Indian Journal of Pain

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 33  |  Issue : 1  |  Page : 15--19

Clinical efficacy of oral gabapentin versus clonidine for preemptive analgesia in knee arthroplasty under epidural anesthesia with 0.75% Ropivacaine – A comparative study


Ivesh Singh, Kumkum Gupta, Salony Agarwal, Manoranjan Kumar Bansal, Abdul Samad, Pavitra Kalra 
 Department of Anaesthesiology and Critical Care, Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India

Correspondence Address:
Dr. Kumkum Gupta
108-109, Chanakyapuri, Shastri Nagar, Meerut - 250 004, Uttar Pradesh
India

Abstract

Background: The preemptive analgesia for knee arthroscopic repair may reduce the postoperative pain without affecting the mobility of patients. The present study was designed to compare the clinical efficacy of oral gabapentin with clonidine as preemptive analgesic to epidural ropivacaine (0.75%) for knee arthroscopic repair, done under epidural anesthesia. Patients and Methods: Sixty adult patients of both genders of the American Society of Anesthesiologists physical status I and II aged 20–58 years, scheduled for knee arthroscopic repair under epidural anesthesia, were randomized into two groups of 30 patients each. Patients of Group RG were given oral gabapentin 300 mg, and patients of Group RC received oral clonidine 100 μg, 90 min before surgery with sip of water. All patients received epidural anesthesia with 15 ml of 0.75% ropivacaine. Groups were compared for onset and duration of sensory and motor blockade and postoperative analgesia as primary end points. Intraoperative hemodynamic changes, sedation score, or any side effects were evaluated as secondary end points. Results: The onset of complete sensory block to T10 (15.4 ± 4.7 vs. 17.5 ± 3.8 min) and time to achieve complete motor block (23.7 ± 3.3 vs. 26.9 ± 1.4 min) was earlier in patients of Group RC. Postoperative analgesia was prolonged in patients of Group RG (248.17 ± 19.6 vs. 217.36 ± 12.3 min). Intraoperative hemodynamic changes showed no significant difference. There was an increased incidence of nausea and vomiting in clonidine group. Conclusion: Oral gabapentin proved to be better as preemptive adjuvant for providing postoperative analgesia and good sedation during knee arthroscopic repair.



How to cite this article:
Singh I, Gupta K, Agarwal S, Bansal MK, Samad A, Kalra P. Clinical efficacy of oral gabapentin versus clonidine for preemptive analgesia in knee arthroplasty under epidural anesthesia with 0.75% Ropivacaine – A comparative study.Indian J Pain 2019;33:15-19


How to cite this URL:
Singh I, Gupta K, Agarwal S, Bansal MK, Samad A, Kalra P. Clinical efficacy of oral gabapentin versus clonidine for preemptive analgesia in knee arthroplasty under epidural anesthesia with 0.75% Ropivacaine – A comparative study. Indian J Pain [serial online] 2019 [cited 2019 Aug 25 ];33:15-19
Available from: http://www.indianjpain.org/text.asp?2019/33/1/15/255712


Full Text

 Introduction



Knee arthroscopic repair is performed as a planned, nonemergency surgical procedure on selected patients, and epidural anesthesia is a technique of choice.[1] It showed definite advantage over general anesthesia by blocking nociceptive impulses from the operative site, reduced blood loss, decreased incidence of deep vein thrombosis, no respiratory depression or cardiovascular instability, patient's ability to communicate, and reduced cost of drugs.[2]

Preemptive analgesia technique involves the introduction of an analgesic regimen before the onset of noxious stimuli, with the goal of preventing sensitization of the nervous system to subsequent stimuli that could amplify pain. Owning to this protective effect on the nociceptive system, preemptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery.[3]

Ropivacaine possesses lesser systemic toxicity than bupivacaine with favorable physiochemical profile and sensory-motor differentiation. Early recovery of motor function is associated with early postoperative mobilization, decreased incidences of deep vein thrombosis, and hence early hospital discharge.[4],[5]

Gabapentin, a structural analogue of γ-aminobutyric acid, is an anticonvulsant that binds to an alpha-2-δ ligand that has analgesic, anxiolytic, and sleep modulation activities. Gabapentin has a selective effect on the nociceptive process involving central sensitization; hence, pretreatment with gabapentin can block the development of hyperalgesia.[6]

Clonidine acts centrally on alpha-2 adrenoreceptors as agonist and has potential benefits as premedication by virtue of its ability to decrease sympathetic outflow. It provides significant benefits for preoperative anxiolysis and analgesia. Clonidine has nonopiate antinociceptive properties and hence may be used as an alternative for postoperative analgesia.[7]

Considering the merits of ropivacaine, gabapentin, and clonidine, the present prospective double-blind randomized study was aimed to compare the clinical efficacy of oral gabapentin with clonidine as preemptive analgesic in knee arthroscopic repair, done under epidural anesthesia with 0.75% ropivacaine.

 Patients and Methods



The study was approved by the Institutional Ethical Committee, and all patients gave written informed consent to participate. Sixty patients of the American Society of Anesthesiologists (ASA) physical status I and II, aged 25–58 years of both genders and <90 kg, scheduled for elective knee arthroscopic repair under epidural anesthesia, were enrolled for this prospective double-blind randomized study.

Patients with a history of opioid dependence or on chronic pain medications, history of pulmonary disease or uncontrolled hypertension, hepatic or renal dysfunction, metabolic disorders, spinal deformity or skin infection, on any anticoagulant therapy, allergy to local anesthetic or known sensitivity to study drugs, or suffering from any neurological disorders were excluded from the study.

All selected sixty patients were randomized into two equal groups of 30 patients each according to computer-generated random number, each receiving a sealed envelope of study medication. Patients of Group RG were given 300-mg oral gabapentin, and patients of Group RC were given 100-μg oral clonidine, 90 min before surgery. All patients received 15 ml of 0.75% ropivacaine epidurally. The identity of the tablet was not revealed to the patients and to the researcher. The resident recording the data and caring the patient was also unaware of the study protocol to ensure the double blindness of the study.

The fasting for all patients was ensured on the day of surgery. On arrival of a patient into operation theater, routine monitoring of noninvasive blood pressure, electrocardiogram (ECG), heart rate (HR), and finger pulse oximetry (SpO2) was commenced and lactated Ringer's solution at rate of 10 ml/kg/h was started, 15 min before initiation of epidural blockade.

Under all aseptic condition, lumbar epidural anesthesia was administered in the sitting position by midline approach at L2–3 or L3–4 intervertebral disc space using an 18-G Tuohy needle, and location of epidural space was confirmed by loss of resistance technique. With the bevel of Tuohy needle in cephalic direction, a test dose of 3 ml of 2% lidocaine with epinephrine was given to detect intrathecal or intravenous injection. Three minutes after test dose, epidural catheter of 18 G was threaded and fix at the patent's back. All patients were aligned into supine position and were given 15 mL of 0.75% ropivacaine to achieve adequate level of surgical anesthesia (T10). All patients were supplemented with 100% oxygen at rate of 4 L/min via venti mask during the surgery.

Epidural block characteristics

The sensory and motor block characteristics were assessed at 2-min interval till the surgical anesthesia was achieved. The segmental level of sensory blockade was assessed by bilateral pin-prick method along the midclavicular line using a short-beveled 26-G hypodermic needle. The onset of motor blockade of lower extremities was evaluated bilaterally by modified Bromage scale (0–3): 0 – full motor activity and able to raise straight leg against resistance, 1 – unable to raise extended leg at hip but able to flex knee, 2 – unable to flex knee but able to move ankle joint, and 3 – unable to move hip, knee, or ankle (no motor activity).

All time intervals were calculated from the time of the end of epidural injection. The onset time of complete sensory block, maximum cephalic sensory blockade, duration of two-segment sensory regression, and time to achieve complete motor blockade, were noted for comparison. The surgical anesthesia was considered effective when T10 dermatome was anesthetized. Duration of sensory analgesia was taken from onset of epidural anesthesia to time of administration of first rescue analgesia with epidural top-up (5 mL of 0.75% ropivacaine with 50 mg tramadol, to make 10-mL solution).

Hemodynamic parameters

The hemodynamic parameters of HR, systemic blood pressure, SpO2, and ECG were recorded preoperatively and then at every 5 min intervals after initiation of epidural block, till the end of surgery, and followed by at every 15 min interval in the postanesthesia room. For the present study, hypotension was defined as a fall in systolic blood pressure of >20% of baseline or <100 mmHg. Bradycardia was defined as HR <60 beats/min.

Level of sedation

Sedation score was explained to the patients and was recorded just before the initiation of surgery and every 15 min. Level of sedation was assessed using a five-point sedation score:[8]

1 – Alert and wide awake, 2 – Arousable to verbal commands, 3 – Arousable to gentle tactile stimulation, 4 – Arousable to vigorous shaking, and 5 – Unarousable even on vigorous shaking.

Visual analog scale

Visual analog scale (VAS) is a psychometric response scale and used for postoperative pain assessment. A patient specified his level of agreement to a statement by indicating a position along a continuous line between two end points of 0–10, where 0 means no pain and 10 means worst possible pain.

Postoperative care

At the end of surgery, the patients were shifted to postanesthesia recovery room and monitored for any changes in vital signs and their sensory and motor blockade profile at every 30-min intervals until they required rescue analgesia (VAS >3).

Side effects

All patients were observed for dizziness, headache, pruritus, nausea, vomiting, respiratory depression, or any other adverse events related to study drugs or technique.

Rescue plan

Hypotension was treated primarily by increasing the rate of lactated Ringer's infusion and additionally with intravenous bolus of mephentermine 6 mg.

Bradycardia was treated with intravenous atropine 0.6 mg.

Respiratory discomfort was managed by increasing the oxygen flow.

Nausea and vomiting were treated by intravenous ondansetron (4 mg).

Study population size and statistical analysis

The sample size was calculated with standard computer program which computed that approximately 25–27 patients should be included in each group to detect at least clinically significant difference of 30 min in mean duration of analgesia between the groups for Type I error of 0.05 with power of 80% and 95% confidence limit. Assuming a 5% dropout rate, the total number of patients was set at 60 for better validation of result.

All recorded data were compiled systematically in tabulated manner and expressed as mean ± standard deviation considering later being best predictor for statistical analysis. Data were analyzed using Statgraphics Centurion, version 16 (StatPoint Technologies Inc., Warrenton, Virginia). The demographic data for categorical variables were compared using Chi-square test, and statistical significance in mean difference was done using analysis of variance. Epidural block characteristics were compared using Mann–Whitney U-test. P < 0.05 was considered statistically significant.

 Results



The present study compared the clinical efficacy of oral gabapentin with clonidine as preemptive analgesia for knee arthroscopic repair, performed under epidural anesthesia with 0.75% ropivacaine on 60 adult patients. The surgery was performed by one of the two orthopedic surgeons, and there was no protocol deviation; thus, the study was successfully completed. Data of all patients were included for statistical analysis.

The demographic data for age, gender, weight, and ASA physical status were comparable between both the groups [Table 1].{Table 1}

Sensory and motor block characteristics

The mean time required to achieve complete sensory analgesia at T10 dermatome was 17.5 ± 3.8 min in patients of Group RG and 15.4 ± 4.7 min in patients of Group RC with no statistically significant difference. The mean time to reach maximum cephalic dermatome level for sensory block was also comparable between the groups. The mean time taken for complete motor block was 23.7 ± 3.3 min in patients of Group RC while it took 26.9 ± 1.4 min in patients of Group RG. The motor block was of shorter duration than sensory analgesia in all patients. The total duration of motor blockade and sensory analgesia varied significantly between the groups (P = 0.001) [Table 2].{Table 2}

Hemodynamic profile

The hemodynamic parameters of mean HR, mean systemic arterial pressure, respiratory rate, and oxygen saturation at baseline were comparable. After 15 min of epidural block, the mean HR and mean systolic blood pressure showed gradual decline in patients of both the groups, but the intraoperative mean values of HR and systolic blood pressure did not show statistically significant decline from the base values [Table 3].{Table 3}

The HR was lower in patients of clonidine group throughout the study period when compared to gabapentin group. There was an insignificant intragroup variation with respect to blood pressure, respiratory rate, and peripheral oxygen saturation. The episodes of bradycardia and hypotension were negligible, and no patient requires any medical intervention.

Sedation scores

Sedation score in patients of gabapentin group was 2 in 7 patients (33.33%) and 3 in 13 patients (43.33%), suggesting that more number of patients were awake and responding to commands. Furthermore, 5 patients (16.66%) had a score of 4 and 2 patients (6.66%) had score of 5, suggesting that they were deeply sedated.

Sedation score in patients of clonidine group was 1 in 10 patients (33.33%) and 2 in 8 patients which suggested that more number of patients were awake and anxious.

Visual analogue scale score

Gabapentin group showed significantly lower VAS postoperatively when compared to patients of clonidine group. Patients who were premedicated with gabapentin showed better pain tolerance compared to those who were given clonidine.

Side effects

Clonidine showed a higher incidence of nausea and vomiting as compared to patients of gabapentin group. The incidence of dizziness was comparable between the groups. Gabapentin showed lesser adverse effects to clonidine [Table 4].{Table 4}

 Discussion



Preoperative anxiety is a major predictor of postoperative pain apart from the type of surgery, age, and related psychological distress. Anxiety lowers pain threshold, resulting in exaggeration of pain intensity and activation of the hippocampal formation. Stress and anxiety activate hypothalamic–pituitary–adrenal axis and increase glucocorticoid level.

Pain is a subjective and multifaceted personal experience which causes significant distress to patients and has adverse effects on the endocrine and immune function, wound healing, and cardiopulmonary diseases; therefore, premedication before surgery is recommended for acute pain management. Epidural analgesia has been considered as a superior form of providing postoperative analgesia.[9]

Opioids are the mainstay of postoperative pain management but with side effects of respiratory depression, pruritus, constipation, and development of tolerance. Hence, there is a need to investigate the role of preemptive analgesia for efficient and safe postoperative management.

Preincisional analgesia is more effective in control of postoperative pain by protecting the central nervous system from deleterious effects of noxious stimuli and resulting allodynia and increased pain. Proving the clinical efficacy of gabapentin and clonidine might incorporate the use of this medication in future as preemptive analgesics to enhance the duration of postoperative analgesia.

The present study was designed with aims of comparing the postoperative analgesic efficacy of oral gabapentin with oral clonidine in knee arthroscopic repair. The study also compare the preoperative sedation, hemodynamic stability, extent of sensory blockade and the side effects of orally administered gabapentin and clonidine.

Gabapentin, a structural analog of γ-aminobutyric acid (GABA), is an anticonvulsant that binds to the alpha-2-δ ligand that has analgesic, anxiolytic, and sleep modulation activities. Despite its structural similarity to GABA, it does not act via mechanisms related to GABA. Pretreatment with gabapentin can block the development of hyperalgesia. Gabapentin has a selective effect on the nociceptive process involving central sensitization. It has been shown in studies that there is a lower pain score, hence significantly less requirement of opioids.

Clonidine is a selective central alpha-2 adrenoreceptor agonist and it decreases the sympathetic outflow by acting on pre- and postsynaptic sympathetic nerve terminal and central nervous system to cause sedation, analgesia, and sympatholytic and hemodynamic effects. The alpha-2 adrenoreceptor agonist has analgesic action at several sites of the peripheral and central nervous system as well as prolongation of epidurally or intrathecally administered local anesthetics and opioids. Oral clonidine in doses of 1.5–2 μg/kg combines the advantages of benzodiazepines and morphine with stable hemodynamics and respiration. It is easily available and does not come under the narcotic act.

Gabapentin and clonidine are given orally in various doses for postoperative pain management. Oral gabapentin is used in dosages of 300–1600 mg in both single and multiple dosages. Oral clonidine is used in dosages of 100–300 μg. We used gabapentin in dose of 300 mg and clonidine in dose of 100 μg because these dosages were used by several previous researchers.

Ghafari et al. studied the effects of preoperative gabapentin or clonidine in decreasing postoperative pain during abdominal hysterectomy and demonstrated that VAS pain score was significantly lower in two groups compared to the placebo group.[10] In the present study, similar results were observed, but patients of gabapentin group showed lesser VAS scores as compared to clonidine group. Our results are also in accordance with studies conducted by Mohammadi and Seyedi [11] and Verma.[12]

Yanagidate et al. premedicated the patients undergoing cesarean delivery with 4 μg/kg of oral clonidine and concluded that oral clonidine reduces the morphine requirement without compromising the fetus.[13] Moore et al. found that preoperative gabapentin 600 mg in the setting of multimodal analgesia reduces postcesarean delivery pain and increases maternal satisfaction.[14]

Singhal et al.[15] and Saini and Anand [16] studied the effects of oral gabapentin and clonidine on preoperative anxiolysis and attenuation of stress response to endotracheal intubation. They used oral gabapentin (900 mg) or oral clonidine (300 μg), 90 min before elective surgical procedure. The authors stated that clonidine is effective in attenuating preoperative anxiety and stress response when compared to gabapentin with statistically significant difference. In the present study, there was a significant difference in sedation score between both the groups. Gabapentin showed better sedative effect.

In the present study, clonidine prolongs the total duration of sensory block by increasing the time for two-segment regression with extension of analgesia, as observed by Toshniwal and Halbe.[17]

Talebi et al. observed decreases in HR and systolic blood pressure,[18] while Fassoulaki et al.[19] observed that gabapentin decreases blood pressure, but HR did not differ at all time intervals in their study. In the present study, both the groups showed fall in hemodynamic parameters, although clonidine showed a significant fall in blood pressure when compared to gabapentin group. There were no changes in hemodynamic parameters in gabapentin group.

The postoperative analgesic efficacy of oral gabapentin showed better pain tolerance compared to clonidine. There was no significant difference in time of sensory onset, maximum sensory block, and duration of two-segment regression between the groups with comparable intraoperative hemodynamic changes of systolic blood pressure and HR. There were increased incidences of nausea and vomiting in clonidine group.

 Conclusion



Preemptive analgesia with oral gabapentin or clonidine can be used for knee arthroscopic repair, but gabapentin 300 mg, given 90 min before as preemptive analgesia, was more effective in reducing postoperative pain and providing better anxiolysis than clonidine 100 μg.

Acknowledgment

The authors would like to thank all the patients who participated in the study and technical staff of orthopedic operation theater for their kind cooperation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Patel NJ, Flashburg MH, Paskin S, Grossman R. A regional anesthetic technique compared to general anesthesia for outpatient knee arthroscopy. Anesth Analg 1986;65:185-7.
2Mingus ML. Recovery advantages of regional anesthesia compared with general anesthesia: Adult patients. J Clin Anesth 1995;7:628-33.
3Koutur PF. Is preemptive analgesia beneficial for postoperative pain management? Indian J Aneasth 2006;50:22.
4Agarwal A, Verma RK, Shrivastava S. Ropivacaine-the latest local anesthetic in the Indian market. J Anesth Clin Pharmacol 2010;26:22-8.
5Peduto VA, Baroncini S, Montanini S, Proietti R, Rosignoli L, Tufano R, et al. Aprospective, randomized, double-blind comparison of epidural levobupivacaine 0.5% with epidural ropivacaine 0.75% for lower limb procedures. Eur J Anaesthesiol 2003;20:979-83.
6Mao J, Chen LL. Gabapentin in pain management. Anesth Analg 2000;91:680-7.
7Tryba M, Gehling M. Clonidine – A potent analgesic adjuvant. Curr Opin Anaesthesiol 2002;15:511-7.
8Stawicki SP. Sedation scales: Very useful, very underused. OPUS 12 Scientist 2007;1:10-2.
9Cortés Román C. Lumbar epidural anesthesia, 1931-1936: A second debut. Rev Esp Anestesiol Reanim 2005;52:159-68.
10Ghafari MH, Akrami M, Nouralishahi B, Sadegh A. Preoperative gabapentin or clonidine decreases postoperative pain and morphine consumption after abdominal hysterectomy. Res J Biol Sci 2009;4:458-63.
11Mohammadi SS, Seyedi M. Effects of gabapentin on early postoperative pain, nausea and vomiting in laparoscopic surgery for assisted reproductive technologies. Pak J Biol Sci 2008;11:1878-80.
12Verma A. To evaluate the role of gabapentin as pre-emptive analgesic in patients undergoing total abdominal hysterectomy in epidural anaesthesia. Indian J Anaesth 2008;52:428-31.
13Yanagidate F, Hamaya Y, Dohi S. Clonidine premedication reduces maternal requirement for intravenous morphine after cesarean delivery without affecting newborn's outcome. Reg Anesth Pain Med 2001;26:461-7.
14Moore A, Costello J, Wieczorek P, Shah V, Taddio A, Carvalho JC, et al. Gabapentin improves postcesarean delivery pain management: A randomized, placebo-controlled trial. Anesth Analg 2011;112:167-73.
15Singhal SK, Kaur K, Arora P. Oral clonidine versus gabapentin as premedicant for obtunding hemodynamic response to laryngoscopy and tracheal intubation. Saudi J Anaesth 2014;8:172-7.
16Saini V, Anand LK. Oral clonidine premedication in patients undergoing intraocular surgery under local anathesia. J Anaesth Clin Pharmacol 2009;25:311-5.
17Toshniwal N, Halbe A, Iyyer H. Study of comparative effects of oral clonidine vs. oral diazepam premedication on the extent and duration of sensory blockade in patients undergoing vaginal hysterectomy under spinal anesthesia. Internet J Anesthesiol 2008;19:2.
18Talebi H, Nourozi A, Fateh S, Mohammadzadeh A, Eghtesadi-Araghi P, Jabbari S, et al. Effects of oral clonidine premedication on haemodynamic response to laryngoscopy and tracheal intubation: A clinical trial. Pak J Biol Sci 2010;13:1146-50.
19Fassoulaki A, Melemeni A, Paraskeva A, Petropoulos G. Gabapentin attenuates the pressor response to direct laryngoscopy and tracheal intubation. Br J Anaesth 2006;96:769-73.