Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease
Intervention: Methylnaltrexone; Placebo; Morphine; Ticagrelor
Intervention description: Methylnaltrexone will be administered diluted with 5 ml of normal saline as a single iv bolus; Placebo will be administered as a 0.9% sodium chloride iv injection; After methylnaltrexone, patients will receive 5-mg intravenous morphine; After morphine administration, patients will receive a 180-mg ticagrelor loading dose
Intervention MeSH terms: Morphine; Methylnaltrexone; Ticagrelor
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      Ticagrelor is associated with more prompt and potent antiplatelet effects compared with
      clopidogrel, leading to better clinical outcomes, including reduced cardiovascular mortality,
      across the spectrum of patients with acute coronary syndrome, including those with
      ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary
      intervention (PCI). However, in this latter setting a delay in the onset of its antiplatelet
      effects has been shown. Morphine has been identified as a cause of delayed P2Y12 inhibition
      in patients with STEMI. Methylnaltrexone is a parenteral peripheral opioid receptor
      antagonist which has the potential to prevent or reverse opioid-induced peripherally mediated
      side effects without affecting analgesia. However, whether the use of intravenous
      methylnaltrexone may overcome the effects of morphine administration on the pharmacokinetic
      (PK) and pharmacodynamics (PD) profiles of ticagrelor has not been investigated yet. The
      proposed investigation will include patients with coronary artery disease and will have a
      prospective, randomized, cross-over design.
    

Eligibility criteria:

        Inclusion criteria:

          -  Patients with angiographically documented CAD.

          -  On treatment with low-dose aspirin (81 mg) for at least 30 days, as per standard of
             care.

          -  Age between 18 and 80 years old.

        Exclusion criteria:

          -  History of prior intracranial bleeding.

          -  On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel,
             ticagrelor) or with vorapaxar in past 30 days.

          -  Known allergies to ticagrelor.

          -  On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran,
             rivaroxaban, apixaban).

          -  Treatment with glycoprotein IIb/IIIa inhibitors in past 7 days.

          -  Known blood dyscrasia or bleeding diathesis.

          -  Platelet count <80x106/mL.

          -  Hemoglobin <10 g/dL.

          -  Active bleeding.

          -  Hemodynamic instability.

          -  Creatinine clearance <30 mL/minute (as estimated by Cockcroft-Gault formula).

          -  Severe hepatic dysfunction.

          -  Acute or severe bronchial asthma or upper airway obstruction.

          -  Known or suspected mechanical gastrointestinal obstruction.

          -  Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker
             protection.

          -  Current treatment with any drug interfering with morphine: central nervous system
             depressants (other narcotic analgesics, general anesthetics, phenothiazines, tricyclic
             antidepressants, tranquilizers, sedatives, hypnotics, antiemetics, and alcohol),
             muscle relaxants, mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine,
             and butorphanol), cimetidine, monoamine oxidase inhibitors (MAOIs), anticholinergics.

          -  Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction
             with ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin,
             nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and
             telithromizycin.

          -  Pregnant females*. *Women of childbearing age must use reliable birth control (i.e.
             oral contraceptives) while participating in the study.