Differential Adrenoreceptor Mediated Tachyphylaxis and Upregulation
Condition: Allergic Rhinitis; Tachyphylaxis; Rhinitis Medicamentosa
MeSH terms: Rhinitis; Rhinitis, Allergic
Study type: Interventional
Phase: Phase 4

Summary: 
      The investigators wish to evaluate the onset of tolerance to nasal decongestants like
      oxymetazoline (available over the counter) and the mechanism of tolerance particularly with
      differential effects on alpha 1 and alpha 2 adrenoreceptors on the nose. The investigators
      will 'tease' out by using an alpha 1 blocker called Prazosin. The investigators hypothesize
      that alpha 1 receptors mediate arterial constriction and this will be captured by measuring
      nasal blood flow. The investigators also hypothesize that alpha 2 receptors mediate venous
      sinusoid constriction and this the investigators will capture by airflow parameters like Peak
      Nasal Inspiratory Flow, Rhinomanometry, Oscillometric indices etc.
    

Detailed description: 
      Allergic rhinitis affects upto 25% of the worldwide population and is associated with asthma.
      Furthermore, nonallergic rhinitis accounts for more than 50% of Rhinitis sufferers. Patients
      with Allergic Rhinitis, Nonallergic Rhinitis and Common cold have nasal blockage as their
      principal symptom. Nasal blockage can affect sleep quality and impairs daytime performance.
      It is a major cause of sickness absenteeism and has been shown to adversely affect quality of
      life. The most efficacious class of drugs for this symptom are the nasal decongestants
      (sympathomimetics acting on alpha receptors). Unfortunately prolonged use of these sprays can
      result in a condition of tolerance (reduced efficacy), rebound nasal congestion and nasal
      hyperreactivity called Rhinitis Medicamentosa. It is a poorly understood condition and the
      mechanism of action is unclear. What is also not clear is the time to onset of tolerance.
      Finally many research studies have demonstrated that use of these nasal sprays for many weeks
      did not result in any side effects. Although evidence for this is conflicting, in vitro
      studies have shown that adrenoreceptors are known to develop tolerance within days of agonist
      use. Moreover beta adrenoreceptors in the lung can be upregulated (i.e., tolerance can be
      reversed) by use of corticosteroids. We have also seen over many years of clinical practise
      that concomitant use of steroid sprays and decongestants does not result in tolerance or
      rebound. Finally, research has shown that rebound congestion can be treated by stopping the
      decongestant spray and starting steroid sprays. We are not studying rebound congestion which
      takes years of decongestant abuse to develop. What we would like to demonstrate is the onset
      of tolerance (which precedes rebound) and its reversal by steroids. We would also find out if
      one of the two alpha receptors is responsible for this, which may lead to a selective alpha 1
      or alpha 2 agonist being used safely in the nose.We, therefore propose to conduct a proof of
      concept study to evaluate the onset of tolerance by nasal decongestant Oxymetazoline (OXY,
      its differential effects on alpha 1 and alpha 2 adrenoreceptors by an alpha 1 blocker
      Prazosin and finally the reversal of this process by intranasal steroid (Fluticasone). We are
      recruiting 31 patients (38 to complete 31) according to previous research studies and PNIF as
      an outcome measure if the true difference between the two arms is 10L/min. There would be a
      total of 7 visits to the Asthma and Allergy group at Ninewells Hospital, Dundee and Perth
      Royal Infirmary. Healthy Volunteers from 18-65 years of age will attend for a screening
      visit. Their Peak Nasal Inspiratory Flow (PNIF) must be more than 100L/min (best of three).
      All patients who satisfy the inclusion criteria and none of the exclusion criteria will be
      included in the trial. They will be issued a Peak Nasal Inspiratory Flow diary and a symptom
      diary. This they will record at home each morning before and 20 min after using their nasal
      sprays and repeated before bedtime. They will be issued with Oxymetazoline nasal spray to be
      used according to the recommended dose of 2 squirts in each nostril three times daily (can be
      used upto four times daily), on waking up, after lunch and before bedtime. The first visit
      will include a baseline nasal blood flow and airflow tests. The order of the tests will be as
      follows: Firstly, nasal peak inspiratory flow (PNIF), secondly, active anterior
      rhinomanometry, thirdly, nasal impulse oscillometry, and finally, nasal blood flow using
      Laser Doppler Flowmetry. They will also have lying/standing blood pressure measurements. This
      will be followed by the administration of 1mg of oral Prazosin/Placebo in a supine position.
      3 hours later a dose response curve (DRC) will be constructed with OXY at 20 minute intervals
      using cumulative sequential doses of 50 µg [1 squirt] , 100 µg[+ 1 squirt ] and 200 µg per
      nostril[+ 2 squirts].After 1st dose and 2nd dose, only PNIF and Rhinomanometry will be
      performed 10 minutes after each dose administration . After the last dose, the order of tests
      will be again PNIF, active anterior rhinomanometry, nasal impulse oscillometry, and laser
      Doppler flowmetry. For the first 2 hours lying/standing BP will be measured at ½ hourly
      intervals; hourly thereafter. They will be asked to lie down till the end of the visit (4
      hours down) or until no postural drop in blood pressure is recorded whichever comes first.
      There is very rarely a drop in blood pressure on giving Prazosin called 'First Dose
      Hypotension'. This happens in hypertensive patients who take a high dose of an alpha blocker
      like Prazosin. Therefore the British National Formulary will advise patients to be given a
      dose of say 0.5 milligrammes thrice daily with the first dose at bedtime and them slowly
      increased to upto a maximum daily dose of 20 milligrammes. We are within this dose range.
      Moreover, in clinical practise, doses of upto 5 milligrammes have been prescribed and in
      previous research trials upto 10 milligrammes have been given to Healthy Volunteers who have
      a lesser risk of this first dose effect. Moreover, according to previous pharmacokinetic and
      pharmacodynamic studies within 4-6 hours Prazosin effect on Blood Pressure wanes. Therefore
      we would conduct the Prazosin challenge test and the OXY dose response in a supine position
      and no patient will be discharged till the postural BP change is within normal limits. Laser
      Doppler Flowmetry is a noninvasive test designed to measure blood flow through the nose.
      Rhinomanometry is another noninvasive test measuring nasal resistance and flow. Oscillometry
      is another parameter measured on the Rhinomanometry machine itself.PNIF is a noninvasive
      measure of airflow which is basically a peak flow meter reversed. Thus no invasive measures
      will be used. This order of tests will be performed on Day 1 and repeated on Day 14 to
      compare acute with chronic agonist use. On day 14 Fluticasone nasal spray 2 squirts twice
      daily will be issued and on Day 17 the same order of tests will be performed. As this is a
      cross over study the patients receiving placebo will have prazosin in the second arm
      following a weeks washout in between. The same procedure for Prazosin/Placebo challenge will
      be followed throughout.
    

Intervention name(s): Oxymetazoline 0.05% w/v; Fluticasone propionate 50 micrograms per actuation; Prazosin hydrochloride; Placebo to Prazosin
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 2 squirts in each nostril thrice daily; 2 Squirts in each nostril twice daily; Prazosin 1mg one dose only; Placebo 1 tablet one dose only
Intervention MeSH terms: Fluticasone; Xhance; Prazosin; Phenylephrine; Oxymetazoline
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: allergic rhinitis; rhinitis medicamentosa; imidazolines; corticosteroid