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

NCT ID: NCT01179828

Last Updated: 2016-04-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-07-31
• Study Completion Date: 2015-12-31

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.

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

Conditions

Low Back Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: TRIPLE

Study Groups

1

Oxycodone 15mg

Group Type: ACTIVE_COMPARATOR

Oxycodone 15mg

Intervention Type: DRUG

15mg single administration p.o.

2

Clobazam 20mg

Group Type: ACTIVE_COMPARATOR

Clobazam

Intervention Type: DRUG

20mg single administration p.o.

3

Imipramine 75mg

Group Type: ACTIVE_COMPARATOR

Imipramine

Intervention Type: DRUG

75mg single administration p.o.

4

Tolterodine 1mg

Group Type: PLACEBO_COMPARATOR

Tolterodine

Intervention Type: DRUG

1 mg single administration p.o.

Interventions

Oxycodone 15mg

15mg single administration p.o.

Intervention Type: DRUG

Clobazam

20mg single administration p.o.

Intervention Type: DRUG

Imipramine

75mg single administration p.o.

Intervention Type: DRUG

Tolterodine

1 mg single administration p.o.

Intervention Type: DRUG

Eligibility 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Bern

OTHER

Sponsor Role: collaborator

University of Zurich

OTHER

Sponsor Role: collaborator

Aalborg University

OTHER

Sponsor Role: collaborator

Insel Gruppe AG, University Hospital Bern

OTHER

Sponsor Role: lead

Responsible Party

Inselspital Bern

Principal Investigators

Michele Curatolo, Prof

Role: STUDY_CHAIR

University Hospital Bern, Switzerland

Andreas Siegenthaler, Dr Med

Role: STUDY_DIRECTOR

University Hospital Bern, Switzerland

Pascal H Vuilleumier, Dr Med

Role: PRINCIPAL_INVESTIGATOR

University Hospital Bern, Switzerland

Locations

Andreas Siegenthaler

Dep. of Anesthesiolgy and Pain Therapy, Bern University Hospital, Switzerland

Countries

Switzerland

References

Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007 Oct 17;2007(4):CD005454. doi: 10.1002/14651858.CD005454.pub2.

Reference Type: BACKGROUND

PMID: 17943857 (View on PubMed)

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.

Reference Type: RESULT

PMID: 19380256 (View on PubMed)

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

Reference Type: RESULT

PMID: 18654615 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16616268 (View on PubMed)

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.

Reference Type: RESULT

PMID: 16215338 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28850362 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26376691 (View on PubMed)

Other Identifiers

grant: SPUM no. 33CM30_124117

Identifier Type: -

Identifier Source: secondary_id

KEK 213/09

Identifier Type: -

Identifier Source: org_study_id