Linking Altered Central Pain Processing and Genetic Polymorphism to Drug Efficacy in Chronic Low Back Pain (Predictio)

Study Overview
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Brief Summary
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Drug therapy in patients with chronic low back pain is a major challenge for physicians. One of the problems is the lacking knowledge in prediction of drug efficacy in a chosen patient. Usually one of the classes of pain medication is given to patients with a similar clinical picture, although different pain mechanisms may be responsible for this clinical picture. Another reason for variable drug efficacy are genetic polymorphisms, this may be the reason why an unique drug produces different responses (from a lacking analgesic effect up to excessive effect or side-effects. Quantitative sensory testing is a method that documents alterations in the pain perception system. Linking genetic polymorphisms to quantitative sensory testing may give us a tool for anticipation of drug efficacy.

Detailed Description
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Background Drug therapy is an essential part of pain treatment. However, only a minor part of pain patients benefits from the available treatments or is able to tolerate the drugs. One important limitation of drug therapy is lack of instruments to predict their effect. Indeed, in clinical practice classes of drugs (e.g. antidepressants) are given to classes of patients (e.g. neuropathic pain patients). However, within those classes of patients very different pain mechanisms are likely to underlie the pain condition in different patients. If drugs affect part of these mechanisms, they will not work in all patients. Another reason for variability in drug responses is genetic variation leading to a spectrum of different responses to analgesics, from lack of efficacy to exaggerated responses, up to intolerable adverse effects. Quantitative sensory testing comprises methods that document alterations and reorganization of the nociceptive system. Measuring an abnormal result in a chronic pain patient may provide us with the information that the underlying pain pathways somehow must be altered. An essential question is whether this information can be linked to drug efficacy in a mechanism-based treatment approach. A further important question is whether assessing genetic polymorphisms can explain different drug effects and hence help selecting the appropriate therapeutic strategy for individual patients. Objective We will test the hypothesis that there is a correlation between disturbances in specific pain mechanisms as assessed by quantitative sensory tests and analgesic efficacy after single-dose drug administration in patients with chronic low back pain. Genetic factors affecting drug metabolism and pain sensitivity will be analyzed as additional explanatory variables for drug efficacy. Methods Quantitative sensory testing: Heat pain threshold and tolerance, Ice water testing with central modulation of nociceptive input (DNIC), electrical pain detection and temporal summation (skin probe), pressure algometry with pain detection and threshold Drugs investigated: Imipramine, Oxycodone, Clobazam Blood samples: pharmacogenetics: Cytochrome variants CYP2D6, CYP2C19, CYP3A4, COMT haplotypes, CGH-1 variants, A118G of mu opioid receptor gene variants pharmacokinetics: kinetics of imipramine and desipramine

Official Title
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Linking Altered Central Pain Processing and Genetic Polymorphism to Drug Efficacy in Chronic Low Back Pain

Conditions
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Low Back Pain

Intervention / Treatment
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* Drug: Oxycodone 15mg
* Drug: Clobazam
* Drug: Imipramine
* Drug: Tolterodine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Low back pain with NRS>2 Chronic low back pain since more than 6 months Exclusion Criteria pregnancy use of pain medication other than paracetamol and ibuprofen in the last 7 days suspicion of radicular pain suspicion of intervertebral disk herniation foraminal intervertebral stenosis suspicion of polyneuropathy diabetes parkinson disease alzheimer disease glaucoma prostata hyperplasia or voiding problems known heart rhythm problems heart insufficiency NYHA 3-4 Systemic inflammatory disease Ongoing oncologic disease drug or alcohol abuse Significant depressive disease (BDI-FS>9)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Oxycodone 15mg | Drug: Oxycodone 15mg<br>* 15mg single administration p.o.<br>|
| Active Comparator: 2<br>Clobazam 20mg | Drug: Clobazam<br>* 20mg single administration p.o.<br>|
| Active Comparator: 3<br>Imipramine 75mg | Drug: Imipramine<br>* 75mg single administration p.o.<br>|
| Placebo Comparator: 4<br>Tolterodine 1mg | Drug: Tolterodine<br>* 1 mg single administration p.o.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in NRS(pain scale) between measurement after and before drug administration |  | 07/2012 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients global impression of change scale after drug administration |  | 07/2012 | 
| Pharmacogenetic variables(see before) |  | 07/2012 | 
| Pharmacokinetics: measure of Imipramine and desipramine blood levels |  | 07/2012 | 
| Reliability of repeated quantitative sensory testing in the same patient |  | 12/2010 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Quantitative sensory testing, Drug efficacy, Low back pain syndrome, Imipramine, Oxycodone, Clobazam, Tolterodine