ORIGINAL ARTICLE

Clinical Study Evaluating Pregabalin Efficacy and Tolerability for Pain Management in Patients Undergoing Laparoscopic Cholecystectomy Mohammad S. Bekawi, BSc,* Lamia M. El Wakeel, PhD,* Waleed M.A. Al Taher, MD,w and Walid M.A. Mageed, MDw

Objectives: To evaluate the efficacy and tolerability of pregabalin in postoperative pain management after laparoscopic cholecystectomy (LC). Patients and Methods: A prospective, randomized, placebo, controlled, double-blinded study was conducted at Anesthesia Department, Laparoscopy Surgery Unit, Ain Shams University Hospital. Ninety patients with ASA physical status I-II scheduled for elective LC under general anesthesia were included. Patients were randomly assigned to the following groups (n = 30 each): pregabalin group (P), received 150 mg pregabalin capsules 2 hours preoperatively, 12 hours postoperatively, and twice daily for 2 days; gabapentin group (G), received 1200 mg gabapentin capsules (400 mg,  3) 2 hours preoperatively, 12 hours postoperatively, and 400 mg three times daily for 2 days; and control group (C), received placebo capsules. Postoperative pain scores were recorded on a visual analogue scale. The following data were recorded: total daily pethidine and diclofenac consumption, numeric sedation score, and the postoperative nausea, vomiting, and dizziness scores. Results: The 24-hour pethidine consumption was significantly lower (P < 0.001) in both pregabalin and gabapentin groups versus control. Both groups had significantly less (P < 0.001) patients with postoperative nausea, vomiting, sedation, and dizziness versus control. Overall patient satisfaction with pain management was significantly higher (P < 0.001) in pregabalin group versus gabapentin or control groups. Conclusions: Gabapentin 1200 mg and pregabalin 150 mg are effective and safe analgesics for reducing postoperative pain in LC. The perioperative oral administration of pregabalin 150 mg in patients undergoing LC is an effective and safe method of analgesia with a low incidence of adverse effects and reduces postoperative pethidine consumption. Key Words: laparoscopic cholecystectomy, pregabalin, gabapentin, pain

(Clin J Pain 2014;30:944–952)

L

aparoscopic cholecystectomy (LC) is one of most popular surgical procedures; however, pain after this surgery

Received for publication June 6, 2013; revised December 13, 2013; accepted November 24, 2013. From the *Department of Clinical Pharmacy, Faculty of Pharmacy; and wDepartment of Anesthesia And Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt. No source of funding from National Institute of Health (NIH); Welcome Trust: Howard Hughes Medical Institute (HHMI) & others. The authors declare no conflict of interest. Reprints: Lamia M. El Wakeel, PhD, 4, street 292, New Maadi, 11566, Cairo, Egypt (e-mail: lamywak @yahoo.com). Copyright r 2013 by Lippincott Williams & Wilkins DOI: 10.1097/AJP.0000000000000060

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presents a major challenge.1,2 It is most intense on the day of surgery and on the following day and subsequently declines to lower levels within 3 to 4 days.3 Intense acute pain after LC might predict the development of chronic pain (eg, postlaparoscopic cholecystectomy syndrome).4 Several medications have been used to treat postoperative pain.5 Opioids are the most commonly used but have been associated with emesis, respiratory depression, and altered mental status. Nonsteroidal anti-inflammatory drugs are frequently used; however, they are associated with the risk of allergy, kidney damage, bleeding, and gastrointestinal dysfunction.6 Another alternative is the use of local anesthetics, although they require interventional procedures and most of them are short or intermediate acting.7 A multimodal approach has been suggested to improve postoperative analgesia and to reduce the above mentioned side effects.8 Both pregabalin and gabapentin are g-amino butyric acid (GABA) analogs8; they do not bind at the GABAA or GABAB receptor. However, they have a high binding affinity for the a2d subunit of the presynaptic voltage-gated calcium channels,9 which inhibits calcium influx and subsequent release of excitatory neurotransmitters in the pain pathways that include glutamate, norepinephrine, substance P, and calcitonin gene–related peptide receptor,9,10 hence reducing the release of several excitatory neurotransmitters and blocking the development of hyperalgesia and central sensitization.11,12 It is probable that this modulation of neurotransmitter release by pregabalin contributes to the drug’s anticonvulsant, analgesic, and anxiolytic effects.9 Pregabalin (S-[ + ]-3-isobutylgaba) is an anticonvulsant agent that is frequently used for the treatment of neuropathic pain.13,14 Pregabalin is similar to gabapentin but is more selective as it has a high-affinity ligand to the a2d binding site.9 Moreover, it has a more favorable pharmacokinetic profile including dose-independent absorption and higher bioavailability.9,12 The agent is also several times more potent than gabapentin with fewer adverse effects, lack of drug interactions, and linear dose-response characteristics.10 The use of pregabalin is increasing because of its efficacy for neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, and fibromyalgia and as an adjunctive therapy for partial-onset seizures.15 Several reports have indicated that the preoperative administration of pregabalin may have a role in the treatment of postoperative pain after different surgical procedures.16 Yet, limited clinical trials have investigated the role of preoperative single-dose administration of pregabalin in attenuating postoperative pain after LC.17 To our knowledge till now, no study was conducted to compare the effects of pregabalin versus gabapentin in postoperative pain management in patients undergoing LC. Hence, Clin J Pain



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the aim of this prospective, randomized, placebo, controlled, double-blinded study was to evaluate the analgesic and opioids sparing effect of perioperative pregabalin administration for patients undergoing LC under general anesthesia.

PATIENTS AND METHODS The current study was a prospective, randomized, placebo, controlled, double-blinded study performed on patients undergoing a LC. The study was conducted at the Anesthesia Department Laparoscopy Surgery Unit of Ain Shams University Hospital. Figure 1 represents patients’ flow chart. All patients admitted to Ain Shams University Hospital for LC were assessed for eligibility according to the following criteria: Inclusion criteria included patients aged between 20 and 60 years. Exclusion criteria included patients with impaired liver or kidney functions, inflammatory bowel disease, chronic pain, a daily intake of analgesics or corticosteroid, or a history of hypersensitivity or serious adverse reaction to pregabalin or gabapentin. A total of a 113 patients were screened. Patients were informed and educated about the study design and a written informed consent was obtained from all patients. The study was approved by the ethical committee of the Anesthesia Department, Laparoscopy Surgery Unit, Ain Shams University Hospital. Before the start of the study, patients were randomized using computer-generated list by computer software system (GraphPad-QuickCalcs) and were then assigned to one of the 3 parallel groups, 30 each, as follows:

Pregabalin Group: Group P This group received pregabalin capsules (Lyrica Capsule; Pfizer, Germany): 150 mg capsules 2 hours before surgery and 12 hours after operation and twice daily for 2 days.

Gabapentin Group: Group G This group received Gabapentin capsules (Neurontin Capsule; Pfizer): 1200 mg (3 capsules of 400 mg dosage) 2 hours before surgery and 12 hours after surgery and 400 mg 3 times daily for 2 days.

Control Group: Group C This group received placebo capsules 2 hours before surgery and 12 hours after operation and twice daily thereafter for 2 days.

IN ALL GROUPS  Intraoperatively: no premedications were administered. Anesthesia was induced with propofol 2 mg/kg IV, fentanyl 1 mcg/kg IV, and atracurium 0.5 mg/kg IV. Anesthesia was maintained with isoflurane inspired at a fresh gas flow rate of 5 L/min in combination with air 30% in oxygen.  At the end of operation, the residual neuromuscular block was antagonized with atropine 0.01 mg/kg and neostigmine 0.04 mg/kg. The trachea was extubated after recovery of adequate spontaneous ventilation. Duration of surgery was recorded for each patient.  A thorough patient, family, and medication histories were gathered on admission.

PAIN ASSESSMENT After surgery, the pain score was recorded at 0-, 2-, 4-, 6-, 12-, and 24-hour postoperatively. For each patient, the r

2013 Lippincott Williams & Wilkins

Pregabalin Efficacy and Tolerability for Pain Management

maximum pain score at different time intervals was evaluated and recorded. Pethidine 1 mg/kg IM was given every 6 hour if pain score was Z3 or if requested by the patient. The pethidine IM route was used according to the hospital’s standard operating protocols. The worst pain score was recorded at the first dose of pethidine administered. The time of first dose of pethidine injection and the total consumption of pethidine within 24 hours was recorded. Diclofenac sodium 75 mg IM was used as rescue analgesia if the pain scores were >4 or if requested by the patient, which was repeated 3 times per day every 8 hours. The total 24-hour postoperative consumption of diclofenac sodium was recorded. If any patient required more frequent rescue analgesia than the maximum recommended dose, another analgesic with different mechanism of action was administered, tramadol 1 mg/kg IV, and the patient was to be excluded from the study. A physician from a different surgical department and who was blinded to the study carried out an assessment of pain.

MEASUREMENT OF THE PAIN SCORE VAS18 During the preoperative visit, the patients were taught how to represent their postoperative pain on a 10 cm VAS: 0 to 10 cm, 0 cm indicated no pain and 10 cm the worst. Pain scores were recorded at fixed intervals and when required by the patient.

MEASUREMENT OF SIDE EFFECTS Postoperative side effects related to pregabalin, such as nausea and vomiting, dizziness, and somnolence, were recorded in the postanesthesia care unit and in the ward. The side effects were reported as follows:

Postoperative Nausea and Vomiting Grading19 The frequency of postoperative nausea and vomiting was recorded in the ward after 6- and 12-hour postsurgery for each patient by using a 4-point scale: none: no nausea, vomiting, and retching; mild (1): happened once; moderate (2): happened 2 to 3 times; and severe (3): continuous or >3 times. For patients who were still fasting 8 hours postoperatively, the vomitus was the gastric juice. Moderate to severe nausea and vomiting were treated with ondansetron 4 mg IV injection.

Numeric Sedation Scale (NSS)20 The conscious level of the patient was observed and graded according to the NSS that was reported at 2-, 6-, 12-, and 24-hour postoperatively on a 5-point numerical scale: 1, completely awake; 2, awake but drowsy; 3, asleep but responsive to verbal order; 4, asleep but responsive to tactile stimulus; and 5, asleep and nonresponsive to any stimuli.

Postoperative Dizziness21 The patient was asked for the presence of postoperative dizziness that was graded as follows: none, mild dizzy but responding to question; moderate, dizzy but hardly responding to question; and severe, not responding to question. www.clinicalpain.com |

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Patient Flow Chart

Assessed for eligibility (n= 113) Enrollment

Excluded (n= 23) • Not meeting inclusion criteria (n= 15) • Declined to participate (n= 5)

Randomized (n= 90)

Allocation

• Allocated to Gp P; Pregabalin (n= 30) • Received 150 mg Pregabalin capsules, 2 hours before surgery and 12 hours after operation and twice daily for 2 days.

• Allocated to Gp G; Gabapentin (n= 30) • Received 1200 mg Gabapentin capsules, 2 hours before surgery and 12 hours after operation and twice daily for 2 days.

• Allocated to Gp C; Control (n= 30) • Received placebo capsules, 2 hours before surgery and 12 hours after operation and twice daily thereafter for 2 days.

Follow-Up

Lost to follow-up; None

Discontinued intervention; None

Pain assessment at 0,2,4,6,12,24 hrs postoperative Assessment of incidence of postoperative; nausea, vomiting, sedation & dizziness Analysis

• Analysed (n= 90) FIGURE 1. Patients flow chart.

GLOBAL SATISFACTION SCORE22 Patient grading for postoperative analgesia was recorded by using the global satisfaction score on a 4-point scale as follows: 4 = very good, 3 = good, 2 = fair, and 1 = poor.

Statistical Analysis Data management and analysis were performed using the Statistical Package for Social Sciences (SPSS) versus 17. The required sample size was calculated using G*Power software version 3.1.0 (Institut fu¨r Experimentelle Psychologie, Heinrich Heine Universita¨t, Du¨sseldorf, Germany). The primary outcome measures were the pain scores and 24-hour pethidine consumption after surgery. It was estimated that a sample size of 30 patients in each group would have a power of 84% to detect a medium to large effect size of 0.35 in these outcome measures. The test statistic used

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was the 2-sided F test and type I error was set at 0.05. Numerical data were summarized using means and SDs. Categorical data were summarized as percentages. Comparisons between the groups with respect to numeric variables were carried out by using the Kruskal–Wallis test, followed by the post hoc Bonferroni test. The w2 test was used to compare between the groups with respect to categorical data. Comparison of the each group overtime was carried out using the Freidman test.23 All P-values were 2-sided. P-values

Clinical study evaluating pregabalin efficacy and tolerability for pain management in patients undergoing laparoscopic cholecystectomy.

To evaluate the efficacy and tolerability of pregabalin in postoperative pain management after laparoscopic cholecystectomy (LC)...
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