Ketamine Analgesia in Third Molar Surgery

An Analysis of Ketamine Analgesia in Third Molar Surgery -Effects, Safety and Influence on Inflammatory Biomarkers in Plasma

BACKGROUND AND PURPOSE Outpatient surgery (day case surgery) is increasing. When the patients go home on the same day, this demands safe pain relief. A reduction of morphine (opioid) use is sought because of side effects and the dependency risk. An effective alternative to opioids is ketamine, which lacks the side effects of opioids but provides powerful analgesic effects.

METHOD At the start of surgery, Ketamine or placebo will be given in a vein to evaluate if the acute pain decreases significantly. Inflammation is known to cause pain. By measuring different proteins in the blood, the investigators want to understand how inflammation links to the pain. Wisdom tooth surgery provides significant post-operative pain and is a widely accepted pain model in drug studies. Patients referred for wisdom tooth surgery are asked to participate in the study. For statistical certainty, in total 165 persons will be enrolled to three groups. Two with active drug (different dose) and one placebo. Everyone gets local anesthesia. The completion of the study will be done in four years. The Ethics Review Board has approved the study.

CLINICAL RELEVANCE Effective pain relief after daily surgical procedures is important for patient´s safety and reducing the risk of long-term pain. It is also ethically necessary for the continued expansion of day case surgery. New knowledge of the mechanisms of pain increases the opportunities for individual and safe pain relief. Day case surgery is performed in all operating specialties, this might affects many patients nationally and internationally.

Study Overview

• Status: Completed
• Conditions: Pain; Postoperative
• Intervention / Treatment: Drug: Sodium Chloride 0.9% Inj; Drug: S-Ketamine

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 4

Contacts and Locations

Study Locations

• Sweden
  • Dalarna
    • Falun, Dalarna, Sweden, 79182
      • Käkkirurgiska kliniken, Falu lasarett

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 44 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy or mild well-compensated systemic disease (ASA I & II)
• 18- <45 years
• 50-100 kg body weight

Exclusion Criteria:

• Medication drugs: analgesics, hypnotics (the last week before surgery), thyroid hormones, psychoactive drugs or monoamine oxidase inhibitors (MAO inhibitors).
• Hypertension [> 150/95 mmHg in screening study]
• Heart failure
• Psychosis
• Epilepsy
• Hyperthyreosis
• Myasthenia gravis
• Glaucoma
• Verified sleep apnea
• Diabetes (insulin treated)
• Porphyria
• Pregnancy
• Breast-feeding
• Blood transmitted infections, such as HIV and hepatitis B and C
• Known hypersensitivity to midazolam, ketamine, ibuprofen, or local anesthetics
• Inability to obtain the requisite written or oral information

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Sodium Chloride solution (9mg / ml) 0.2ml / kg slow intravenous injection (2ml / min).	Drug: Sodium Chloride 0.9% Inj; Patients are randomized to three groups. Randomization in blocks of six patients stratified by sex. A list of serial numbers and randomized group affiliation is produced which is open to the pharmacy's manufacturing staff and closed to the staff of the trial. The pharmacy prepares filled syringes with investigation drug in accordance with randomized group affiliation. All groups are sedated with midazolam intravenously to a defined end point. A syringe pump with volume accuracy ± 2% injects the test drug (P, K1 or K2). One infusion set is coupled between the syringe and a three-way connection, which in turn is connected to a peripheral venous catheter (PVK). This PVK is also used for blood sampling. Blood is sampled at two occasions. Directly preoperatively and two hours after surgery. The third molar is surgically removed.
Active Comparator: K1; S-Ketamine (0.125 mg / kg body weight). (0.625mg / ml x 0.2ml / kg) slow intravenous injection (2ml / min).	Drug: S-Ketamine; Patients are randomized to three groups. Randomization in blocks of six patients stratified by sex. A list of serial numbers and randomized group affiliation is produced which is open to the pharmacy's manufacturing staff and closed to the staff of the trial. The pharmacy prepares filled syringes with investigation drug in accordance with randomized group affiliation. All groups are sedated with midazolam intravenously to a defined end point. A syringe pump with volume accuracy ± 2% injects the test drug (P, K1 or K2). One infusion set is coupled between the syringe and a three-way connection, which in turn is connected to a peripheral venous catheter (PVK). This PVK is also used for blood sampling. Blood is sampled at two occasions. Directly preoperatively and two hours after surgery. The third molar is surgically removed.
Active Comparator: K2; S-Ketamine (0.25 mg / kg body weight). (1.25mg / ml x 0.2ml / kg) slow intravenous injection (2ml / min).	Drug: S-Ketamine; Patients are randomized to three groups. Randomization in blocks of six patients stratified by sex. A list of serial numbers and randomized group affiliation is produced which is open to the pharmacy's manufacturing staff and closed to the staff of the trial. The pharmacy prepares filled syringes with investigation drug in accordance with randomized group affiliation. All groups are sedated with midazolam intravenously to a defined end point. A syringe pump with volume accuracy ± 2% injects the test drug (P, K1 or K2). One infusion set is coupled between the syringe and a three-way connection, which in turn is connected to a peripheral venous catheter (PVK). This PVK is also used for blood sampling. Blood is sampled at two occasions. Directly preoperatively and two hours after surgery. The third molar is surgically removed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain (VAS)	Postoperative pain measured by Visual analog scale (VAS). From minimum 0mm to maximum 100mm. 0mm is no pain and 100mm is worst pain imaginable. Changes in Visual Analog Scale value from preoperatively to 4 hours postoperatively	4 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Oxygen saturation)	Change in oxygen saturation measured by pulseoximeter %. Intra individually and between the groups. From start to completion of the ketamine infusion.	Up to 2 hours.

Collaborators and Investigators

• Sponsor: Dalarna County Council, Sweden
• Collaborators: Uppsala University; Center for Clinical Research Dalarna, Sweden
• Investigators: Study Director: Lars Sand, Professor, DDS, MD, Uppsala University

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2017
• Primary Completion (Actual): March 10, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: July 1, 2020
• First Submitted That Met QC Criteria: July 1, 2020
• First Posted (Actual): July 7, 2020

Study Record Updates

• Last Update Posted (Actual): October 12, 2022
• Last Update Submitted That Met QC Criteria: October 10, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Ketamine; Pain management; Postoperative; Third molar
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Psychotropic Drugs; Antidepressive Agents; Ketamine; Esketamine
• Other Study ID Numbers: 20140929sketamine; 2014-004235-39 (EudraCT Number)

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