The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients

Patients with a daily use of opioids may develop higher postoperative pain levels, often need high doses of morphine and therefore their pain may be difficult to treat. A low dose of an old anesthetic drug, ketamine, administered during surgery can possibly reduce pain and morphine consumption in these patients. Our purpose is to investigate the effect of low dose ketamine on morphine consumption and pain after spine surgery in patients with a daily use of opioids. Our hypothesis is that low dose ketamine can reduce morphine consumption, pain and side-effects after spine surgery.

Study Overview

• Status: Completed
• Conditions: Chronic Pain; Postoperative Pain; Analgesics
• Intervention / Treatment: Drug: (S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml; Drug: Paracetamol 1 g; Drug: Morphine Sulphate 1 mg/ml; Drug: Morphine Sulphate 1 mg/ml; Drug: Ondansetron 2 mg/ml; Drug: Usual daily opioids; Drug: Morphine Sulphate 1 mg/ml; Drug: Sufentanil 5 microgram/ml; Drug: Isotonic sodium chloride 0.9 percent

Detailed Description

Opioid-dependent patients can develop hyperalgesia and often have a high opioid consumption postoperatively due to opioid tolerance. Intraoperative ketamine in subanesthetic doses can possibly reduce hyperalgesia and reduce opioid-tolerance in these patients. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that works by blocking the NMDA receptors in the central and peripheral nerve system. It can be used for general anesthesia but the drug also has other properties including lowering of central excitability and reducing postoperative opioid tolerance by modeling the opioid receptors. Further more it can possibly reduce chronic pain by blocking wind-up effect when blocking the NMDA receptors.

Our purpose is to investigate the effect of intraoperative ketamine on opioid consumption and pain after spine surgery in opioid-dependent patients. Our hypothesis is that ketamine can reduce opioid consumption and reduce postoperative pain and side effects compared to placebo.

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Glostrup, Denmark, 2600
    • Department of Anaesthesiology, Glostrup Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients undergoing lumbar spinal fusion surgery in general anesthesia.
• Daily use of opioids for a minimum of 6 weeks preoperatively (morphine, ketobemidone, oxycodone, fentanyl, tramadol and/or buprenorphine).
• Back pain for a minimum of 3 months preoperatively.
• Age > 18 years and < 85 years.
• ASA 1-3.
• BMI > 18 and < 40.
• Fertile women need to have a negative urine HCG pregnancy test.
• Patients who have given their written informed consent to participate in the study after understanding the content and limitations of the study

Exclusion Criteria:

• Participation in another concomitant drug trial.
• Patients who do not understand or speak Danish.
• Allergy to the drugs used in the trial.
• Abuse of drugs - as assessed by the investigator.
• Daily methadone use.
• Increased intraocular pressure - assessed from the patients chart.
• Uncontrolled hypertension - assessed from the patients chart.
• Previous and current psychotic episodes - assessed from the patients chart

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ketamine; (S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml bolus 0.5 mg/kg administered immediately after induction of anesthesia, followed by infusion ketamine 0,25 mg/kg/h terminated at last suture to the skin.; Morphine. Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 min before expected awakening.; Escape sufentanil. Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.; Morphine. PCA-morphine, bolus 2.5 mg, lock-out-time 5 min. Concentration : Morphine sulphate 1 mg/ml.; Escape morphine. Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.; Ondansetron 2 mg/ml, 4 mg iv in case of moderate to severe nausea, supplemented by 1 mg iv if needed; Paracetamol 1 g orally 1 h preoperatively and every 6 h after extubation time during the first 24 h.; The patients usual daily opioids	Drug: (S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml; Ketamine (25 mg/ml) bolus 0.5 mg/kg administered immediately after induction of anesthesia, followed by infusion ketamine 0,25 mg/kg/hour that is terminated when the last suture to the skin has been performed.; Other Names: Ketamine; Drug: Paracetamol 1 g; Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.; Other Names: Paracetamol; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml administered as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 5 minutes) 0-24 hours postoperatively; Other Names: Morphine; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.; Other Names: Morphine; Drug: Ondansetron 2 mg/ml; Ondansetron 2 mg/ml 4 mg iv in case of moderate to severe nausea, supplemented by Ondansetron 1 mg iv if needed; Other Names: Zofran; Drug: Usual daily opioids; The patients usual daily opioid consumption are administered during the study period; Other Names: Morphine; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.; Other Names: Morphine; Drug: Sufentanil 5 microgram/ml; Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.; Other Names: Sufentanil
PLACEBO_COMPARATOR: Placebo; Isotonic sodium chloride 0.9 percent 0.02 ml/kg administered immediately after induction of anesthesia, followed by infusion isotonic sodium chloride 0.01 ml/kg/h terminated at last suture to the skin.; Morphine. Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 min before expected awakening.; Escape sufentanil. Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.; Morphine. PCA-morphine, bolus 2.5 mg, lock-out-time 5 min. Concentration : Morphine sulphate 1 mg/ml.; Escape morphine. Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.; Ondansetron 2 mg/ml, 4 mg iv in case of moderate to severe nausea, supplemented by 1 mg iv if needed; Paracetamol 1 g orally 1 h preoperatively and every 6 h after extubation time during the first 24 h.; The patients usual daily opioids	Drug: Paracetamol 1 g; Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.; Other Names: Paracetamol; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml administered as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 5 minutes) 0-24 hours postoperatively; Other Names: Morphine; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.; Other Names: Morphine; Drug: Ondansetron 2 mg/ml; Ondansetron 2 mg/ml 4 mg iv in case of moderate to severe nausea, supplemented by Ondansetron 1 mg iv if needed; Other Names: Zofran; Drug: Usual daily opioids; The patients usual daily opioid consumption are administered during the study period; Other Names: Morphine; Drug: Morphine Sulphate 1 mg/ml; Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.; Other Names: Morphine; Drug: Sufentanil 5 microgram/ml; Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.; Other Names: Sufentanil; Drug: Isotonic sodium chloride 0.9 percent; Isotonic sodium chloride 0.9 percent 0.02 ml/kg administered immediately after induction of anesthesia, followed by infusion isotonic sodium chloride 0.01 ml/kg/hour that is terminated when the last suture to the skin has been performed.; Other Names: Isotonic saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morphine consumption	Total intravenous morphine consumption, other than the patients usual opioid use, 0- 24 hours postoperatively, administered as patient-controlled analgesia ((PCA), bolus 2.5 mg, lockout 5 minutes)	0-24 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain during mobilization	Pain score during active mobilization, measured on a visual analogue scale (VAS) (0-100 mm), defined as a standardized movement from recumbent position to sitting on the bedside at 2, 6, 12, 18 and 24 hours postoperatively, the worst pain from the movement is registered. The endpoint, VAS-mobilization, will be calculated as area under the curve (AUC) (2-24h) from these measurements.	2, 6, 12, 18 and 24 hours postoperatively
Pain at rest	Pain score at rest, measured on a visual analogue scale (VAS) (0-100 mm), at 2, 6, 12, 18 and 24 hours postoperatively. The endpoint, VAS-rest, will be calculated as area under the curve (AUC) (2-24h) from these measurements.	2, 6, 12, 18 & 24 hours postoperatively
Nausea	Level of nausea (none, mild, moderate, severe) (0-24h), measured at 2, 6, 12, 18 and 24 hours postoperatively.	2, 6, 12, 18 & 24 hours postoperatively
Vomiting	Number of vomiting episodes (0-24 hours), registered in the periods 0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively.	0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively
Ondansetron	Consumption of ondansetron (mg) during 0-24 hours postoperatively.	0-24 hours postoperatively
Sedation	Level of sedation (none, mild, moderate, severe) (0-24 h) registered at time 2, 6, 12, 18 and 24 hours postoperatively.	2, 6, 12, 18 & 24 hours postoperatively
Hallucinations and nightmares	Episodes of hallucinations and nightmares (yes/no) in the period 0-24 hours postoperatively.	0-24 hours postoperatively
Chronic pain	Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 6 months postoperatively.	6 months postoperatively
Chronic pain	Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 12 months postoperatively.	12 months postoperatively

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Glostrup University Hospital, Copenhagen
• Investigators: Principal Investigator: Rikke V Nielsen, MD, Glostrup University Hospital, Copenhagen

Publications and helpful links

General Publications

• Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK, Beach ML. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010 Sep;113(3):639-46. doi: 10.1097/ALN.0b013e3181e90914.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): November 1, 2016

Study Registration Dates

• First Submitted: March 11, 2014
• First Submitted That Met QC Criteria: March 12, 2014
• First Posted (ESTIMATE): March 13, 2014

Study Record Updates

• Last Update Posted (ACTUAL): April 28, 2017
• Last Update Submitted That Met QC Criteria: April 27, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Chronic pain; Ketamine; Postoperative pain; Side effects; Spine surgery; Morphine consumption
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Chronic Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Non-Narcotic; Antipyretics; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Analgesics, Opioid; Narcotics; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Adjuvants, Anesthesia; Anti-Anxiety Agents; Antipruritics; Ketamine; Acetaminophen; Morphine; Ondansetron; Sufentanil; Dsuvia
• Other Study ID Numbers: SM3-RS-2014; 2014-000839-16 (EUDRACT_NUMBER)