Comparative analgesic efficacy of different doses of dexamethasone during infraumbilical surgery: A Randomized controlled trial.

BACKGROUND: Postoperative pain is a common complaint and despite the availability of various drugs, is still not managed well. Analgesic effects of glucocorticoids are still to be substantially established. Hence, we designed randomized, double-blind, placebo-controlled trial to compare the effect of two different doses of dexamethasone on postoperative pain in patients undergoing infra-umbilical surgeries under spinal anesthesia.
METHODS: Ninety American Society of Anesthesiologists Grade I and II patients were randomized to receive injection dexamethasone 8 mg (Group DI), dexamethasone 16 mg (Group DII) or placebo (Group C) prior to performance of intrathecal block. Outcome studied was postoperative pain on the rest and motion and nausea and vomiting. RESULT: There was no difference in Visual Analog Scale (VAS) scores during rest in all the three groups. However, VAS scores on motion showed a significant decrease in Group DII at 24 and 36 h when compared to Group C (95% confidence interval [CI] of mean at 24 h for Group C = 5.6093-7.1049 and Group DII = 4.8709-5.9567, P = 0.04; 95% CI of mean at 36 h for Group C = 4.5868-5.8418 and Group DII = 3.5388-4.7378, P = 0.01). There was no significant difference in the incidence of postoperative nausea and vomiting or additional analgesic requirements.
CONCLUSION: Dexamethasone 16 mg reduces postoperative pain on motion at 24 and 36 h. It has no effect on postoperative pain at rest or on nausea and vomiting.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Pain is a common complaint in a patient undergoing abdominal surgeries. 30–80% of postoperative patients complain about moderate to severe postsurgical pain.[1] Despite the availability of various analgesic drugs, patient survey has indicated that moderate-to-severe postoperative pain is not managed well and is still the subject of extensive research.[23] Inadequate pain relief delays recovery and prolongs hospital stay, increasing healthcare cost and reducing patient satisfaction.[456]

Although opioids are highly effective, their side-effects have resulted in diminution in their use, especially in high doses or for prolonged periods. With the advent of the concept of multimodal analgesia, numerous drugs have been evaluated to cater to postoperative pain relief with minimal side effects. Dexamethasone is a potent anti-inflammatory glucocorticoid, which also possess anti-emetic properties.[2] Dexamethasone has shown promising result in postoperative pain relief, but there are discrepancies in the doses used to elucidate this effect.[789] Till date, there are no studies comparing the effect of different doses of dexamethasone on postoperative pain relief.

Hence, we designed this double bind, randomized, placebo-controlled trial to compare the effect of two different doses of dexamethasone (8 mg and 16 mg) on postoperative pain in patients undergoing infra-umbilical surgeries under spinal anesthesia. Our primary outcome was the postoperative pain on motion. Secondary outcome included pain at rest, nausea and vomiting, and additional analgesic requirements.

METHODS

After taking institutional ethical clearance and informed consent, 90 adult American Society of Anesthesiologists Grade I and II patients, age between 18 and 65 years undergoing infra-umbilical surgeries under spinal anesthesia were randomized into three groups of 30 patients each. Patients undergoing emergency surgeries, patients with signs of endocrine, renal, hepatic or immunological diseases, alcoholic and pregnant patients or patients whose surgery was expected to last more than 3 h were excluded from the study. Randomization was done using random number table. Group DI patients received dexamethasone in doses of 8 mg diluted to 4 ml with normal saline. Group DII patients received dexamethasone 16 mg with total volume of 4 ml and Group C patients received 4 ml of normal saline. The drugs were prepared and given by a trained Anesthesiologist who was no further involved in the study. Study parameters were collected by another Anesthesiologist who was in-charge of the case. Both the Anesthesiologist collecting data and patient were unaware of the type of drug being administered. Hence, the study proceeded as double-blind, randomized and placebo-controlled trial. Tablet alprazolam 0.50 mg was given orally night before the operation. In the operation theater, baseline hemodynamic parameters and oxygen saturation on the room air were noted. Injection ondansetron 4 mg was given intravenously. This was followed by slow intravenous administration of the study drug. Patients were turned to left lateral position, part painted and draped, and spinal anesthesia was given in 3rd or 4th lumbar space with 3 ml of 0.5% bupivacaine after the free flow of cerebro-spinal fluid demonstrated. After the achievement of adequate block to T4 level, surgery was allowed to commence. Intraoperative monitoring of blood pressure, heart rate, oxygen saturation, and if needed electrocardiography was done. Fluid administration was done in accordance with preoperative fluid deficit and intraoperative fluid requirements. If blood pressure decreased to <80 mmHg or heart rate <50/min, injection ephedrine 3 mg or injection atropine 0.6 mg, respectively, was given. After the operation, patients were shifted out of the operation theater to the recovery area. Injection diclofenac 75 mg was given intramuscularly at the time of skin closure and thereafter at 8 hourly intervals. Injection tramadol 100 mg in infusion twice daily was given, with the first dose given when the regression of neuraxial block has started. All the additional analgesic and antiemetic drugs given were recorded along with their doses.

Data collection

Pain scores on ten point Visual Analog Scale (VAS) (0 – no pain; 10 – worst possible pain) were assessed at rest every 4 hourly till 24 h and then 6 hourly till 48 h. Pain on motion was assessed by asking the patient to try to sit from the supine position at the following hours: 24, 36 and 48 h. Rescue analgesic was injection pentazocine 30 mg intravenous and injection promethazine 25 mg intramuscular given if VAS scores were 4 or more than 4.

Incidence of postoperative nausea and vomiting was assessed till the study duration of 48 h. Nausea and vomiting was taken as a single entity and was recorded as a dichotomous variable (yes/no).

Statistical analysis

Primary outcome was the postoperative pain on motion. Secondary outcome was pain scores at rest, incidence of postoperative nausea and vomiting, and incidence of additional analgesic requirements. Continuous data were presented as mean ± standard deviation. Demographic and VAS score were compared between the three groups by one-way analysis of variance (ANOVA) test, and if significant, this was followed by comparative analysis between two groups. Categorical data were compared by Chi-square test or Fischer's exact test. From the previous studies mean VAS in the control group was reported to be 5.[1011] Assuming 30% reduction in dynamic pain scores in our experimental group, that is, taking mean VAS as 3.5 and standard deviation as 2, we calculated the sample size of 28 patients in each group to achieve the power of 80% with significance at 5%. To compensate for drop-outs, we increased the sample size to 30 patients in each group. Statistical analysis was done using. Epi Info 7- Epi Info 7.1.3.3 is trademark of Centers for Disease Control and Prevention (CDC) Microsoft excel- 2007.

RESULTS

Out of thirty patients randomized in each group, two patients in Group C (control group) and one each in Group DI (dexamethasone 8 mg) and Group DII (dexamethasone 16 mg) had to be dropped from the study. One patient each of Group C and Group DII had failed spinal anesthesia and general anesthesia had to be administered. In remaining two cases which were dropped, ketamine had to be supplemented intraoperatively. The demographic and surgical details of the rest of the patients are given in Table 1. The maximum number of patients underwent appendicectomy, inguinal hernia, or total abdominal hysterectomy.

Table 1

Demographic and surgical characteristics

We assessed not just the static pain, which was the pain on rest but also the dynamic pain or pain on motion, which we assessed by asking the patient to sit from supine position at 24 h and later. Postoperative VAS scores at rest were comparable in all the three groups throughout the study period of 48 h [Figure 1]. However, VAS scores on motion showed a significant decrease in Group DII at 24 and 36 h when compared to Group C (95% confidence interval [CI] of mean at 24 h for Group C = 5.6093–7.1049 and Group DII = 4.8709–5.9567, P = 0.04; 95% CI of mean at 36 h for Group C = 4.5868–5.8418 and Group DII = 3.5388–4.7378, P = 0.01). The significance of VAS scores on motion was more evident at 36 h in Group DII as compared to the scores at 24 or 48 h with respect to Group C and Group DI. At 48 h, the VAS scores on motion were comparable in all the three groups (P = 0.16 by ANOVA) [Table 2]. Patients in Group C and Group DI had comparable VAS score at all the time intervals either at rest or on motion.

Figure 1

Postoperative Visual Analog Scale (VAS) scores at rest. There is no significant difference in VAS scores between the three groups

Table 2

Postoperative VAS scores on motion

The percentage of patients requiring additional analgesic was 57% (n = 16) in Group C, 48% (n = 14) in Group DI and 31% (n = 9) in Group DII (P = 0.13). Incidence of postoperative nausea and vomiting was also comparable in all the three groups (P = 0.63) [Table 3].

Table 3

Incidence of additional effects

DISCUSSION

Acute postoperative pain is usually considered as inflammatory and nociceptive, but neurogenic mechanism may also contribute.[12] Glucocorticoids, with potent anti-inflammatory effects, produce analgesia by reducing proinflammatory cytokines and induce the expression of anti-inflammatory cytokines. They also suppress glial activation and inhibit the prostaglandin synthesis by suppressing phospholipase A2.[712] The inflammatory, metabolic, hormonal, and immune responses to surgery are activated immediately after the surgical incision. Dexamethasone may prove beneficial in reducing these responses by the virtue of their anti-inflammatory and immunosuppressive effects.[2] C-reactive protein levels, a marker of inflammation, are shown to be decreased by dexamethasone.[79] Some surgeons are concerned about the steroid masking the clinical signs of infection, delaying wound healing or precipitating gastrointestinal hemorrhage. However, such concern should not apply to a single low dose steroid if one considers the biologic half-life of dexamethasone (36–58 h).[2] Sustained analgesic and antihyperalgesic effects, no problem with bleeding or allergy, no increase in infection risk, no increase in wound dehiscence, potent antiemetic effects, and a more rapid convalescence are all arguments in for a single perioperative dose of glucocorticoid.[12]

The present study demonstrated a significant decrease in postoperative pain at 24 and 36 h on movement, but there was no decrease at 48 h with motion or during any studied time at rest. Furthermore, there was no significant difference in the incidence of additional postoperative analgesic requirements. In accordance with our study, Kardesh have also shown significant decrease in dynamic postoperative pain scores 24 h after total hip arthroplasty, and no significant effect on pain at rest or postoperative morphine consumption with doses of 40 mg dexamethasone.[9] Same findings are echoed by Tan et al. with 10 mg of dexamethasone given just before spinal anesthesia for inguinal herniorrhaphy.[13] The reason for two different doses of dexamethasone in above studies yielding similar results could be due to difference in their type of surgeries which caused variable degree of tissue trauma and inflammation, resulting in different postoperative pain intensities.[13]

In contrast, Bisgaard et al. have shown a significant decrease in postoperative pain at rest in patients undergoing laparoscopic surgery as well as a significant decrease in postoperative opioid consumption. Here they had administered the drug 90 min prior to skin incision. They and other authors have reasoned that the predominant effect of glucocorticoid is through an altered protein synthesis via gene transcription. Hence, the onset time of the drug is generally 1–2 h. Giving drug immediately before the incision does not suppress early mediators of inflammation released in response to surgery.[712]

A meta-analysis has shown that intermediate dose dexamathasone (0.11–0.2 mg/kg) is a safe and effective multimodal pain strategy after surgical procedures.[14] Waldron et al. in their meta-analysis have reported not only significant decrease in postoperative pain at 24 h on movement, but also decrease in immediate as well as late postoperative pain at rest.[15]

Dexamethasone has a proven antiemetic efficacy in chemotherapy and following general anesthesia.[10] Its antiemetic effect has been postulated to be due to the central inhibition of prostaglandins related to the triggering of emesis and decrease in 5-HT turnover in the central nervous system or changes in the permeability of blood cerebrospinal fluid barrier to serum proteins.[1113] In contrast to our study showing negligible effect of dexamethasone on nausea and vomiting, other studies on children undergoing adenotonsillectomy or strabismus depicted significantly decreased incidence of nausea and vomiting with dexamethasone.[816] The reason for difference in the effect is probably due to the fact that adenotonsillectomy or strabismus repair and general anesthesia, both in themselves carry a high incidence of nausea and vomiting, and also doses used in children were 1 mg/kg, while doses in present study ranged from 0.13 to 0.27 mg/kg for an average 60 kg adult. However, our study echoes the findings of Nortcliff et al. who showed dexamethasone to have no significant effect on nausea and vomiting during cesarean section.[10] Another study by Liu has shown that dexamethasone 10 mg reduces postoperative nausea and vomiting in major gynecological surgery patients, but have no effect on pain when given immediately before skin incision during general anesthesia.[11]

In the present study, antinociceptive effects of dexamethasone on chronic neuropathic pain have not been studied due to poor patient compliance. Further studies in these directions are needed to fully elucidate the beneficial effects of dexamethasone.

CONCLUSION

Dexamethasone in doses of 16 mg given just prior to the performance of the intrathecal block in patients scheduled for infra-umbilical surgeries decreases postoperative pain on motion at 24 and 36 h. However, 8 mg dexamethasone has no significant effect on postoperative pain on the rest or motion. Both doses failed to demonstrate any significant antiemetic effects in these surgeries.