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

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

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.

Study Overview

• Status: Completed
• Conditions: Low Back Pain
• Intervention / Treatment: Drug: Oxycodone 15mg; Drug: Clobazam; Drug: Imipramine; Drug: Tolterodine

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Bern University Hospital
    • Dep. of Anesthesiolgy and Pain therapy, Bern University Hospital, Switzerland, 3010 Bern
      • Andreas Siegenthaler

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University of Zurich; University of Bern; Aalborg University
• Investigators: Study Chair: Michele Curatolo, Prof, University Hospital Bern, Switzerland; Study Director: Andreas Siegenthaler, Dr Med, University Hospital Bern, Switzerland; Principal Investigator: Pascal H Vuilleumier, Dr Med, University Hospital Bern, Switzerland

Publications and helpful links

General Publications

• Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454. doi: 10.1002/14651858.CD005454.pub2.
• Arendt-Nielsen L, Yarnitsky D. Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain. 2009 Jun;10(6):556-72. doi: 10.1016/j.jpain.2009.02.002. Epub 2009 Apr 19.
• Foulkes T, Wood JN. Pain genes. PLoS Genet. 2008 Jul 25;4(7):e1000086. doi: 10.1371/journal.pgen.1000086.
• Curatolo M, Arendt-Nielsen L, Petersen-Felix S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys Med Rehabil Clin N Am. 2006 May;17(2):287-302. doi: 10.1016/j.pmr.2005.12.010.
• Markenson JA, Croft J, Zhang PG, Richards P. Treatment of persistent pain associated with osteoarthritis with controlled-release oxycodone tablets in a randomized controlled clinical trial. Clin J Pain. 2005 Nov-Dec;21(6):524-35. doi: 10.1097/01.ajp.0000146215.86038.38.
• Schliessbach J, Siegenthaler A, Butikofer L, Vuilleumier P, Juni P, Arendt-Nielsen L, Curatolo M. Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain. Scand J Pain. 2017 Oct;17:107-115. doi: 10.1016/j.sjpain.2017.07.004. Epub 2017 Aug 9.
• Siegenthaler A, Schliessbach J, Vuilleumier PH, Juni P, Zeilhofer HU, Arendt-Nielsen L, Curatolo M. Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain. BMC Pharmacol Toxicol. 2015 Sep 16;16:23. doi: 10.1186/s40360-015-0023-z.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: August 10, 2010
• First Submitted That Met QC Criteria: August 10, 2010
• First Posted (Estimate): August 11, 2010

Study Record Updates

• Last Update Posted (Estimate): April 6, 2016
• Last Update Submitted That Met QC Criteria: April 5, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Clobazam; Quantitative sensory testing; Tolterodine; Oxycodone; Imipramine; Drug efficacy; Low back pain syndrome
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Low Back Pain; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Urological Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Anti-Anxiety Agents; GABA Agents; Anticonvulsants; Antidepressive Agents, Tricyclic; Adrenergic Uptake Inhibitors; GABA-A Receptor Agonists; GABA Agonists; Oxycodone; Tolterodine Tartrate; Clobazam; Imipramine
• Other Study ID Numbers: KEK 213/09; grant: SPUM no. 33CM30_124117