Effect of Perioperative Oral Pregabalin in Total Knee Replacement for Postoperative Pain
Phase: PHASE4
Conditions: Postoperative Pain
Sponsor: Bahrain Defence Force Hospital

Effect of Perioperative oral pregabalin in Total Knee replacement for 
postoperative pain. 
INTRODUCTION:  
Total knee arthroplasty is among the most common orthopaedic surgeries that is 
being performed to relieve joint pains in patients who had advanced osteoarthritis 
and rheumatoid arthritis (1). This procedure is associated with moderate to severe 
postoperative pain which requires pre-emptive planning of multimodal analgesia. 
Although Opioids are the mainstay treatment for postoperative acute pain 
management, they are associated with adverse side effects which limit 
postoperative rehabilitation, reduce patient satisfaction and overall outcome. 
Opioids are well documented for their adverse effects, especially in geriatric 
patients presenting for Orthopaedic surgeries. The tolerance and physical 
dependence can develop at prescribed doses even (2). Opioids are associated with 
sedation, respiratory depression, paralytic ileus, immunosuppression and opioid-
induced endocrinopathy to name a few. 
Pregabalin is analogue of neurotransmitter gamma-aminobutyric acid (GABA) (3) 
anticonvulsant and has wide range of clinical uses which encompass treatment of 
not only seizures but also neuropathic pains, adjuvant analgesia in general 
anaesthesia as part of multimodal analgesia plan, to limit Opioids use. It mainly 
acts through binding on alpha-2 and delta receptors and act as antihyperalgesic 
agent (4). Pregabalin delays or offsets the sensitization of dorsal horn neurons, 
possibly leading to augmentation of surgical stimulation that affects changes in 
the central and peripheral nervous system. Postoperative pain of Total knee 
replacement and total Hip replacement has profound effects on patient 
rehabilitation and satisfaction postoperatively. Mohsen Ziyaeifard et el had 
studied its effects in patients undergoing CABG that showed its safety profile 
along with opioid sparing properties. (5) 

Multimodal analgesia is a term that encompass more than one intervention 
simultaneously to aim multiple receptors within nociceptive and neuropathic 
pathways to control postoperative pain by providing opioid-free or opioid-
reduced anesthesia. This includes regional anesthesia as core component. 
Femoral nerve block is one standard intervention which has documented 
analgesia for lower limb surgeries with wide range of safety profile. It reduces 
the incident of chronic postoperative pain as well. (6) 
In all efforts to develop an opioids free or opioid reduced anesthesia practice, we 
try to use adjuvants in our practices to improve the outcome without adverse 
effects. One such practice is addition of Dexmedetomidine in femoral nerve block 
to enhance the postoperative analgesia duration and quality. Qianchuang Sun et 
el meta-analysis has shown that dexmedetomidine prolongs the duration of Tap 
block as well as improve the quality of analgesia (7). Another study reported 30% 
increase in duration of ulnar nerve block with IV dexmedetomidine, and 100% 
increase in duration of ulnar nerve block with perineural treatment(8), compared 
with an identical dose of ropivacaine alone.  Dexmedetomidine is alpha-2 
adrenoceptor agonist who act centrally and produce sedative and analgesic effects 
without respiratory depression or paralytic ileus. 
 
 
OBJECTIVE: this study aim to determine efficacy and safety of perioperative 
Oral pregabalin in improving postoperative pain control in patients undergoing 
total knee replacement surgeries under regional anesthesia. 
HYPOTHESIS: 
Pregabalin reduces postoperative pain, analgesia and opioid requirement, 
MATERIAL AND METHODS:  

STUDY TYPE:                                 Interventional (clinical trial) 
STUDY SETTING:                        Operation Theatres, Bahrain defence forces 
DURATION OF STUDY:               12-18 months after the approval of synopsis 
SAMPLING TECHNIQUE:         Non probability conservative sampling 
OFFICIAL TITLE: Effect of Perioperative oral pregabalin in Total Knee 
replacement for postoperative pain. A randomized Controlled Single blind trial. 
SAMPLE SIZE:  sample size of 120 cases (60 in each group) is calculated with 
80% power of test, 5% level of significance and taking expected percentage of 
Pain scores in both groups. 
Inclusion criteria:- 
1. Age between 18 to 85 year 
2. Elective Regional anesthesia. 
3. Able to follow study protocol 
Exclusion Criteria: 
1.  ASA -IV 
2. Age <18 & > 85 years 
3. Patients on pregabalin for chronic neuropathic pain. 
4. Patient under General anesthesia 
5. Patients with chronic liver failure  
6. Patients with chronic renal failure on Hemodialysis 
7. Patients on opioid  (>3 month) 
8. Patient with complicated knee surgery. 

 
DATA COLLECTION PROCEDURE:  
After obtaining approval from the institutional ethical committee and informed 
written consent, 120 patients fulfilling the inclusion criteria will be included in 
this study. The patients will be randomly assigned into two equal groups; Group 
P: Pregablain group and Group C: control group. Group P will receive oral 
capsule pregabalin 75mg one hour preoperatively and Group C will not receive 
any premedication preoperatively. 
Intraoperatively both groups will receive inj. Midazolam 2 mg before 
subarachnoid block with hyperbaric Bupivacaine 0.5% 2.5-3ml and fentanyl 
15mcg in the operation theatre (OT). Both groups will also receive parecoxib 
40mg IV and paracetamol 1G Intravenous (IV) as part of multimodal analgesia. 
Both groups will receive dexamethasone 8mg IV prophylactically.  
Postoperatively both group will receive Ultrasound guided Adductor canal 
saphenous Nerve block in the PACU with 0.2% Bupivacaine 20-30ml & 
dexmeditomidine1.0mcg/kg. Group P will receive oral capsule pregabalin 75 mg 
Q12hrly from the 1st dose for next 60 hrs. Group C will not receive any 
medication. Both groups will receive paracetamol 1G IV Q6Hrly for 24 hrs and 
rescue Analgesia will be provided with oral oxycodone 5mg TDS as PRN and 
Morphine PCA, in escalating manner as per patient requirement.  
After 24 hrs both group will continue with paracetamol 1G Q6Hourly and tab 
Ibuprofen 400mg Q8 Hourly along with oxycodone or PCA morphine as per 
requirement.for 72 hrs. 
 DATA ANALYSIS: SPSS 
Outcome measure: 

Primary outcome: 
 VAS score at 4hrs, 8hrs, 12hrs, 24hrs, 36 hrs, 48hrs, 60hrs, and 72hrs. 
Annexure attached 
Secondary outcome: 
 Sedation score: RASS score at 4hrs, 8hrs, 12hrs, 24hrs, 36 hrs, 48hrs, 
60hrs, 72hrs. Annexure attached 
 VAS at 1st CPM : 
 Time of 1st analgesia request 
 Incident of bradycardia in 1st 24 Hrs 
 Incident of Hypotension in 1st 24 Hrs 
 Total opioid consumption in 72hrs: Oxycodone/Morphine 
 Patient satisfaction at  72 hrs : rated as numeric 1-5 (1=not satisfied, 5=fully 
satisfied) 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
ANNEXURE FOR VAS score 
 
 
 

ANNEXURE FOR RASS score 
The Richmond Agitation–Sedation Scale 
Score Term 
Description 
+4 
Combative 
Overtly combative or violent; immediate danger to 
staff 
+3 
Very agitated 
Pulls on or removes tube(s) or catheter(s) or has 
aggressive behaviour toward staff 
+2 
Agitated 
Frequent non purposeful movement or patient–
ventilator dyssynchrony 
+1 
Restless 
Anxious or apprehensive but movements not 
aggressive or vigorous 
0 
Alert and calm Spontaneously pays attention to caregiver 
-1 
Drowsy 
Not fully alert, but has sustained (more than 10 
seconds) awakening, with eye contact, to voice 
-2 
Light sedation 
Briefly (less than 10 seconds) awakens with eye 
contact to voice 
-3 
Moderate 
sedation 
Any movement (but no eye contact) to voice 
-4 
Deep sedation 
No response to voice, but any movement to physical 
stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
  
 

REFERENCES: 
1. Jing-wen Li, MSc1,2, Ye-shuo Ma, PhD3 , Liang-kun Xiao, MSc: 
Postoperative Pain Management in Total Knee Arthroplasty: review article 
2. Anesth Analg. 2017 November ; 125(5): 1733–1740. 
doi:10.1213/ANE.0000000000002458. 
3. https://reference.medscape.com/drug/lyrica-cr-pregabalin-343368 
 
4.  Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, et al. 
EFNS guidelines on the pharmacological treatment of neuropathic pain: 
2010 revision. Eur J Neurol. 2010;17(9):1113–e88. doi: 10.1111/j.1468-
1331.2010.02999.x. [PubMed] [CrossRef] [Google Scholar] 
5. Mohsen Ziyaeifard, Mohammad Javad Mehrabanian, Seyedeh Zahra 
Faritus, Mehrdad Khazaei Koohpar, Rasool Ferasatkish, Heidar 
Hosseinnejad, and Mohammadreza Mehrabanian:  Premedication With 
Oral Pregabalin for the Prevention of Acute Postsurgical Pain in 
Coronary Artery Bypass Surgerysatkish,1 Heidar 
Hosseinnejad,3 and Mohammadreza Mehrabanian:  
6. The role of regional anaesthesia and multimodal analgesia in the 
prevention of chronic postoperative pain: a narrative review: Y.-Y.K. 
Chen,1 K.A. Boden,2 and K.L. Schreiber, Assistant Professor3: 
Anaesthesia. 2021 Jan; 76(Suppl 1): 8–17. 

7. Dexmedetomidine as an Adjuvant to Local Anesthetics in Transversus 
Abdominis Plane Block: A Systematic Review and Meta-analysis: 
Qianchuang Sun 1, Shuyan Liu 2, Huiying Wu 3, He Ma 1, Wei Liu 1, 
Meidan Fang 1, Kexiang Liu 4, Zhenxiang Pan : Clin J Pain 2019 
Apr;35(4):375-384.doi: 10.1097/AJP.0000000000000671. 
8. Andersen JH, Jaeger P, Grevstad U, et al. Systemic dexmedetomidine is 
not as efficient as perineural dexmedetomidine in prolonging an ulnar 
nerve block. Reg Anesth Pain Med. 2019;44:333–40. 
 
 
 
 
 
 
 
 
 
 

PERFORMA: Effect of Perioperative oral pregabalin in Total Knee 
replacement for postoperative pain. 
Serial N0:      ________________                    Hospital Record NO:     _________________ 
Date:              ________________                    Patient Age:                  _________________ 
Gender:         _________________                    ASA Status:                  _________________ 
 
 
Preoperative Oral capsule pregabalin time: ______________________. 
 
 
Subarachnoid block given (Bupivacain+fentanyl) (Start point time) ____________________ 
 
Postoperative USG guided femoral nerve block (Bupivacaine + dexmedetomidine): start point 
time. ________ 
 
VAS SCORE: (0-10) 
 
Time:Start point
At 4Hrs 
8Hrs 
12Hrs 
24Hrs 
 
 
 
 
 
 
36 Hrs 
48Hrs 
60Hrs 
72Hrs 
 
 
 
 
 
 
Sedation score: RASS attached {0- (-5)} 
+4 
+3 
+2 
+1 
0 
-1 
-2 
-3 
-4 
-5 
 
Time:Start point
At 4Hrs 
8Hrs 
12Hrs 
24Hrs 
 
 
 
 
 
 
36 Hrs 
48Hrs 
60Hrs 
72Hrs 
 
 
 
 
 
 
VAS at 1st CPM : 
 
Time of 1st analgesia request:_________________ 
 
Incident of bradycardia in 1st 24 Hrs: Y/N ___________ 
 
Incident of Hypotension in 1st 24 Hrs: Y/N ___________ 
 
Total opioid consumption in 72hrs: Oxycodone: _________mg    Morphine: __________ mg. 
 
Patient satisfaction (1-5): at 72 Hrs(1: Not satisfied, 5: fully satisfied) 
1 
2 
3 
4 
5 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANNEXURE FOR ASA STATUS 
 
ASA I 
Patients are considered to be normal and healthy.  Patients are able to walk up one flight of 
stairs or two level city blocks without distress.  Little or no anxiety.  Little or no risk 
  
ASA II 
Patients have mild to moderate systemic disease or are healthy ASA I patients who demonstrate 
a more extreme anxiety and fear toward dentistry.  Patients are able to walk up one flight of 
stairs or two level city blocks, but will have to stop after completion of the exercise because of 
distress.  Examples: History of well-controlled disease states including non-insulin dependent 
diabetes, prehypertension, epilepsy, asthma, or thyroid conditions; ASA I with a respiratory 
condition, pregnancy, and/or active allergies. May need medical consultation. 
   
ASA III 
Patients have severe systemic disease that limits activity, but is not incapacitating.  Patients are 
able to walk up one flight of stairs or two level city blocks, but will have to stop enroute because 
of distress.  If dental care is indicated, stress reduction protocol and other treatment 
modifications are indicated.  Examples: History of angina pectoris, myocardial infarction, or 
cerebrovascular accident. 
  
ASA IV  
Patients have severe systemic disease that limits activity and is a constant threat to life.  Patients 
are unable to walk up one flight of stairs or two level city blocks.  Distress is present even at 
rest. Patients pose significant risk since patients in this category have a severe medical problem 
of greater importance to the patient than the planned dental treatment. Examples: History of 
unstable angina pectoris, myocardial infarction or cerebrovascular accident within the last six 
months, severe congestive heart failure. 
ASA V 
Patients are moribund and are not expected to survive more than 24 hours with or without an 
operation.  These patients are almost always hospitalized, terminally ill patients.  Elective 
dental treatment is definitely contraindicated; however, emergency care, in the realm of 
palliative treatment may be necessary.   
ASA VI                                                                                                       

Clinically dead patients being maintained for harvesting of organs. 
  
ASA-E: Emergency operation of any variety (used to modify one of the above classifications, 
i.e., ASA III-E). 
  
* Status can change as medical history changes; adapted by Margaret J. Fehrenbach, RDH, 
MS, from the American Society of Anesthesiologists, Medical Emergencies in the Dental 
Office (Malamed, Mosby, 2008), and included in Saunders Review of Dental Hygiene 
(Fehrenbach and Weiner, Elsevier, 2009).