Gabapentin vs pregabalin as a premedication in lower limb orthopaedics surgery under combined spinal epidural technique.

BACKGROUND: Pregabalin and gabapentin are the gamma-aminobutyric acid analogs used as a part of multimodal analgesic regimen. AIM: To compare the postoperative analgesic benefits of gabapentin or pregabalin as a premedication for lower limb orthopedic surgery under combined spinal-epidural techniques. SETTINGS AND
DESIGN: Randomized double-blind study.
MATERIALS AND METHODS: A total of 90 patients were divided into three groups: G, P, C who received gabapentin 1200 mg, pregabalin 300 mg, and placebo, respectively 1.5 h before surgery. All patients received combined spinal-epidural block with 3 ml of 0.5% intrathecal bupivacaine. Assessment of pain was made with visual analog scale (VAS). Postoperative analgesia was provided with epidural top-ups with 2.5 ml of 0.5% bupivacaine and fentanyl 25 μg when VAS >3. Rescue analgesia in the form of injection diclofenac (75 mg) intramuscularly was given if VAS >3 even after epidural top-up. A total number of epidural top-ups, rescue analgesia, pain-free interval postspinal anesthesia, and sedation score were noted. STATISTICAL ANALYSIS: This was done using SPSS version 17. Mean and standard deviation were calculated using Chi-square test and analysis of variance.
RESULTS: The total postoperative analgesic time was 7.23 h in Group G, 14.80 h in Group P, and 4.17 h in Group C. A total number of epidural top-ups were 2.43 in Group G, 0.77 in Group P, and 4.43 in Group C.
CONCLUSION: Pregabalin 300 mg and gabapentin 1200 mg significantly reduce the need of postoperative rescue analgesia, epidural top-ups, and increase the duration of postspinal anesthesia without altering hemodynamics with sedation as a major side effect.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Proper relief of postoperative pain is a matter of concern to both patients and the anesthesiologists. Principles of pain management include assessment of the severity of pain, meticulous use of analgesic drugs to anticipate the response to treatment to maximize the functional status, and quality of life. In spite of numerous analgesic drugs available, none is able to provide optimal pain relief without undesirable side effects. The use of two or more analgesic drugs or techniques acting via different mechanisms to improve the degree of pain relief and decreasing the incidence of undesirable side effects known as multimodal analgesia techniques. This includes drugs such as nonsteroidal anti-inflammatory drugs, opioids, local anesthetic drugs, gabapentinoids, clonidine, and dexmedetomidine. The techniques used are epidural analgesia,[1] patient-controlled analgesia (PCA), and nerve blocks. Gabapentin and pregabalin are the gabapentinoids used as part of multimodal analgesia regimen.

In recent years, role of pregabalin and gabapentin in acute postoperative pain[23] has been studied indicating its useful in preventing the acute nociceptive pain of surgery. Both these drugs have been found to decrease postoperative opioid requirement.[45] Pregabalin and gabapentin both reduce the preoperative anxiety and induce sedation without producing undesirable side effects.[6] Due to fewer studies conducted comparing pregabalin and gabapentin for postoperative pain management, we planned this study to compare pregabalin 300 mg and gabapentin 1200 mg with the control group to evaluate their analgesic potential.

The aim of this study was to compare the postoperative analgesic benefits in patients administrated gabapentin or pregabalin as a premedication for lower limb orthopedic surgery under combined spinal-epidural technique.

MATERIALS AND METHODS

The study was approved by the Institutional Ethical Committee, Government Medical College. A written informed consent was obtained from all the patients who were scheduled to undergo lower limb orthopedics surgery after undergoing preanesthetic assessment according to the inclusion criteria. Inclusion criteria include hemodynamically stable patients of age group 20–65 years of American Society of Anesthesiologists (ASA) grades I and II with weight range up to 20% of ideal body weight for either sex. Patients with a history of chronic systemic disease, pregnancy, known psychiatric disorders, anticipated difficult airway, on drugs with an effect on the central nervous system including oral pregabalin or gabapentin, allergic to opioids were excluded from our study.

Study design

This was a prospective randomized double-blind comparative study. Ninety patients in the age group of 20–65 years, in the ASA grades I and II admitted to the Department of Orthopedics of our hospital and scheduled for elective lower limb orthopedics surgery were taken up. The patients were randomly divided into three groups of 30 patients each in a double-blind study manner. A list of random numbers were generated by a statistician. Each patient received an appropriate randomization number and was assigned to their group according to the number. Neither the patient nor the doctor was aware of group assignment until all the 90 patients are included and assessment was complete. These 90 patients were divided into Group G - received gabapentin 1200 mg, Group P - received pregabalin 300 mg, Group C - received placebo. The study drug was given orally 1.5 h before surgery with a sip of water. The interpretation of visual analog scale (VAS) was explained before the procedure to the patients taken up for a study to determine the pain experienced after surgery. The first mark “0” means “no pain” and the end marked “10” means “severe pain.”

In the operation theater, baseline value of heart rate (HR), blood pressure (BP), oxygen saturation, and respiratory rate were recorded. Intravenous (IV) line was secured, and patients were preloaded with Ringer lactate 10 ml/kg body weight in 20–30 min. No premedication was given apart from the study drug. The patients received a combined spinal-epidural in L2–3 or L3–4 intervertebral space under strict aseptic conditions with the of 18-gauge Tuohy's needle using loss of resistance technique. A 25-gauge Whitacre spinal needle was passed in the same space through the lateral eye of the epidural needle. Patient was given 3 ml of 0.5% intrathecal bupivacaine over 10 s. Patients were turned supine after the epidural catheter was inserted into epidural space, secured, and dressed. Motor block was assessed by using modified Bromage score: 0 - Able to raise the whole lower limb at the hip, 1 - Able to the flex the knee but unable to raise the leg at hip, 2 - Able to plantar flex the ankle but unable to flex the knee, 3 - No movements of lower limb. Time to onset of score 3 in minutes after spinal anesthesia was noted in all patients. Sensory block was assessed by loss of sensation to pinprick using a 22-gauge blunt hypodermic needle at 1, 2, 5, and 10 min and the highest level of sensory block was noted. Intraoperative vitals were monitored, and any reduction of > 20% of BP from the baseline was promptly treated with IV fluids. If not effective, injection ephedrine 3 mg was given in incremental dosages, and HR <50 was treated with 0.3 mg injection atropine.

After surgery, patient were shifted to the recovery room and assessment of VAS pain score was made at 1, 2, 4, 6, 8, 12, 16, and 24 h in the postoperative period. If the VAS score was greater than three, patient was given an epidural top-up with 2.5 ml of 0.5% bupivacaine with fentanyl 25 µg (0.5 ml) diluted with normal saline to make the volume up to 10 ml. Time of first epidural top-up and number of top-ups given to the patient in 24 h were recorded. If in spite of epidural top-ups, patient's pain was not relieved, rescue analgesia in the form of injection diclofenac 75 mg intramuscularly was given. A total number of doses of diclofenac used in each group were noted. Assessment of sedation score was made at 1, 2, 4, 6, 8, 12, 16, and 24 h using sedation scores: 0 = alert, conversant, 1 = awake but drowsy, 2 = asleep but arousable, 3 = asleep and not arousable. Side effects and complications (sedation, dizziness, nausea, vomiting, somnolence, diarrhea, gastrointestinal disturbances) were noted. Monitoring of vitals was done for 24 h postoperatively.

Statistical analysis

Data were analyzed using SPSS version 17 (IBM). Patients were allocated into either of three groups with sample size 30. The sample size was calculated on the basis of the various variable, for example, analgesic duration, event rate in the population, effect size, P value, confidence interval, and power of study that was taken to be > 85%. Data such as ASA grade, type of surgery, sex distribution, the level of sensory block were inferred by Chi-square test. Data such as age, weight, mean duration of surgery, preoperative temperature, onset of motor block, VAS, number of epidural top-ups, time of first epidural top-up, number of doses of diclofenac used, intraoperative and postoperative vitals were expressed as mean and standard deviation; difference in the means were inferred by analysis of variance. Post-hoc test was used in intergroup comparison. For significance, P < 0.05 was considered to be significant and <0.01 as highly significant.

RESULTS

In our study, the three groups were comparable with respect to age, sex, weight, ASA grade, duration of surgery, preoperative temperature [Table 1], and type of surgery [Table 2]. Sensory block and the onset of motor block until Bromage 3 was comparable in the three groups [Table 3]. Hemodynamics were recorded as a secondary outcome, and it was observed that in all three groups, patients were hemodynamically stable in the intraoperative and postoperative period.

Table 1

Patient variables

Table 2

Distribution according to types of surgery

Table 3

Sensory and motor block

The VAS score was noted 1 h after spinal anesthesia at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 h. There was a significant difference in VAS score among all groups from 1 to 10 h except at 5 and 10 h between Group G and Group C [Table 4]. At 5 h, VAS score in Group C decreased due to the analgesic effect of epidural top-up. Hence, the VAS score in Group G and Group C were comparable; therefore, statistically nonsignificant (P = 0.989). At 10 h, in Group G, VAS score was greater than three and epidural top-up was administered whereas in Group C, VAS score did not decrease despite epidural top-up given at 8 h, therefore rescue analgesia in form of diclofenac intramuscular 75 mg was given, due to which VAS score was observed to be less than at 12 and 16 h. At 12 h, VAS score was greater than three in Group P, hence first epidural top-up was given to nine patients at this hour. At 12 h VAS score in Group G and Group C was comparable because of the pain relief due to epidural top-up in Group G and pain relief in Group C due to the synergistic effect of epidural and intramuscular diclofenac. Similarly, VAS score in all the three groups were observed at 16, 20, and 24 h, and when VAS score was observed to be greater than three, epidural top-up was administered. The VAS scores in Group P and Group G were comparable at 20 and 24 h but when compared to Group C, were found to be highly significant [Figure 1].

Table 4

VAS score

Figure 1

Visual analog scale score over 24 h postoperative period. Group receiving pregabalin had longest pain-free time interval. Data are expressed as mean ± standard deviation

The mean time of first epidural top-up/pain-free interval was observed in all the three groups [Table 5]. It was found that in pregabalin group, patients were given the first top-up on an average at 14.80 h, in gabapentin group at 7.23 h, and at the earliest in the control group at 4.17 h in 24 h period. Mean of total number of epidural top-ups given in 24 h was calculated in all the three groups. Mean number of top-ups given in pregabalin group was (0.77 ± 0.626), in gabapentin group was (2.43 ± 0.626), and were lesser as compared to control group (4.43 ± 0.68). In Group P, 10 patients did not require any epidural top-up in the first 24 h.

Table 5

Comparison of time of first epidural requirement, number of epidural doses required and number of doses of diclofenac used

Therefore, in this study, we observed that in Group P, the patient had a longest pain-free interval post spinal anesthesia followed by Group G patients followed by patients in Group C. Rescue analgesia was used in patients if the pain was not relieved by epidural analgesia. Mean number of doses of rescue analgesia was compared among the three groups, and it was found that control group required highest number of rescue doses (mean = 0.37) required. In pregabalin group, none of the patients required rescue analgesia and in gabapentin group only two patients required.

Sedation score [Figure 2] were compared in postoperative period, and no significant difference was found in pregabalin and gabapentin group, but significant difference was noted between control versus gabapentin and control versus pregabalin. Other side effects [Table 6] and hemodynamics were comparable among all groups.

Figure 2

Sedation score in three groups for 24 h postoperative

Table 6

Comparison of side effects

DISCUSSION

In this study, we observed that the single preoperative dose of pregabalin 300 mg was a better premedicant than 1200 mg gabapentin and placebo in prolonging postoperative pain-free interval in patients undergoing lower limb orthopedic surgery under combined spinal epidural anesthesia. The VAS scores were significantly lower in pregabalin as compared to gabapentin and control. Sedation score was comparable in pregabalin and gabapentin group, but significant difference was there between control versus gabapentin and control versus pregabalin. Rescue analgesia was not required in any patient given pregabalin group.

Gabapentin, a structural analog of gamma-aminobutyric acid, was introduced as an antiepileptic drug. It binds to calcium channel and inhibits calcium influx and reduces excitatory neurotransmitter release in pain pathways in the central and peripheral system.[7] It has been used in patients with postherpetic neuralgia,[8] diabetic neuropathy,[9] trigeminal neuralgia,[10] neuropathic pain in malignancy[11], and complex regional pain syndromes.[12] Pregabalin, different from its predecessor gabapentin, in having amino acid substitution at third position making it more lipid soluble with better pharmacokinetic profile such as higher bioavailability, rapid absorption, and linear increase in its plasma concentration.[13] The peak blood concentrations of pregabalin are attained within 1 h. The maximum rate of absorption of pregabalin is approximately 3-fold greater than that of gabapentin. Pregabalin binds to the same calcium channels as gabapentin but with greater affinity, making it a more potent analgesic. All these characteristics possibly are responsible for longer pain-free interval postspinal anesthesia.

The dose of 300 mg pregabalin and gabapentin 1200 mg were used as these are the highest safe single dose used in previous studies on postoperative pain. The drug was given 1.5 h before surgery with a sip of water under direct observation. Their administration 1–2 h before surgery appeared rational to attain maximal plasma concentration at the time of surgical stimuli. Though pregabalin is rapidly absorbed (peak: within 0 min to 2 h) and gabapentin is slowly absorbed (peak: 2 h); sufficient time is given to achieve peak effect of both these drugs. Control group was added for additional inferences as it could help in comparison of each drug to placebo.

In 2011, study was conducted[13] regarding preoperative administration of gabapentin 1200 mg and pregabalin 300 mg for pain following lumbar laminectomy and discectomy. It was observed that during the first six postoperative hours patients in both pregabalin and gabapentin groups reported less pain than patients in placebo group except pain score at 12th and 24thh. It was due to higher morphine consumption in the placebo group after 6thh, decreasing the VAS score in placebo group, hence making the VAS score comparable in three groups. In our study, at 12 h VAS score in gabapentin group and control group was comparable because of the pain relief due to epidural top-up in gabapentin group and pain relief in control group due to the synergistic effect of epidural and intramuscular diclofenac. The VAS scores in pregabalin group and gabapentin group were comparable at 24 h but when compared to control group they were found to be highly significant as morphine was not used in our study as rescue analgesia.

A study was conducted in 2008[14] comparing effect preemptive gabapentin 1200 mg versus pregabalin 300 mg for acute postoperative pain after surgery under spinal anesthesia. It was observed that total postoperative analgesic duration was 8.98 h in Group G whereas 14.17 h in Group P, which was highly significant. Two patients in Group G and four in Group P did not need any analgesia. Total number of analgesic doses was lower in Group P. The parameters in our study were in accordance with this study.

In a study conducted in June 2014 by Bafna et al.,[15] comparison of effect of preemptive use of oral gabapentin (600 mg) and pregabalin (150 mg) for acute postoperative pain after surgery under spinal anesthesia was done, and it was concluded that use of gabapentin 600 mg and pregabalin 150 mg orally significantly reduces the postoperative rescue analgesic requirement and increases the duration of postoperative analgesia in patients undergoing elective gynecological surgeries. A significantly longer duration of effective analgesia was found in pregabalin group (9 h).

A prospective, randomized, double-blinded controlled trial of gabapentin and pregabalin as preemptive analgesia in patients undergoing lower abdominal and limb surgery under spinal anesthesia[16] was conducted in 2014 and it was observed that single preoperative dose of pregabalin 300 mg resulted in significant reduction in postoperative analgesic requirement compared to gabapentin (900 mg) and placebo in infra umbilical surgeries under spinal anesthesia. The VAS scores in pregabalin group were observed to be less than three until 8thh. In gabapentin group, VAS greater than three was observed at 4thh, and in control group, it was greater than three in the first postoperative hour. It was also observed that total analgesic consumption (tramadol) for 72 h, was significantly less with pregabalin compared to gabapentin and control. These observations are similar to the one observed in our study. In our study, the VAS scores in pregabalin group were observed to be less than three until 12 h. In gabapentin group, VAS was observed to be greater observed than three at 6 h, and in control group it was greater than three at 4 h in 18 patients and at 3 h in 4 patients.

Limitations

Limitations of our study are that due to lack of facility in our setup, we could not measure the levels of the study drugs, and only single doses of pregabalin and gabapentin was used which may have resulted in decreased effect over time and does not reflect on the long-term benefits to the patients. More studies need to be conducted to compare the pre- and post-operative analgesic effects of gabapentin and pregabalin. Studies are needed to find out the optimal dose of pregabalin and gabapentin that can provide adequate analgesia with minimal side effects. Further studies should investigate the range of doses with PCA machine. More controlled trials are required to define benefits and outcome with different doses of pregabalin and gabapentin.

CONCLUSION

Hence, it can be concluded from our study that pregabalin 300 mg and gabapentin 1200 mg significantly reduce the need of postoperative rescue analgesia, epidural top-ups, and increase the duration of postspinal anesthesia without altering the intraoperative hemodynamics. Pregabalin was found to be better analgesic than gabapentin and placebo with sedation as a major side effect with both pregabalin and gabapentin.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest