Pain and its alleviation have been a challenge for humans for centuries. Bupivacaine is the most widely used anesthetic for subarachnoid block and is three to four times more potent than lignocaine and has a longer duration of action. Its prominent disadvantages are slow onset of action and postoperative analgesia is not addressed. Intrathecal opioids are considered the gold standard in the treatment of
postoperative pain with morphine adjudged as the most effective due to its potent and prolonged effect.[ ] Morphine was very popular in the past year but at the cost of respiratory depression and pruritus. The introduction of α 1 2 adrenoreceptor agonist-like dexmedetomidine goals of anesthesia was actually met without any pertinent side effects. In our study, we compared the low dose of morphine with dexmedetomidine in spinal anesthesia for lower limb surgery. MATERIALS AND METHODS
The study was approved by the Institutional Ethics Committee (Memo No: 204 IEC, RIMS, Ranchi, dated December 21, 2019) and carried out in tertiary care government medical college. The study was carried out after written and informed consent. This study was conducted as per the ethical principles of the Declaration of Helsinki 2013.[
] The study is a randomized prospective trial and the duration of the study was 1 year. The primary aim was to determine the duration of analgesia determined by the first demand for rescue analgesia in two groups of a defined study population. The secondary objectives were to compare intraoperative hemodynamics between the two groups and to find the incidence of any complications in either group. 2
After obtaining written informed consent, this prospective, randomized, double-blind study was conducted on 120 patients of either gender, aged between 18 and 65 years, weighing between 30 and 80 kg, and belonging to the American Society of Anesthesiologist physical status Classes I and II undergoing orthopedic lower limb and lower abdominal surgeries under
spinal anesthesia. Patients with known allergy to study drugs, all well-known contraindications to spinal anesthesia, patients with a history of respiratory, cardiac, diabetes mellitus, neurological, hepatic, or renal disease, patients having local infection of the back, coagulopathy or anticoagulant therapy, and any cardiovascular disease, and patients with raised intracranial pressure and preexisting neurological disease or severe deformity of the spine were excluded from the study. The group allocation and analysis are shown in the CONSORT flow diagram [ Figure 1]. The study population was randomly divided into two groups with 60 patients in each group by computer-generated random numbers. Group allocation was done in a sealed opaque envelope. Group A ( n = 60) – Received 2.5 mL of intrathecal hyperbaric bupivacaine with 5 μg of preservative-free dexmedetomidine. Group B ( n = 60) – Received 2.5 mL of intrathecal hyperbaric bupivacaine with 150 μg of preservative-free morphine. Pulse rate (PR), blood pressure (BP), and oxygen saturation (SpO 2) were recorded as per protocol in case of record form till the completion of surgery. Perioperative data collection was done by anesthesia nurse who was blinded for group allocation. In the postoperative period, they were recorded in the immediate postoperative period and thereafter at different time intervals by anesthesia residents who were blinded for the study group. Figure 1:
CONSORT flow diagram
Monitoring of all the parameters BP, PR, respiratory rate, and SpO
2 was recorded after spinal injection and during surgery were compared with baseline (preoperative). Changes in the parameters were recorded and mean changes in each group at different periods of observation were calculated for intergroup comparisons.
Heart rate (HR) is said as bradycardia when HR <50/min. HR >120/min was graded as tachycardia. Atropine 0.6 mg was kept ready for bradycardia if needed.
Variations in BP were observed, and hypotension was recorded. A fall in BP >20% from the baseline was considered hypotension and was treated by intravenous (i.v.) mephentermine.
Respiratory rate and SpO
2 were monitored intraoperatively in all patients. Any variations from the preoperative readings were recorded in case record form.
In our study, surgeons were allowed to start the operation once the maximum level of analgesia was confirmed by the hot/cold cotton swab method. The duration of surgery in this study was taken as time from the incision to skin closure.
Motor blockade was recorded as time taken from the onset of the motor block and to the time when the patient was able to move his/her leg.
The assessment of
postoperative pain and pain relief was studied before shifting the patient to the ward. Strict instructions were given to not give any narcotics, analgesics, or sedatives. The assessment of pain was done by patients themselves by the Visual Analog Scale (VAS). Injection of paracetamol 1 g i.v. was given for rescue analgesia when the VAS score reaches above 5. The time for first rescue analgesia was noted. After 30 min of infusion if pain still persists tramadol 50 mg i.v. was supplemented. Successful control of pain was achieved when the VAS score reduces below 3. Monitoring and analgesia were continued up to 24 h of the postoperative period. After 24 h, patients were managed by primary surgeons.
For statistical analysis, data were entered into a Microsoft Excel spreadsheet and then analyzed by SPSS and Graph pad Prism version 5. (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp and Graph pad Prism version 5: Prism 5, 2007, GraphPad Software Inc., San Diego CA). Data had been summarized as mean and standard deviation for numerical variables and count and percentages for categorical variables. Two-sample
t-tests for a difference in mean involved independent samples or unpaired samples. Paired t-tests were a form of blocking and had greater power than unpaired tests. A Chi-squared test was any statistical hypothesis test wherein the sampling distribution of the test statistic is a Chi-squared distribution when the null hypothesis is true. Without other qualifications, the “Chi-squared test” often is used as short for Pearson's Chi-squared test. Unpaired proportions were compared by Chi-square test or Fischer's exact test, as appropriate.
Explicit expressions that can be used to carry out various
t-tests are given. In each case, the formula for a test statistic that either exactly follows or closely approximates a t-distribution under the null hypothesis is given. Furthermore, the appropriate degrees of freedom are given in each case. Each of these statistics can be used to carry out either a one-tailed test or a two-tailed test.
Once a t-value is determined, a P can be found using a table of values from the Student's t-distribution. If the calculated P is below the threshold chosen for statistical significance (usually the 0.10, 0.05, or 0.01 level), then the null hypothesis is rejected in favor of the alternative hypothesis.
P ≤ 0.05 was considered statistically significant. RESULTS
The demographic profile was similar in both groups, as shown in
Table 1. The comorbidities in both groups were comparable with P = 0.69, as shown in Table 2. The duration of surgery was similar in both groups with P = 0.952 (CL 95%). The mean arterial BP was comparable at baseline, but after 3 readings, after subarachnoid block, the change in MBP was significant in Group A with P < 0.0019, as shown in Table 3. Similar findings are shown in Table 4, where PR was comparable at baseline, but after 15 min of the block, PR was reduced in Group A. This was found to be significant with P < 0.0131 (CL 95%). The mean duration of motor block in Group A was 359.33 ± 34.4 and in Group B was 265.71 ± 28.47, as shown in Table 5. The duration of rescue analgesia was almost double in Group A as compared to Group B with P < 0.0001 (CL 95%), as shown in Table 6. We compared the adverse events among the groups and found that side effects were more in Group A than in Group B, as shown in Table 7. It yielded significant results with P < 0.0009 (CL 95%). Table 1:
Mean duration of motor block
Duration from surgery to rescue analgesia
Bupivacaine is a well-established drug for lower limb surgeries. In view of postoperative analgesia and duration of surgery, there are some well-noted modifications in the subarachnoid block. Adjuvants such as opioids, Alpha 2 agonists, and magnesium sulfate are commonly used to achieve desirable analgesic effects. Dexmedetomidine in doses of 3–15 μg is commonly used in the subarachnoid block.[
] Morphine in doses of 100–200 mg intrathecal is found to be safe.[ 3 ] In our study, both groups were comparable in terms of demography. The present study was designed with the aim of comparing the postoperative analgesic efficacy of intrathecal dexmedetomidine with intrathecal morphine in patients who underwent lower limb surgery. 4
The results of the present study showed that the supplementation of spinal bupivacaine with 5 μg of dexmedetomidine produced a prolonged analgesic effect and motor blockade as compared to 150 μg of intrathecal morphine.
Patients with comorbid illnesses were comparable in both groups [
Table 2] with P = 0.690. The durations of surgery were comparable [ Table 8]. The hemodynamics were affected with the use of dexmedetomidine as shown in Tables 3 and 4. Intrathecal morphine and dexmedetomidine both are known to cause hypotension by action on alpha receptors.[ ] The mean BPs were initially similar up to 8 min then MAP became significantly lower in Group A as compared to Group B. The study by Qi 5 et al. obtained similar results in terms of hemodynamics but used 100 μg of morphine instead of 150 μg as in our study.[ ] Khandelwal M used 200 μg of intrathecal morphine and did not find any statistically significant difference in hemodynamic profile.[ 6 ] 7 Table 8:
Duration of surgery
Time to first request for analgesia was significantly prolonged in Group A than in Group B. Intrathecal dexmedetomidine acts by the inhibition of nociceptive neurons by stimulation of α-ARs at the substantia gelatinosa of the dorsal horn in the spinal cord. The activation of both α
2C and α 2A receptors reduces pain transmission by reducing the release of pronociceptive transmitter, substance P, and glutamate from primary afferent terminals and by hyperpolarizing spinal interneurons through G-protein-mediated activation of potassium channels. Prolongation of the duration of analgesia in the dexmedetomidine group may be due to an additive or synergistic effect secondary to the different mechanisms of action of local anesthetic and α 2-AR agonists.[ ] 8
Opioid is the most established analgesic for
postoperative pain control but has drawbacks such as respiratory depression, vomiting, nausea, and pruritus in terms of adverse effects; the most obvious benefit of dexmedetomidine is that this drug does not cause pruritus. In our study, 11 patients in Group B developed bradycardia and hypotension, whereas 19 patients had bradycardia and hypotension in Group A. There was no case of respiratory depression or pruritus in Group B. Morphine in lower doses is appear safe in terms of respiratory complications.[ ] In our study, the overall adverse effects were lesser in Group B. The results were statistically significant; however, the reported side effects were mild. We concluded that this result was due to the possible use of low dose of morphine for intrathecal use and characteristics attributed to demographic profile. 9
The limitation of our study was a single-center study which could have contributed in hospital bias and the speed of injection while giving
spinal anesthesia was not decided which could have played role in the onset of analgesia and reaching the T 10 level. Another limitation of the study was rescue analgesic was given on demand by the patient, and pain score was not monitored. Furthermore, there was no control group such as bupivacaine without adjuvant to compare these drugs. CONCLUSION
Intrathecal dexmedetomidine and morphine both provided good postoperative analgesia. Dexmedetomidine provided a longer duration of analgesia than morphine, thereby increasing the time for first rescue analgesia. However, the adverse effects were more with dexmedetomidine than morphine. Further studies are needed to compare different doses of dexmedetomidine with morphine as an intrathecal adjuvant in a larger study sample.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Kurhekar P, Kumar SM, Sampath D. Comparative evaluation of intrathecal morphine and intrathecal dexmedetomidine in patients undergoing gynaecological surgeries under spinal anaesthesia: A prospective randomised double blind study Indian J Anaesth. 2016;60:382–7
2. World Medical Association. . World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects JAMA. 2013;310:2191–4
3. Gupta R, Bogra J, Verma R, Kohli M, Kushwaha JK, Kumar S. Dexmedetomidine as an intrathecal adjuvant for postoperative analgesia Indian J Anaesth. 2011;55:347–51
4. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphine and respiratory depression: Finding the right balance Drugs. 2011;71:1807–19
5. Abdel-Ghaffar HS, Mohamed SA, Fares KM. Combined intrathecal morphine and dexmedetomidine for postoperative analgesia in patients undergoing major abdominal cancer surgery Pain Med. 2016;17:2109–18
6. Qi X, Chen D, Li G, Huang X, Li Y, Wang X, et al Comparison of intrathecal dexmedetomidine with morphine as adjuvants in cesarean sections Biol Pharm Bull. 2016;39:1455–60
7. Khandelwal M, Rao H, Kumar P, Bafna U, Beniwal S. Comparative study of morphine or dexmedetomidine as intrathecal adjuvants to 0.5% hyperbaric bupivacaine in infraumbilical surgeries Indian J Pain. 2019;33:156
8. Ishii H, Kohno T, Yamakura T, Ikoma M, Baba H. Action of dexmedetomidine on the substantia gelatinosa neurons of the rat spinal cord Eur J Neurosci. 2008;27:3182–90
9. Gehling M, Tryba M. Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: A meta-analysis Anaesthesia. 2009;64:643–51