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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Postoperative Pain, Chronic Pain, Analgesics

Intervention / Treatment
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* Drug: (S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml
* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>(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<br>* 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.<br>* Other names: Ketamine;Drug: Paracetamol 1 g<br>* Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.<br>* Other names: Paracetamol;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml administered as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 5 minutes) 0-24 hours postoperatively<br>* Other names: Morphine;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.<br>* Other names: Morphine;Drug: Ondansetron 2 mg/ml<br>* Ondansetron 2 mg/ml 4 mg iv in case of moderate to severe nausea, supplemented by Ondansetron 1 mg iv if needed<br>* Other names: Zofran;Drug: Usual daily opioids<br>* The patients usual daily opioid consumption are administered during the study period<br>* Other names: Morphine;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.<br>* Other names: Morphine;Drug: Sufentanil 5 microgram/ml<br>* Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.<br>* Other names: Sufentanil;|
| Placebo Comparator: Placebo<br>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: Isotonic sodium chloride 0.9 percent<br>* 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.<br>* Other names: Isotonic saline;Drug: Paracetamol 1 g<br>* Paracetamol 1 g orally 1 hour preoperatively and every 6 hours after extubation time during the first 24 hours.<br>* Other names: Paracetamol;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml administered as patient-controlled analgesia (PCA, bolus 2.5 mg, lockout 5 minutes) 0-24 hours postoperatively<br>* Other names: Morphine;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml, bolus 2.5 mg administered by the PACU nurse on request of the patient for the first hour postoperatively.<br>* Other names: Morphine;Drug: Ondansetron 2 mg/ml<br>* Ondansetron 2 mg/ml 4 mg iv in case of moderate to severe nausea, supplemented by Ondansetron 1 mg iv if needed<br>* Other names: Zofran;Drug: Usual daily opioids<br>* The patients usual daily opioid consumption are administered during the study period<br>* Other names: Morphine;Drug: Morphine Sulphate 1 mg/ml<br>* Morphine Sulphate 1 mg/ml, bolus 0.4 mg/kg administered 45 minutes before expected awakening.<br>* Other names: Morphine;Drug: Sufentanil 5 microgram/ml<br>* Sufentanil 5 microgram/ml, bolus 5 micrograms administered by the anaesthetic nurse in the operating room if the patient is in pain upon awakening.<br>* Other names: Sufentanil;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative pain, Ketamine, Morphine consumption, Side effects, Spine surgery, Chronic pain