Introduction

Tracheal intubation can cause undesirable responses in the cardiovascular system, such as increases in heart rate and blood pressure, as well as in the respiratory system (e.g. bronchospasm). These changes typically peak one to two minutes after the onset of laryngoscopy and return to baseline levels within five minutes. Although such transient changes are generally well tolerated in healthy individuals, they may be problematic in susceptible patients, particularly those with systemic hypertension, coronary artery disease, abdominal or intracranial aneurysms, and recent myocardial infarction, potentially leading to adverse outcomes such as myocardial ischaemia and cerebral haemorrhage.

Various drugs, including vasodilators, adrenergic receptor blockers, and calcium channel blockers, have been used to attenuate these unwanted haemodynamic responses. A common approach is the administration of a short-acting opioid, such as fentanyl, and intravenous lidocaine before laryngoscopy. Propofol or sodium thiopental are commonly used for the induction of anaesthesia. However, the combination of these agents with fentanyl may increase the risk of side effects, including cardiovascular and respiratory depression, hypotension, and apnoea during anaesthetic induction.

Spine surgeries are increasingly performed in both paediatric and adult populations, presenting multiple challenges for anaesthesiologists. Many of these patients have comorbidities such as severe cardiovascular and respiratory failure, making haemodynamic management particularly demanding. In addition, the surgical procedure itself, with associated blood loss, prolonged anaesthesia, and postoperative pain, places further stress on the cardiovascular system. Factors such as the timing of awakening and extubation, duration of stay in the recovery unit, and postoperative side effects including pain, nausea, vomiting, and dizziness are important, as they influence recovery and may affect surgical outcomes, including haematoma formation or surgical failure.

Pregabalin, a gamma-aminobutyric acid (GABA) analogue, exerts analgesic, anticonvulsant, and anxiolytic effects by reducing glutamate synthesis. Its reported side effects include dizziness, insomnia, peripheral oedema, and dry mouth. Previous studies have shown that a single oral dose of pregabalin administered one to two hours before induction of anaesthesia can reduce changes in blood pressure and heart rate during and after laryngoscopy and endotracheal intubation.

Fentanyl is a synthetic opioid with an analgesic potency several times greater than that of heroin. It is primarily used as a pre-anaesthetic medication and sedative in the operating theatre and is widely employed for anaesthesia and pain management. Fentanyl is approximately 75–125 times more potent than morphine, with an onset of action of 2–3 minutes and a duration of 30–60 minutes, and it has no amnestic effect. It is administered intravenously at a dose of 0.5–1 µg/kg over three minutes and may be repeated every two minutes to achieve the desired effect, with a maximum dose of 5 µg/kg. Reported side effects include reductions in diastolic blood pressure, decreased arterial oxygen saturation, nausea, and vomiting; however, the most significant adverse effect is respiratory depression, which is exacerbated by the concurrent use of sedative agents.

Although previous studies have demonstrated the beneficial effects of pregabalin, the available evidence remains limited. Therefore, the present study was conducted to compare the haemodynamic responses of pregabalin combined with fentanyl versus fentanyl alone following tracheal intubation in patients undergoing lumbar spine surgery.

Materials and methods

Study Design and Patient Selection

This randomised, double-blind clinical trial was conducted from December 2020 to January 2022 on patients scheduled for elective lumbar spine surgery at Ayatollah Rouhani Hospital in Babol.

Inclusion and Exclusion Criteria

Patients were included if they were aged 20–65 years, classified as American Society of Anesthesiologists (ASA) physical status I or II, scheduled for lumbar spine surgery, had no history of hypertension, and were not taking antihypertensive medications. Exclusion criteria included age under 20 or over 65 years, ASA class ≥ III, bradycardia, systolic blood pressure < 90 mmHg, opioid addiction, difficult intubation, hypertension, use of antihypertensive drugs, and surgical procedures lasting longer than three hours.

The study was approved by the Ethics Committee of Babol University of Medical Sciences (Code: IR.MUBABOL.HRI.REC.1400.128) and registered in the Iranian Registry of Clinical Trials (IRCT) under the number IRCT20111010007752N12. Written informed consent was obtained from all participants.

Initially, the study was designed to compare pregabalin alone with fentanyl alone. However, due to unfavourable haemodynamic conditions observed in the first few patients in the pregabalin-only group, the study protocol was modified to an add-on design. Consequently, both groups received fentanyl; one group (P) additionally received pregabalin, while the other group (F) received a placebo.

Randomization and Blinding

After obtaining written informed consent, patients were randomly assigned to one of two groups, the pregabalin plus fentanyl group (P) or the fentanyl-only group (F), with 40 patients allocated to each group. Randomisation was performed using permuted blocks of size four, with each block consisting of random combinations of two allocations to group A (pregabalin) and two to group B (placebo). The random sequence was generated by a statistician.

Capsules containing pregabalin and placebo were prepared to be identical in shape, size, and appearance and were placed in identical containers, each labelled with a three-digit code. Upon enrolment, one container was assigned to each patient, and the corresponding code was recorded in the patient’s file. The allocation codes were disclosed only after completion of the study.

This study was conducted in a double-blind manner; patients, the attending anaesthesiologist, and the anaesthesia assistant responsible for data collection were all unaware of the treatment allocation.

The intervention group (P) received a single oral capsule of pregabalin 75 mg eight hours before surgery. The control group (F) received an oral placebo capsule eight hours before surgery.

Anaesthetic Procedure

Both groups received fentanyl at a dose of 1 µg/kg administered over 10 minutes before tracheal intubation. All patients were given 2 mg of intravenous midazolam prior to intubation. Anaesthesia was induced in all patients with propofol 2 mg/kg. Atracurium 0.5 mg/kg was used as a muscle relaxant in both groups, followed by tracheal intubation. Anaesthesia was maintained with a mixture of 50% O₂ and N₂O and 1.2% isoflurane under controlled ventilation. In addition, both groups received morphine 0.01 mg/kg before skin incision.

Data Collection and Outcomes

The primary outcomes were systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate. These variables were recorded at baseline, before induction of anaesthesia, after induction, and at 1, 3, 5, and 10 minutes following tracheal intubation. The secondary outcome was postoperative pain, assessed using the Visual Analogue Scale (VAS). After admission to the recovery room, pain was measured every 15 minutes until discharge from recovery. On the VAS, a score of 0 indicated no pain, 5 indicated moderate pain, and 10 indicated severe pain.

Statistical Analysis

The sample size was calculated based on a previous study, with a significance level (α) of 0.05 and a statistical power of 80%. A minimum sample size of 22 patients per group was required. Statistical analysis was performed using SPSS software, version 22. Descriptive statistics, the chi‑square test, independent t‑test, Mann–Whitney U test, and Kaplan–Meier analysis were used as appropriate. A p‑value of < 0.05 was considered statistically significant.

Results

In this research, 80 patients were enrolled (Figure 1).

Fig 1. Flowchart of patients participating in the clinical Trial

Patient Characteristics

No significant differences were observed in the demographic characteristics between the two groups (P > 0.05), indicating that the groups were homogeneous in this regard. The mean pain score was 5.88 in the fentanyl group (F) and 4.98 in the pregabalin plus fentanyl group (P), with no statistically significant difference between the groups (P = 0.313). The mean age was 46.98 ± 8.91 years in group F and 45.43 ± 12.49 years in group P. The mean body mass index (BMI) was 34.7 ± 1.30 kg/m² in group F and 35.0 ± 1.34 kg/m² in group P (Table 1).

According to the results presented in Table 1, no statistically significant difference was observed in the demographic characteristics between the two groups (P>0.05); thus, the groups were considered homogeneous at baseline.

Medication and Haemodynamics

Analysis of mean heart rate at different time points using repeated‑measures ANOVA showed that the overall group effect was not statistically significant (P = 0.517) (Figure 2).

Fig 2. Mean Heart Rate at Different Times in the Two Study Groups .

The mean heart rate at one minute after induction increased significantly more in the fentanyl group than in the pregabalin group (effect size= 0.625, P < 0.001) (Figure 3).

Fig 3. Mean Heart Rate at Post-Induction and One-Minute Post-Induction in Two Study Groups .