Comparison of intravenous pethidine and sublingual buprenorphine on postoperative pain severity in patients with vertebral fracture surgery: a randomized multicenter, double-blind controlled trial

Abstract

Background:

The present study aims to compare the efficacy of intravenous pethidine with sublingual buprenorphine in pain relief following surgical intervention for vertebral fractures.

Method:

This study is a randomized, double-blind clinical trial conducted among individuals undergoing surgery for thoracic and lumbar vertebral fractures. Before surgery, all patients received 1 g of intravenous acetaminophen. Sublingual buprenorphine was administered at 0.4 mg in three doses before surgery and two doses after surgery. Alternatively, patients received intravenous pethidine at a dose of 25 mg in two doses before surgery and one dose after surgery. Postoperative pain was monitored for the first 24 h using the Visual Analog Scale, and any treatment-related adverse effects were also assessed.

Results:

In this study, the mean age of patients was 55.10 ± 13.24 years, with 55% being male. Only 16 (13.3%) of the patients evaluated experienced nausea and vomiting. The most common fracture site among the subjects was lumbar, with a frequency of 72 patients (60%). The mean pain scores increased postoperatively compared to preoperative scores and decreased over time. No statistically significant differences were observed between the two groups at any time point. According to the repeated measures analysis of variance statistical test, two groups had no significant changes in pain levels.

Discussion:

Sublingual buprenorphine does not differ from intravenous pethidine regarding pain intensity following vertebral fracture surgery; however, it is considered safer with fewer side effects. Furthermore, the trend of pain changes in both treatment groups did not show significant differences.

Introduction

Spinal fractures can vary in severity. Some fractures are serious injuries resulting from high-energy trauma that require emergency treatment, while others may occur from less significant events, such as a minor fall, particularly in older individuals whose bones have been weakened by osteoporosis^[1]. Most spinal fractures occur in the thoracic or lumbar regions or at the junction of these two areas, and treatment depends on the severity of the fracture and whether the patient has any associated injuries^[2].

HIGHLIGHTS

• Spinal fractures are serious injuries resulting from high-energy trauma that require emergency treatment

• Fractures of the thoracic or lumbar spine can lead to moderate-to-severe back pain that worsens with movement.

• Sublingual buprenorphine is considered safer with fewer side effects.

Fractures of the thoracic or lumbar spine can lead to moderate-to-severe back pain that worsens with movement^[3]. If the spinal cord or nerves are involved, patients may experience bowel/bladder dysfunction along with numbness, tingling, or weakness in the limbs. In cases where the fracture results from high-energy trauma, there may be a risk of brain injury, loss of consciousness, or visible bone protrusion. Additional injuries may also be present, referred to as distracting injuries, that can overshadow the back pain. In such instances, it should be assumed that the patient has sustained a spinal fracture, especially following a high-energy event such as a motor vehicle accident^[4].

Spinal surgery plays a significant role in the treatment of vertebral fractures, to the extent that the frequency of such surgical procedures has notably increased during this period^[5,6].

Postoperative pain is one of the most common issues faced by patients hospitalized for vertebral fractures, and its reduction can significantly impact surgical outcomes and patient satisfaction with the results of spinal fracture surgeries. This issue may also be accompanied by other problems such as nausea and vomiting, hypotension, and shivering; hence, preventing this problem is of paramount importance^[1]. An appropriate medication for postoperative pain management should possess the following characteristics: minimize adverse effects, and ideally be chosen by the patient . Additionally, it should allow for minimal time spent on medical personnel interactions and offer various formulations with different dosages to accommodate individual patient needs based on body weight^[7–9]. the medication must be “patient-acceptable,” has minimal side effects, presents no significant drug interactions, and does not impair the patient’s level of consciousness^[10].

To treat such complications, various therapeutic approaches are employed, including analgesics (both opioids and nonsteroidal anti-inflammatory drugs), anesthetics, acupuncture, and others. The most commonly used treatment involves injectable opioids, which are typically administered before, during, and after surgical procedures. However, due to the numerous side effects associated with injectable opioids, such as cardiovascular and respiratory complications, as well as their sometimes-inadequate efficacy, there is a tendency to favor the use of medications that offer higher effectiveness, greater ease of use, and fewer side effects, among such medications is buprenorphine, which acts as a partial agonist at opioid receptors. It is not only used sublingually but has also demonstrated good analgesic effects in certain types of surgical procedures, according to some studies^[1]. The present study aims to compare the efficacy of intravenous pethidine with sublingual buprenorphine in terms of pain relief in patients with surgical intervention for thoracic and lumbar vertebral fractures.

Method

Study design

The present study was conducted as a multicenter, double-blind, randomized, placebo-controlled clinical trial. The Ethics Committee of the University of Medical Sciences and the National Ethics Committee approved this study, which was carried out by the principles of the Declaration of Helsinki. This study has been reported in compliance with the CONSORT guidelines^[11].

Participants

Individuals who presented to the Educational and Therapeutic Hospitals with thoracic or lumbar fractures during the period from 2022 to 2023 were enrolled as participants in this study. Written informed consent was obtained from all patients before their enrollment.

Sampling

The sample size for this study was determined based on the values reported for pain scores in the two treatment groups of pethidine and buprenorphine, as referenced in the study by Ellis et al^[12]. Considering a statistical power of 80% and a type I error rate of 0.05, a minimum of 60 patients was required for this investigation based on an expected medium-to-large effect size (Cohen’s d = 0.72).

Inclusion criteria

Patients meeting the following criteria were included in the study: (1) Age between 20 and 75 years. (2) Patients with thoracic or lumbar vertebral fractures who were candidates for surgery according to the TLICS criteria with a score ≥5 points. (3) No history of underlying conditions that may increase or decrease the likelihood of experiencing neck pain.

Exclusion criteria

Patients with any of the following conditions were excluded from the study: (1) Inability to provide consent for participation in the study. (2) Cardiovascular disease. (3) Fractures of bones other than vertebrae. (4) Pain originating from sources other than the spine. (5) Uncontrolled hypertension (BP > 160/90 mmHg). (6) Obesity (BMI > 30 kg/m²). (7) History of substance addiction.

Blinding and randomization

To ensure allocation concealment, the SNOSE (Sequentially Numbered Opaque Sealed Envelope) method was employed. This method is a common approach to maintain the integrity of random allocation concealment. Initially, a random sequence was generated using specified software. Subsequently, based on the sample size of the study, several opaque envelopes with aluminum foil linings (to obscure the contents) were prepared. Each random sequence was recorded on a card, which was then placed in the envelopes in sequential order. To preserve the random sequence, the exterior of the envelopes was numbered accordingly. Finally, the envelopes were sealed and placed in a box in order. At the time of participant enrollment, one envelope was opened based on the sequence of qualified participants entering the study, thereby revealing the assigned group for that participant.

Anesthesia method

Induction was achieved using atropine (0.02 µg/kg), fentanyl (2 µg/kg), and propofol (3 mg/kg). Following the administration of intravenous atracurium (0.5 mg/kg) for muscle relaxation, intubation was performed. Anesthesia was maintained with a sevoflurane minimum alveolar concentration, 50% N₂O, 50% O₂, and a flow rate of 2 L/min. After the procedure, atropine (0.02 mg/kg) and neostigmine (0.05 mg/kg) were administered to reverse muscle relaxation. The amount of anesthetic administered to each group was identical.

Intervention

Before surgery, all patients received 1 g of intravenous acetaminophen. In the buprenorphine group, patients received sublingual tablets at a dose of 0.4 mg before surgery in three doses (at 2, 4, and 6 h before the procedure), followed by sublingual buprenorphine at a dose of 0.4 mg in two doses (at 2 and 6 h postoperatively). In the control group, intravenous pethidine at a dose of 25 mg was administered before surgery in two doses (at 2 and 6 h before the procedure) and subsequently given as a single dose (25 mg) 6 h after surgery.

Neurologic examination and postoperative care

In this study, following the surgical procedure, periodic neurological examinations were conducted at regular intervals to assess sensory and motor function. Additionally, postoperative monitoring included wound infection control and timely suture removal. All patients were also prescribed orthopedic braces to maintain sagittal balance for a duration of up to 3 months.

Patient assessment

Postoperatively, patients were monitored for pain during the first 24 h based on the Visual Analog Scale (VAS), and any treatment-related adverse effects were assessed. In cases of adverse effects, the medication was promptly discontinued, and standard care was provided. VAS assessments were conducted at preoperative phases, immediately after surgery, 12 h postoperatively, and 24 h postoperatively. Additional variables evaluated included age, weight, gender, and level of spinal involvement in each patient. The VAS is a standardized tool widely used for measuring pain intensity. The validity and reliability of this pain measurement scale have been examined in multiple studies. Findings from Williamson and Hoggart^[13] indicate that this tool possesses adequate validity and reliability, making it practically applicable in clinical settings. Additionally, its validity and reliability are documented in nursing reference texts (Brunner Suddarth’s Textbook of Medical-Surgical Nursing, Potter Perry’s Fundamentals of Nursing). The VAS consists of a 10-cm line with “no pain” labeled at the far left and “worst possible pain” at the far right. Participants indicate their pain level over the past 48 h by marking a point on the continuum, ensuring that only one point is marked. Pain intensity was measured by the researcher using the standardized VAS, which classifies pain from 0 to 10 as follows: no pain (0–1), mild pain (2–3), moderate pain (4–5), severe pain (6–7), worst pain imaginable (8–9), and unbearable pain^[14].

Statistical analysis

To describe the variables, frequency counts and percentages were reported for qualitative variables, while means and standard deviations were provided for quantitative variables. The normality of pain intensity was assessed using the Shapiro–Wilk test. To compare pain scores between the intervention and control groups, an independent t-test was utilized if the data were normally distributed; otherwise, the non-parametric Mann–Whitney U test was employed. The chi-squared test and Fisher’s exact test were used to assess relationships between qualitative variables. We chose repeated measures analysis of variance (ANOVA) to evaluate changes in pain scores over time due to its ability to detect within-subject differences across multiple time points under the assumption of normally distributed residuals. All statistical analyses were conducted using SPSS version 26 at a significance level of 0.05.

Results

In this study, initially, 283 patients were assessed for eligibility. Of these patients, 163 patients were excluded, and the remaining patients (n = 120) were divided into the pethidine group and buprenorphine group based on the randomization method (Fig. 1).

Figure 1.

Study flowchart (CONSORT format).

Baseline characteristics

A total of 120 participants were enrolled in the study, with 60 receiving pethidine and 60 receiving buprenorphine for analgesia. The age range of participants was from 23 to 80 years, with a mean age of 55.10 ± 13.24 years. The majority of the subjects were male, with a frequency of 66 individuals (55.0%). Additionally, 98 participants (81.7%) were married (Table 1).

Table 1.

Baseline and clinical characteristics

Sex
Female	54 (45.0%)
Male	66 (55.0%)
Marital status
Divorced/single	22 (18.3%)
Married	98 (81.7%)
Age
Middle	52.50
Mean (SD)	55.10 (13.24)
Min	23
Max	80
Nausea and vomiting
No	104 (86.7%)
Yes	16 (13.3%)
Fracture location
Thoracic	48 (40.0%)
Lumbar	72 (60.0%)

Clinical characteristics

The predominant site of fracture among the participants was lumbar, with a frequency of 72 individuals (60.0%), while the remaining 48 individuals (40.0%) had thoracic fractures. Among the patients assessed, only 16 individuals (13.3%) reported experiencing nausea and vomiting (Table 1). (Fig. 2)

Figure 2.

Patient’s CT scan.

Association between baseline and clinical factors with analgesic type

None of the demographic data, including gender, marital status, nausea and vomiting, and fracture location, showed a statistically significant association with the analgesic used in the two groups (P = 0.299, P = 0.506, P = 0.706, and P = 1.000, respectively) (Table 2).

Table 2.

Correlation between baseline and clinical factors with the type of analgesic medication used

		Pethidine		Buprenorphine		Total
	Number	Percent	Number	Percent	Number	Percent	P-value
Sex
Male	22	36.7	32	53.3	54	45.0	0.299
Female	38	63.3	28	46.7	66	55.0
Marital status
Divorced/single	14	23.3	8	13.3	22	18.3	0.506
Married	46	76.6	52	86.7	98	81.7
Nausea and vomiting
No	54	90.0	50	83.3	104	86.7	0.706
Yes	6	10.0	10	16.7	16	13.3
Fracture location
Thoracic	24	40.0	24	40.0	48	40.0	0.999
Lumbar	36	60.0	36	60.0	72	60.0

Pain levels at different time points

In this study, pain intensity was measured at four time points: preoperatively, immediately postoperatively, 12 h postoperatively, and 24 h postoperatively. In three out of the four assessments, the highest reported pain score was the maximum score of 10; however, at the 24-h mark postoperatively, the highest score reported was 8. Notably, at 24 h postoperatively, there was an individual who reported having no pain, scoring a 0. The average pain scores increased after surgery compared to preoperative levels and decreased over time (Table 3).

Table 3.

Pain severity

	VAS score
Pain severity before surgery	5.50
Middle	5.5
Mean (SD)	5.68 (1.97)
Min	1
Max	10
Pain severity immediately after surgery	6.00
Middle	6.00
Mean (SD)	5.75 (2.12)
Min	2
max	10
Pain severity 12 h after surgery	5.00
Middle	5.00
Mean (SD)	5.12 (2.07)
Min	1
Max	10
Pain severity 24 h after surgery	3.00
Middle	3.00
Mean (SD)	3.35 (1.76)
Min	0
Max	8

Comparison of pain intensity between pethidine and buprenorphine groups

No statistically significant differences in pain intensity were observed between the two groups at any of the time points measured. Additionally, the trend of pain scores over time in both groups was analyzed using repeated measures ANOVA, which revealed no significant changes in pain levels between the two groups (P = 0.243) (Table 4 and Fig. 3).

Table 4.

The average pain score of patients in the two groups, pethidine and buprenorphine

	Mean	SD	95% CI	P-value
Age
Pethidine	53.70	13.55	50.27–56.12	0.417
Buprenorphine	56.50	12.99	53.21–59.78
Pain severity before surgery
Pethidine	5.47	2.03	4.95–5.98	0.401
Buprenorphine	5.90	1.93	5.41–6.38
Pain severity immediately after surgery
Pethidine	5.75	2.28	5.17–6.32	0.509
Buprenorphine	5.93	1.98	5.42–6.43
Pain severity 12 h after surgery
Pethidine	5.20	1.76	4.75–5.64	0.759
Buprenorphine	5.03	2.37	4.43–5.62
Pain severity 24 h after surgery
Pethidine	2.93	1.76	2.48–3.37	0.067
Buprenorphine	3.77	1.69	3.34–4.19

Statistical significance was set at P < 0.05.

Figure 3.

The trend of the average pain score of patients in the two studied groups over time.

Discussion

In the present study, no significant differences were observed between sublingual buprenorphine and injectable pethidine regarding pain intensity following thoracic and lumbar vertebral fracture surgery. This lack of significant difference was consistent across all time points assessed, including pain intensity immediately postoperatively, 12 h postoperatively, and 24 h postoperatively. Aligning with our findings, a study conducted by Azizi et al reported no significant difference in pain intensity between the sublingual buprenorphine and injectable pethidine groups following colorectal surgeries. However, while our study indicated that pain intensity in the sublingual pethidine group was consistently lower than that in the buprenorphine group, Azizi et al found the opposite, with pain intensity in the buprenorphine group being consistently lower than in the pethidine group^[10].

Statistically, there were no significant differences in the occurrence of adverse effects between the two groups. Patient satisfaction was higher in the sublingual buprenorphine group compared to the injectable pethidine group. In the current study, pain intensity in the sublingual pethidine group significantly decreased over 24 h compared to the buprenorphine group, with adverse effects such as nausea and vomiting being similar in both groups. In the study conducted by Heldreich et al, which compared the effects of sublingual buprenorphine and oxycodone in 146 patients undergoing abdominal surgery, the results indicated that analgesic consumption within 24 h postoperatively was significantly lower in the buprenorphine group compared to the oxycodone group. However, unlike our study, this trial did not assess postoperative nausea and vomiting^[15]. In a clinical trial conducted by Desai et al, oral tramadol and transdermal buprenorphine were compared in 50 patients undergoing surgery for femoral neck fracture. The results strongly demonstrated that the postoperative analgesic requirement in the buprenorphine group was significantly lower than in the tramadol group. Moreover, postoperative complications such as nausea and vomiting were also markedly reduced in the buprenorphine group^[16]. Chang et al also reported that among 50 patients undergoing elective lumbar fusion, buprenorphine and morphine administered via patient-controlled analgesia pump exhibited similar analgesic effects at 6, 24, and 48 h postoperatively^[17]. In a clinical trial by Saini et al, the analgesic effects of buprenorphine and diclofenac were evaluated. The findings revealed that buprenorphine exhibited substantially superior analgesic effects. Except for the first 4 h postoperatively, during which the pain intensity between the two groups did not differ significantly at all subsequent time points, reported pain levels were lower in the buprenorphine group compared to the diclofenac group^[18]. Nevertheless, there were no significant differences in the occurrence of adverse effects between the two groups. Additionally, studies have indicated that chronic pain patients on high doses of opioids may be transitioned to sublingual buprenorphine^[19].

The results of the study by Ghasem Soltani et al indicated that the use of sublingual buprenorphine half an hour before surgery resulted in a greater reduction in postoperative pain compared to intravenous morphine following anesthesia induction after orthopedic closed reduction surgery^[20]. This finding is consistent with other similar studies. In the study conducted by Oifa et al, pain scores were compared between buprenorphine infusion (BUP-i) + buprenorphine bolus (BUP-b) and morphine injection (MO-i) + (BUP-b) in patients undergoing abdominal surgery. The results showed that the buprenorphine infusion group experienced lower pain scores during the hours 3–12 postoperatively. An important point in this study was that no significant difference in pain scores was recorded during the first 2 h after surgery. This aligns with our findings, where no significant differences in pain scores were observed postoperatively^[21]. In the study by van den Berg et al, based on postoperative pain severity following otolaryngological surgery, patients receiving intravenous buprenorphine reported less postoperative pain and recovery compared to those receiving other analgesics such as diclofenac, fentanyl, and morphine^[22]. Maunuksela et al conducted a study on children aged 4–8 years who underwent orthopedic surgery, finding that sublingual buprenorphine demonstrated longer-lasting effects than intravenous morphine^[23]. In another study, the analgesic effects of sublingual buprenorphine were reported to be equivalent to intramuscular morphine in relieving pain during the postoperative period^[24]. Consistent with our results, two other studies found that sublingual buprenorphine had similar analgesic effects compared to morphine infusion and intramuscular buprenorphine compared to intramuscular morphine following surgery^[25,26]. Overall, it appears that the use of buprenorphine in both forms has less sedative effect than morphine infusion, while the use of other noninvasive forms of buprenorphine, such as oral or sublingual formulations, leads to greater patient acceptance due to their ease of use. Pharmacologically, buprenorphine has a greater potency and duration of effect than morphine. Various sources report the average duration of action for morphine as 3–4 h, while this duration for buprenorphine is 10 h, which further supports our findings^[27]. Although underlying factors were assessed in this study, many elements – particularly psychological factors such as preoperative anxiety, depression, and psychological distress, can influence the intensity of acute postoperative pain. In the study by Periañez et al, results indicated that baseline psychological factors can significantly impact pain perception^[28]. While no statistically significant differences were observed between the two drug groups in some of the evaluated parameters, oral medications are generally more favored by patients, leading to better adherence in terms of timing and proper administration. Given that buprenorphine is administered orally, it is prioritized in this context. Another advantage of buprenorphine over pethidine is its lower cost, which, considering the outcomes of this study, supports its use as a more suitable alternative to pethidine.

Conclusion

Sublingual buprenorphine does not differ from injectable pethidine in terms of pain intensity following thoracic and lumbar vertebral fracture surgery; however, it is safe and associated with fewer side effects. There were no significant associations between sublingual buprenorphine and variables such as gender, education, marital status, occupation, nausea and vomiting, or fracture location compared to the analgesic used. Additionally, the trend of pain changes in both treatment groups did not show significant differences.

Limitation

The primary limitation of this study is the small sample size and the limited number of centers involved in the investigation. Additionally, this study did not assess the effects of the medications under investigation on parameters such as hemodynamics, including blood pressure, heart rate, and respiratory rate. Therefore, further studies with varying doses, additional variables, and larger sample sizes are needed to evaluate the outcomes more comprehensively.

Ethical approval

The Ethics Committee of the University of Medical Sciences approved this study, and Informed consent was obtained from all patients and their legal guardians to participate in this study.

Consent

Written Informed consent was obtained from all patients and their legal guardians to participate in this study.

Sources of funding

The authors didn’t use any sources of funding, and this study has no sponsors.

Author contributions

S.K., S.E., and A.L involved in interpretation and collecting of data, and editing the manuscript. M.J. and S.N. involved in writing, editing and preparing the final version of manuscript. All authors reviewed the paper and approved the final version of the manuscript.

Conflicts of interest disclosure

There are no conflicts of interest for the authors in this study.

Guarantor

Sajjad Najafi.

Research Registration Unique Identifying Number (UIN)

https://www.researchregistry.com:researchregistry10918.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.