INTRODUCTION:

The term pain expresses an uncomfortable sensation in the body that varies from annoying to debilitating. The perioperative period describes three following distinct phases: initial phase is a preoperative phase, second phase is an intraoperative phase, and final phase is a postoperative phase¹.

Perioperative pain is an outcome of inflammation produced by tissue trauma or direct nerve injury. Further, the frequency and severity of pain postoperative pain rely upon the nature, location, and extent of surgery.

Excessive level of postoperative pain impairs the quality of recovery, affects patient satisfaction, and rising healthcare costs². Adequate pain control in patients undergoing orthopedic surgery is pivotal in improving patient comfort and satisfaction in the postoperative period. Evidence suggests that approximately 70% of patients suffer from moderate to severe pain during the perioperative period³. Although NSAIDs are considered as safe medications in general, but serious side effects are still present and can affect different parts of the body. Inadequately managed postoperative pain may predispose to complications and extended rehabilitation⁴. Suitable pain relief during post-operative period leads to reduced hospital stays, and better patient satisfaction⁵. Improved interventions can enhance patients’ attitudes to and perceptions of pain⁶. Rational combinations of analgesic with different mechanisms of action can improve efficacy and/or tolerability and safety compared with full analgesic dose individually⁷. Recent advance in the knowledge of pathophysiology of pain and improvement of analgesic drugs and techniques, little improvement will show in post- operative pain management^8. Reducing patients' pain is one of the main medical goals which is often executed by giving them narcotic drugs but these drugs usually have side effects that make them less effective⁹. Pain assessment plays a major role in the management of chronic and acute pain. If assessment was done, we can improve the pharmaceutical care and improved socio-economic status of the patients¹⁰. Pain management is reflected on patient satisfaction. Improving patient satisfaction in hospitals is a high priority for organizations seeking to improve patient care¹¹. A large class of medications useful against both pain and inflammation, NSAIDs are staples in arthritis treatment. A number of NSAIDs, such as Ibuprofen (Advil, Motrin), Naproxen Sodium (Aleve), and Ketoprofen (Orudis, Oruvail) are available over the counter.¹² The main task of each therapist is to prescribe the right course of treatment, mainly appointment of the most effective drug. Despite the large number of NSAID their effectiveness may vary significantly^13.

The goal of perioperative pain management is to relieve pain, bring down the length of hospital stay, promote early motion after surgery, and accomplish patients’ satisfaction¹⁴. The conception of the multimodal approach was initiated to achieve these goals. This approach combines various classes of drugs and different analgesic techniques to improve the outcome of the postoperative period. This concept is introduced mainly to reduce or eliminate the need for opioids. The cause behind the failure of the multimodal analgesic concept to improve the clinical outcome is due to improper combination and dosage of analgesics^15,16.

The most commonly used analgesics in perioperative pain management are opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, gabapentin/pregabalin, tramadol, and other non-opioid analgesics, and their combinations¹⁷. Pain due to fractures and surgeries over the bone need tenacious administration of pain medication. NSAIDs are primarily used for this purpose but there is a need for supplementation of opioids or other medicine. Recent literature has shown the importance of antidepressants over chronic pain conditions¹⁸. Antidepressants include a wide range of medications such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors. Among those, TCA plays a significant role in the treatment of chronic pain.

The dose of TCA required in the treatment of pain management is much lower than the dose required to treat depression. The main reason for the analgesic effect of TCAs is inhibition of norepinephrine reuptake¹⁹. In addition to this, TCAs also antagonize peripheral sodium channels and spinal N-methyl-d-aspartate receptors. These mechanisms suppress central sensitization that is important in the pathophysiology of acute postoperative pain²⁰. The purpose of this study was to compare the effect of NSAIDs with opioids and NSAIDs with TCAs in the perioperative pain management of orthopedic patients.

METHODOLOGY:

Study Design and Subjects:

A prospective observational study conducted for six months at the Inpatient Unit Department of Orthopaedics of tertiary care Hospital, Hyderabad. This study was approved by the institutional review board (IRB) of Deccan College of Medical Sciences with IRB project No.2021/32/007. Written informed consent was obtained from all study participants. All subjects aged more than 18 years who got admitted to the hospital with the problem of any type of fracture (upper and lower limb) were allowed to participate in this study. Patients who were not willing to participate were excluded from this study.

Treatment and Data Collection:

The participants were randomly divided into two groups. In group I, perioperative treatment with opioids and postoperative treatment with NSAIDs + opioids were given. In group II, perioperative treatment with TCAs and post-operative treatment with NSAIDs + TCAs were given. The pain intensity of perioperative patients was assessed using the visual analogue scale (VAS). Pain outcome was evaluated using the pain outcome questionnaire (POQ). Data relevant to the study was obtained from the patient’s case sheet, history interview, and patients’ previous medical records The collected data were documented in a designed case report form.

Study Outcomes:

The primary outcome was to reduce pain intensity and minimize side effects using opioids and TCAs. The secondary outcome was to compare the analgesic and cognitive effects of opioids and TCAs in perioperative pain management.

Statistical analysis:

Mean and standard deviation (SD) were provided for continuous variables whereas numbers and percentages for qualitative variables. The study data were analyzed using Statistical Package for the Social Sciences version 26.0 software. Descriptive statistics were performed to analyze demographic profile, complaints, adverse events, BP, HR, pain outcome, patient satisfaction, and length of hospital stay. Comparative analysis was performed using a chi-square test for categorical variables and independent t-test was used for continuous variables. The 5% level was used to identify the differences between groups that were of statistical significance (P-value <0.05) since the CI is 95%.

RESULTS:

AGE AND GENDER:

A total of 80 participants were enrolled in this study based on the inclusion criteria, of which 54% were males and 46% were females. They were randomized into two study groups namely Group I and II. Each group consists of 40 patients.

The mean age of two group patients was 43.27±17.81 and 51.92±17.13 years. No significant differences in gender and age were observed between the two groups.

Figure 1: Comparison of Age and Gender

Patients receiving Opioids were seen to have effect on cognitive function: Change in their sleep pattern and mood/behavior (1.5%), confusion (0.12%), difficulty with memory and impaired balance and coordination (0.07%).

Table 1: Effect on Cognitive Function

Effect on cognitive function	No. of patients
Change in sleep pattern	6(1.5%)
Change in mood Behavior	6(1.5%)
Difficulty with memory	3(0.07%)
Confusion	5(0.12%)
Impaired balance and Co ordination	3(0.07%)

Comparison Based on Complaints and Adverse Events:

The highest frequency of complaints seen in both groups was pain, swelling, and deformity of limbs. There was no significant difference in the complaints between the study groups.

Figure 2: Complaints in Group 1 and Group 2

On comparing adverse events between the study groups, a significant difference exists in the occurrence of the following adverse events: nausea and vomiting, flushing, headache and constipation(P<0.05)

Figure 3: Adverse Events in group 1 and group 2

Comparison of Pain Outcome

Table 2: Comparison Based on Pain Outcome

Pain Outcome
GROUP			Frequency	%	Valid %	Cumulative %
Group I	Valid	Mild Improvement	6	15.0	15.0	15.0
		Moderate Improvement	22	55.0	55.0	70.0
		Significant Improvement	12	30.0	30.0	100.0
		Total	40	100.0	100.0
Group I	Valid	Mild Improvement	4	10.0	10.0	10.0
		Moderate Improvement	20	50.0	50.0	60.0
		Significant Improvement	16	40.0	40.0	100.0
		Total	40	100.0	100.0

X²=4.186; p>0.05

Pain outcome had been assessed. Both the groups have shown notable improvement after the treatment. But significant difference was not found in the pain outcome between group I and group II patients.

Figure 4: Pain outcome

Comparison of Patient Satisfaction and Length of Hospital Stay

Figure 5: Patient satisfaction and length of hospital stay

On evaluating patient satisfaction, 38% of patients in group I reported no pain and mild pain whereas, 40% of patients reported no pain and mild pain in group II. However, a significant difference was not found in the patient satisfaction and length of hospital stay between the two study groups.

Comparision of Blood Pressure and Heart Rate:

Pre and postoperative blood pressure and heart rate were compared. No significant difference exists in the pre and postoperative blood pressure as well as heart rate in both the groups.

Table 3: Blood pressure and heart rate

Paired Sample Test [BP]
Group			Paired Differences					T	Df	Sig. (2-tailed)
			Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
			Mean	Std. Deviation	Std. Error Mean	Lower	Upper
Group I	Pair 1	Blood Pressure-Pre-OP - Blood Pressure-Post-OP	0.000	0.226	0.036	-0.072	0.072	0.320	39	1.000
Group II	Pair 1	Blood Pressure-Pre-OP - Blood Pressure-Post-OP	0.050	0.450	0.071	-0.094	0.194	0.703	39	0.486
Paired samples Test (HR)
Group			Paired Differences					T	Df	Sig. (2-tailed)
			Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
			Mean	Std. Deviation	Std. Error Mean	lower	Upper
Group I	Pair 1	Heart Rate-Pre-OP - Heart Rate-Post-OP	0.42500	5.05299	0.79895	-1.19102	2.04102	0.532	39	0.598
Group II	Pair 1	Heart Rate-Pre-OP - Heart Rate-Post-OP	-0.67500	6.05694	0.95769	-2.61210	1.26210	-0.705	39	0.485

Group I- Paired sample t test based on pre and post day

Table 4: Paired sample t test based on pre and post op day

Paired Samples Test
		Paired Differences					t	df	Sig. (2-tailed)
		Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
		Mean	Std. Deviation	Std. Error Mean	Lower	Upper
Pair 1	Pre-OP-Day 1 - Post OP-Day 3	-4.200	4.43298	.70092	-5.61773	-2.78227	-5.992	39	.000
Pair 2	Pre-OP-Day 1 - Post OP-Day 4	1.3250	5.66767	.89614	-.48761	3.13761	1.479	39	.147
Pair 3	Pre-OP-Day 1 - Post OP-Day 5	5.8500	6.10401	.96513	3.89784	7.80216	6.061	39	.000
Pair 4	Pre-OP-Day 2 - Post OP-Day 3	-5.300	2.84830	.45036	-6.21093	-4.38907	-11.768	39	.000
Pair 5	Pre-OP-Day 2 - Post OP-Day 4	.22500	4.21528	.66649	-1.12311	1.57311	.338	39	.737
Pair 6	Pre-OP-Day 2 -Post OP-Day 5	4.7500	5.27573	.83417	3.06274	6.43726	5.694	39	.000

Group II- Paired sample t test based on pre and post day

Table 5: Group II- Paired sample t test based on pre and post day

Paired Samples Test
		Paired Differences					t	df	Sig. (2-tailed)
		Mean	Std. Deviation	Std. Error Mean	95% Confidence Interval of the Difference
		Mean	Std. Deviation	Std. Error Mean	Lower	Upper
Pair 1	Pre-OP-Day 1 - Post OP-Day 3	-6.050	5.69278	.90011	-7.87064	-4.22936	-6.721	39	0.000
Pair 2	Pre-OP-Day 1 - Post OP-Day 4	-1.525	5.93118	.93780	-3.42188	.37188	-1.626	39	0.112
Pair 3	Pre-OP-Day 1 - Post OP-Day 5	3.8750	7.25077	1.14645	1.55609	6.19391	3.380	39	0.002
Pair 4	Pre-OP-Day 2 - Post OP-Day 3	-6.675	4.07863	.64489	-7.97941	-5.37059	-10.351	39	0.000
Pair 5	Pre-OP-Day 2 - Post OP-Day 4	-2.150	4.14822	.65589	-3.47666	-.82334	-3.278	39	0.002
Pair 6	Pre-OP-Day 2 - Post OP-Day 5	3.2500	5.93015	.93764	1.35345	5.14655	3.466	39	0.001

Different set of days were considered to assess the effect of opioids and TCAs on pain intensity. A significant difference was noticed in most of all the pairs except between day 1 and day 4 in both the groups and between day 2 and day 4 in group I.

DISCUSSION:

NSAIDs are the primary agent to treat perioperative pain effectively followed by opioids and non-opioid medicines. Many shreds of literature favour the use of TCAs in pain management²¹. Choice of a drug to relieve pain relies on the severity of pain. There are numerous pain scales available that helps in measuring the extent of one’s pain. The VAS is one among them. VAS is a validated scale to assess acute and chronic pain. Though there is conflicting evidence concerning the benefit of VAS, it is still commonly used clinically²². In this study, we studied 80 patients who were administered with NSAIDs plus opioids and NSAIDs plus TCAs as a perioperative pain management regimen. Gender is one of the important factors in the modulation of pain. Some data strongly suggest that females experience increased pain sensitivity and more painful diseases²³. The present study comprises 43 males and 37 females. The Success of opioid therapy depends on attaining a balance between analgesic effects and side effects. The cognitive impairment induced by opioids hampers physicians and patients from commencing opioid therapy. Certain studies reveal that chronic pain itself impairs cognitive functions²⁴. The present study findings exhibited patients who received opioids have shown changes in the sleep pattern and mood/behaviour, confusion, poor memory, and impaired balance/coordination.

Both the study groups displayed various adverse events. Patients treated with opioids were highly reported nausea/vomiting, headache, flushing, respiratory depression, and constipation that is consistent with the report of Benyamin et al²⁵. Patients treated with TCAs were mostly reported prolonged QT interval, weight gain, and xerostomia which is similar to the findings of Gillman et al²⁶. In this study, pain outcome was assessed using the POQ. 30% of patients in group I showed significant improvement whereas, in group II, 40% of patients displayed significant improvement. Although, a statistically significant difference was not found between the groups. In addition, both the study groups have disclosed similar levels of patient satisfaction. Length of hospital stay is influenced by the choice of pain medication administered to the patients²⁷. The maximum length of hospital stay observed in the present study was 7 days whereas, the minimum was 4 days. We found that patients of both the treatment groups have not shown a significant difference in their length of stay. Studies have shown that the administration of opioids led to a decrease in blood pressure and heart rate while on the contrary, TCAs led to an increase in blood pressure and heart rate^{28, 29}. A significant pre and postoperative difference were not noticed in the blood pressure and heart rate of patients in both the study groups.

By binding to opioid receptors, opioids block the pain signals that transmit from the body through the spinal cord to the brain thereby imparts pain relief³⁰. As mentioned earlier, TCAs impart pain relief through inhibiting presynaptic reuptake of the biogenic amine’s serotonin and noradrenaline along with other mechanisms like N-methyl-D-aspartate receptor and ion channel blockade¹⁹. Both group I and group II patients have exhibited a marked reduction in their pain severity. A significant pre and postoperative difference were found in the pain intensity of patients in both groups. Therefore, the findings of this study suggest that both opioids and TCAs along with a combination of NSAIDs provide better pain control in the participants.

We confess that our study has few limitations. First, the study was limited by a smaller sample size and shorter duration of the study. Second, follow-up of patients could not be done after discharge which would have assisted us to rule out better outcomes. Hence, Large, multi-centric studies are required in the future to evaluate the outcomes.

CONCLUSION:

Perioperative pain management is an important factor in measuring the intensity of pain. Poorly controlled pain has a pessimistic influence on the patients’ wellbeing and delays wound healing correspondingly. Based on our observations, we conclude that both opioids and TCAs have similar potential to manage perioperative pain. But blood pressure and heart rate were raised in patients receiving TCAs although this difference was not statistically significant. The frequency of adverse events was more in patients receiving opioids than patients receiving TCAs. Moreover, the use of a combination regimen proved to be more efficacious than an individual regimen. The addition of NSAID in postoperative management should be increased to reduce the dose of opioids thereby it decreases the frequency of adverse events. Further studies are recommended to validate the results as well as to explore new outcomes with the use of TCAs for perioperative pain management.

ACKNOWLEDGEMENT:

We would like to thank all professors and colleagues for their invaluable help in the preparation of this manuscript.

CONFLICTS OF INTEREST:

The authors declare no conflicts of interest.

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Received on 09.08.2021 Modified on 18.11.2021

Research J. Pharm. and Tech 2022; 15(12):5501-5506.

DOI: 10.52711/0974-360X.2022.00928