Genetic Determinants of Amitriptyline Efficiency for Pain Treatment - Part II
Condition: Chronic Pain
MeSH terms: Chronic Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      Low dose tricyclic antidepressant drugs are routinely administered co-analgesics in pain
      medicine. Amitriptyline is largely considered as a gold standard. Amitriptyline underlies
      cytochrome CYP2D6 and CYP2D19 metabolism. CYP2D6 is highly polymorphic; numerous genetic
      variants result in 4 major classes characterizing enzymatic activity: poor metabolizers,
      intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers. It is not
      known to which extent metabolizer classes determine pain outcomes or side-effects. As only
      one in three pain patients is considered to be a responder to amitriptyline's co-analgesic
      effect, prediction of treatment efficacy with a fast and easy to perform bedside test may
      contribute to the patients quality of life. The aim of this study is to determine the
      influence of cytochrome variants on experimental pain, drug related side-effects and finally
      identification of active metabolites.
    

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). This 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.
    

Intervention name(s): Amitriptyline; Tolterodine
Intervention type(s): Drug; Drug
Intervention description(s): 25 mg / day for 10 days; Placebo 1 mg / day for 10 days
Other intervention name(s): Tryptizol
Intervention MeSH terms: Amitriptyline; Tolterodine Tartrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pharmacogenetics of Amitriptyline