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

Primary Purpose

Postoperative Pain, Chronic Pain, Analgesics

Status
Completed
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
(S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml
Isotonic sodium chloride 0.9 percent
Paracetamol 1 g
Morphine Sulphate 1 mg/ml
Morphine Sulphate 1 mg/ml
Ondansetron 2 mg/ml
Usual daily opioids
Morphine Sulphate 1 mg/ml
Sufentanil 5 microgram/ml
Sponsored by
Rigshospitalet, Denmark
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Postoperative Pain focused on measuring Morphine consumption, Postoperative pain, Ketamine, Side effects, Spine surgery, Chronic pain

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Anaesthesiology, Glostrup Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ketamine

Placebo

Arm Description

(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

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

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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.
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.
Nausea
Level of nausea (none, mild, moderate, severe) (0-24h), measured at 2, 6, 12, 18 and 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.
Ondansetron
Consumption of ondansetron (mg) during 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.
Hallucinations and nightmares
Episodes of hallucinations and nightmares (yes/no) in the period 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.
Chronic pain
Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 12 months postoperatively.

Full Information

First Posted
March 11, 2014
Last Updated
April 27, 2017
Sponsor
Rigshospitalet, Denmark
Collaborators
Glostrup University Hospital, Copenhagen
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1. Study Identification

Unique Protocol Identification Number
NCT02085577
Brief Title
The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients
Official Title
The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients
Study Type
Interventional

2. Study Status

Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
May 2014 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
November 1, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rigshospitalet, Denmark
Collaborators
Glostrup University Hospital, Copenhagen

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Postoperative Pain, Chronic Pain, Analgesics
Keywords
Morphine consumption, Postoperative pain, Ketamine, Side effects, Spine surgery, Chronic pain

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
147 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ketamine
Arm Type
Experimental
Arm Description
(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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
(S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml
Other Intervention Name(s)
Ketamine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Isotonic sodium chloride 0.9 percent
Other Intervention Name(s)
Isotonic saline
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Paracetamol 1 g
Other Intervention Name(s)
Paracetamol
Intervention Description
Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.
Intervention Type
Drug
Intervention Name(s)
Morphine Sulphate 1 mg/ml
Other Intervention Name(s)
Morphine
Intervention Description
Morphine Sulphate 1 mg/ml administered as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 5 minutes) 0-24 hours postoperatively
Intervention Type
Drug
Intervention Name(s)
Morphine Sulphate 1 mg/ml
Other Intervention Name(s)
Morphine
Intervention Description
Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.
Intervention Type
Drug
Intervention Name(s)
Ondansetron 2 mg/ml
Other Intervention Name(s)
Zofran
Intervention Description
Ondansetron 2 mg/ml 4 mg iv in case of moderate to severe nausea, supplemented by Ondansetron 1 mg iv if needed
Intervention Type
Drug
Intervention Name(s)
Usual daily opioids
Other Intervention Name(s)
Morphine
Intervention Description
The patients usual daily opioid consumption are administered during the study period
Intervention Type
Drug
Intervention Name(s)
Morphine Sulphate 1 mg/ml
Other Intervention Name(s)
Morphine
Intervention Description
Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.
Intervention Type
Drug
Intervention Name(s)
Sufentanil 5 microgram/ml
Other Intervention Name(s)
Sufentanil
Intervention Description
Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.
Primary Outcome Measure Information:
Title
Morphine consumption
Description
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)
Time Frame
0-24 hours postoperatively
Secondary Outcome Measure Information:
Title
Pain during mobilization
Description
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.
Time Frame
2, 6, 12, 18 and 24 hours postoperatively
Title
Pain at rest
Description
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.
Time Frame
2, 6, 12, 18 & 24 hours postoperatively
Title
Nausea
Description
Level of nausea (none, mild, moderate, severe) (0-24h), measured at 2, 6, 12, 18 and 24 hours postoperatively.
Time Frame
2, 6, 12, 18 & 24 hours postoperatively
Title
Vomiting
Description
Number of vomiting episodes (0-24 hours), registered in the periods 0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively.
Time Frame
0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively
Title
Ondansetron
Description
Consumption of ondansetron (mg) during 0-24 hours postoperatively.
Time Frame
0-24 hours postoperatively
Title
Sedation
Description
Level of sedation (none, mild, moderate, severe) (0-24 h) registered at time 2, 6, 12, 18 and 24 hours postoperatively.
Time Frame
2, 6, 12, 18 & 24 hours postoperatively
Title
Hallucinations and nightmares
Description
Episodes of hallucinations and nightmares (yes/no) in the period 0-24 hours postoperatively.
Time Frame
0-24 hours postoperatively
Title
Chronic pain
Description
Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 6 months postoperatively.
Time Frame
6 months postoperatively
Title
Chronic pain
Description
Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 12 months postoperatively.
Time Frame
12 months postoperatively

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rikke V Nielsen, MD
Organizational Affiliation
Glostrup University Hospital, Copenhagen
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Anaesthesiology, Glostrup Hospital
City
Glostrup
ZIP/Postal Code
2600
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
20693876
Citation
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.
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The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients

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