ANZCTR - Registration

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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]

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

Condition category

Condition code

Respiratory

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]

Prevention

Intervention code [2]

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]

SpO2 (Oxygen Saturation) nadir during sleep

Timepoint [1]

at two cross-over polysomnography (PSG) nights and at screening (baseline) PSG night

Primary outcome [2]

%Total sleep time SpO2 <90% during sleep. The parameter is part of the PSG measurement.

Timepoint [2]

at two cross-over PSG nights and at screening (baseline) PSG night

Primary outcome [3]

Central chemosensitivity tested by ventilatory chemoreflex tesing system

Timepoint [3]

at two cross-over PSG evenings during awake and at screening (baseline) examination

Secondary outcome [1]

Oxygen desaturation index (ODI) as part of PSG assessment

Timepoint [1]

at two cross-over PSG nights and at screening (baseline) PSG night

Secondary outcome [2]

CO2 recruitment threshold tested by chemoreflex testing system

Timepoint [2]

at two cross-over PSG evenings during awake and at screening (baseline) examination

Secondary outcome [3]

Pain threshold (Mechanical Detection Threshold) tested by Von Frey Hair

Timepoint [3]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

University

Name [1]

Sydney Medical School New Staff Awards

Address [1]

Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe. NSW 2037

Country [1]

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]

Hospital

Name [1]

RPAH

Address [1]

Missenden Rd, Camperdown 2050 NSW

Country [1]

Australia

Other collaborator category [1]

University

Name [1]

University of Adelaide

Address [1]

Discipline of Pharmacology
Faculty of Health Sciences
The University of Adelaide
Adelaide 5005 SA

Country [1]

Australia

Other collaborator category [2]

Other Collaborative groups

Name [2]

Pain Management Research Institute

Address [2]

Royal North Shore Hospital, St Leonards NSW 2065

Country [2]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health Service

Ethics committee address [1]

Research Development Office
Level 3, Building 92 
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

12/09/2010

Approval date [1]

28/10/2010

Ethics approval number [1]

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

Address

Country

Phone

Fax

Contact person for public queries

Name

Dr David Wang

Address

Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe, 2037, NSW

Country

Australia

Phone

+61 2 9114 0446

Fax

+61 2 9114 0014

david.wang@sydney.edu.au

Contact person for scientific queries

Name

Dr David Wang

Address

Woolcock Institute of Medical Research
431 Glebe Point Rd, Glebe, 2037, NSW

Country

Australia

Phone

+61 2 9114 0446

Fax

+61 2 9114 0014

david.wang@sydney.edu.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

Current supporting documents:

Updated to:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
New Record*	Clinical study report	Wang D†, Somogyi AA, Yee BJ, Wong KK, Kaur J, Wrigley PJ, Grunstein RR. The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea. Resp Physio Neuro 2013; 185:526-532.				336268-(Uploaded-12-08-2024-09-24-28)-David-Resp-Physio-Neuro-2013.pdf

Results publications and other study-related documents

Documents added manually

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Documents added automatically

No additional documents have been identified.

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