INTRODUCTION:

Tramadol is one of the commonly preferred analgesics due to its less incidence of respiratory depression.^1,2 It is an opioid analgesic that not only acts at the mu opioid receptor agonist for its analgesic action but also has a central analgesic action that blocks the reuptake and enhances the release of serotonin at spinal antinociceptive pathways.^3‑5

Ondansetron is a serotonin 5‑HT3 receptor antagonist. Its use as an antiemetic in the postoperative period, chemotherapy drugs, radiation therapy is well established.⁶ Due to the different actions of tramadol and ondansetron on serotonin receptors, few previous studies have shown that ondansetron and tramadol administration increased tramadol requirement and decreased tramadol analgesic efficacy.^7,8 On the contrary, there were studies also stating that administration of these drugs together neither increased analgesic consumption nor emesis⁹.

The primary objective was to determine the analgesic effectiveness of tramadol when given alone versus when given along with ondansetron by measuring VAS with regard to the quality of analgesia. Secondary goals were to compare the need for rescue analgesia and side effects such as nausea and vomiting by evaluating the scoring scale of condition [CSS] between two groups.

METHODS

A prospective randomized study was conducted at surgical ICU in our hospital, included 60 patients with pain after obtaining an informed consent. Patients have been classified into two classes of 30 each.

Group A- Tramadol injection 100milligrams intravenously over 10minutes, accompanied by 12 milligrams/hour of tramadol plus 0.8milligrams/hour of ondansetron as an infusion.

Group B- Injection of tramadol 100milligrams intravenously over 10 minutes, followed by 12 milligrams per hour of tramadol as an infusion. Criteria for inclusion: Age: 18-70 years, post-operative patients who underwent GA surgery.

Exclusion criteria: age < 18 years, pregnant patients, lactating mothers, reported cases of seizure disorder, elevated intracranial pressure, antidepressant patients, patients with drug abuse, patients with compromised renal or hepatic function, patients with mechanical ventilation, reported allergies to tramadol or ondansetron.

Hemodynamic parameters and pain assessment based on the Visual Analogue Scale (VAS) were evaluated at 0, 3, 6, 12 and 24 h in both groups A and B. Analgesic rescue in the form of paracetamol 1 g was supplemented intravenously at any time if VAS was > 4. Side effects such as nausea, vomiting, and degree of sedation were measured using a 4-point ordinal scale.

Scoring for nausea, vomiting, and sedation

Condition scoring criteria

Nausea

0 ‑ No nausea

1 ‑ Mild nausea, not requesting pharmacological rescue

2 ‑ Nausea, requesting pharmacological rescue

3 ‑ Nausea resistant to pharmacological treatment

Vomiting

0 ‑ No vomiting

1 ‑ Vomiting, single event

2 ‑ Vomiting, repeated events requesting pharmacological rescue

3 ‑ Vomiting resistant to pharmacological treatment

Sedation

0 ‑ Patient fully awake

1 ‑ Patient slightly drowsy

2 ‑ Patient sleeping but easily arousable

3 ‑ Patient unconscious, not arousable

RESULTS:

Table 1: Age wise distribution of two classes of patients

Age Group	Group A	Group B	p-value
Mean ± SD	50.36±13.17	47.56±14.08	P = 0.82,NS
Range	23-70 yrs	19-68 yrs	P = 0.82,NS

Table 2: Gender wise distribution of two classes of patients

Gender	Group A	Group B	p-value
Male	21(70%)	18(60%)	p=0.41, NS
Female	9(30%)	12(40%)
Total	30(100%)	30(100%)

Graph: 1

Table 3: Comparison of pain on VAS in two groups

	Group	N	Mean	Std. Deviation	Std. Error Mean	p-value
0 hrs	Group A	30	8.26	0.44	0.08	p=0.54,NS
0 hrs	Group B	30	8.20	0.40	0.07	p=0.54,NS
3 hrs	Group A	30	3.66	0.71	0.12	p=0.0001,S
3 hrs	Group B	30	2.50	0.73	0.13	p=0.0001,S
6 hrs	Group A	30	3.06	0.58	0.10	p=0.0001,S
6 hrs	Group B	30	2.10	0.66	0.12	p=0.0001,S
12 hrs	Group A	30	2.13	0.50	0.09	p=0.0001,S
12 hrs	Group B	30	1.36	0.55	0.10	p=0.0001,S
24 hrs	Group A	30	1.96	0.71	0.13	p=0.0001,S
24 hrs	Group B	30	1.30	0.53	0.09	p=0.0001,S

On comparing both the groups, group A and B, group A had a mean value of 8. 26 at 0 hours and group B had a mean value 8.20 at 0 hours, hence there was no significant difference between the groups (P value=0.54 NS). On comparing mean values at 3 hours, there was a significant difference on VAS. There was also a significant difference found in mean VAS at 6 hours. at 12 hours, there was a significant difference observed in VAS when both the groups were compared. At 24 hours, there was a significant difference observed when both the groups were compared.

Graph 2: Comparison of mean difference in pain on VAS in two groups

Graph 3. Rescue analgesia requirement

Table. 3 Rescue analgesia requirement

Time In hours	Group-A	Group-B	p-value
0	0	0	-
3	4	0	P value-0.04, S
6	0	0	-
12	0	0	-
24	0	0	-

Graph 3, shows 4 patients in group A required rescue analgesia at 3 hrs with inj. paracetamol 1 gram who were having VAS above 4 and no patient in group B required rescue analgesic. Hence there was a significant difference (p-0.04). When both the groups were compared with respect to requirement of rescue analgesia.

Table 4: Comparison of condition scoring criteria in two groups

Criteria	Group A	Group B	p-value
Nausea	1(3.33%)	3(10%)	P = 0.30, NS
Vomiting	1(3.33%)	3(10%)	P = 0.30, NS
Sedation	3(10%)	3(10%)	-

As seen above in table.4 depicted in graph 4, one patient (3.33%) had grade 1 nausea or vomiting in Group A and 3 patients (10%) had grade 2 nausea vomiting in Group B requiring pharmacological rescue according to CSC.

Graph 4: Comparison of condition scoring criteria in two groups

DISCUSSION:

Tramadol demonstrates its analgesic activity via its affinity with the mu receptor, and has a poor affinity with κ and δ opioid receptors. Recent studies have also shown that by inhibiting serotonin and nor-epinephrine reuptake and preventing nociceptive impulses, tramadol exhibits a key analgesic action.¹⁰

On comparing group A and B in our study, we found that, group A has shown mean value of 8.26 at 0 hours i.e, when the patients gets admitted postoperatively in SICU and group B has shown mean value 8.20 at 0 hours, hence there is no significant difference between both the groups (P value equal to 0.54 NS). On comparing mean values at 3 hours, group A has shown mean value 3.66 and group B showed mean value 2.50, hence a significant difference was found on VAS at 3 hours (P value 0.00001, S). There was also a significant difference seen in mean VAS at 6 hours with group A having mean value 3.06 and group B having mean value 2.10 (P value 0.001, S). Group A has a mean value of 2.13 at 12 hours and group B had a mean value of 1.36 at 12 hours showed a significant difference in VAS at 12 hours when both the groups were compared (P value 0.0001, S). At 24 hours, group A has a mean value of 1.96 and group B it is 1.30 showing a significant difference when both the groups were compared (P value 0.0001, S).

Thus we have observed that giving ondansetron with tramadol infusion though decreases pain seen by VAS when compared with baseline VAS on admission, but still the VAS score is higher postoperatively till 24 hrs when compared with only tramadol infusion group indicating better analgesia in only tramadol infusion group.

Also, patients in group A required rescue analgesia at 3 hrs with inj paracetamol 1 gm who were having VAS above 4 and no patient in group B required rescue analgesic. Hence it showed a significant difference (p-0.04) when both the groups were compared with respect to requirement of rescue analgesia.

As seen in table.4 depicted in graph 4, one patient (3.33%) had grade 1 nausea or vomiting in Group A and 3 patients (10%) had grade 2 nausea vomiting in Group B requiring pharmacological rescue according to CSC (P = 0.30, NS). Hence there was not a significant difference with respect to nausea and vomiting when both the group were compared.

Cui et al. stated that there could be the release of 5‑HT in dorsal horns of the spinal cord by stimulation of periaqueductal gray matter and results in inhibition of nociception of dorsal horn neurons.¹¹ These statements prove that serotonin has a role in nociceptive pathways. Similar receptors are present on nociceptive primary afferent fibers not only on peripheral free terminal but also centrally on the spinal terminal, and these receptors are also present on neurons of the dorsal horn. Ondansetron, a serotonin 5 HT3 receptor antagonist, exerts its antiemetic properties by blocking the stimulus zone of the chemoreceptor and 5hydroxytryptamine 3 (5HT3) enteric neuron receptors. In the postoperative period, studies compared tramadol as an analgesic with either oral or intravenous intermittent bolus versus infusion and concluded that tramadol infusion was successful as an analgesic compared to oral or intravenous intermittent bolus.¹²

On the postoperative period, co‑administration of ondansetron with tramadol by patient‑controlled analgesia resulted in the decreased analgesic effect of tramadol probably due to blocking of 5‑HT3 spinal receptors¹³. A study by Rauers NI, et al stated co-administration of ondansetron neither increased tramadol consumption nor frequency of postoperative nausea and vomiting in the postoperative setting¹⁴. Vale C, et al¹⁵ studied by patient controlled analgesia in the postoperative period and reported that ondansetron acutely decreases human analgesic efficacy of tramadol. ⁸

We conducted the study in surgical intensive care patients experiencing postoperative pain and not any other pain. At 0, 3, 6, 12, and 24hrs pain assessment was done in both the groups by VAS and patients were substituted rescue analgesia in the form of intravenous paracetamol when required.

The limitations we had were, we concluded our study in surgical I.C.U patients postoperatively. Though all the patients admitted to S.I.C.U at 0 hrs had a VAS score of >8, doesn’t mean patients who underwent different surgeries could have same pain threshold throughout during recovery and for same duration. Hence we consider this to be a limitation of our surgery. Also there can be multiple causes for post operative nausea and vomiting which can be present even before study drugs are started or can develop later on not related to study drugs which can be another limitation for our study. Hence we recommend comparison of analgesia in postoperative patient undergoing same type of surgeries.

CONCLUSION:

We have concluded that administration of tramadol along with ondansetron should not be practiced in ICU patients as ondansetron decreases analgesic efficacy of tramadol and nausea and vomiting with tramadol should be managed with any other antiemetic other than ondansetron.

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Received on 16.04.2020 Modified on 01.08.2020

Research J. Pharm. and Tech. 2021; 14(6):3157-3160.

DOI: 10.52711/0974-360X.2021.00550