Opiate dependence Not Applicable
Conditions
Interventions
Participants will be randomised in a 3:1 ratio to baclofen or placebo. Participants allocated to baclofen will be dosed in groups of up to 3, with a maximum available sample size of 64 (up to 48 on ba
Sponsors
Imperial College London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female 2. Aged over 21 years 3. Willing and able to comply with protocol 4. Able to read, comprehend and record information written in English 5. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 6. Healthy as determined by a responsible physician, based on a medical evaluation which includes medical history, a physical examination, laboratory tests (if required), and a psychiatric evaluation. A volunteer with clinical parameters outside the reference range for the population being studied may be included, only if the investigators concur that the finding is unlikely to jeopardize either subject safety or study integrity. 7. DSM-5 diagnosis of current severe opioid use disorder 8. Treated with methadone substitution therapy and able to maintain the same stable dose for screening and experimental visit. 9. Ability to receive an acute dose of up to 90mg baclofen or up to 4800IU vitamin D (placebo).
Exclusion criteria
Exclusion criteria: 1. Intoxication on any of the visits, as assessed by difficulty in walking, the slurring of speech, difficulty concentrating or drowsiness. This exclusion criteria would exclude a subject from that study day only and not the whole study, at the discretion of the research team. 2. Positive urine drug screens or breath alcohol at screening or experimental testing visits. A minimum list of drugs that will be screened for include amphetamines, cocaine, opiates, methadone, cannabinoids and benzodiazepines. Positive results for methadone will be allowed for those opiate dependent participants still undergoing OST. Positive results for cannabinoids will be allowed given the long half-life of cannabinoid metabolites. This exclusion criteria would exclude a subject from that study day only and not the whole study, at the discretion of the research team. 3. Current DSM-5 substance dependence disorder for any other substance except for opiates and nicotine. Lifetime history of dependence on other substances will be allowed given very high incidence of co-dependence. 4. Regular on-top use of heroin or other opiates or other illicit substances in combination with OST, which in the opinion of the investigators will interfere with subject safety or study integrity. 5. Any participant taking over 120mg/day of prescribed methadone. 6. Current severe DSM-5 mental health disorder (excluding opiate dependence). Current moderate or mild DSM-5 depressive, anxiety, sleep or personality disorders will be allowed given the high levels of comorbidity, provided in the opinion of the investigators, the participant is able to complete study procedures satisfactorily.. 7. Current or past history of enduring severe mental illness e.g. psychotic disorder (excluding drug induced), schizophrenia, bipolar affective disorder). 8. Active suicidality. 9. Use of regular prescription medications which in the opinion of the investigators will interfere with subject safety or study integrity. Regular use of psychotropic medication will be permitted e.g. antidepressants, provided the participant is compliant with administration and the investigators concur that they will not interfere with subject safety or study integrity. 10. Participants are taking any medication that is contraindicated with baclofen or placebo (vitamin D3), or are hypersensitive to them or any of their excipients. 11. Participants that are taking any medication that in the opinion of the investigators may impact on the outcome measures during the experimental session. 12. Use of intermittent psychotropic medication which in the opinion of the investigators will interfere with subject safety or study integrity. 13. End stage or acute renal failure. 14. Severe chronic obstructive pulmonary disease (COPD) or Type 2 respiratory failure. 15. Pulse rate 100 BPM OR systolic blood pressure >160 and 95 and 500 msec or an ECG that is not suitable for QT measurements (e.g. poorly defined termination of the T-wave) and/or with another ECG abnormality which in the opinion of the study physician is cli
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The maximum safe dose of baclofen at which 15-25% of evaluable participants experience a dose limiting toxicity (DLT) for prescribed doses of methadone, where a DLT is comprised of the following components: 1. Intervention level (0 to 4) 2. National Early Warning Score (NEWS2), measured at discrete time-points 3. Glasgow Coma Scale (GCS) score, measured at discrete time-points 4. QTc on ECG trace, measured at discrete time-points 5. Measures of respiratory function, measured continuously at discrete time-points 5.1. Oxygen saturation (SPO2) 5.2. Respiratory (ventilation) rate 5.3. Incidence of apnoea. Dose Limiting Toxicity (DLT) is defined as: 1. Situation requiring intervention level =4 at any time 2. NEWS2 score >4 or score of 3 in any parameter (threshold for trigger of urgent ward-based response) 3. Measures of respiration with a persistent change in at least one of: 3.1. Reduction in SPO2 [=91% for more than 30 seconds or >5% reduction in SpO2 for more than 30 seconds 3.2. Reduced respiratory rate (=8/min) 3.3. Absence of inspiratory airflow for >30s combined with a sustained fall in SpO2 4. GCS score 500ms or increase of >60ms; if the initial QTc value at any time-point is prolonged, the ECG should be repeated two more times- with 5 minutes between ECG readings- and the average of the 3 QTc values used to determine DLT). | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Respiratory measures: These will be investigated at each baclofen dose level, for signs of sub-threshold respiratory depression. 1.1. SpO2- instances of 5% reduction for more than 10 seconds 1.2. CO2- instances of ETCO2% per breath exceeding 6.5% (Jolley et al., 2015) or a partial pressure CO2 increase by 1kPa (advice from respiratory physician) 1.3. Respiratory rate- instances of absence of inspiratory airflow for more than 10 seconds or respiratory rate drops <9/min 1.4. Time course of SpO2, CO2 and respiratory rate following baclofen dosing, relative to placebo. 2. Sedation measures: 2.1. T-SHAS score (total score on Subjective High Assessment Scale) 2.1.1. Mean Total-SHAS score at peak PD response (2-3h) at each baclofen dose level, relative to placebo 2.1.2. Time-course of T-SHAS at each baclofen dose level, relative to placebo 3. Symptom measures: 3.1. Drug Effects Questionnaire (DEQ) 3.1.1. Mean ‘Drug liking’ and ‘want more’ scores at peak PD response (2-3h) at each baclofen dose level, relative to placebo 3.1.2. Time-course of DEQ scale at each baclofen dose level, relative to placebo | — |
Countries
England, United Kingdom
Outcome results
None listed