Effect of Psychosocial and Psychophysical Factors and Preemptive Analgesia on Postoperative Pain in Upper Limb Surgery

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to define the role of preemptive systemic analgesia in combination with regional anesthetic techniques on postoperative pain following upper limb surgery in different subgroups of patients with different psychosocial and psychophysical characteristics.

Detailed Description
-----------------
After being informed about the study and potential risks, patients will be given written informed consent. The study will include patients between the ages of 18 and 65, rated 1 or 2 by the American Society of Anesthesiologists (ASA) classification scheduled for distal radius surgery. We will exclude patients with a known allergy to or adverse reaction to a local anesthetic, opioid, paracetamol or non-steroidal anti-inflammatory drugs, patients with a known opioid dependence, injection site infection, chronic pain, renal disease, known neuropathy, liver disease, with psychiatric disorders and diabetics. The study will be randomized, prospective and double-blind. We will study the effect of preemptive dose of paracetamol and ibuprofen and pregabalin on postoperative pain after distal radius surgery in patients with different psychosocial and psychophysical characteristics. Patients will be admitted to the ward the day before surgery. At that time, we will explain to them the course of the research and offer them participation. For those with a written consent we will perform preoperative quantitative sensory tests on the same day and give them pain questionnaires. We will determine conditional pain modulation by first applying a mechanical test stimulus of increasing intensity with an algometer to the skin of the volar side of the forearm and the skin in the middle of the front of the thigh contralateral to the injury until the patient experiences pain on the visual analog scale (VAS) 4/10. At that point the patients will press the patient operated button on the algometer and the stimulus will be stopped with the measurement stored. We will then repeat the same test together with a conditional stimulus - immersion of the ipsilateral lower extremity in cold water at 2 degrees Celsius. Conditional pain modulation will be calculated by subtracting the intensity of the independent primary stimulus from the intensity of the primary stimulus together with a concomitant conditioned stimulus. The end result will be the average of the values obtained on the skin of the volar side of the forearm and the skin in the middle of the front of the thigh. On the same day the patients will also complete a Pain Catastrophising Scale (PCS) Questionnaire and a Brief Pain Inventory (BPI). They will also receive a short questionnaire to assess the pain and quality of sleep on the first night after surgery, which they will complete together with an anesthesiologist the morning after surgery. On the day of surgery, patients will be divided into 3 groups: The first group will receive pregabalin 150 mg per os 1 hour before arrival in the operating room and two intravenous doses of 100 ml of saline within 30 minutes before the surgical incision. The second group will receive a placebo capsule per os 1 hour before arrival in the operating room and a preemptive intravenous dose of paracetamol 1 g and ibuprofen 400 mg within 30 minutes before the surgical incision. The third group will receive a placebo capsule per os 1 hour before arrival in the operating room and two intravenous doses of 100 ml of saline within 30 minutes before the surgical incision. All three groups will then receive an axillary block under ultrasound control by an experienced anesthesiologist. They may receive midazolam and/or fentanyl/sufentanil for anxiolysis and analgesia during the blockade. The surgery will be performed with of without sedation with propofol, titrated to desired effect. In the event of a failed block, patients will be placed under general anesthesia and excluded from the study. For postoperative nausea and vomiting they will not receive dexamethasone. Postoperative analgesia: For the postoperative analgesia, patients will receive a PCA (patient controlled analgesia) pump with Piritramide 45 mg diluted to 90 ml of saline. The PCA pump will have no continuous flow. The PCA boluses will be 3 mg every 20 minutes, with a 2 hour limit of 9 mg and a 6 hour limit of 15 mg. The PCA pump will be connected to the patients for at least 24 hours. If necessary, the ward nurse will administer an additional intravenous dose of Piritramide 3 mg every 4 hours in case of insufficient analgesia (pain on VAS > 3/10). Patients will additionally receive intravenous Paracetamol 1 g every 6 h and intravenous Ibuprofen 400 mg every 8 hours. For 24 hours after surgery we will record pain experienced by the patients, based on the VAS. Opioid consumption will be recorded by the PCA pump, any additional boluses by the nurses will be added to the total consumption. The first day after surgery, 14 days after surgery and 3 months after surgery the patients will again complete a BPI questionnaire. We will also document the interval between the injury and surgery, time of surgery, AO Distal Radius Fracture Classification, surgical approach and type of osteosynthesis. We will study the impact of psychosocial, psychophysical and preemptive systemic analgesia on acute and chronic postoperative pain in distal radius surgery. We will examine whether patients with different psychosocial and psychophysical characteristics benefit differently from different regimens of preemptive systemic analgesia.

Official Title
-----------------
Psychosocial and Psychophysical Factors Influencing the Effect of Preemptive Systemic Analgesia in Combination With Regional Anesthesia on Postoperative Pain Following Upper Limb Surgery

Conditions
-----------------
Postoperative Pain

Intervention / Treatment
-----------------
* Combination Product: Paracetamol and Ibuprofen
* Drug: Pregabalin 150mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: American Society of Anesthesiologists (ASA) classification score 1 and 2 Patients with a distal radius fracture, scheduled for surgery Exclusion Criteria: Allergy to a local anesthetic, opioid, paracetamol or a non-steroidal antirheumatic drug Opioid addiction Infection at the injection site Chronic pain syndromes Neuropathies Liver cirrhosis Chronic kidney disease stage 3 or higher Diabetes Psychiatric illness

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Three groups of patients with three different treatment regimens
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Patients will receive a placebo capsule in the hour before surgery and two intravenous doses of saline before surgical incision. | Drug: Placebo<br>* Patients will receive a placebo capsule in the hour before surgery and two intravenous doses of saline before surgical incision.<br>|
| Experimental: Pregabalin<br>Patients will receive pregabalin 150 mg in the hour before surgery and two intravenous doses of saline before surgical incision. | Drug: Pregabalin 150mg<br>* Patients will receive pregabalin 150 mg in the hour before surgery<br>|
| Experimental: Paracetamol and Ibuprofen<br>Patients will receive a placebo capsule in the hour before surgery and an intravenous dose of paracetamol 1 g and ibuprofen 400 mg before surgical incision. | Combination Product: Paracetamol and Ibuprofen<br>* Patients will receive paracetamol 1g and ibuprofen 400 mg before surgical incision.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Opioid consumption in the first 24 hours | Piritramide consumption will be obtained from the PCA pumb, manual boluses will be added. | First 24 hours, starting at time of surgery | 
| Worst pain in the first 24 hours | Worst pain in the first 24 hours after surgery on the visual analog scale (VAS) will be obtained the day after surgery | First 24 hours, starting at time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of chronic pain | The presence of chronic pain will be defined as pain persisting at the three month interval | Three months after surgery | 
| Sleep quality on the night after surgery | Sleep quality will be obtained by a questionnaire, raging from 1-5, where 1 is described as very poor sleep quality and 5 as very good sleep quality | First 24 hours, starting at time of surgery | 
| Opioid consumption in the first 24 hours in correlation with preoperative Pain catastrophising scale (PCS) | PCS will be obtained preoperatively, we will investigate, whether there is a positive correlation between opioid consumption in the first 24 hours and preoperative PCS greater than 30. PCS is a questionnaire, consisting of 13 questions, each ranging from scores 0 to 4, so the final score is in the range of 0 to 52. A total PCS score of 30 or more represents clinically relevant level of pain catastrophizing. | First 24 hours, starting at time of surgery | 
| Worst pain in the first 24 hours in correlation with preoperative Pain catastrophising scale (PCS) | PCS will be obtained preoperatively, we will investigate, whether there is a positive correlation between the worst pain in the first 24 hours and preoperative PCS greater than 30. PCS is a questionnaire, consisting of 13 questions, each ranging from scores 0 to 4, so the final score is in the range of 0 to 52. A total PCS score of 30 or more represents clinically relevant level of pain catastrophizing. | First 24 hours, starting at time of surgery | 
| Opioid consumption in the first 24 hours in correlation with preoperative Conditioned pain modulation (CPM) | CPM will be obtained preoperatively, we will investigate, whether there is a correlation between opioid consumption in the first 24 hours and preoperative CPM. CPM will be determined by first applying a mechanical test stimulus of increasing intensity with an algometer to the skin of the volar side of the forearm and the skin in the middle of the front of the thigh contralateral to the injury until the patient experiences pain on the visual analog scale (VAS) of 4/10. The same stimulus will then be applied together with a conditional stimulus - immersion of the ipsilateral lower extremity in cold water at 2 degrees Celsius. Conditional pain modulation will be calculated by subtracting the intensity of the independent primary stimulus from the intensity of the primary stimulus together with a concomitant conditioned stimulus. CPM is a centrally processed measure of the net effect of the descending pain pathway. Higher CPM scores signify better pain control. | First 24 hours, starting at time of surgery | 
| Worst pain in the first 24 hours in correlation with preoperative Conditioned pain modulation (CPM) | CPM will be obtained preoperatively, we will investigate, whether there is a correlation between the worst pain in the first 24 hours and preoperative CPM. CPM will be determined by first applying a mechanical test stimulus of increasing intensity with an algometer to the skin of the volar side of the forearm and the skin in the middle of the front of the thigh contralateral to the injury until the patient experiences pain on the visual analog scale (VAS) of 4/10. The same stimulus will then be applied together with a conditional stimulus - immersion of the ipsilateral lower extremity in cold water at 2 degrees Celsius. Conditional pain modulation will be calculated by subtracting the intensity of the independent primary stimulus from the intensity of the primary stimulus together with a concomitant conditioned stimulus. CPM is a centrally processed measure of the net effect of the descending pain pathway. Higher CPM scores signify better pain control. | First 24 hours, starting at time of surgery | 
| The incidence of chronic pain in correlation with preoperative Conditioned pain modulation (CPM) | CPM will be obtained preoperatively, we will investigate, whether there is a correlation between the incidence of chronic pain at three months after surgery and preoperative CPM. CPM will be determined by first applying a mechanical test stimulus of increasing intensity with an algometer to the skin of the volar side of the forearm and the skin in the middle of the front of the thigh contralateral to the injury until the patient experiences pain on the visual analog scale (VAS) of 4/10. The same stimulus will then be applied together with a conditional stimulus - immersion of the ipsilateral lower extremity in cold water at 2 degrees Celsius. Conditional pain modulation will be calculated by subtracting the intensity of the independent primary stimulus from the intensity of the primary stimulus together with a concomitant conditioned stimulus. CPM is a centrally processed measure of the net effect of the descending pain pathway. Higher CPM scores signify better pain control. | 3 months after surgery | 
| The incidence of chronic pain in correlation with preoperative Pain catastrophising scale (PCS) | PCS will be obtained preoperatively, we will investigate, whether there is a positive correlation between the incidence of chronic pain at three months after surgery and preoperative PCS greater than 30. PCS is a questionnaire, consisting of 13 questions, each ranging from scores 0 to 4, so the final score is in the range of 0 to 52. A total PCS score of 30 or more represents clinically relevant level of pain catastrophizing. | 3 months after surgery |