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Effect of Morphine on Dyspnea and 6-Minute Walk Distance in Pulmonary Arterial Hypertension

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03401476
Recruitment Status : Unknown
Verified January 2018 by John Granton, University Health Network, Toronto.
Recruitment status was:  Enrolling by invitation
First Posted : January 17, 2018
Last Update Posted : January 18, 2018
Sponsor:
Information provided by (Responsible Party):
John Granton, University Health Network, Toronto

Brief Summary:
Despite advances in treatment and corresponding improvements in survival, patients with pulmonary arterial hypertension (PAH) remain highly symptomatic. In one survey of 315 patients with PAH, sixty-eight percent had moderate or severe dyspnea on exertion and 40% had a profound and clinically significant deficit in quality of life. Palliative care is being increasingly investigated in life-limiting cardiovascular diseases to alleviate symptoms. In PAH, its implementation is frequently delayed until end-of-life. Opioids are a common palliative care intervention, however the efficacy and safety of opioids for symptom relief in PAH has not been evaluated.

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Morphine Sulfate Phase 2

Detailed Description:

There is biologic plausibility for opioids in the treatment of dyspnea in PAH. Opioids have widespread effects including venodilation, vasodilation, reducing sympathetic outflow, blunting hypercapnic and hypoxic ventilatory responses, and altering the central perception of dyspnea. Although the origins of dyspnea in PAH are incompletely understood and multifactorial, right ventricular dysfunction reduces exercise capacity and likely also plays a role in the development of dyspnea. Mechanoreceptors situated in the right atrium and right ventricle sense elevated pressures and via sympathetic afferents may lead to an augmentation of ventilatory response and hence dyspnea. Morphine may specifically antagonize this feedback loop by causing venodilation and blunting sympathetics. Morphine also reduces central chemosensitivity and perceptions of dyspnea. Therefore, the drug may antagonize both peripheral and central drivers of dyspnea in PAH.

Investigators will conduct a single-center feasibility study of morphine for treatment of dyspnea and exercise intolerance in PAH. Participants will complete two 6-minute walk tests (6MWT) within one week. Participants will be randomly assigned to receive morphine prior to either the first or second 6MWT. Symptoms and 6-minute walk distance (6MWD) will be compared between the two tests.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effect of Morphine on Dyspnea and 6-Minute Walk Distance in Pulmonary Arterial Hypertension
Actual Study Start Date : May 8, 2017
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
Active Comparator: Morphine sulfate - Visit 1
Patients who are randomized to this group will be administered a fixed 5mg dose of oral morphine sulfate prior to performing their 6MWT at Visit 1.
Drug: Morphine Sulfate
Morphine Sulfate Tablets
Other Name: Statex

Active Comparator: Morphine sulfate - Visit 2
Patients who are randomized to this group will be administered a fixed 5mg dose of oral morphine sulfate prior to performing their 6MWT at Visit 2.
Drug: Morphine Sulfate
Morphine Sulfate Tablets
Other Name: Statex




Primary Outcome Measures :
  1. Change in Borg Dyspnea Score [ Time Frame: The Peak Borg Dyspnea Score will be determined over 6 minutes of observation during the conduct of each 6-minute walk test. The 6-minute walk tests and assessments of the peak Borg Dyspnea Score will be recorded within 1 and 7 days of each other. ]
    Change in peak Borg dyspnea score (morphine versus control)


Secondary Outcome Measures :
  1. Change in 6-Minute Walk Distance [ Time Frame: The distance travelled during each 6 minute walk will be determined at completion of the 6-minute walk test. The distance travelled during the 6-minute walk test will be recorded within 1 and 7 days of each other. ]
    Change in six-minute walk distance (morphine versus control)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged 18 or older
  • Diagnosis of Group 1 pulmonary hypertension including idiopathic PAH, heritable PAH, and PAH that is drug- or toxin-induced, associated with connective tissue disease, human immunodeficiency virus (HIV) infection, congenital heart disease, or schistosomiasis23
  • PAH confirmed by means of a right heart catheterization demonstrating:24

    • Mean pulmonary arterial pressure of ≥ 25 mmHg
    • Pulmonary capillary wedge pressure ≤ 15 mmHg
    • Pulmonary vascular resistance of ≥ 3 Wood units
  • World Health Organization (WHO) Functional Class III or ambulatory Class IV
  • Six-minute walk test performed within the past 6 months demonstrating a distance of at least 50 metres.
  • Unchanged PAH medication regimen for 30 days prior to enrolment. Therapy may include endothelin-receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, or oral or parenteral prostacyclin analogues. Diuretic doses may change.

Exclusion Criteria:

  • Group 1 pulmonary hypertension due to portal hypertension
  • Group 1 pulmonary hypertension due to pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
  • Groups 2, 3, 4, or 5 pulmonary hypertension
  • Severe renal impairment (estimated glomerular filtration rate < 30 mL/minute/1.73m2 measured within 6 months)
  • Severe hepatic impairment (INR > 2.0 in absence of vitamin K antagonist therapy, serum bilirubin > 50mmol/L, cirrhosis on imaging or liver biopsy, prior hepatic encephalopathy, or Model for End-Stage Liver Disease (MELD) score > 19, measured within 6 months, as required based on clinical suspicion)
  • Women who are pregnant or breastfeeding (beta-human chorionic gonadotropin (hCG) to confirm non-pregnant status in all females below age 50)
  • Hypersensitivity to opioid analgesic, concomitant use with Monoamine Oxidase (MAO) inhibitor or within 14 days of such treatment, concomitant use with barbiturates. Concomitant use with benzodiazepines and/or antipsychotics is permissible provided doses are stable over preceding 1 month.
  • Daily use of an opioid-containing medication
  • Unstable condition that is a contraindication to opioid use: Central Nervous System (CNS) depression, acute respiratory disease or impairment (acute hypoxia or hypercapnia), acute asthma or Chronic Obstructive Pulmonary Disease (COPD) exacerbation, untreated symptomatic obstructive sleep apnea, unstable cardiac arrhythmias, suspected hypovolemia, recent seizures (within 1 month), active drug abuse, abdominal disease and/or recent GI surgery (within 1 month), active gallbladder disease/biliary colic, untreated depression/suicidality, recent head injury (within 1 month), pre-existing intracranial lesion or increased intracranial pressure, untreated urinary tract obstruction, untreated hypothyroidism, hypopituitarism or Addison's disease.
  • Hypotension (resting systolic blood pressure less than or equal to 80mmHg)
  • Active or unstable coronary artery disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03401476


Locations
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Canada, Ontario
University Health Network, Toronto General Hospital
Toronto, Ontario, Canada, M5G 2N2
Sponsors and Collaborators
John Granton
Investigators
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Principal Investigator: John Granton, MD, FRCPC University Health Network, Toronto

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Responsible Party: John Granton, Principal Investigator, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT03401476    
Other Study ID Numbers: MorPHine
First Posted: January 17, 2018    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Dyspnea
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Signs and Symptoms, Respiratory
Signs and Symptoms
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents