed recovery and prolonged hospitalizations. Untreated severe pain causes stimulation of the sympathetic component of the autonomic nervous system resulting in increased release of catecholamines. This stress response (increased heart rate, blood pressure, etc.) has many negative effects including postoperative ileus and cardiac ischemia in susceptible individuals.

Pain is known to contribute to improper postoperative coughing and deep breathing exercises, which predispose patients to pulmonary complications. Similarly, the presence of postoperative pain is a factor in delayed mobility, as patients with pain are often more reluctant to get out of bed. One of the more serious complications of delayed mobility after surgery is the development of deep vein thrombosis. Postoperative pain has been shown to be ameliorated effectively by epidural opioid administration. The drug of choice is one which alleviates postoperative pain with the fewest unwanted side effects. Morphine and clonidine are commonly used adjuvants to epidural local anesthetics. No study has been conducted to compare analgesic efficacy, hemodynamic changes, and side effects between epidural clonidine and morphine combined with local anesthetic in adult patients.

Hence, we will compare the analgesic efficacy of a combination of the following groups of two drugs used in patients undergoing major abdominal surgeries.

Morphine and bupivacaine (0.125%)

Clonidine and bupivacaine (0.125%).

Aims and objectives of the study

To evaluate and compare the efficacy, onset, and duration of epidural analgesia with bupivacaine (0.125%) plus morphine (0.1 mg/kg) and bupivacaine (0.125%) plus clonidine (2 μg/kg)

To study hemodynamic effects as well as side-effects of epidural block in both groups.

METHODOLOGY

Prospective randomized controlled study design was selected, and 30 patients were allocated to each of two groups.

Patients of age between 18 and 60 years with American society of Anesthesiologists (ASA) physical status I and II who were to undergo abdominal surgeries like exploratory laparotomy, intestinal obstruction, open cholecystectomy etc., were included.

Patients of ASA status III, IV, and V, known case of asthma, hypertension, ischemic heart disease, congestive heart failure, terminal valvular insufficiency, substance abuse, hypotension, severe anemia, bleeding and coagulation disorder, allergy to opioids, hepatic or renal disease, pregnancy, skin infection at a site of epidural injection, Psychosis and who were undergoing spinal anesthesia were excluded.

Postoperative pain relief was evaluated in 60 patients undergoing abdominal surgery. The subjects were randomly allocated to Group A (Group M) and Group B (Group C). The aforementioned groups received epidural morphine plus bupivacaine and epidural clonidine plus bupivacaine, respectively. Morphine used was preservative free including phenol, formaldehyde, chlorobutanol, sodium biphosphate, and sodium bisulfite.

The study was approved by ethical committee of B J Medical College, Civil Hospital Ahmedabad. Written informed consents had been taken before surgeries. All patients were given general anesthesia after doing adequate investigations preoperatively. In the operating room, gazettes according to minimum monitoring standards were applied, and baseline vitals were noted. Premedication in form of injection glycopyrrolate 0.004 mg/kg intravenous (IV), injection ondansetron 0.15 mg/kg, and injection fentanyl (2 mcg/kg) IV were administered and IV fluid was started as well. Epidural catheter was inserted after taking all aseptic precautions. Then test dose with 3 ml bupivacaine (0.5%) was given. After confirmation of the placement of the catheter in the epidural space, the catheter was fixed.

Group A (Group M) - Morphine 0.1 mg/kg + bupivacaine (0.125%)

Group B (Group C) - Clonidine 2 μg/kg + bupivacaine (0.125%).

Drugs given after negative aspiration test and post dose vitals were recorded.

Postoperatively in the recovery room, various parameters were monitored for first 2 h at intervals of 30 min and later on in the ward at 4, 8, 12, 16 24 hourly intervals after giving 1st dose. Subsequent doses were given 8 hourly or when visual analog scale (VAS) >5 for total 24 h. Rescue analgesia in the form of injection diclofenac 1 mg/kg IV was given. Epidural catheter was removed after 48 h under all aseptic and antiseptic precautions, patency and intact tip of the catheter was checked. Different parameters like pain by VAS, Sedation by Ramsay scale, Heart rate, respiratory rate, blood pressure, urine output and side effects like nausea, vomiting, retention of urine, pruritus, lower extremity motor block, and respiratory distress were observed.

Statistical analysis

Descriptive data were presented as mean ± standard deviation and number and percentages. Continuous data are analyzed by Student's “t”-test (paired “t”-test for intragroup variations and unpaired ‘t’-test for intergroup variations). Chi-square test was used for categorical data. Power of the study was determined on the basis of the literature review of previous study by R. Singh et al. with alpha = 0.05 and beta = 0.2 with an effect size of 0.84.[1] Sample size of 24 subjects is the minimal sample size required to achieve reliable results. We, therefore, recruited 30 subjects in each group to make a study more credible.

RESULTS

The present study was conducted in 60 patients belonging to ASA physical status Class 1 and 2 scheduled for different surgeries in New Civil Hospital, Ahmedabad.

The patients were randomly divided into two groups of 30 patients each. The following drugs were given epidurally.

The mean age of the patients was comparable in both the groups, being 51.17 ± 11.75 years in Group I and 46.23 ± 16.64 years in Group II. In the group, I 52% were male and in group II 56% were male. Statistically no significant difference was observed in sex distribution between the two groups.

Heart rate

Preoperative pulse was comparable in both the groups. Within 1 h after epidural dose, Heart rate varied from 63.27 ± 6.23 to 93.10 ± 8.15 in clonidine group and 73.63 ± 4.65–84.03 ± 10.5 in morphine group, postoperatively, there is significant decrease in pulse rate from baseline in both groups, more in clonidine group (P < 0.05). Pulse rate in the clonidine group was significantly increased just before subsequent second dose [Figure 1].

Figure 1

Heart rate comparison between two groups

Mean arterial pressure

There was no statistically significant difference in Mean arterial pressure (MAP) in baseline values. MAP changes in the clonidine group varied from 73.27 ± 6.69 mm Hg to 94.37 ± 5.97 mm Hg while MAP changes in the morphine group varies from 82.83 ± 4.27 mm Hg to 94.77 ± 3.48 mm Hg. After epidural dose, a significant difference exists in MAP, which is lower in the clonidine group than morphine group (P < 0.05). In group clonidine, the maximum fall in mean arterial blood pressure (73 mm Hg) as compared to the baseline value (94.56 mm Hg) was 15% which occurred at 1 h after epidural injection.

In this study, statistically no significant difference (P > 0.05) was observed in the SpO2 between the two groups. The SpO2 did not fall below 95% in any of the subjects in Postoperatively. Statistically no significant difference (P > 0.05) was observed in the respiratory rate between the two groups [Figure 2].

Figure 2

Mean arterial pressure comparison between two groups

Onset of analgesia

The onset of analgesia was defined as the time from injection of the study medication to the first reduction in pain intensity by at least 1 cm in VAS. The mean time from the epidural injection to onset of analgesia was 21.67 ± 2.65 min in Group M and 15.17 ± 2.22 min in Group C. This difference was found to be statistically significant (P < 0.05) [Table 1].

Table 1

Onset of analgesia

Duration of analgesia

Duration of analgesia was defined as the time from the epidural injection to the time of the first request for additional pain medication. The mean duration of analgesia was 8.35 ± 0.42 h in group morphine and 7.45 ± 0.44 h in group clonidine. This difference was statistically significant (P < 0.05), indicating a prolongation of analgesia in group morphine. There was no need of rescue analgesia in any subjects [Table 2].

Table 2

Duration of analgesia

Visual analog scale

In this study, there was no significant difference in analgesia between groups morphine and clonidine at rest and till 2 h after epidural dose, whereas significantly higher pain (VAS) scores during cough, mobilization and after 2 h of epidural dose were observed in the Clonidine group (P < 0.05).

Sedation

Statistically significant sedation difference was observed between the two groups. The sedation appeared approximately 45–60 min after epidural injection in both the groups, which lasted for 5–6 h. During this period, the patients were easily aroused but asleep when not disturbed. All patients of clonidine group show sedation score between 2 and 4. Subjects in group clonidine remained sedated for a longer period (7.1 [0.8] h) when compared with those in group morphine (3.8 [0.7] h; P < 0.01) [Figure 3].

Figure 3

Sedation score comparison between two groups

In this study, in group morphine, 10 patients complained of nausea, vomiting which was treated with injection ondansetron and six patients complained of pruritus, itching which was treated with antihistamines.

DISCUSSION

Management of postoperative pain still poses a lot of challenges to anesthetists after all the efforts taken to make the intraoperative and postoperative period pain-free. Morphine and clonidine are commonly used adjuvants to epidural local anesthetics.

Comparison between morphine and clonidine has been studied in two randomized controlled trials in children, which have shown contradictory results.[12] The disparity in the results may be explained due to varying doses. Moreover, one of the studies was focused on comparing the side effects.[2] Based on MedLine database search and literature review searches, no study has been conducted to compare analgesic efficacy, hemodynamic changes, and side effects between epidural clonidine and morphine combined with local anesthetic in adult patients.

Pain can greatly impede the return of normal pulmonary function, promote immobility and subsequently lead to the development of deep vein thrombosis, alteration in the stress response to surgery, increased catecholamine release, increased oxygen demand and cardiac work, Increased catabolic response to surgical trauma, impaired immune mechanisms, and delayed wound healing. Hence, its relief undoubtedly decreases morbidity and mortality.

Epidural Morphine is a potent opiate analgesic drug that provides better and long lasting pain relief postoperatively. In our study, epidural morphine 0.1 mg/kg + Bupivacaine (0.125%) are given at 8 h interval.

Clonidine is a centrally acting, selective partial α2 adrenergic agonist and reduces central epinephrine release. Epidural Clonidine has been shown to have anesthetic sparing effects and analgesic property.[3]

A total number of 60 patients, aged between 18 and 60 years are selected. Of these, the mean age in Group-M (receiving epidural Morphine) was 51.17 ± 11.75 years and in Group-C (receiving epidural Clonidine) was 46.23 ± 16.64 years. Both groups were comparable with respect to age and gender distribution.

In this study, Epidural morphine 0.1 mg/kg + 0.125% bupivacaine diluted in 10 ml of normal saline used because it was found an optimal dose in regards to efficacy and side effects by Lanz et al.[4]

In Group C, Epidural Clonidine 2 μg/kg + 0.125% bupivacaine diluted in 10 ml of normal saline as previous study by Jyothi et al. showed epidural clonidine 150 mcg with bupivacaine provides a rapid, excellent, and longer duration of analgesia when compared to epidural bupivacaine.[5]

Lund and Mogensen found that no patients in their study group receiving epidural morphine developed any clinically important change in heart rate.[6] In this study, preoperative pulse was comparable in both the groups. Heart rate varied from 63.27 ± 6.23 to 93.10 ± 8.15 in Clonidine group and from 73.63 ± 4.65 to 84.03 ± 10.5 in Morphine group. Within 1 h of epidural dose postoperatively, there is significant decrease in pulse rate from baseline in both groups, more so in the clonidine group (P < 0.05) which is comparable to the studies conducted by Rockemann et al. and Bonnet et al.[78]

Clonidine decreases heart rate by direct cardiac as well as central mechanisms. A decrease in pulse rate after administration of the drug might be due to adequate analgesia resulting in sedation and less sympathetic discharge.

Mean arterial pressure changes in the clonidine group vary from 73.27 ± 6.69 to 94.37 ± 5.97 while MAP changes in the Morphine group vary from 82.83 ± 4.27 to 94.77 ± 3.48. There is no statistically significant difference in MAP in baseline values. But after epidural dose, a significant difference exists in MAP, which is lower in the clonidine group (P < 0.05). In group clonidine, the maximum fall in mean arterial blood pressure (73 mm Hg) as compared to the baseline value (94.56 mm Hg) was 15% which occurred at 1 h after epidural injection. It shows in our study that clonidine causes decrease in mean arterial blood pressure similar to observation by Lund and Mogensen, Rockemann et al. (1995), Bonnet et al. (1989), and Glynn et al.[6789]

No significant respiratory depression has been noticed in either of the two groups. A limitation of our study is that we used respiratory rate alone to assess respiratory depression which may not be the sole indicator of respiratory depression.

No significant difference was found in VAS between morphine and clonidine groups at rest and up to 2 h in both groups. However, there was significantly higher pain score in the clonidine group during cough and mobilization (P < 0.05) as well as after 2 h of epidural dose compare to group morphine. This is due to hydrophilic feature of morphine, which ensures that the drug remains at target site for a prolonged period and this delayed absorption explains its intense analgesia.

Thus, quality of analgesia has been proven to be better with Morphine group in our study, which is contrary to study by Jain et al. and Glynn et al. which shows no difference in VAS score between clonidine and morphine group during coughing and mobilization.[910]

In a study conducted by Jain et al., no significant difference was found in duration of analgesia.[10]

In this study, the mean duration of analgesia was 8.35 ± 0.42 h in group morphine and 7.45 ± 0.44 h in group clonidine. This difference was statistically significant (P < 0.05), indicating a prolongation of analgesia in group morphine. There was no need of rescue analgesia in any subjects.

In a study by Glynn et al., duration of analgesia in morphine group higher compared to clonidine group which is comparable to our study.[9]

In the comparison of two different methods of analgesia by Kestutis et al. (2003), it was found that systemic Opioids cause more profound sedation.[11] In this study, sedation score was recorded according to the Ramsay Scale. The sedation appeared approximately 45–60 min after epidural injection in both the groups. All patients of clonidine group showed sedation score between 2 and 4 and remained sedated for a longer period (7.1 [0.8] h) when compared with those in group morphine (3.8 [0.7] h; P < 0.01) which is comparable to result of the study by Singh et al. (2011) though this study differs from the above mentioned studies in using Ramsay sedation scale.[1]

The sedation seen after epidural administration of clonidine likely reflects systemic absorption and vascular redistribution to higher centers. Locus coeruleus is associated with regulation of sleep and wakefulness and is inhibited by alpha-2 agonists. The sedative effects evoked by alpha-2 agonist most likely reflect inhibition of this nucleus.

In this study, in group morphine, 10 patients complained of nausea, vomiting who were treated with injection ondansetron and six patients complained of pruritus, itching which was treated with antihistamines. Nausea and vomiting are thought to be the result of central stimulation of the chemoreceptor trigger zone. Thus, the increased frequency of side effects was seen in the morphine group, which is comparable to comparable to study by Jorgensen et al. (2001) and Carey et al. (2002).[1213]