ConstipationPhase 2NCT02137213
Feasibility Study of Oral Naloxone for Treatment of Methadone-induced Constipation
A Phase 2 study testing Naloxone in people with Constipation, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial summary
At least 30% of patients receiving methadone maintenance therapy (MMT) are suffering from constipation that often affects effectiveness of MMT and increases its impact on health care system. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Constipation
- What is being tested?
- Naloxone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- Aug 2014to Mar 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years of age or older
- must be a registered CAMH methadone maintenance program client
- must be in a maintenance stage of MMT program (at least 6 weeks in MMT)
- stable methadone dose taken once daily (no methadone dose change in the past 4 weeks)
- methadone dose between 20 mg and 140 mg/day (normal range of methadone doses prescribed in CAMH opioid dependence clinic)
- Bowel Functioning Index score ≥ 30 (reference range for non-constipated patients is 0-28.8)
- less than 3 bowel movements in the week prior to initiation
Who cannot join
- patients prescribed opioids other than methadone
- patients who use opioids recreationally
- patients prescribed methadone for pain management
- patients receiving methadone in split doses
- pregnancy
- allergy or sensitivity to naloxone
- current gastrointestinal disorder (chronic colitis, Crohn disease etc.)
- taking medications with known strong anticholinergic effects (e.g. amitryptiline)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Oral Naloxone for Treatment of Opioid-induced Constipation in Patients Receiving Methadone Maintenance Treatment
At least 30% of patients receiving methadone maintenance therapy (MMT) are suffering from constipation that often affects effectiveness of MMT and increases its impact on health care system. Existing treatments include several over-the-counter medications which do not target the pathobiological basis of opioid-induced constipation and have limited effectiveness. At the same time well-known medication, naloxone, was already shown to help with constipation in patients receiving methadone for chronic pain, but was never tried in patients receiving methadone for opioid dependence. This study is aimed to try naloxone for treatment of opioid-induced constipation in MMT settings.
The investigators will enroll 20 patients receiving MMT and suffering from opioid-induced constipation. The study has a crossover design - all patients will receive one week of their regular methadone doses and one week of their regular methadone doses with naloxone added. Normal saline will be added to methadone-only formulations as placebo. Order of the weeks will be chosen randomly. Both subjects and investigators will be blinded to the study condition (i.e. whether naloxone or normal saline is added to methadone preparation on a given week).
Read more
Primary hypothesis: Patients receiving combination of oral methadone/naloxone in ratio 50:1 will have less severe symptoms of constipation compared to those receiving methadone only.
Secondary hypothesis: Addition of oral naloxone to methadone in a ratio 50:1 will not cause clinically significant opioid withdrawal symptoms.
Read the detailed description
Background and rationale Opioid-induced constipation is the most common side effect of opioid therapy - depending on the settings up to 90% of patients taking opioids experience constipation with the most conservative estimate among MMT patients being 30%. Currently, the recommended treatment for opioid-induced constipation includes a combination of stool softeners, stimulants and osmotic laxatives - increased gastrointestinal secretions result in increased volume and softness of fecal masses, and more intense peristalsis promotes bowel voiding. The effectiveness of existing treatments for opioid-induced constipation is limited - they are effective in approximately 50% of cases, often have side effects such as abdominal cramping and diarrhea and, most importantly, do not address the pathobiological basis of opioid-induced constipation. Opioids in general and methadone in particular act on peripheral opioid receptors located in myenteric and submucosal plexus and cause relaxation of longitudinal and increased tone of inner circular smooth muscles as well as decreased gastrointestinal secretions that in turn result in constipation. The most logical therapeutic approach to the treatment of opioid-induced constipation in MMT would be using opioids that cause selective local reversal of μ-opioid activation with a peripherally-acting opioid antagonist such as naloxone, which when administered orally does not have systemic effects due to extremely low oral bioavailability.
Objectives The primary objective is to evaluate the effectiveness of a combination of methadone and naloxone in 50:1 for treatment of opioid-induced constipation in MMT patients. The secondary objective of the study is to assess the likelihood of development of opioid withdrawal symptoms in MMT patients who receive combination of methadone and naloxone compared to those who receive methadone only.
Design Study has a double-blind placebo-controlled crossover design: following signing informed consent and initial assessment 20 subjects who meet eligibility criteria will be randomized into one of two groups: group A will receive combination of methadone and naloxone in a ratio of 50:1 shown to be safe and effective in other trials during week 1 of the study and methadone only during week 2 of the study. Group B will receive methadone only during week 1 of the study and combination of methadone and naloxone in a ratio of 50:1 during week 2 of the study. Thus, all participants will receive combination of methadone and naloxone for one week and methadone alone for one week. Neither study participants, nor the pharmacists observing the doses, nor study personnel will know if naloxone is added to subjects' methadone preparations. Allocation to Group A or Group B will be done by random assignment. The pharmacy research medication management service will prepare the randomization code such that there will be a balanced assignment after every 4 subjects. Bowel functioning will be assessed quantitatively primarily using the Bowel Function Index (BFI) at initial assessment and at the end of weeks one (day 8) and two of the study (day 15). Also data on the number of complete spontaneous bowel movements (CSBMs), their temporal relationship to medication administration and outcome will be collected every day prior to administration of the next dose of methadone. In addition to parameters of bowel functioning Subjective Opiate Withdrawal Scale (SOWS) will be administered daily in order to assess potential opioid withdrawal symptoms.
Statistical Methods/Data Analysis Primary endpoint of the study is the reduction of constipation symptoms severity as measured by the difference between BFI scores taken after one week of receiving combination of methadone and naloxone and after one week of receiving methadone only. Secondary endpoint of the study is the occurrence of opioid withdrawal symptoms as measured by the difference between the mean SOWS scores taken daily during each of two weeks of the study. Paired t-test will be used to compare BFI and mean number of CSBMs between the weeks of treatment with a combination of methadone and naloxone and methadone alone as well as to compare average SOWS scores between the weeks of treatment with a combination of methadone and naloxone and methadone alone.
- Conditions
- Constipation
- Being tested
- Naloxone, Placebo
- Keywords
- Opioid-induced constipation, Methadone, Naloxone
- Medical subject headings
- Constipation, Opioid-Induced Constipation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NaloxoneDrug
Also called Naloxone hydrochloride solution for injections 0.4 mg/ml
Naloxone will be added to oral methadone preparation in methadone:naloxone ratio of 50:1
PlaceboDrug
Also called Bacteriostatic normal saline
Normal saline will be added to oral methadone preparations as placebo.
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Naloxone then placebo | Experimental | Subjects assigned to Arm A will receive methadone with naloxone for one week and then methadone with placebo for one week Receives: Drug: Naloxone; Drug: Placebo |
| Arm B: Placebo then naloxone | Experimental | Subjects assigned to Arm B will receive methadone with placebo for one week and then methadone with naloxone for one week Receives: Drug: Naloxone; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Severity of constipation symptoms
Severity of constipation symptoms will be measured after one week of receiving methadone with naloxone and after one week of receiving methadone alone in both arms of the study.
Measured: One week
Secondary outcomes (1)
Severity of opioid withdrawal symptoms
The severity of opioid withdrawal symptoms will be assessed using Subjective Opioid Withdrawal Scale (SOWS) over the course of the study (2 weeks for each participant)
Measured: Two weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 May 2014 (estimated)
- Study startAug 2014
- Primary completionMar 2015
- Study completionMar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for ConstipationStudies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Collaborators
- Academic Health Science Centres
- Responsible party
- Principal investigator, Andriy V. Samokhvalov, MD, PhD, Centre for Addiction and Mental Health
- Investigators
- Andriy V Samokhvalov, MD, PhD, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02137213
- Sponsor's protocol ID
- 083/2013
- Status last verified
- Jun 2015
- First submitted
- 12 May 2014
- Last updated
- 24 Jun 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oral Naloxone for Treatment of Opioid-induced Constipation in Patients Receiving Methadone Maintenance Treatment
- ClinicalTrials.gov ID
- NCT02137213
- Acronym / sponsor ID
- 083/2013
- Conditions
- Constipation
- Keywords
- Opioid-induced constipation, Methadone, Naloxone
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Collaborators
- Academic Health Science Centres
- Study start
- Aug 2014
- Primary completion
- Mar 2015 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 13 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
At least 30% of patients receiving methadone maintenance therapy (MMT) are suffering from constipation that often affects effectiveness of MMT and increases its impact on health care system. Existing treatments include several over-the-counter medications which do not target the pathobiological basis of opioid-induced constipation and have limited effectiveness. At the same time well-known medication, naloxone, was already shown to help with constipation in patients receiving methadone for chronic pain, but was never tried in patients receiving methadone for opioid dependence. This study is aimed to try naloxone for treatment of opioid-induced constipation in MMT settings.
The investigators will enroll 20 patients receiving MMT and suffering from opioid-induced constipation. The study has a crossover design - all patients will receive one week of their regular methadone doses and one week of their regular methadone doses with naloxone added. Normal saline will be added to methadone-only formulations as placebo. Order of the weeks will be chosen randomly. Both subjects and investigators will be blinded to the study condition (i.e. whether naloxone or normal saline is added to methadone preparation on a given week).
Primary hypothesis: Patients receiving combination of oral methadone/naloxone in ratio 50:1 will have less severe symptoms of constipation compared to those receiving methadone only.
Secondary hypothesis: Addition of oral naloxone to methadone in a ratio 50:1 will not cause clinically significant opioid withdrawal symptoms.
Detailed description
Background and rationale Opioid-induced constipation is the most common side effect of opioid therapy - depending on the settings up to 90% of patients taking opioids experience constipation with the most conservative estimate among MMT patients being 30%. Currently, the recommended treatment for opioid-induced constipation includes a combination of stool softeners, stimulants and osmotic laxatives - increased gastrointestinal secretions result in increased volume and softness of fecal masses, and more intense peristalsis promotes bowel voiding. The effectiveness of existing treatments for opioid-induced constipation is limited - they are effective in approximately 50% of cases, often have side effects such as abdominal cramping and diarrhea and, most importantly, do not address the pathobiological basis of opioid-induced constipation. Opioids in general and methadone in particular act on peripheral opioid receptors located in myenteric and submucosal plexus and cause relaxation of longitudinal and increased tone of inner circular smooth muscles as well as decreased gastrointestinal secretions that in turn result in constipation. The most logical therapeutic approach to the treatment of opioid-induced constipation in MMT would be using opioids that cause selective local reversal of μ-opioid activation with a peripherally-acting opioid antagonist such as naloxone, which when administered orally does not have systemic effects due to extremely low oral bioavailability.
Objectives The primary objective is to evaluate the effectiveness of a combination of methadone and naloxone in 50:1 for treatment of opioid-induced constipation in MMT patients. The secondary objective of the study is to assess the likelihood of development of opioid withdrawal symptoms in MMT patients who receive combination of methadone and naloxone compared to those who receive methadone only.
Design Study has a double-blind placebo-controlled crossover design: following signing informed consent and initial assessment 20 subjects who meet eligibility criteria will be randomized into one of two groups: group A will receive combination of methadone and naloxone in a ratio of 50:1 shown to be safe and effective in other trials during week 1 of the study and methadone only during week 2 of the study. Group B will receive methadone only during week 1 of the study and combination of methadone and naloxone in a ratio of 50:1 during week 2 of the study. Thus, all participants will receive combination of methadone and naloxone for one week and methadone alone for one week. Neither study participants, nor the pharmacists observing the doses, nor study personnel will know if naloxone is added to subjects' methadone preparations. Allocation to Group A or Group B will be done by random assignment. The pharmacy research medication management service will prepare the randomization code such that there will be a balanced assignment after every 4 subjects. Bowel functioning will be assessed quantitatively primarily using the Bowel Function Index (BFI) at initial assessment and at the end of weeks one (day 8) and two of the study (day 15). Also data on the number of complete spontaneous bowel movements (CSBMs), their temporal relationship to medication administration and outcome will be collected every day prior to administration of the next dose of methadone. In addition to parameters of bowel functioning Subjective Opiate Withdrawal Scale (SOWS) will be administered daily in order to assess potential opioid withdrawal symptoms.
Statistical Methods/Data Analysis Primary endpoint of the study is the reduction of constipation symptoms severity as measured by the difference between BFI scores taken after one week of receiving combination of methadone and naloxone and after one week of receiving methadone only. Secondary endpoint of the study is the occurrence of opioid withdrawal symptoms as measured by the difference between the mean SOWS scores taken daily during each of two weeks of the study. Paired t-test will be used to compare BFI and mean number of CSBMs between the weeks of treatment with a combination of methadone and naloxone and methadone alone as well as to compare average SOWS scores between the weeks of treatment with a combination of methadone and naloxone and methadone alone.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A: Naloxone then placebo | Experimental | Drug: Naloxone, Drug: PlaceboSubjects assigned to Arm A will receive methadone with naloxone for one week and then methadone with placebo for one week |
| Arm B: Placebo then naloxone | Experimental | Drug: Naloxone, Drug: PlaceboSubjects assigned to Arm B will receive methadone with placebo for one week and then methadone with naloxone for one week |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 18 years of age or older
- must be a registered CAMH methadone maintenance program client
- must be in a maintenance stage of MMT program (at least 6 weeks in MMT)
- stable methadone dose taken once daily (no methadone dose change in the past 4 weeks)
- methadone dose between 20 mg and 140 mg/day (normal range of methadone doses prescribed in CAMH opioid dependence clinic)
Key exclusion criteria (8 listed)
- patients prescribed opioids other than methadone
- patients who use opioids recreationally
- patients prescribed methadone for pain management
- patients receiving methadone in split doses
- pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NaloxoneAlso: Naloxone hydrochloride solution for injections 0.4 mg/mlNaloxone will be added to oral methadone preparation in methadone:naloxone ratio of 50:1 | Drug | Arm A: Naloxone then placebo, Arm B: Placebo then naloxone |
| PlaceboAlso: Bacteriostatic normal salineNormal saline will be added to oral methadone preparations as placebo. | Drug | Arm A: Naloxone then placebo, Arm B: Placebo then naloxone |
Primary outcome
Severity of constipation symptoms
Time frame: One week
Severity of constipation symptoms will be measured after one week of receiving methadone with naloxone and after one week of receiving methadone alone in both arms of the study.
1 secondary outcome
Severity of opioid withdrawal symptoms
Time frame: Two weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2015.
- Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching hospital, fully affiliated with the University of Toronto, and a PAHO/WHO Collaborating Centre.Link provided by the sponsor.
Related trials for Constipation
Recruiting
Effects of a Prebiotic-Probiotic Combination on Constipation Symptoms and Quality of Life
Constipation, Abdominal Pain
RecruitingPhase 2
A Study of Brenipatide (LY3537031) in Participants With Irritable Bowel Syndrome-Constipation (IBS-C)
Irritable Bowel Syndrome, Constipation
Recruiting
Outcome Research in Bowel Irrigation Techniques for the Treatment of Chronic Constipation and/or Faecal Incontinence
Faecal Incontinence, Chronic Constipation
Active, not recruitingPhase 2
This is a Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study of the Efficacy and Safety of 2 Weight-based Treatment Groups of Plecanatide Versus Placebo in Children and Adolescent Participants 6 to Less Than 18 Years of Age With FC
Functional Constipation (FC)
Not yet recruiting
Acupuncture Combined With Transcutaneous Electrical Acupoint Stimulation for Constipation-Predominant Irritable Bowel Syndrome With Anxiety State
IBS, Constipation Predominant, Anxiety State
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andriy V Samokhvalov, MD, PhD principal investigator
Centre for Addiction and Mental Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Naloxone in people with Constipation, run by Centre for Addiction and Mental Health at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Severity of constipation symptoms (time frame: One week). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2015.