Wound Infiltration With Tramadol, Dexmedetomidine, or Magnesium Plus Ropivacaine for Pain Relief After Spine Surgery

Effect of Wound Infiltration With Tramadol, Dexmedetomidine, or Magnesium Sulfate as Adjuncts to the Local Anesthetic on Pain Relief After Spine Surgery

The rationale for multimodal analgesia is to achieve additive or synergistic analgesic properties while decreasing the incidence of side effects by reducing the dose of each agent. Nociceptive stimuli are known to activate the release of the excitatory amino acid glutamate in the dorsal horn of the spinal cord. The resultant activation of NMDA receptors causes calcium entry into the cell and triggers central sensitization. This mechanism is involved in the perception of pain and mainly accounts for its persistence during the postoperative period.

Peri-incisional injection of local anesthetics is an effective method for pain relief after many surgical procedures, as it can reduce postoperative analgesic consumption. Ropivacaine is a propyl analog of bupivacaine with a longer duration of action with a much safer cardiotoxicity profile than bupivacaine. Thus, a combination of local anesthetic with other analgesic factors, such as opioids, dexmedetomidine, clonidine, ketamine, magnesium sulfate, dexamethasone is suggested for a better analgesic outcome.

Dexmedetomidine, a highly selective a2-adrenergic receptor agonist, has been the focus of interest for its broad spectrum (sedative, analgesic, and anesthetic sparing) properties, making it a useful and safe adjunct in many clinical applications. The intravenous, intramuscular, intrathecal, epidural, and perineural use of this agent enhances analgesic effects.

Tramadol hydrochloride is a synthetic analog of codeine that acts on both opioid (weak m receptor agonist) and nonopioid receptors (inhibits the reuptake of noradrenaline and serotonin as well as release stored serotonin from nerve endings) which play a crucial role in pain inhibition pathway. It also blocks nerve conduction which imparts its local anesthetics like action on peripheral nerves.

It was reported that NMDA antagonists could prolong the analgesic effect of bupivacaine to even a week, as well as inhibit hyperalgesia. Magnesium sulfate (MGS) is a non-competitive antagonist of N-methyl, D-aspartate (NMDA) receptors with an analgesic effect and is essential for the release of acetylcholine from the presynaptic terminals and, similar to calcium channel blockers (CCB), can prevent the entry of calcium into the cell.

Aim of the study is to evaluate and compare the postoperative analgesic efficacy of tramadol, dexmedetomidine, and magnesium when added to ropivacaine as an adjuvant for wound infiltration following spine surgery.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Analgesia; Spinal Stenosis; Spinal Disease
• Intervention / Treatment: Drug: Tramadol with ropivacaine; Drug: Dexmedetomidine with ropivacaine; Drug: Magnesium with ropivacaine; Drug: Ropivacaine plus normal saline

Detailed Description

Each participant will receive standard monitoring (ECG, SpO2, capnography, SBP, oesophageal temperature) and intravenous access will be established. A standard anesthesia protocol will be applied involving propofol 2mg/kg (iv) and remifentanil in TCI (target-controlled infusion). Cis-atracurium 0.2 mg/kg (iv) will be given to facilitate endotracheal intubation. Anesthesia will be maintained with desflurane in a 50% air/O2 mixture A standard anesthesia protocol will be applied involving propofol 2mg/kg (iv) and remifentanil in TCI (target-controlled infusion). Cis-atracurium 0.2 mg/kg (iv) will be given to facilitate endotracheal intubation. Anesthesia will be maintained with air to oxygen mixture of 50%, and desflurane adjusted to achieve a target BIS between 40 and 50. Remifentanil target level will be titrated according to analgesic demands defined by a > 20% change of heart rate or blood pressure compared with baseline. The duration of both anesthesia and surgical procedure will be registered. Furthermore, the level of sedation upon anesthesia emergence will be recorded using the Ramsey sedation scale.

Postoperatively pain assessment will be performed by the Visual Analogue Scale (VAS) and Numerical Rating Scale (NRS) at anesthesia emergence and at 2, 4, 6, 12, 18, and 24 h after surgery conclusion. Time to first analgesic request and total analgesics consumption postoperatively (morphine equivalents) will be recorded.

Episodes of shivering, as well as episodes of nausea and vomiting (PONV) and other postoperative adverse events, will be recorded at emergence and 24 hours thereafter.

Finally, patients' global satisfaction will be assessed the second day and one month after surgery using the Quality of Recovery Scale(QoR-40). In the meantime, blood samples will be taken at the time before the surgical stimulus, 6 hours and 24 hours after wound infiltration to measure cortisol, TNF-a, and IL-6 plasma concentration.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Georgia Tsaousi; Phone Number: 00302310994855; Email: tsaousig@otenet.gr
• Study Contact Backup: Name: Anastasia Nikopoulou; Phone Number: 00302310994862; Email: anastasian1991@windowslive.com

Study Locations

• Greece
  • Thessaloniki, Greece, 54636
    • Ahepa University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients aged between 18 and 80 years
• ASA Physical status 1 to 3
• Elective or semi-elective one-level lumbar laminectomy or discectomy surgery
• Signed informed consent

Exclusion Criteria:

• Chronic use of opioids
• Drugs or alcohol abuse
• Neurological disorders
• Local anesthetics toxicity
• Myopathy
• Cardiac conductance disturbances
• Hepatic failure
• Renal failure
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tramadol with ropivacaine; Tramadol 2mg/kg with ropivacaine (10mg/ml) 100mg for wound infiltration	Drug: Tramadol with ropivacaine; A solution of tramadol 2mg/kg with ropivacaine hydrochloride (10mg/ml) 100mg mixture making up a total volume of 15ml will be infiltrated in the surgical trauma area before closure.; Other Names: TR
Experimental: Dexmedetomidine with ropivacaine; Dexmedetomidine 1μg/kg with ropivacaine (10mg/ml) 100mg for wound infiltration	Drug: Dexmedetomidine with ropivacaine; A solution of dexmedetomidine 1μg/kg with ropivacaine hydrochloride (10mg/ml) 100mg mixture making up a total volume of 15ml will be infiltrated in the surgical trauma area before closure.; Other Names: DR
Experimental: Magnesium with ropivacaine; Magnesium sulfate 10 mg/kg with ropivacaine (10mg/ml) 100mg for wound infiltration	Drug: Magnesium with ropivacaine; A solution of magnesium 10 mg/kg with ropivacaine hydrochloride (10mg/ml) 100mg mixture making up a total volume of 15ml will be infiltrated in the surgical trauma area before closure.; Other Names: MR
Placebo Comparator: Placebo with ropivacaine; Ropivacaine (10mg/ml) 100mg with 5ml isotonic saline for wound infiltration	Drug: Ropivacaine plus normal saline; A solution of ropivacaine hydrochloride (10mg/ml) 100mg with 5ml of isotonic saline 0.9% mixture making up a total volume of 15ml will be infiltrated in the surgical trauma area before closure.; Other Names: R

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first analgesic request in minutes	The difference in the time frame (minutes) for analgesia request after emergence from anesthesia after wound infiltration with tramadol plus ropivacaine, tramadol plus ropivacaine, magnesium sulfate plus ropivacaine or ropivacaine plus isotonic saline 0.9%	24 hours after the emergence from anesthesia

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity postoperatively	The difference in pain intensity postoperatively assessed by Visual Analogue Scale (graded from 0 defining absence of pain to 10 meaning extreme pain) or Numerical Pain Scale (graded from 0 defining no pain to 10 the worst pain ever experienced) after wound infiltration with tramadol plus ropivacaine, tramadol plus ropivacaine, magnesium sulfate plus ropivacaine or ropivacaine plus isotonic saline 0.9%	At 10 minutes after emergence from anesthesia, and 2, 4, 6, 12, 18 and 24 hours after the emergence from anesthesia
Analgesics consumption postoperatively in morphine equivalents	The difference in analgesic consumption (assessed as mg of morphine equivalents) postoperatively after wound infiltration with tramadol plus ropivacaine, tramadol plus ropivacaine, magnesium sulfate plus ropivacaine or ropivacaine plus isotonic saline 0.9%	24 hours after the emergence from anesthesia
Plasma concentration of TNF-a and IL-6	Levels of TNF-a and IL-6 in pg/ml will be measured from blood samples at the times before surgical stimulus, at 6 hours and 24 hours after wound infiltration, as stress-response biomarkers.	Before wound infiltration, and at 6 and 24 hours thereafter
Plasma concentration of cortisol	Levels of cortisol (in mcg/dL) will be measured from blood samples at the times before surgical stimulus, at 6 hours and 24 hours after wound infiltration, as stress-response biomarkers.	Before wound infiltration, and at 6 and 24 hours thereafter

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patients' sedation level after emergence	The level of sedation will be assessed after emergence using the Ramsey sedation scale in each participant, which ranges between 1 (anxious and restless patient) to 6 (unresponsive patient).	At 5 minutes after emergence from anesthesia
Postoperative adverse effects	The incidence of shivering, pruritus, nausea /vomiting, or any other adverse effect postoperatively after wound infiltration with tramadol plus ropivacaine, tramadol plus ropivacaine, magnesium sulfate plus ropivacaine or ropivacaine plus isotonic saline 0.9%	24 hours after the emergence from anesthesia
Quality of Recovery	The quality of recovery and overall satisfaction of each participant will be assessed using the Quality of Recovery Scale (QoR-40) ranging from 0 the worst to 200 the best value.	At 48 hours postoperatively and one month after hospital discharge

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Investigators: Principal Investigator: Georgia Tsaousi, Aristotle University Of Thessaloniki

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2020
• Primary Completion (Actual): November 8, 2022
• Study Completion (Actual): December 10, 2022

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 15, 2020
• First Posted (Actual): May 18, 2020

Study Record Updates

• Last Update Posted (Actual): December 20, 2022
• Last Update Submitted That Met QC Criteria: December 17, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: dexmedetomidine; analgesia; tramadol; magnesium; spine surgery; pain score; opioid consumption
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Musculoskeletal Diseases; Bone Diseases; Pain, Postoperative; Spinal Diseases; Spinal Stenosis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Anesthetics, Local; Dexmedetomidine; Ropivacaine; Tramadol
• Other Study ID Numbers: SpinInf

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No