- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02256943
Genetic Determinants of Amitriptyline Efficiency for Pain Treatment
Effects of Amitriptyline on Central Pain Processing in Healthy Volunteers Depending on CYP Pharmacogenetics
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background
Pain is defined as an ongoing unpleasant sensory experience, which can be classified according to three major, although overlapping, etiologies: nociceptive, inflammatory and neuropathic pain.
Antidepressants are widely used as co-analgesics in the management of chronic pain. An overview of different substances and their relation to their mechanism of action is presented in the review of Dharmashaktu et al. Low-dose tricyclic antidepressants are well established in the treatment of neuropathic pain. Amitriptyline and imipramine are two widely used substances of this group. The hypoalgesic effect of amitriptyline is mainly mediated by inhibiting serotoninergic and noradrenergic reuptake. When administered at night time, amitriptyline's sedating effect enhances sleep quality, considered as an important improvement in quality of life in chronic pain patients.
Tricyclic antidepressants undergo biotransformation in the liver with CYP2D6 catalyzing hydroxylation, whereas CYP2C19 mediates demethylation of the parent drug. The demethylated metabolites are partially tricyclic drugs by themselves, such as nortriptyline and desipramine, which are demethyl-metabolites of amitriptyline and imipramine. It is unknown whether the analgesic effect of amitriptyline is mediated through its precursor or the metabolites.
The CYP2D6 gene is highly polymorphic and the numerous genetic variants result in 4 major metabolizer classes characterizing enzyme activity: poor metabolizers (PM) with no enzyme activity, intermediate metabolizers (IM) with reduced enzyme activity, (EM) extensive metabolizers carrying two functionally active alleles and ultrarapid metabolizers (UM) carrying a gene duplication or multi-duplication resulting in increased enzyme activity.
CYP2D6 PMs have higher plasma concentrations of the parent drug than EMs and are, therefore, more likely to experience dose-dependent adverse drug reactions. In 50 psychiatric patients receiving amitriptyline 150 mg/d, carriers of two functional CYP2D6 alleles (EMs) had a significantly lower risk of side effects than IM (12.1% vs. 76.5%). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele. The combination of normal (fast) CYP2C19 and slightly diminished CYP2D6 function leads to high concentrations of toxic intermediate metabolites and an increase of adverse events. On the other hand, CYP2D6 UMs may be at risk for sub-therapeutic concentrations resulting in poor therapeutic response. Thus, genetically determined differences in blood concentrations of antidepressants make dose adjustments advisable. However, these findings and dose recommendations have only been evaluated for psychiatric patients and no investigation on antidepressants as low-dosed co-analgesics are available up to now.
Quantitative sensory tests (QST) have been intensively used for more than three decades to explore the central processing of painful stimuli in patients and healthy volunteers. QST were developed to assess the responses to sensory stimuli, providing psychophysical methods for the assessment of the nociceptive system. In addition, large cohorts of healthy volunteers have been investigated using QST measures to produce reference values.
QST measures are based on a multimodal and multi-tissue approach, combining different pain modalities applied to different tissues in order to gather sufficient and discriminative information about the human nociceptive system. QST will be our tool to characterize analgesic efficacy of amitriptyline. QST offers the unique opportunity of experimentally induced pain being quantitatively measured by psychophysical, behavioural and neurophysiological responses.
Objective
We test the hypothesis that the extensive and ultrarapid CYP2D6 metabolizers are associated with a higher analgesic effect of amitriptyline, compared to the poor and intermediate metabolizers, as assessed by quantitative sensory tests. Plasma concentrations of amitriptyline and its metabolites will be analysed as co-variates for drug efficacy.
Two sub-studies, one peak-level, single-dose administration and one steady-state, repeated dose administration, are needed to assess the pharmacokinetics of amitriptyline and its active metabolites.
Statistics are provided by José A. Biurrun Manresa.
Methods
Two consecutive randomized placebo-controlled two-way crossover sub-studies on amitriptyline will be conducted in consenting, healthy, male volunteers. Both sub-studies have the same aim: to determine the association between CYP2D6 genotype, drug response measured by QST and plasma concentrations of amitriptyline and its metabolites. The first sub-study will be conducted with a single high dose of amitriptyline (100 mg). The second sub-study will be conducted with repeated low doses of amitriptyline (25 mg) once a day for 10 days.
In both sub-studies the same experimental procedures and statistical analyses will be performed. The only difference between the sub-studies is the dose of amitriptyline and the duration of drug intake.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
-
Bern, Switzerland, 3010
- Dep. of Anesthesiology, Bern University Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Healthy
- Male
- >7 Metabolic Equivalents
- Written informed consent
Exclusion Criteria
- Chronic pain syndrome
- Drug abuse
- Alcohol abuse
- Suspicion of neurologic dysfunction at tested sites
- Ongoing treatment with antidepressants
- Ongoing treatment with analgesics
- Pretreatment with any CYP3A inducers or inhibitors
- Known allergy to tested drugs
- Elevated eye pressure
- Obstructive uropathy
- Heart disease
- Pulmonary disease
- Neurological disease
- Psychiatric illness
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Amitriptyline first, Placebo second
|
100 mg single dose
Other Names:
Placebo 1 mg single dose
|
Active Comparator: Placebo first, Amitriptyline second
|
100 mg single dose
Other Names:
Placebo 1 mg single dose
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Nociceptive withdrawal reflex
Time Frame: During measurement, expected to be ca. 2-3 minutes
|
Measure of involuntary electromyographic amplitude
|
During measurement, expected to be ca. 2-3 minutes
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacogenetic information on CYP2D6 metabolism
Time Frame: At baseline, i.e. on day 1
|
Laboratory measurement (genotyping)
|
At baseline, i.e. on day 1
|
Changes in plasmatic metabolite level
Time Frame: Throughout study duration, expected to be ca. 20 days
|
Metabolite level in plasma
|
Throughout study duration, expected to be ca. 20 days
|
Collaborators and Investigators
Investigators
- Principal Investigator: Pascal H Vuilleumier, MD, Bern University Hospital
- Study Chair: Ulrike Stamer, Professor, Bern University Hospital
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pain
- Neurologic Manifestations
- Chronic Pain
- Physiological Effects of Drugs
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Peripheral Nervous System Agents
- Muscarinic Antagonists
- Cholinergic Antagonists
- Cholinergic Agents
- Urological Agents
- Analgesics
- Sensory System Agents
- Analgesics, Non-Narcotic
- Psychotropic Drugs
- Neurotransmitter Uptake Inhibitors
- Membrane Transport Modulators
- Antidepressive Agents
- Antidepressive Agents, Tricyclic
- Adrenergic Uptake Inhibitors
- Amitriptyline
- Tolterodine Tartrate
Other Study ID Numbers
- 133/12
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Chronic Pain
-
Pain ConcernThe Thistle Foundation; Health and Social Care Alliance Scotland (the ALLIANCE) and other collaboratorsCompletedChronic Pain | Chronic Pain Syndrome | Chronic Pain, Widespread | Chronic Pain Due to Trauma | Chronic Pain Due to Malignancy (Finding) | Chronic Pain Due to Injury | Chronic Pain Post-Procedural | Chronic Pain HipUnited Kingdom
-
Consorci Sanitari de l'Alt Penedès i GarrafRecruitingChronic Post Operative Pain | Chronic Post-surgical Pain | Chronic Knee PainSpain
-
Dow University of Health SciencesRecruitingLow Back Pain | Chronic Low-back Pain | Low Back Pain, Mechanical | Mechanical Low Back Pain | Pain, Chronic | Pain, Back | Lower Back Pain Chronic | CLBP - Chronic Low Back PainPakistan
-
University of Alabama, TuscaloosaPatient-Centered Outcomes Research Institute; East Carolina University; Whatley...CompletedPain | Chronic Pain | Chronic Pain Syndrome | Widespread Chronic Pain | Chronic Pain Due to InjuryUnited States
-
University of UtahRecruitingChronic Pain | Chronic Pain Syndrome | Widespread Chronic PainUnited States
-
Evolve Restorative CenterFlowonix Medical; Celéri Health, Inc.; Advanced Infusion SolutionsCompletedPain, Chronic | Pain, Intractable | Chronic Nonmalignant PainUnited States
-
Assiut UniversityNot yet recruiting
-
Atatürk Chest Diseases and Chest Surgery Training...RecruitingPostoperative Pain | Thoracotomy | Postoperative Pain, Acute | Postoperative Pain, ChronicTurkey
-
Vastra Gotaland RegionActive, not recruitingPain, Chronic | Widespread Chronic PainSweden
-
Istanbul UniversityCompletedLow Back Pain, Mechanical, Biofeedback, Pain, Chronic
Clinical Trials on Amitriptyline
-
National Institute of Allergy and Infectious Diseases...CompletedHIV Infections | Peripheral Nervous System DiseaseUnited States
-
First Affiliated Hospital of Zhejiang UniversityHunan DongtingPharm.Co.LtdCompleted
-
Gil YosipovitchTerminated
-
AlgoTherapeutixRecruiting
-
University of Missouri, Kansas CityRecruitingAutism Spectrum Disorder | Repetitive Compulsive BehaviorUnited States
-
UMC UtrechtUtrecht UniversityTerminatedChronic Neuropathic PainNetherlands
-
University Hospital TuebingenCompletedCystic Fibrosis | Infection | Pseudomonas AeruginosaGermany
-
CAMC Health SystemNational Institutes of Health (NIH); National Institute of General Medical... and other collaboratorsUnknownGallbladder DyskinesiaUnited States
-
Tufts Medical CenterNational Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)Completed
-
Mayo ClinicRecruitingInterstitial Lung DiseaseUnited States