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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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ClinicalTrials.gov Identifier: NCT02085577
Recruitment Status : Completed
First Posted : March 13, 2014
Last Update Posted : April 28, 2017
Sponsor:
Collaborator:
Glostrup University Hospital, Copenhagen
Information provided by (Responsible Party):
Rikke Vibeke Nielsen, MD, Rigshospitalet, Denmark

Tracking Information
First Submitted Date  ICMJE March 11, 2014
First Posted Date  ICMJE March 13, 2014
Last Update Posted Date April 28, 2017
Study Start Date  ICMJE May 2014
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2014)
Morphine consumption [ Time Frame: 0-24 hours postoperatively ]
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)
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2014)
Morphine consumption [ Time Frame: 0-24 hours postoperatively ]
Total morphine consumption, other than the patients usual opioid use, 0- 24 hours postoperatively, administered on as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 10 minutes)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2014)
  • Pain during mobilization [ Time Frame: 2, 6, 12, 18 and 24 hours postoperatively ]
    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 [ Time Frame: 2, 6, 12, 18 & 24 hours postoperatively ]
    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 [ Time Frame: 2, 6, 12, 18 & 24 hours postoperatively ]
    Level of nausea (none, mild, moderate, severe) (0-24h), measured at 2, 6, 12, 18 and 24 hours postoperatively.
  • Vomiting [ Time Frame: 0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively ]
    Number of vomiting episodes (0-24 hours), registered in the periods 0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively.
  • Ondansetron [ Time Frame: 0-24 hours postoperatively ]
    Consumption of ondansetron (mg) during 0-24 hours postoperatively.
  • Sedation [ Time Frame: 2, 6, 12, 18 & 24 hours postoperatively ]
    Level of sedation (none, mild, moderate, severe) (0-24 h) registered at time 2, 6, 12, 18 and 24 hours postoperatively.
  • Hallucinations and nightmares [ Time Frame: 0-24 hours postoperatively ]
    Episodes of hallucinations and nightmares (yes/no) in the period 0-24 hours postoperatively.
  • Chronic pain [ Time Frame: 6 months postoperatively ]
    Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 6 months postoperatively.
  • Chronic pain [ Time Frame: 12 months postoperatively ]
    Level of chronic pain and daily use of opioids assessed by the validated questionnaires EQ50, OWESTRY and DN4 at 12 months postoperatively.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2014)
  • Pain score during active mobilization [ Time Frame: 2, 6, 12, 18 and 24 hours postoperatively ]
    Pain score during active mobilisation, measured on a visual analogue scale (VAS), defined ad a standarised 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. Endpoint is AUC-VAS-mob (2-24 t) calculated from these measurements.
  • Pain score during rest [ Time Frame: 2, 6, 12, 18 and 24 hours postoperatively ]
    Pain score during rest (VAS), at 2, 6, 12, 18 and 24 hours postoperatively. Endpoint is AUC-VAS-mob (2-24 t) calculated from these measurements.
  • Degree of nausea [ Time Frame: 2, 6, 12, 18 og 24 hours postoperatively ]
    Degree of nausea 0-24 hours at time 2, 6, 12, 18 og 24 hours postoperatively.
  • Number of episodes vomiting [ Time Frame: 0-2, 2-6, 6-12, 12-18, 18-24 hours ]
    Number of episodes vomiting 0-24 hours, registered in periods 0-2, 2-6, 6-12, 12-18, 18-24 hours postoperatively.
  • Use of ondansetron [ Time Frame: 0-24 hours postoperatively ]
    Use of ondansetron during the period 0-24 hours postoperatively.
  • Degree of sedation [ Time Frame: 2, 6, 12, 18 og 24 hours postoperatively ]
    Degree of sedation 0-24 hours, at time 2, 6, 12, 18 og 24 hours postoperatively.
  • Hallucinations and nightmares [ Time Frame: 0-24 hours ]
    Hallucinations and nightmares 0-24 hours postoperatively.
  • Chronic pain [ Time Frame: 6 months postoperatively ]
    Chronic pain and daily use of opioids assessed by questionnaire 6 months postoperatively.
  • Chronic pain [ Time Frame: 12 months postoperatively ]
    Chronic pain and daily use of opioids assessed by questionnaire 12 months postoperatively.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients
Official Title  ICMJE The Effect of Intraoperative Ketamine on Opioid Consumption and Pain After Spine Surgery in Opioid-dependent Patients
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Postoperative Pain
  • Chronic Pain
  • Analgesics
Intervention  ICMJE
  • 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 Name: Ketamine
  • 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 Name: Isotonic saline
  • Drug: Paracetamol 1 g
    Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.
    Other Name: 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 Name: 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 Name: 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 Name: Zofran
  • Drug: Usual daily opioids
    The patients usual daily opioid consumption are administered during the study period
    Other Name: Morphine
  • Drug: Morphine Sulphate 1 mg/ml
    Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.
    Other Name: 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 Name: Sufentanil
Study Arms  ICMJE
  • 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
    Interventions:
    • 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
  • 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
    Interventions:
    • Drug: Isotonic sodium chloride 0.9 percent
    • 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
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 27, 2017)
147
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2014)
160
Actual Study Completion Date  ICMJE November 1, 2016
Actual Primary Completion Date October 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02085577
Other Study ID Numbers  ICMJE SM3-RS-2014
2014-000839-16 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rikke Vibeke Nielsen, MD, Rigshospitalet, Denmark
Study Sponsor  ICMJE Rigshospitalet, Denmark
Collaborators  ICMJE Glostrup University Hospital, Copenhagen
Investigators  ICMJE
Principal Investigator: Rikke V Nielsen, MD Glostrup University Hospital, Copenhagen
PRS Account Rigshospitalet, Denmark
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP