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Trial registered on ANZCTR


Registration number
ACTRN12610001074088
Ethics application status
Approved
Date submitted
23/11/2010
Date registered
6/12/2010
Date last updated
11/04/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
Can minocycline reverse morphine-induced respiratory depression in obstructive sleep apnea patients?- A pilot study
Scientific title
Obstructive sleep apnea patients administrated minocycline may reverse morphine-induced respiratory depression without reducing the analgesic effects
Secondary ID [1] 253151 0
Protocol number X10-0268, Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health Service.
Universal Trial Number (UTN)
Trial acronym
The ROD study (Reverse Opioid-respiratory-Depression)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
obstructive sleep apnea 258700 0
Condition category
Condition code
Respiratory 258853 258853 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a double-blind, placebo-controlled, cross-over study. All subjects will undergo 2 overnight sleep studies separated by an interval of at least 1 week. The Sleep Study measures the effects of the drug on breathing and oxygen levels during sleep.

After signed and informed consent is given, participants would be prescribed a 3 day course of either active or placebo oral minocycline, depending on their randomisation. Patients will be asked to take a single loading dose of 200 mg of minocycline/placebo at around 8pm two days before the first sleep study. For the next two days patients take 100 mg minocyclin/placebo twice a day (8am and 8pm approximately), including the sleep testing day.

First PSG study: Patient finishes dinner at 5pm, and takes a single dose of 30mg MS Contin (oral slow release morphine)at 5:30pm. At 8pm, the patient takes scheduled 100mg minocycline/placebo. At 9pm, patient will be tested for pain threshold (Von Frey hair test), and a short 10 minute clinical test of breathing, the central ventilatory chemosensitivity test. An indwelling venous catheter will be inserted and 5ml of venous blood will be taken for drug concentration/metabolites analysis. At 10pm, PSG sleep study starts. After awakening the next morning the patient will be discharged with the 3 days dose of cross-over minocycline/placebo to be taken at home before the next scheduled sleep study.

The second arm of the study, the procedure is identical to the first arm except the patient has been provided the opposite treatment according to the randomization schedule.

Second PSG study: The procedure is identical to the first PSG night, except that the subject takes 100mg cross-over minocycline/placebo at 8pm (the second dose of the day).
Intervention code [1] 257656 0
Prevention
Intervention code [2] 257710 0
Treatment: Drugs
Comparator / control treatment
Oral slow release morphine plus either active or placebo oral minocycline. Placebos are lactose filled capsules. More details can be found in "Descrptions of interventions".
Control group
Placebo

Outcomes
Primary outcome [1] 259705 0
SpO2 (Oxygen Saturation) nadir during sleep
Timepoint [1] 259705 0
at two cross-over polysomnography (PSG) nights and at screening (baseline) PSG night
Primary outcome [2] 259706 0
%Total sleep time SpO2 <90% during sleep. The parameter is part of the PSG measurement.
Timepoint [2] 259706 0
at two cross-over PSG nights and at screening (baseline) PSG night
Primary outcome [3] 259707 0
Central chemosensitivity tested by ventilatory chemoreflex tesing system
Timepoint [3] 259707 0
at two cross-over PSG evenings during awake and at screening (baseline) examination
Secondary outcome [1] 266423 0
Oxygen desaturation index (ODI) as part of PSG assessment
Timepoint [1] 266423 0
at two cross-over PSG nights and at screening (baseline) PSG night
Secondary outcome [2] 266424 0
CO2 recruitment threshold tested by chemoreflex testing system
Timepoint [2] 266424 0
at two cross-over PSG evenings during awake and at screening (baseline) examination
Secondary outcome [3] 266425 0
Pain threshold (Mechanical Detection Threshold) tested by Von Frey Hair
Timepoint [3] 266425 0
at two cross-over PSG evenings during awake

Eligibility
Key inclusion criteria
Aged between 18-60 years who have previously been tested by a polysomnography (PSG) study that shows they have sleep apnoea, with Apnea Hypopnea Index >15/hr and SpO2 nadir 90-70%.
Minimum age
18 Years
Maximum age
60 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of adverse effects from opioids or minocycline. 2. History of drug abuse. 3. Regular use of opiates. 4. Current or recent severe physiological or psychological illness including severe cardiovascular (hypertension) or CNS diseases. 5. Presence of another severe sleep disorders (such as period limb movement disorders or shift work sleep disorder). 6. Concurrent using CPAP or taking of other medications which might interfere with the study drugs.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All sleep apnea patients will undergo a medical examination by a physician. A detailed medical history will be obtained with particular reference to history of drug allergy, respiratory illness, past and current substance abuse, sleep patterns and snoring. Patients will be fully informed of the details of the project and invited to sign the consent form if they are willing and able to participate in the study. Allocation of either active or placebo minocycline is administrated by a research pharmacist at RPA Hospital Pharmacy who is not an investigator of the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The order of the active or placebo minocycline was decided using simple procedure of coin-tossing
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
23/11/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 258123 0
University
Name [1] 258123 0
Sydney Medical School New Staff Awards
Country [1] 258123 0
Australia
Primary sponsor type
Government body
Name
NHMRC Training Fellowship
Address
Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe. NSW 2037
Country
Australia
Secondary sponsor category [1] 257300 0
Hospital
Name [1] 257300 0
RPAH
Address [1] 257300 0
Missenden Rd, Camperdown 2050 NSW
Country [1] 257300 0
Australia
Other collaborator category [1] 251674 0
University
Name [1] 251674 0
University of Adelaide
Address [1] 251674 0
Discipline of Pharmacology
Faculty of Health Sciences
The University of Adelaide
Adelaide 5005 SA
Country [1] 251674 0
Australia
Other collaborator category [2] 251717 0
Other Collaborative groups
Name [2] 251717 0
Pain Management Research Institute
Address [2] 251717 0
Royal North Shore Hospital, St Leonards NSW 2065
Country [2] 251717 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260105 0
Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health Service
Ethics committee address [1] 260105 0
Research Development Office
Level 3, Building 92
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 260105 0
Australia
Date submitted for ethics approval [1] 260105 0
12/09/2010
Approval date [1] 260105 0
28/10/2010
Ethics approval number [1] 260105 0
X10-0268

Summary
Brief summary
Opioids are commonly used for a number of clinical settings, including treatment of acute pain, trauma, cancer, non-malignant chronic pain and in methadone maintenance treatment programs. In Australia, the number of PBS opioid prescriptions increased three-fold, from 2.4 million in 1992 to 7.0 million in 2007.

Due to the rapid increase in opioid prescriptions, unintentional drug poisoning mortality rates have also increased substantially, with deaths attributed primarily to prescription opioid analgesics. A US study reported that more than 90% of unintentional medication poisoning deaths were caused by opioid analgesics. In Australia, the National Hospital Morbidity Database showed a three-fold increase in the number of separations from hospitals as a result of unintentional poisoning by opioids other than heroin or methadone from 1998/99 to 2006/07. Death from opioids is nearly always due to respiratory arrest.5,6 Acute opioid use can reduce vital ventilatory chemoreflexes and cause severe hypoventilation. The immediate cause of death is often pulmonary oedema secondary to prolonged hypoventilation.

The sleep state is the most vulnerable time for patients using opioids. During sleep, respiration is naturally depressed and mainly under automatic neural-chemical control. Acute opioid use significantly reduces vital chemoreflexes, and patients have an increased risk of respiratory arrest during sleep. In addition, recent studies found that acute opioid use reduces upper airway patency during sleep. It is therefore not surprising that OSA is reported to be a major risk factor for postoperative morbidity and mortality.

There are only two clinically available classes of drugs that can potentially reduce the respiratory depressant effect of opioids without reducing the analgesic effects. One is 5HT4a receptor agonists. Animal studies indicate that this drug class can reverse opioid-related respiratory depression without affecting sedation. However, the only clinical study found that it did not antagonize morphine-induced respiratory depression. In addition, the drug class was reported to cause the long QT syndrome and has been not registrated for clinical use in many countries, such as USA.

In contrast, the tetracycline antibiotic Minocycline, a microglial inhibitor, is a commonly used antibiotic for many years particularly for acne. It is known to reduce opioid-induced glial activation which could enhance the analgesic effect of opioids and reduce the development of opioid tolerance. Dr Hutchinson from Prof Somogyi (AIB)’s laboratory found that in rats, Minocycline reversed morphine-induced respiratory depression while enhancing morphine-induced analgesia. However, the effect has not been tested in humans. If the findings can be verified in humans, the study may be a pivotal study in reducing the striking number of opioids-related deaths. The proposed double-blinded, cross-over study is a pilot study which may lead to a major NHMRC project grant application.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31946 0
Address 31946 0
Country 31946 0
Phone 31946 0
Fax 31946 0
Email 31946 0
Contact person for public queries
Name 15193 0
Dr David Wang
Address 15193 0
Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe, 2037, NSW
Country 15193 0
Australia
Phone 15193 0
+61 2 9114 0446
Fax 15193 0
+61 2 9114 0014
Email 15193 0
[email protected]
Contact person for scientific queries
Name 6121 0
Dr David Wang
Address 6121 0
Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe, 2037, NSW
Country 6121 0
Australia
Phone 6121 0
+61 2 9114 0446
Fax 6121 0
+61 2 9114 0014
Email 6121 0
[email protected]

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