|Year : 2019 | Volume
| Issue : 3 | Page : 266-272
A comparative study of postoperative effects of two doses of preemptive pregabalin after tibial fracture fixation under spinal anesthesia
Ahmed M Abdou, Rabab S Saleh, Mariam H Mossad Samaan
Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||11-Feb-2017|
|Date of Acceptance||28-Oct-2017|
|Date of Web Publication||29-Aug-2019|
MD Ahmed M Abdou
Professor of Anaesthesia and Intensive Care, Faculty of Medicine, Alexandria Faculty of Medicine, El-Azareeta, Champollion St., Alexandria, 21131
Source of Support: None, Conflict of Interest: None
Background Orthopedic patients experience severe immediate postoperative pain, and they require more analgesia. Effective management of perioperative and postoperative pain after lower extremity orthopedic surgery represents an important component of early postoperative recovery. It is essential to facilitate rehabilitation and accelerate functional recovery, enabling patients to return to their normal activity more quickly. Moreover, treating patient’s preoperative anxiety improves postoperative pain. Pregabalin was found to be useful in decreasing postoperative pain and analgesic requirements as well as anxiolytic and sleep-modulating effects.
Objective This study compares analgesic, anxiolytic, and sedative effects of pregabalin 75 and 150 mg versus placebo in patients undergoing surgery for fixation of traumatic tibial fractures under spinal anesthesia.
Patients and methods This blind study contained 45 patients scheduled for fixation of tibial fractures under spinal anesthesia using a closed envelope technique. The patients were divided into three groups (15 patients each). Group P75 received 75 mg pregabalin capsule, group P150 received 150 mg pregabalin capsule, and group P0 received matching placebo capsule. In the preoperative holding area, patients were randomly divided into three groups. Then, an intravenous line was secured. Then, an hour before the surgery, all patients underwent assessment of level of anxiety using visual analog scale and assessment of degree of sedation using Ramsay Sedation Scale. Thereafter, the drug selected for the study was given with a sip of water by a staff nurse who was not involved in the study. Before anesthesia, anxiety and sedation were reassessed for the second time for all patients using visual analog scale for anxiety and Ramsay Sedation Scale, respectively. Spinal anesthesia was instituted at L3–L4 interspace, and a volume of 2.5–3.5 ml (according to the patient’s height and weight) of 0.5% heavy bupivacaine was injected over 30 s through a 25-G spinal needle. In the postoperative period, all patients received ketorolac 30 mg/kg, and they were observed for pain score and level of sedation for 24 h postoperatively.
Results The use of pregabalin 150 mg preoperatively succeeded in significantly decreasing the postoperative pain and analgesic requirements and increasing the sedation score in comparison with 75 mg dose. Both doses succeeded in significantly decreasing the preoperative anxiety.
Conclusion The use of pregabalin before surgery for fixation of traumatic tibial fractures could achieve good postoperative analgesia, preoperative anxiolysis, and perioperative sedation.
Keywords: postoperative pain, pregabalin, preemptive analgesia, perioperative anxiety, trauma patient
|How to cite this article:|
Abdou AM, Saleh RS, Mossad Samaan MH. A comparative study of postoperative effects of two doses of preemptive pregabalin after tibial fracture fixation under spinal anesthesia. Res Opin Anesth Intensive Care 2019;6:266-72
|How to cite this URL:|
Abdou AM, Saleh RS, Mossad Samaan MH. A comparative study of postoperative effects of two doses of preemptive pregabalin after tibial fracture fixation under spinal anesthesia. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2020 Jan 20];6:266-72. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/266/265714
| Introduction|| |
Postoperative appropriate pain control plays an important role in preventing complications such as tachycardia, hypertension, myocardial ischemia, decreased alveolar ventilation, and poor wound healing .
Preemptive analgesia is defined as an antinociceptive treatment that prevents establishment of altered central processing of afferent input from injuries , such as hyperalgesia, allodynia, and increased pain . The magnitude of postoperative pain differs owing to type of surgery. Orthopedic patients experience severe immediate postoperative pain, and they require more analgesia . Extreme noxious input may produce central sensitization and pain hypersensitivity .
Effective management of perioperative pain after lower extremity orthopedic surgery represents an important component of early postoperative recovery. It is essential to facilitate rehabilitation and accelerate functional recovery, enabling patients to return to their normal activity more quickly .
Treating patient’s preoperative anxiety improves postoperative pain. Several studies have shown that pregabalin is effective in treatment of anxiety, and it was recently approved by the European Commission for the treatment of generalized anxiety disorders ,,.
Spinal anesthesia is a safe, reliable, and inexpensive regional anesthetic technique that is used for most lower limb orthopedic surgeries. The only drawback of spinal anesthesia is limited postoperative analgesia .
Pregabalin is a new synthetic molecule and a structural derivative of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). It is an α2δ ligand that has analgesic, anticonvulsant, and anxiolytic effects. Pregabalin binds potently to the α2δ subunit of calcium channels, resulting in a reduction in the release of several neurotransmitters .
It plays a role in treatment of acute postoperative pain by decreasing the excitability of dorsal horn neurons caused by tissue damage. Moreover, as most patients are afflicted with stress and emotion preoperatively, the antiexcitement effects of pregabalin can be effective ,.
| Patients and methods|| |
After approval of the study proposal from the Faculty of Medicine Ethics Committee, the present study was carried out in El Hadara University Hospital on 45 adult patients of both sexes between the ages of 18 and 50 years, with BMI between 18.5 and 30, and with American Society of Anesthesiologists grade I or II. Patients were scheduled for fixation of tibial fractures under spinal anesthesia. The sample size was calculated by Medical Research Institute, Department of Medical Statistics. The patients were prospectively randomized in a blinded study using closed envelope method into three equal groups (15 patients each).
After an informed consent from each patient, all the patients were assessed preoperatively by detailed history taking, complete clinical examination, and routine laboratory investigations, and the concept of a visual analog scale (VAS) for pain and anxiety was introduced to the patient.
In the preoperative holding area, an intravenous line was secured by using 18 G cannula. An hour before surgery, all patients were assessed for the level of anxiety using visual analogue scale (VAS-A), and the degree of sedation using Ramsay Sedation Scale (RSS), and then the drug selected for the study was given with a sip of water by a staff nurse who was not involved in the study. Group P75 received 75 mg pregabalin capsule, group P150 received 150 mg pregabalin capsule, and group P0 received matching placebo capsule.
Before anesthesia, anxiety and sedation were reassessed for the second time for all patients using VAS-A and RSS, respectively. On arrival to the operating room, patients were connected to the standard monitoring. Anesthesia technique was standardized in all the groups. Spinal anesthesia has been instituted at L3–L4 interspace and a volume of 2.5–3.5 ml (according to the patient’s height and weight) of 0.5% heavy bupivacaine was injected over 30 s through a 25-G spinal needle. Patient has been placed in the supine position immediately after spinal injection. In the postoperative period, all patients received ketorolac 30 mg/8 h, and they were observed for pain score and level of sedation for 24 h postoperatively.
The following measurements were taken:
- Demographic data: age, sex, and BMI.
- Duration of surgery.
- Postoperative pain (the primary end point) was assessed using a VAS. Assessment of pain was done on arrival of patient to the ward, and then at 2, 6, 12, 18, and 24 h from the end of the operation using VAS for pain assessment. When postoperative pain was VAS of at least 4, patients received nalbuphine 5 mg intravenously. The time to first analgesic request and total administered doses were recorded.
- Anxiety level (secondary end point) was assessed using VAS-A . Assessment of anxiety was done 1 h preoperatively before administration of the selected drug and 1 h later before administration of the spinal anesthesia using VAS-A.
- Level of sedation (secondary end point): It was assessed with the RSS. Assessment was done in the following periods:
- 1 h preoperatively before administration of the selected drug.
- Immediately before administration of the spinal anesthesia after entering the operating room.
- On arrival of patient to the ward.
- 2, 4, and 6 h postoperatively.
Data were fed to the computer and analyzed using IBM SPSS 20.0 (IBM, Armonk, NY, USA).
Qualitative data were described using number and percentage. Quantitative data were described using range (minimum and maximum), mean, SD, and median.
Comparison between different groups regarding categorical variables was tested using χ2-test. When more than 20% of the cells have expected count less than 5, correction for χ2 was conducted using Fisher’s exact test or Monte Carlo correction.
For normally distributed quantitative data, comparison between more than two groups was analyzed using F-test (analysis of variance) and post-hoc test (least significant difference) for pair-wise comparisons.
For abnormally distributed quantitative data, Kruskal–Wallis test was used to compare between different groups, and pair-wise comparison was assessed using Mann–Whitney test.
To compare between the different periods, Wilcoxon-signed ranks test was applied.
Significance of the obtained results was judged at the 5% level.
| Results|| |
There was no statistically significant difference between the three groups regarding age, sex, BMI, or duration of surgery.
Regarding comparison between the three groups in VAS-A ([Figure 1]), it was found that there was a statistically significant decrease in the anxiety level after the administration of pregabalin in the groups P75 and P150. However, there was no statistically significant difference between the anxiety level before and after administration of placebo in group P0.
|Figure 1 Comparison between the three studied groups according to visual analog scale for anxiety (VAS-A).|
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On comparing pain VAS scores with the baseline, in groups P0 and P75, there was no significant difference at 2 h, but at 4, 6, 12, 18, and 24 h, there was a significant increase in pain scores. However, in group P150, there was no statistically significant difference at 2 and 4 h, but at 6, 12, 18, and 24 h, there was a significant increase in pain scores, which means that the analgesic effect of pregabalin was extending up to 4 h postoperatively, and at 6 h, the pain level started to increase and was increasing by time. On comparing the three groups regarding the pain level ([Figure 2]), there was a statistically significant difference between P0 and P75 at 12 h postoperatively, whereas there was no statistically significant difference at all the other readings. There was statistically significant difference at all readings on comparing P0 and P150. There was a statistically significant difference at all readings on comparing P75 and P150.
|Figure 2 Comparison between the three studied groups according to visual analog scale (VAS).|
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Regarding the time to first rescue analgesic (nalbuphine) dose in the postoperative period ([Figure 3]), there was a statistically significant difference among them when comparing the three groups. The longest period of time that the patient can afford without demanding more analgesic was seen with pregabalin 150 mg, with the mean time of 8.13±3.34 h, which was shorter with pregabalin 75 mg, with the mean time of 5.87±2.67 h, and placebo, with the mean time of 4±1.69 h.
|Figure 3 Comparison between the three studied groups according to time to first rescue analgesia (h).|
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Regarding the total number of doses of the rescue analgesic drug (nalbuphine) in the first 24 h postoperatively in the three studied groups ([Figure 4]), there was a statistically significant difference seen between them (P1=0.003, P2<0.001, and P3<0.001), which means that the patients in the group which received pregabalin 150 required the least number of doses of nalbuphine.
|Figure 4 Comparison between the three studied groups according to total number of administered doses of the rescue analgesic drug (nalbuphine).|
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On comparing the sedation scores with the baseline (1 h preoperative) ([Figure 5]), in group P0, there was a statistically significant increase in the level of sedation at arrival to the ward, but there was no statistically significant difference with the other readings. In group P75, there was a statistically significant difference at 1 h later, on arrival to the ward, and at 2 and 4 h postoperatively (P<0.001, <0.001, P=0.002, and P=0.046, respectively). But with 6 h. postoperatively, no statistically significant difference was observed. This means that the sedative effect of pregabalin was extending up to 4 h postoperatively. In group P150, there was a statistically significant difference at 1 h later, on arrival to the ward, and at 2, 4, and 6 h postoperatively (P<0.001, <0.001, <0.001, <0.001, and 0.001, respectively). This means that the sedative effect of pregabalin was extending up to 6 h postoperatively. When comparing P0 and P75, there was a statistically significant difference seen at 1 h later, on arrival to the ward, and 2 h postoperatively (P1<0.001, P=0.017, and P=0.008, respectively), whereas there was no statistically significant difference at all the other readings, which means that the level of sedation was higher in the group P75 up to 2 h postoperatively.
|Figure 5 Comparison between the three studied groups according to Ramsay Sedation Scale (RSS).|
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On comparing P0 and P150, there was a statistically significant difference seen at 1 h later, on arrival to the ward, and at 2, 4, and 6 h, postoperatively (P2<0.001, <0.001, <0.001, <0.001, and <0.001, respectively). However, there was no statistically significant difference at 1 h, preoperatively. This means that the level of sedation was higher in the group P150 up to 6 h postoperatively.
On comparing P75 and P150, there was a statistically significant difference seen at 1 h later, on arrival to the ward, and at 2, 4, and 6 h postoperatively (P3=0.001, <0.001, <0.001, <0.001, and <0.001, respectively). However, there was no statistically significant difference seen at 1 h preoperatively. This means that the level of sedation was higher in the group receiving pregabalin 150 mg than the group receiving pregabalin 75 mg.
| Discussion|| |
Multimodal approach is the most common practice to treat perioperative pain, as no single agent has yet been identified to specifically inhibit nociception without associated adverse effects . Different techniques and drugs has been studied to prolong the duration of regional anesthesia and to achieve postoperative pain relief .
Preemptive analgesia has been shown to be more effective in control of postoperative pain by protecting the central nervous system from deleterious effects of noxious stimuli.
The choice between regional and general anesthesia has been extensively evaluated for lower limb orthopedic surgeries. Many studies have found a lower mortality in the early postoperative period following regional anesthesia, presumably because of a decrease in thromboembolic disease ,.
Regional anesthesia for lower limb has been provided by central neuraxial blockade. Local anesthetics alone for subarachnoid block provide good operative conditions but have shorter duration of postoperative analgesia .
Anxiety is a relevant perioperative source of distress, affecting the quality of life, increasing perioperative pain perception, and impairing outcome ,.
Patients who are about to undergo a surgery generally develop anxiety about death, not waking up from anesthesia, disability, pain, and loss of ability to work. Moreover, 60–80% of the patients develop anxiety during the preoperative phase ,.
Reduction in preoperative anxiety is good for the patient’s preoperative well-being and is associated with decreased levels of postoperative pain, per se, independent of drug effect .
Gabapentin and its developmental successor pregabalin are structural derivatives of the inhibitory neurotransmitter GABA, although they neither bind to GABAA, GABAB, or benzodiazepine receptors nor do they metabolically convert to GABA or alter its uptake or degradation ,.
Pregabalin is an easily tolerated drug with limited adverse effects and low potential for interaction with other drugs. Different studies reported adverse effects such as somnolence, dizziness, confusion, headache, ataxia, and weight gain . Although most of these adverse effects were reported for long-term use, the most common adverse effects for postoperative patients were dizziness, somnolence, and sedation. In our study, we considered its sedative effect as an advantage for patients undergoing surgery under spinal anesthesia so we included it in our measurements, and no other adverse effects were reported.
Yet what was agreed upon by most authors is the explanation as to why pregabalin is now gaining greater popularity in controlling acute postoperative pain ,. This resides on the drug’s ability to reduce hyperexcitability of dorsal horn neurons induced by tissue damage rather than to suppress the afferent input from the site of tissue injury ,,. This is achieved by binding of the drug to the α2δ subunit of presynaptic, voltage-dependent calcium channels that are widely distributed there . This will stabilize their cellular trafficking to allow for the transient inhibition of calcium influx, thereby reducing release of several excitatory neurotransmitters (glutamate, norepinephrine, serotonin, dopamine, substance P, and calcitonin gene-related peptide) involved in such sensitization ,,.
In the present study, there were no significant differences between the three groups regarding age, sex, BMI, or duration of surgery.
During the postoperative period, the primary end point of the present work was targeted to compare the effect of preoperative 150–75 mg pregabalin to placebo on pain intensity as scored by VAS. In this respect, current results did verify the efficacy of pregabalin 150 mg to induce significant reduction in VAS at 0 time postoperatively as compared with placebo and the 75 mg dose. The reduction in VAS was pertained highly significant, lasting up to 6 h postoperatively, and then it became less significant at the interval time between 12 and 24th hours postoperatively. However, regarding the 75 mg dose, it showed no added benefits superior to placebo in controlling the postoperative pain.
In agreement with our study, Akhavanakbari et al.  observed that preoperative pregabalin 150 mg was effective in reduction of postoperative pain along with postoperative pethidine consumption in patients undergoing lower limb orthopedic surgery. Moreover, Sebastian et al.  noted that preoperative pregabalin 150 mg reduced postoperative pain and total rescue analgesic consumption as well as increased the time to first analgesic requirement in patients undergoing lower limb orthopedic surgery.
However, in a study conducted by Yadeau et al.  on patients undergoing ankle surgery using 100 mg pregabalin preoperatively then 50 mg every 12 h postoperatively versus placebo, they found that the mean pain scores and opioid use were similar in both groups. This may be because of a lower initial dose of pregabalin, which was considered in another study as a subtherapeutic dose .
Differences in the pregabalin dosages and the different types of patients and surgeries investigated can explain these contrasting results.
In the present study, opioid consumption was taken as a surrogate indicator, when assessing the efficacy of pregabalin in reducing immediate postoperative pain following fixation of traumatic tibial fracture.
Current results cleared that the total dose of nalbuphine consumed during the studied time postoperatively was significantly less in group pregabalin 150 mg versus pregabalin 75 mg and placebo throughout the 24 h postoperatively. Moreover, the time to first request of rescue analgesia (nalbuphine) was significantly longer in group pregabalin 150 mg than 75 mg and placebo.
Such result is in agreement with the opioid-sparing potentialities of pregabalin, generally observed in most of the studies enrolled in the different aforementioned studies ,,.
A study conducted by Kim et al.  revealed that perioperative administration of pregabalin 75 mg before and after spinal fusion surgery exerted similar efficacy as placebo, and only pregabalin 150 mg was effective in terms of reducing opioid consumption and the use of rescue analgesic.
However, in the studies that were conducted by Jokela et al. , Mathiesen et al. , George et al. , and Paech et al.  imply that a single dose or two doses of pregabalin failed to decrease the postoperative consumption of opioids or other analgesics recorded during the first 24 h.
The delayed time to first rescue analgesic request was also found in previous studies conducted on patients undergoing abdominal hysterectomy, as Ghai et al.  concluded that time to first analgesic requirement was longest in pregabalin group as compared with gabapentin group which may be because of quicker onset and better analgesia owing to pregabalin.
Regarding its anxiolytic effect, the current study found that pregabalin significantly decreased the preoperative anxiety.
Pande et al.  determined that pregabalin is an effective, fast, and reliable treatment in common anxiety disorders.
When focusing on perioperative sedation, current findings revealed a significant difference in Ramsay sedation score when patients receiving single dose of 75 or 150 mg pregabalin were compared with controls, with patients taking 150 mg pregabalin having higher sedation scores and longer effect than those taking 75 mg.
Our results were consistent with some previous studies such as Ghai et al. , Rajappa et al. , and Akhavanakbari et al. , as they found that the patients were adequately sedated and had better sleep profiles postoperatively.
| Conclusion|| |
- The administration of a single dose of pregabalin before surgery under spinal anaesthesia is a simple and pragmatic approach to optimize postoperative pain management.
- Usage of a dose 150 mg of pregabalin was more effective in reducing pain intensity and postoperative analgesic consumption in the first 24 h and delaying the time needed for initiation of analgesics in comparison with 75 mg dose of pregabalin as a preemptive analgesia measure in surgeries for fixation of traumatic tibial fractures.
- Both doses had a preoperative anxiolytic effect.
- Usage of a dose of 150 mg of pregabalin had a perioperative sedative effect more than a dose of 75 mg pregabalin.
- Neither doses caused postoperative adverse effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]