None listed
Conditions
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.
Interventions
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 minocyc
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).
Sponsors
NHMRC Training Fellowship
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Prevention
Masking
Blinded (masking used)
Eligibility
Sex/Gender
Male
Age
18 Years to 60 Years
Healthy volunteers
No
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%.
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.
Outcome results
None listed