Paracetamol versus paracetamol/tramadol in postoperative intertrochanteric fracture: A noninferiority,randomized,controlled,double-blind study

Abstract

Background

One of the most common osteoporotic fractures among the elderly is hip fracture with tramadol frequently being prescribed for these patients. To decrease the risk of falling from tramadol, this study aimed to ascertain the effectiveness of paracetamol compared to paracetamol/tramadol for pain control following hip fixation surgery.

Method

This was a noninferiority, double-blind, randomized, controlled trial at a tertiary care hospital. All patients were recruited between February 2020 and March 2022. Patients were randomly assigned to paracetamol alone (Group A) or paracetamol/tramadol (Group B). All patients in both groups followed the same protocol for the first two days after surgery. To ascertain differences in pain control between the two groups, different regimens were followed from postoperative days 3–5. Pain scores were assessed by a visual analog scale (VAS). All patients were asked to complete a satisfaction questionnaire on day 5.

Result

A total of 30 patients were randomly allocated into Group A (paracetamol alone) and 30 into Group B (paracetamol + tramadol). The mean pain score for Group A was 5.85 ± 0.52 and 5.35 ± 0.74 for Group B. Mean cumulative doses in Group A were 4.50 ± 1.33 and 4.06 ± 1.18 in Group B. Although the mean satisfaction with pain management was higher in Group B, this was not statistically significant.

Conclusion

VAS scores from Group A were slightly higher than Group B. Based on a 2.0-point noninferiority margin of pain, paracetamol alone was not inferior to paracetamol/tramadol in postoperative intertrochanteric fracture.

Keywords

hip fracture postoperative pain paracetamol tramadol side effect

Introduction

Tramadol is a well-known, addictive, synthetic painkiller that is often prescribed for patients with acute and chronic pain.^1–5 Its side effects include nausea and decreased bowel motility which has been reported in 7% of tramadol users.^1,6–8 Since non-steroid anti-inflammatory drugs (NSAIDs) present potential life-threatening complications such as gastrointestinal bleeding or acute renal failure, especially among the elderly,⁹ the prescription of tramadol has steadily increased.^1,10,11

The most common osteoporotic fracture in geriatric patients is a hip fracture,^12,13 and paracetamol appears to be a reliable painkiller.^5,13–19 Unfortunately, the frequency of tramadol prescription instead of NSAIDs or paracetamol for hip fracture patients is likely to increase. Tramadol, a weak opioid, is frequently prescribed in these patients in combination with paracetamol.²⁰ Previous studies have shown that the analgesic effects of a weak opioid in combination with paracetamol were not different from the use of paracetamol alone.^5,15–18 Following hip fractures, it is essential to try to prevent the patient from falling; however, weak opioids such as tramadol can increase the chance of falling by 60%.^21,22 For this reason, the use of weak opioids for patients with a hip fracture needs to be raised as a concern.

Previous studies have noted that paracetamol is noninferior to paracetamol in combination with tramadol (paracetamol/tramadol) as far as analgesic effect, and paracetamol alone has fewer side effects.¹⁷ However, confounding factors in these studies need to be taken into consideration and interpreted with caution when assessing the effectiveness of paracetamol alone.

The aim of the present study was to ascertain the effectiveness of paracetamol in pain modulation compared with paracetamol/tramadol in postoperative hip fracture fixation. The study’s hypothesis was that the pain modulation effects of paracetamol alone were not inferior to paracetamol/tramadol in postoperative pain management among elderly patients.

Materials and methods

Study design

This study was a prospective, noninferiority, double-blind, randomized, controlled trial at a tertiary care hospital. The eligible participants were recruited between February 2020 and March 2022. Participants were randomly allocated to Group A (paracetamol-based pain regimen) or Group B (paracetamol/tramadol-based regimen). The outcome parameters were collected from both groups. The CONSORT study diagram is described in Figure 1.

Figure 1.

The Consolidated Standards of Reporting Trials (CONSORT) flow diagram.

Ethical considerations

Ethical approval was obtained from the research ethics committee (study number 60/2564), and the study was registered at the Thai Clinical Trial Registry (TCTR; TCTR20200201001). Before participants’ enrollment, the eligible patients were informed of the objectives of the study and the risks and benefits of participating in this trial. Written informed consent was obtained from all participants.

Study population

Patients with intertrochanteric fractures diagnosed by plain film hip X-ray, with anteroposterior and cross-table lateral views, were eligible to enroll in the study. Fractures were classified by the AO/OTA classification.²³ All patients were >60 years old and diagnosed with an intertrochanteric fracture either in the emergency room or out-patient department. All patients were required to understand the written and spoken Thai language. Patients with multiple traumas, liver cirrhosis, disorientation, or a history of allergy to paracetamol, morphine, or tramadol were excluded from the study. Patients who were undergoing procedures other than a cephalomedullary nail placement were also excluded from the study. Other reasons for patient exclusion are described in Figure 1.

Sample size calculation

Based on a previous study,¹⁷ the sample size was calculated using a 2.0-point noninferiority margin. Based on a 2-group noninferiority T-test with 80% power, it was determined that 27 patients would need to be enrolled in each group. To compensate for a possible drop-out of 10% of the participants, 30 patients were enrolled in each group.

Randomization and masking

All patients who were enrolled in the study were randomly assigned by a computerized number generator with a 1:1 allocation ratio. Moreover, a block of four was used to balance the total number of patients in each group resulting in 30 participants per group. Concealed opaque envelopes of the randomized package were prepared to allocate patients after their surgical intervention. Both the data collector and all of the patients were masked and blinded.

Outcome measurement

The mean postoperative pain assessment using a visual analog scale (VAS) every 4 h until discharge was the primary outcome. The mean pain for each day (day 3–5) and the worst pain score were collected and analyzed. The daily number of individual doses used and additional doses related to breakthrough pain were also collected for both groups. The overall satisfaction with each protocol, based on a Likert scale, and adverse effects which were defined as the secondary outcome, were evaluated on the day of discharge.

Intervention and data collection

Baseline characteristics of the enrolled patients consisted of age, sex, weight, body mass index (BMI), pre-injury ambulation status, and fracture pattern. Blood samples were taken for routine preoperative evaluation. All patients were admitted to the orthopedics ward and further assessed for preoperative baseline pain scores via VAS. Within 72 h after being admitted to the orthopedics ward, eligible patients underwent surgery by board-certificated orthopedists.

During surgery, a spinal block anesthetic procedure was used with 0.5% bupivacaine (MARCAIN®, Aspen Pharmacare HLDGS, LTD., Durban, South Africa) without morphine. No additional regional anesthesia was used. The surgical intervention followed the clinical practice guideline for intertrochanteric fracture.

Following surgery, all patients were transferred to the orthopedics ward, and the concealed envelope was opened to randomly allocate them into Group A or B (Figure 1). The nurses on the ward opened the envelope and administered the assigned regimen in the suggested sequence. The initial medication was paracetamol 500 mg (PATBLU®, Thai Nakorn Patana Co, Ltd. Nonthaburi Thailand) orally every 6 h on days 0–2 following surgery. Intravenous (IV) morphine was simultaneously prescribed at a dose of 0.1 mg/kg or 3 mg (maximum dose) every 3 h continuously on days 0–2. A VAS pain assessment was recorded every 4 h beginning immediately after surgery. Postoperative rehabilitation was begun on day 2 with weight-bearing as tolerated using a walker. Morphine was discontinued at midnight on day 2, while paracetamol continued to be administered to all patients.

To ascertain whether paracetamol was noninferior to tramadol, a placebo was prepared in the same color, size, and shape as tramadol. Patients in Group A received a placebo tablet orally every 8 h starting at 8 a.m. on day 3. The patients in Group B started tramadol 50 mg (PAINDOL®, Polipharm Co, Ltd. Samutprakarn, Thailand) every 8 h beginning at 8 a.m. on day 3. A VAS pain assessment was recorded every 4 h with routine vital signs monitoring. Physicians and ward nurses were notified of any adverse events or complications among patients participating in the protocol. In the case of an adverse event, all medications were discontinued, and appropriate care was provided.

The total number of doses of morphine, 0.1 mg/kg or 3 mg (maximum dose) IV PRN for pain every 3 h, were determined for each patient and used as one of the outcome parameters. All patients were asked to provide their level of satisfaction, as measured on a Likert scale, for the treatment provided and any adverse event management on day 5. Patients were discharged from the ward on day 5 and prescribed home medication consisting of paracetamol one tab orally PRN for pain every 6 h and tramadol 50 mg orally PRN for pain every 8 h.

Statistical analysis

Data were analyzed using IBM SPSS Statistics version 25. Descriptive statistics were used to ascertain demographic data. Mean and standard deviation were calculated for age, BMI, weight, VAS of pain from postoperative surgery to discharge, pain VAS during the day (days 3–5), the worst pain, additional pain medication, cumulative doses, and satisfaction level. Categorical data such as sex, fracture pattern, and pre-injury status were described by frequency and percentage. Chi-square test was used to determine proportion differences between the two groups. Data was proved normal distribution by Shapiro-Wilk Test. The noninferiority T-test was used to compare continuous outcome parameters, and a p-value of <0.05 was considered significant.

Results

A total of 69 eligible patients were recruited during the study period. 60 patients met the inclusion criteria and completed the protocol. A total of nine patients were excluded with the reasons for exclusion noted in Figure 1. There was no need for an intention-to-treat analysis, because all patients received the study medications as per the study design.

Baseline characteristics are noted in Table 1. The ratio of 33A1:33A2:31A3 fracture types in Group A was 21:5:4 and Group B was 24:5:1, respectively. Other baseline characteristics showed no significant differences between the two groups. There was also no significant difference in mean preoperative pain between the two groups (Group A, VAS = 9.3 ± 0.75; Group B, VAS = 9.23 ± 0.68).

Table 1.

Demographics.

Baseline characteristics	Paracetamol + placebo (group a; N = 30)	Paracetamol + tramadol (group B; N = 30)	p-value
Age, years (mean ± SD)	80.70 ± 8.02	77.70 ± 7.93	0.146
Sex (n, %)			1.000^d
Male	23 (76.67%)	23 (76.67%)
Female	7 (23.33%)	7 (23.33%)
BMI,^a kg/m² (mean ± SD)	26.28 ± 2.71	25.42 ± 3.51	0.291
Weight, kg (mean ± SD)	67.52 ± 11.30	62.87 ± 10.65	0.103
Pre-injury ambulation status			0.774
Without gait aids	22 (73.33%)	21 (70.00%)
With gait aids	8 (26.67%)	9 (30.00%)
Fracture pattern^b			0.367
AO33A1	21 (70.00%)	24 (80.00%)
AO33A2	5 (16.67%)	5 (16.67%)
AO33A3	4 (13.33%)	1 (3.33%)
Preoperative VAS^c (mean ± SD)	9.30 ± 0.75	9.23 ± 0.68	0.719

^aBody mass index.

^bFracture pattern was classified by AO/OTA system.

^cVisual analog scale.

^dChi-square test.

The primary outcomes of this study, mean pain on each day, mean pain from day of surgery to day of discharge, and worst pain are noted in Table 2. There was a significant difference in VAS pain during day 4, day 5, and the mean VAS of three consecutive days between the two groups. The mean VAS difference was 0.49 ± 0.64, 0.34 ± 0.42 and 0.50 ± 0.40 on day 4, day 5, and the mean of three consecutive days, respectively. The worst pain difference between the two groups was a 0.10 ± 0.80.

Table 2.

Clinical outcome parameters.

Outcome measure	Paracetamol + placebo (group a, N = 30)	Paracetamol + tramadol (group B, N = 30)	p-value
VAS^a of postoperative pain (mean ± SD)
Day 3	6.89 ± 1.39	6.21 ± 1.68	0.069
Day 4	5.97 ± 0.79	5.48 ± 0.81	0.019
Day 5	4.70 ± 0.54	4.36 ± 0.74	0.037
Overall; day 3 to day 5	5.85 ± 0.52	5.35 ± 0.74	0.003
Worst postoperative pain (mean ± SD)	8.63 ± 0.72	8.53 ± 1.04	0.667
Additional medication (dose; mean ± SD)
Day 3	2.30 ± 0.79	2.06 ± 0.87	0.282
Day 4	1.80 ± 0.55	1.63 ± 0.67	0.297
Day 5	0.40 ± 0.50	0.37 ± 0.50	0.795
Cumulative dose	4.50 ± 1.33	4.06 ± 1.18	0.186
Satisfaction^b (mean ± SD)	4.76 ± 0.44	4.73 ± 0.45	0.770
The number of adverse events	3	5	0.447

^aVisual analog scale.

^bSatisfaction was determined at postoperative Day 5 on a Likert scale (0–5).

Based on a noninferiority difference of 2.0 points, paracetamol alone was not inferior to paracetamol/tramadol following intertrochanteric fracture surgery. Despite more additional medication and more doses of medication in Group A, the mean differences between the two groups were not statistically significant (Table 2).

The mean satisfaction with pain management was high in both groups, with a mean difference of 0.03 ± 0.19 on the Likert scale. A total of eight patients had a side effect of nausea with three from Group A (10%) and five from Group B (16.67%).

Discussion

From this study, we can conclude that Paracetamol alone is not inferior to Paracetamol/Tramadol. Nevertheless, nowadays analgesic drugs used following postoperative hip fracture procedures include strong opioids, weak opioids, NSAIDs, and paracetamol.^8,13,24–26 However, patients with contraindications for NSAIDs tend to have weak opioids, such as tramadol, prescribed. There are concerns that weak opioids may decrease the efficacy of strong opioids by blocking receptors, and they may also increase the side effects of opioid usage.^6,7,22 Furthermore, there is no evidence supporting the benefit of strong opioids being prescribed with weak opioids.^27,28

Tramadol often causes side effects such as nausea, vomiting, and constipation which may lead to a decrease of a patient’s quality of life.^6,7,22,29,30 In addition, there is significant concern about the over prescription of opioids. As noted in a previous study, the analgesic effect of tramadol in combination with paracetamol was not different from paracetamol alone.¹⁷ However, the results were limited due to the small sample size, study design, and drug prescribing protocol. Additionally, this study only evaluated the self-administration of analgesic drugs thereby resulting in multiple confounding variables.

In this study, elderly patients who tend to be prescribed tramadol, and have a higher risk of side effects, were selected as the study population.²² The study was conducted on an in-patient ward which eliminated potential confounding factors such as the method and timing of drug administration and allowed for close monitoring by healthcare providers. Fall prevention is one of the essential elements of a hip fracture treatment protocol. Tramadol increases the risk of falling by about 1.6 times. Therefore, avoiding opioids and prescribing alternative analgesic drugs should be part of fall prevention.^21,22

In this study there was no statistical difference in the baseline characteristics of the two groups. The greater incidence of pertrochanteric fractures was higher in females than males in this study which is in accord with other studies.¹² Despite the 10% higher incidence of type 31A1 fractures in Group A, the overall proportion of fracture types was not significantly different between the two groups. Therefore, fracture type did not affect postoperative VAS after hip fixation surgery.

Although the mean pain VAS on each day, and the overall pain VAS from surgery to discharge day were higher in Group A (paracetamol + placebo) than in Group B (paracetamol/tramadol), these scores did not exceed the predetermined 2.0 points to indicate inferior treatment. Therefore, paracetamol alone could be considered noninferior to paracetamol/tramadol for treating pain following intertrochanteric fracture surgery. Given the higher baseline preoperative pain score in Group B (0.5-point difference), one possible explanation may be that the patients in Group A had a slightly lower pain threshold and responsiveness to pain; however, the mean difference in preoperative pain was not statistically significantly different. The mean score for worst pain measured during hospitalization did not differ between the groups, 8.63 ± 0.72 in Group A and 8.53 ± 1.04 in Group B, indicating that pain responsiveness was not different between the groups.

The side effects of nausea and vomiting in Group A cannot only be attributed to being prescribed paracetamol with a placebo. The most likely explanation is the number of other medications which were injected including morphine IV 7, 7, and 8 times, respectively among these three patients. It is also likely that the side effects of nausea and vomiting in Group B were also caused by morphine.

This study does have some limitations. First, a total of 5 days on the in-patient ward did not provide a sufficient period of follow-up to determine both the outcomes and side effects of tramadol, no incidence of falling and derilium due to all patients were closely observed by health care providers. Additional studies should be conducted over a longer period of time and include additional side effect such as falling risk and stability test. Second, this study was conducted at a single-center. While this may help to reduce variability in the treatment protocol, the findings may not be generalizable to other tertiary care centers or different populations. A multicenter study should be considered in future studies. Finally, the patients’ surgical interventions were performed by different orthopedic surgeons. Despite using the same treatment protocols and standard clinical practice guidelines for hip fractures, each individual orthopod may still operate somewhat differently.

Conclusion

The mean pain VAS on each day after surgery, and the overall mean pain VAS from surgery to discharge day were slightly higher in paracetamol alone group compared to the paracetamol/tramadol group. However, based on the predetermined 2.0-point difference in pain score to indicate noninferiority, paracetamol alone appears to be noninferior to paracetamol/tramadol for the management of postoperative pain in patients undergoing intertrochanteric fracture surgical repair.

Footnotes

Acknowledgements

The authors would like to thank all of the patients for participating in this study and Enago () for the English language review.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Todsaporn Sirithiantong

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