The Analgesic Effect of Combined Treatment With Intranasal S-ketamine and Intranasal Midazolam

Study Overview
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Brief Summary
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Introduction Ketamine is an old and generally well accepted analgesic used in the intra- and perioperative setting. Several studies demonstrated the effectiveness of ketamine in the postoperative setting. A new formulation of S-ketamine as an intranasal spray device was tested in our hospital in 8 healthy volunteers (unpublished data, EKBB 351/08). 20 mg of S-ketamine were administered intranasally and compared with S-ketamine i.v. and i.m.. None of the volunteers had serious adverse effects or complications. A preliminary data analysis shows a clear analgesic effect and good absorption of the intranasal S-ketamine. As a next step we would like to investigate the effect of S-ketamine intranasal spray combined with midazolam intranasal spray in a group of postoperative spinal surgery patients. The rational for the combination of intranasal S-ketamine and midazolam is the well known midazolam antagonising effect of ketamine induced psychomimetic adverse effects. Furthermore we know from other studies (EKBB 106/06) that midazolam intranasal spray has relaxant and anxiolytic effects. As far as we know, this is the first study which will examine the combination of S-ketamine and midazolam intranasal sprays in adult patients. Study work plan This prospective, randomized, double-blinded non inferiority study will address pain ratings and patient satisfaction in a postoperative setting in two treatment scenarios: Alternating S-ketamine intranasal unit-dose spray (6 mg per dose) with midazolam intranasal spray (0.75 mg per dose) patient controlled application with a lock-out interval of 20 minutes between two applications and placebo patient controlled analgesia (PCA) with a lock-out interval of 12 minutes with saline 0.9% i.v. for 72 hours or until 40 unit-dose sprays are delivered PCA with 2 mg morphine with a lock-out interval of 12 minutes i.v. with placebo intranasal spray (saline 0.9% + chitosan) with a minimum lock-out interval of 20 minutes for 72 hours or until 40 unit-dose sprays are delivered Patient number We will examine 36 patients, 18 patients in each group. The study duration for an individual patient will be at latest 72 hours, the total study duration is 4 to 5 months. Study importance An intranasal spray is an ideal application form for surgery patients, either in- or outpatients. On the other hand, ketamine and S-ketamine is quite often used in the perioperative setting as a rescue analgesic. In higher doses it could be used as an emergency tool in emergency prehospital medicine. In the perioperative setting it is important to evaluate the efficacy and safety of S-ketamine intranasal spray combined with midazolam intranasal spray in patients. If our study shows that S-ketamine intranasal spray is effective as an analgesic and has good patient acceptance, S-ketamine intranasal spay could be considered as an alternative, completely non-invasive analgesic procedure in a postoperative outpatient setting. As a consequence development of a nasal multidose-applicator combining S-ketamine and midazolam would be of interest.

Official Title
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The Analgesic Effect of Combined Treatment With Intranasal S-Ketamine and Intranasal Midazolam Compared With Morphine Patient Controlled Analgesia in Spinal Surgery Patients

Conditions
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Analgesia, Patient-controlled, Spinal Stenosis

Intervention / Treatment
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* Drug: s-ketamine & midazolam
* Drug: Morphine PCA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Spinal surgery patients with: decompression because of spinal stenosis laminectomy because of spinal stenosis Age > 18 years BMI 18 - 39.9 (kg/m2) Exclusion Criteria: Patients unable to give written informed consent Known drug allergies or intolerance to the study medications morphine, midazolam, ketamine, paracetamol or metamizol Known allergy to crustacea or chitosan Patients using snuff at a regularly basis Recreational drug addiction or abuse Preexisting opioid (tramadol excluded), ketamine or midazolam therapy General physical condition ≥ ASA IV Serious intranasal or epipharyngeal problems Mental / psychiatric disorder Pregnancy Patients with renal failure (clearance < 30 ml/min) Patients with liver failure (MELD score > 25) Investigational Product Morphine / S-ketamine / midazolam

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S-ketamine & midazolam spray<br>all 20 minutes as a patient controlled analgesia alternating s-ketamine / midazolam | Drug: s-ketamine & midazolam<br>* s-ketamine 6 mg intranasal midazolam 0.75 mg intranasal<br>|
| Active Comparator: morphine, patient controlled analgesia<br>morphine as an active comparator as a patient controlled analgesia system | Drug: Morphine PCA<br>* 2 mg Morphine i.v. all 12 minutes as a patient controlled system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numeric rating scale 24 hours after surgery | NRS after 24 hours after finishing surgery | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of PCA boli | Amount of demanded / delivered unit doses of intranasal S-ketamine / midazolam or morphine PCA-boli | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patient controlled analgesia, Morphine, S-Ketamine intranasal, Midazolam intranasal