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

• ClinicalTrials.gov Identifier: NCT01179828
• Recruitment Status: Completed
• First Posted: August 11, 2010
• Last Update Posted: April 6, 2016
• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University of Bern; University of Zurich; Aalborg University
• Information provided by: University Hospital Inselspital, Berne

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Low Back Pain	Drug: Oxycodone 15mg; Drug: Clobazam; Drug: Imipramine; Drug: Tolterodine	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Linking Altered Central Pain Processing and Genetic Polymorphism to Drug Efficacy in Chronic Low Back Pain
• Study Start Date: July 2010
• Actual Primary Completion Date: April 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Difference in NRS(pain scale) between measurement after and before drug administration [ Time Frame: 07/2012 ]

Secondary Outcome Measures :

1. Patients global impression of change scale after drug administration [ Time Frame: 07/2012 ]
2. Pharmacogenetic variables(see before) [ Time Frame: 07/2012 ]
3. Pharmacokinetics: measure of Imipramine and desipramine blood levels [ Time Frame: 07/2012 ]
4. Reliability of repeated quantitative sensory testing in the same patient [ Time Frame: 12/2010 ]

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

Switzerland

Andreas Siegenthaler

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

Sponsors and Collaborators

University Hospital Inselspital, Berne

University of Bern

University of Zurich

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

More Information

Publications of Results:

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. Review.

Foulkes T, Wood JN. Pain genes. PLoS Genet. 2008 Jul 25;4(7):e1000086. doi: 10.1371/journal.pgen.1000086. Review.

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. Review.

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.

Other Publications:

Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005454. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schliessbach J, Siegenthaler A, Bütikofer L, Vuilleumier P, Jüni 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.

• Responsible Party: Dr Med Andreas Siegenthaler, Inselspital Bern
• ClinicalTrials.gov Identifier: NCT01179828
• Other Study ID Numbers: KEK 213/09; grant: SPUM no. 33CM30_124117
• First Posted: August 11, 2010
• Last Update Posted: April 6, 2016
• Last Verified: April 2016

Keywords provided by University Hospital Inselspital, Berne:

Quantitative sensory testing; Drug efficacy; Low back pain syndrome; Imipramine; Oxycodone; Clobazam; Tolterodine

Additional relevant MeSH terms:

Back Pain; Low Back Pain; Pain; Neurologic Manifestations; Oxycodone; Clobazam; Imipramine; Tolterodine Tartrate; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Antidepressive Agents, Tricyclic; Antidepressive Agents; Psychotropic Drugs; Adrenergic Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Agents; Anticonvulsants; Anti-Anxiety Agents