|Year : 2017 | Volume
| Issue : 1 | Page : 287-292
Ketamine versus pregabalin as an adjuvant to epidural analgesia for acute post-thoracotomy pain
Ahmed H Bakeer1, Nasr M Abdallah2
1 Department of Anaesthesia and Pain Relief, National Cancer Institute, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Anaesthesia, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Web Publication||3-Aug-2018|
Ahmed H Bakeer
13 Mohamed Shokry. Agouza, Giza; Department of Anaesthesia and Pain Relief, National Cancer Institute, Cairo, 12411
Source of Support: None, Conflict of Interest: None
Objective The aim was to compare analgesic effect of ketamine versus pregabalin as adjuvant to post-thoracotomy epidural analgesia in the National Cancer Institute.
Patients and methods This randomized controlled trial involved 60 adults planned for thoracotomy under general anesthesia for management of lung cancer. They were randomly assigned into one of two groups. Group K (n=30) received three doses of ketamine 0.5 mg/kg intravenously, that is, after induction of anesthesia and at 6 and 30 h postoperatively. Group P (n=30) received oral pregabalin 150 mg 2 h before surgery and at 6 and 30 h postoperatively. The endpoints were pain reduction using visual analog score (VAS) score, frequency of rescue morphine doses, hemodynamic parameters, and adverse effects in the first 48 h.
Results VAS score was significantly lower in ketamine group than that in the pregabalin group from 8 up to 48 h postoperatively. In group P, VAS score decreased after 16 h (P<0.001) and continued to decrease up to 48 h. Rescue analgesia was required after 2 h by 11 (36.7%) patients in group K and 15 (50%) patients in group P (P=0.297). The two drugs were accompanied by hemodynamic stability. Patients in group P were more sedated 2 h after surgery compared with those in group K (P=0.006). No cases of nausea and vomiting or psychological adverse effects related to ketamine use were recorded.
Conclusion Ketamine and pregabalin are good alternatives for augmentation of the efficacy of thoracic epidural analgesia following thoracotomy in patients with lung cancer. Ketamine has the advantage of more rapid action and higher efficacy in addition to less sedation in early postoperative period.
Keywords: adjuvants, epidural analgesia, ketamine, pregabalin, thoracotomy
|How to cite this article:|
Bakeer AH, Abdallah NM. Ketamine versus pregabalin as an adjuvant to epidural analgesia for acute post-thoracotomy pain. Ain-Shams J Anaesthesiol 2017;10:287-92
|How to cite this URL:|
Bakeer AH, Abdallah NM. Ketamine versus pregabalin as an adjuvant to epidural analgesia for acute post-thoracotomy pain. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2019 Sep 18];10:287-92. Available from: http://www.asja.eg.net/text.asp?2017/10/1/287/238466
| Introduction|| |
Pain after thoracotomy is the worst and most severe pain experienced after surgery. A thoracotomy incision involves multiple muscle layers with rib resection and continuous movement during patient breathing . Severe acute post-thoracotomy pain is an expected response to rib retraction, resection, or fracture; dislocation of costovertebral joints; and intercostal nerve injury in addition to pleura irritation by chest tubes .
Consequently, an effective analgesia after thoracotomy is critical not only to keep the patient comfortable but also to minimize serious pulmonary complications. Pain leads to limitation of inspiration with subsequent reflex contraction of expiratory muscles and diaphragmatic dysfunction. Inadequate analgesia prevents deep breathing that leads to ineffective cough, and retention of secretions, leading to airway closure and atelectasis . Effective analgesia reduces perioperative morbidity, shortens hospitalization times, improves patient satisfaction, and lowers cost ,,.
Many strategies have been suggested for pain management in these cases. Nevertheless, the ideal strategy is still an open issue. Owing to multifactorial origin of pain after thoracotomy, a multimodal analgesic approach rather than a single method seems to be more effective because it blocks noxious input at different targets and levels of pain pathways .
A multimodal analgesic strategy that includes regional anesthesia is considered as a gold standard for patients undergoing thoracotomy .
Pregabalin − a structural analog to γ-amino butyric acid − was first used as an antiepileptic but later on was found to have antinociceptive effects. Pregabalin has been used in many studies for control of postoperative pain and was found to have a good analgesic profile in many types of surgery ,,,,.
Ketamine is an antagonist of N-methyl-d-aspartate receptor. It eliminates peripheral afferent noxious stimulation and can also prevent central sensitization of nociceptors as shown in animal studies. Contradictory results on the efficacy of ketamine for controlling post-thoracotomy pain have been reported ,.
The aim of this study was to compare the analgesic effect of ketamine versus pregabalin as an adjuvant to epidural analgesia in patients undergoing thoracotomy in the National Cancer Institute.
| Patients and methods|| |
This was a unicenter, parallel-group randomized controlled trial conducted in the Department of Surgery in the National Cancer Institute, Cairo University, during the period from June to December 2015. The study was approved by the Research Ethical Committee of the institute. All procedures in this study were in accordance with the Helsinki Declaration amended by the 59th WMA General Assembly, Seoul, 2008. A written informed consent was provided by each participant.
All consecutive patients aged greater than 18 years old and planned for an elective thoracotomy for management of lung cancer were eligible for the study. Inclusion criteria were age 18–60 years, American Society of Anesthesiologists class I or II, and normal pulmonary function. The latter is defined as forced expiratory volume in first second/forced vital capacity greater than 70%, that is, the ratio between forced expiratory volume in first second and forced vital capacity greater than 70%. Patients with renal insufficiency, hepatic insufficiency (Child–Pugh class C), sepsis, coagulopathy, allergy to the used drugs, or receiving immunosuppressive diseases were excluded from the study.
In the operating room, ECG, pulse oximetry, and invasive arterial blood pressure were monitored. After skin disinfection, 20 mg lidocaine was administered for local anesthesia. An 18 G epidural catheter was inserted at T7/T8 intervertebral spaces in the lateral decubitus position, and epidural analgesia was started using bupivacaine 0.125% plus fentanyl 1 µg/ml at a rate of 4 ml/h. Midazolam 2 mg was given at first, and then induction of anesthesia was carried out after proper preoxygenation using propofol 1–2 mg/kg, fentanyl 1–2 µg/kg, and atracurium 0.5 mg/kg. A proper double-lumen endotracheal tube was inserted. Anesthesia was maintained using sevoflurane 1–2% in oxygen and atracurium. At the end of the operation, inhalational anesthetic was discontinued and neuromuscular blockade was reversed by intravenous neostigmine 0.05 mg/kg and intravenous atropine 0.02 mg/kg, and the patient was extubated in the operating room when the patient was fully awake with adequate motor power. After extubation, the patients were transferred to the surgical ICU for postoperative monitoring. In surgical ICU, pain scores and hemodynamic parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)] were assessed and recorded by a blinded observer physician at 2, 8, 16, 24, 36, and 48 h.
Morphine in a bolus dose of 2 mg was given if the visual analog score (VAS) goes above 4 and repeated if needed.
Using permuted block method, participants were randomly assigned into one of two equal groups. Group K (n=30) received three doses of ketamine 0.5 mg/kg intravenously, that is, after induction of anesthesia and at 6 and 30 h postoperatively. Group P (n=30) received oral pregabalin (Lyrica 150 mg; Pfizer, Cairo, Egypt), 2 h before surgery and at 6 and 30 h postoperatively. There was no change to methods after trial commencement.
The primary endpoint was reduction of pain score during the first 48 postoperative hours. The pain intensity was scored using a VAS score ranging from 0 cm (absence of pain) to 10 cm (maximal level of pain). The measurements were carried out only at 2, 6, 12, 24, 36, and 48 h after surgery. The secondary endpoints were frequency of rescue morphine doses in the first 48 h and the occurrence of adverse effects. Moreover, hemodynamic parameters were assessed during the first 48 h. Sedation was measured using Ramsay sedation scale .
The sample size was based on the primary outcome measure of pain relief expressed as VAS score. A total sample size of 60 patients was required to detect an effect size of 0.7 in the mean difference of the VAS score with an alpha error of 0.05 and 80% power of the study.
Statistical analysis was done using IBM© SPSS© Statistics version 22 (IBM© Corp., Armonk, NY, USA). Numerical data were presented as mean±SD or median and range as appropriate. Categorical data were presented as frequency and percentages. Comparisons of numeric variables between the two groups were done using t-tests or Mann–Whitney test as appropriate. The χ2-test or Fisher’s exact test was used to compare categorical data. Consecutive measures of hemodynamic variables and VAS scores were compared using Friedman’s two-way analysis of variance by Ranks because of non-normal distribution of these variables. All tests were two-tailed. A P value less than 0.05 was considered significant.
| Results|| |
[Table 1] shows that the two groups were comparable in age, sex, BMI, American Society of Anesthesiologists class, and duration of surgery. The two drugs were accompanied by hemodynamic stability, i.e. despite the statistically significant changes of blood pressure and rate, all readings were within the clinically accepted ranges. There was an initial decrease of SBP followed by an increase by 36 h in ketamine group. Relative to the 2 h reading, the decrease in SBP was significant after 8 h (P=0.006), 16 h (P=0.001), 24 h (P=0.001) and after 48 h (P=0.003) in ketamine group. In pregabalin group, the SBP after 48 h was significantly lower than readings after 24 and 36 h. However, relative to 2 h reading, no significant change of SBP was observed. Relative to the 2 h reading, DBP did not show significant change in the two groups up to 48 h. DBP showed significant decrease after 48 h relative to the 36 h reading in pregabalin group only (P=0.025). Relative to the 2 h reading, HR showed a significant decrease after 16 h (P=0.006) and 24 h (P=0.036) in ketamine group. In pregabalin group, the HR was significantly lower relative to the 2 h reading after 16 h (P<0.001), 24 h (P=0.003), 36 h (P<0.001), and 48 h (P<0.001). However, all values were within the clinically accepted ranges ([Figure 1],[Figure 2],[Figure 3]).
|Table 1 Demographic and clinical characteristics of the two studied groups|
Click here to view
|Figure 1 Changes of systolic blood pressure during the first 48 postoperative hours in the two studied groups. Data are presented as mean±SD. *Significantly different relative to 2 h reading. SBP, systolic blood pressure.|
Click here to view
|Figure 2 Changes of diastolic blood pressure during the first 48 postoperative hours in the two studied groups. Data are presented as mean±SD. DBP, diastolic blood pressure.|
Click here to view
|Figure 3 Changes of heart rate during the first 48 postoperative hours in the two studied groups. Data are presented as mean±SD. *Significantly different relative to 2 h reading.|
Click here to view
In group K, the VAS score was relatively lower than that in group P 2 h after the end of surgery, but the difference was statistically nonsignificant (P=0.124). Then, VAS score was significantly lower in group K compared with group P from 8 to 48 h ([Table 2]). After 8 h, the VAS score decreased significantly in group K compared with the 2 h reading, and this decrease continued up to 48 h. In group P, VAS score did not decrease after 8 h (P=0.235), but decreased after 16 h (P=0.001) and continued as such up to 48 h. However, rescue analgesia was required after 2 h by 11 (36.7%) patients in group K and 15 (50%) patients of group P (P=0.297). After 8 h, only one patient of group K and four of group P requested rescue analgesia (P=0.353). No rescue analgesia was required after 16, 24, 36, or 48 h. Two hours after the end of surgery, the median sedation score was 3 (range: 2–3) in group K compared with 3 (range: 2–4) in group P (P=0.006). Afterward, all cases were cooperative and oriented (score 2) up to 24 postoperative hours. Otherwise, no cases of nausea and vomiting or psychological adverse effects related to ketamine use were recorded.
|Table 2 Visual analog score in the two studied groups during the first 48 postoperative hours|
Click here to view
| Discussion|| |
The results of this study demonstrated that both ketamine and pregabalin can be used effectively and safely as an adjuvant to thoracic epidural analgesia in a multimodal analgesic method for the management of short-term post-thoracotomy pain. Ketamine was superior to pregabalin as it has more rapid and more powerful analgesic effect during the first 2 postoperative days. The two drugs were hemodynamically safe without significant adverse effects.
In the current study, we tested the value of adding systemic analgesics, ketamine and pregabalin, to thoracic epidural local anesthetic plus opioid in a multimodal analgesic strategy to manage post-thoracotomy pain in patients with lung cancer. Post-thoracotomy pain is a typical model of mixed pain that can benefit from multimodal strategy, which is considered a gold standard in such patients to provide effective analgesia and consequently convey a morbidity benefit. This strategy adopted the notion that interrupting pain signaling at numerous locations will be more effective than attacking one site of the pain pathway .
In one group, we added pregabalin starting 2 h before surgery, which exerts its analgesic effect through suppression of the release of neurotransmitters in nerve presynapses . Pregabalin was introduced as anticonvulsant and has been shown to alleviate central sensitization by calming down hyperexcited dorsal horn neurons .
Many studies evaluated the use of pregabalin for the management of acute postoperative pain in different doses. A recent meta-analysis concluded that pregabalin reduces pain and has opioid-sparing effects when administered postoperatively in all doses and regimens. However, adverse effects in the form of increased sedation and visual disturbances were common . In the current study, pregabalin reduced postoperative pain similar to that of ketamine.
Another meta-analysis of 74 studies found pregabalin to be effective in reduction of postoperative pain scores after all types of surgery including cardiothoracic, laparoscopic cholecystectomy, otorhinolaryngology, gynecologic orthopedic, and spine procedures. It reduced morphine consumption in gynecologic, laparoscopic cholecystectomy, orthopedic, and spine procedures. Pregabalin resulted in significant sedation in all surgical categories except otorhinolaryngology, laparoscopic cholecystectomy, and gynecologic procedures. Postoperative nausea and vomiting were only significant after pregabalin in miscellaneous procedures . In the current study, no cases of nausea and vomiting related to pregabalin use were recorded.
This meta-analysis involved one Egyptian study that evaluated perioperative pregabalin for the management of post-thoracotomy pain in a placebo-controlled trial involving 60 patients. They used a 150 mg daily dose 5 days before and 5 days after surgery. Pregabalin decreased short-term postoperative pain intensity and hospital stay, and it was effective in reducing the incidence of long-term postoperative pain at 3 and 6 months .
Recent studies evaluated pregabalin for relief of post-thoracotomy pain. Postoperative administration of pregabalin with acetaminophen and codeine phosphate effectively reduced post-thoracotomy pain at 2 weeks compared with the latter two drugs alone . Another study compared pregabalin in a dose of 150 mg/day starting on the day of surgery and continued for 2 weeks with a nonsteroidal anti-inflammatory drug loxoprofen. Pain scores and incidence of neuropathic pain were significantly lower in pregabalin group .
Pregabalin was shown to be highly effective for treatment of intercostal neuralgia associated with thoracotomy in a dose of 150 mg/day . In another study on a group of 20 patients undergoing thoracic surgery for lung cancer, the postoperative administration of pregabalin for treatment of shoulder pain was evaluated. Pregabalin administration was associated with significantly less shoulder pain on postoperative day 2 compared with the control group receiving nonsteroidal anti-inflammatory drugs .
Conversely, Brulotte et al.  found that pregabalin did not reduce the incidence of post-thoracotomy pain syndrome in this study. Pregabalin was administered in a dose of 150 mg daily initiated 1 h before thoracotomy and continued until 4 days after as an adjuvant to thoracic epidural analgesia. However, in the pregabalin group, pain was less intense, and patients required significantly less analgesics.
The other group in the current study received three subanesthetic doses of ketamine (0.5 mg/kg) after induction of anesthesia and during the first 2 postoperative days. Ketamine abolishes peripheral afferent noxious stimulation and can prevent central sensitization of nociceptors as well . Previous studies have reported contradictory results on the efficacy of ketamine in pain management in thoracic surgery. This may be owing to difference in type of thoracotomy, disease, and used doses.
Mathews et al.  presented a review for nine studies evaluating the effectiveness of ketamine when added to morphine-based patient-controlled analgesia after thoracic surgery. In general, adding ketamine was found to be safe, with a low incidence of central nervous system adverse effects. Ketamine reduced pain scores with significantly lower morphine requirements. Through pain reduction, ketamine was reported to improve respiratory complications disorders .
Nesher et al.  tested the concomitant administration of ketamine 500 µg/kg and morphine in 58 patients undergoing anterolateral thoracotomy, or median sternotomy. This combination resulted in lower pain scores, reduced total dose of morphine, and higher respiratory rate and pulse oximetry readings. The same authors confirmed reduction of morphine dose in a subsequent study .
In a recent double-blind, placebo-controlled trial, pre-emptive administration of 1 mg/kg ketamine produced significant reduction of pain scores and morphine consumption after thoracotomy . This study involved 75 patients with lung cancer undergoing standard lateral thoracotomy.
We can conclude that ketamine and pregabalin are good alternatives for augmentation of the efficacy of thoracic epidural analgesia following thoracotomy in patients with lung cancer. Ketamine has the advantage of more rapid action and higher efficacy in addition to less sedation in early postoperative period.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gerner P. Post-thoracotomy pain management problems. Anesthesiol Clin 2008; 26:355–367.
Ochroch EA, Gottschalk A. Impact of acute pain and its management for thoracic surgical patients. Thorac Surg Clin 2005; 15:105–121.
Bottiger BA, Esper SA, Stafford-Smith M. Pain management strategies for thoracotomy and thoracic pain syndromes. Semin Cardiothorac Vasc Anesth 2014; 18:45–56.
Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A et al.
Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 2000; 321:1493.
Brodner G, Mertes N, Buerkle H, Marcus MA, van Aken H. Acute pain management: analysis, implications and consequences after prospective experience with 6349 surgical patients. Eur J Anaesthesiol 2000; 17:566–575.
Stadler M, Schlander M, Braeckman M, Nguyen T, Boogaerts JG. A cost-utility and cost-effectiveness analysis of an acute pain service. J Clin Anesth 2004; 16:159–167.
Fiorelli A, Mazzella A, Passavanti B, Sansone P, Chiodini P, Iannotti M et al.
Is pre-emptive administration of ketamine a significant adjunction to intravenous morphine analgesia for controlling postoperative pain? A randomized, double-blind, placebo-controlled clinical trial. Interact Cardiovasc Thorac Surg 2015; 21:284–290.
Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology 1995; 82:1474–1506.
Agarwal A, Gautam S, Gupta D, Agarwal S, Singh PK, Singh U. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth 2008; 101:700–704.
Alimian M, Imani F, Faiz SH, Pournajafian A, Navadegi SF, Safari S. Effect of oral pregabalin premedication on post-operative pain in laparoscopic gastric bypass surgery. Anesth Pain Med 2012; 2:12–16.
Bafna U, Rajarajeshwaran K, Khandelwal M, Verma AP. A comparison of effect of preemptive use of oral gabapentin and pregabalin for acute post-operative pain after surgery under spinal anesthesia. J Anaesthesiol Clin Pharmacol 2014; 30:373–377.
] [Full text]
Ahiskalioglu A, Ince I, Aksoy M, Yalcin E, Ahiskalioglu EO, Kilinc A. Effects of a single-dose of pre-emptive pregabalin on postoperative pain and opioid consumption after double-jaw surgery: a randomized controlled trial. J Oral Maxillofac Surg 2016; 74:53.
Ahn S, Byun SH, Park K, Ha JL, Kwon B, Kim JC. Analgesic efficacy of preemptive pregabalin administration in arthroscopic shoulder surgery: a randomized controlled trial. Can J Anaesth 2016; 63:283–289.
Mathews TJ, Churchhouse AM, Housden T, Dunning J. Does adding ketamine to morphine patient-controlled analgesia safely improve postthoracotomy pain? Interact Cardiovasc Thorac Surg 2012; 14:194–199.
Tena B, Gomar C, Rios J. Perioperative epidural or intravenous ketamine does not improve the effectiveness of thoracic epidural analgesia for acute and chronic pain after thoracotomy. Clin J Pain 2014; 30:490–500.
Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974; 2:656–659.
Kavoussi R. Pregabalin: from molecule to medicine. Eur Neuropsychopharmacol 2006; 16(Suppl 2):S128–S133.
Stahl SM. Anticonvulsants and the relief of chronic pain: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry 2004; 65:596–597.
Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth 2015; 114:10–31.
Lam DM, Choi SW, Wong SS, Irwin MG, Cheung CW. Efficacy of pregabalin in acute postoperative pain under different surgical categories: a meta-analysis. Medicine (Baltimore) 2015; 94:e1944.
Fawzi H, El-Tohamy S. Effect of perioperative oral pregabalin on the incidence of post-thoracotomy pain syndrome. Ain Shams J Anaesth 2014; 7:143–147.
Yoshimura N, Iida H, Takenaka M, Tanabe K, Yamaguchi S, Kitoh K et al.
Effect of postoperative administration of pregabalin for post-thoracotomy pain: a randomized study. J Cardiothorac Vasc Anesth 2015; 29:1567–1572.
Matsutani N, Dejima H, Takahashi Y, Kawamura M. Pregabalin reduces post-surgical pain after thoracotomy: a prospective, randomized, controlled trial. Surg Today 2015; 45:1411–1416.
Matsutani N, Kawamura M. Successful management of postoperative pain with pregabalin after thoracotomy. Surg Today 2014; 44:712–715.
Imai Y, Imai K, Kimura T, Horiguchi T, Goyagi T, Saito H et al.
Evaluation of postoperative pregabalin for attenuation of postoperative shoulder pain after thoracotomy in patients with lung cancer, a preliminary result. Gen Thorac Cardiovasc Surg 2015; 63:99–104.
Brulotte V, Ruel MM, Lafontaine E, Chouinard P, Girard F. Impact of pregabalin on the occurrence of postthoracotomy pain syndrome: a randomized trial. Reg Anesth Pain Med 2015; 40:262–269.
Michelet P, Guervilly C, Hélaine A, Avaro JP, Blayac D, Gaillat F et al.
Adding ketamine to morphine for patient-controlled analgesia after thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal desaturation. Br J Anaesth 2007; 99:396–403.
Nesher N, Serovian I, Marouani N, Chazan S, Weinbroum AA. Ketamine spares morphine consumption after transthoracic lung and heart surgery without adverse hemodynamic effects. Pharmacol Res 2008; 58:38–44.
Nesher N, Ekstein MP, Paz Y, Marouani N, Chazan S, Weinbroum AA. Morphine with adjuvant ketamine vs. higher dose of morphine alone for immediate postthoracotomy analgesia. Chest 2009; 136:245–252.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]