Chronic Pain, Opioid Induced Constipation
Conditions
Keywords
pain, opioid, constipation, Subjects taking opioids for chronic non-cancer pain, who, experience symptoms of opioid induced constipation
Brief summary
For many patients taking opioids for pain relief one of the most distressing side effects is constipation. Naloxone is effective in the reversal of the effects of opioids and is used following opioid overdose. If naloxone is given by mouth it would relieve the effects of constipation but as it goes into the blood stream very quickly, it would also reverse the effects of the opioid and therefore stop the pain relief. The aim of this study is to examine a slow release formulation of naloxone to see if is can reduce constipation without reducing the pain relieving effects of the opioid.
Detailed description
Naloxone has been used for many years as an IV or IM injection for the reversal of opioid effects (following opioid overdose) and has been evaluated as an oral formulation to manage opioid-induced constipation. Immediate release oral naloxone preparations have however led to reversal of opioid effects and withdrawal. This has initiated the development of prolonged (slow release) naloxone preparations which prevent the systemic levels of naloxone reaching levels where the central opioid effects may be reversed. Naloxone has a high first pass metabolism (98%) and short half life (\ 1hr). The objectives of this trial are to identify the optimum dosage regime of Naloxone SR capsules based on tolerability level, to improve spontaneous bowel movement frequency, and relieve GI symptoms, in patients suffering with opioid induced constipation.
Interventions
DRUGNaloxone SR 5 mg capsules
DRUGPlacebo
DRUGNaloxone SR 10 mg capsules
DRUGNaloxone SR 20mg capsules
DRUGNaloxone SR 2.5 mg capsules
Sponsors
S.L.A. Pharma AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All subjects must give written informed consent * Male or female subjects greater than 18 years of age * Taking opioid full agonist therapy(oral or transdermal) for persistent non-cancer pain, for at least 4 weeks prior to baseline visit * Subjects with at least a 3 week history of OIC prior to baseline; where bowel dysfunction is predominantly due to opioids and started following commencement of opioid therapy * Subjects with \<3 SBMs a week and experiencing one or more bowel symptoms (incomplete evacuation, straining, hard/small pellets) for 25% or more of bowel movements during the screening period * Subjects must be willing to discontinue all current laxative (constipation) therapy. Bisacodyl will be provided and taken as required
Exclusion criteria
* Women of childbearing potential, unless surgically sterile or using adequate contraception (either IUD, oral or depot contraceptive, or barrier plus spermicide). Women using oral contraception must have started using it at least 2 months prior to enrolment * Women who are pregnant or breastfeeding * Symptoms suggestive of non-opioid related bowel dysfunction (e.g. IBS - intermittent constipation or diarrhoea) or have diarrhoea or loose stools in the 4 weeks prior to baseline * History of chronic constipation prior to commencing opioid therapy * Gastrointestinal disorders known to affect bowel transit, or contribute to bowel dysfunction (other than OIC) * Chronic faecal incontinence * Subjects who have a colostomy, ileostomy, or colectomy with ileorectal anastomosis * Subjects with a history of neoplastic disease within 5 years (except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin) * Subjects taking opioids for the management of drug addiction Subjects who do not meet any of the following criteria regarding baseline medications. Analgesia (including opioids and NSAIDs) should be stable throughout the trial. * Any baseline analgesia must have been administered at a stable dose for a minimum of 4 weeks. If non-opioid analgesia recently discontinued, must have stopped at least 4 weeks prior to baseline * Laxatives (outside that allowed by the protocol) are not permitted; these agents must have been discontinued at the screening visit. * Use of drugs known to affect gut transit time (other than opioids) are not permitted (see Section 6.9 for exceptions) * Use of mixed agonist/antagonist, or partial agonist opioids are not permitted (e.g. buprenorphine, pentazocine, cyclazocine, nalbuphine, nalorphine) * Experimental agents must have been discontinued at least 8 weeks prior to screening, or for a period equivalent to 5 half-lives (t½) of the agent (whichever is longer) * Subjects with a history of clinically significant and/or persistent disorder that, in the investigators opinion, may affect the clinical trial assessments * Subjects with any laboratory tests considered clinically significant at screening. * Subjects not ambulatory i.e. bedridden or require use of a commode * Subjects who will be unavailable for the duration of the trial, likely to be non-compliant with the protocol, or who are felt to be unsuitable by the Investigator for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 3 weeks | Incidence and severity of treatment emergent adverse events on single dosing. |
Countries
Germany, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Capsules With no Active Drug Placebo capsules once daily for three weeks then twice daily for three weeks.
Placebo : | 8 |
| Naloxone SR 10mg Capsules Naloxone SR 10 mg capsules once daily for three weeks then twice daily for three weeks.
Naloxone SR 10 mg capsules : | 8 |
| Naloxone SR 2.5 mg Capsules Naloxone SR 2.5 mg capsules once daily for three weeks then twice daily for three weeks.
Naloxone SR 2.5 mg capsules : | 8 |
| Naloxone SR 20 mg Capsules Two Naloxone SR 10 mg capsules once daily for three weeks then twice daily for three weeks.
Naloxone SR 20mg capsules : | 8 |
| Naloxone SR 5mg Capsules Naloxone SR 5 mg capsules once daily for three weeks then twice daily for three weeks.
Naloxone SR 5 mg capsules : | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Capsules With no Active Drug | Naloxone SR 10mg Capsules | Naloxone SR 2.5 mg Capsules | Naloxone SR 20 mg Capsules | Naloxone SR 5mg Capsules | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 7 Participants | 8 Participants | 7 Participants | 35 Participants |
| Age Continuous | 53.3 years STANDARD_DEVIATION 10.2 | 53.4 years STANDARD_DEVIATION 15.7 | 50.6 years STANDARD_DEVIATION 12.7 | 48.6 years STANDARD_DEVIATION 8.6 | 60.5 years STANDARD_DEVIATION 8.8 | 53.3 years STANDARD_DEVIATION 11.6 |
| Region of Enrollment Germany | 5 participants | 6 participants | 2 participants | 5 participants | 8 participants | 26 participants |
| Region of Enrollment United Kingdom | 3 participants | 2 participants | 6 participants | 3 participants | 0 participants | 14 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 4 Participants | 1 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 7 Participants | 3 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 5 / 8 | 5 / 8 | 6 / 8 | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 1 / 8 | 0 / 8 |
Outcome results
Primary
Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing.
Incidence and severity of treatment emergent adverse events on single dosing.
Time frame: 3 weeks
Population: Intent to treat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Capsules With no Active Drug | Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 8 participants |
| Naloxone SR 10mg Capsules | Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 5 participants |
| Naloxone SR 2.5 mg Capsules | Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 4 participants |
| Naloxone SR 20 mg Capsules | Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 6 participants |
| Naloxone SR 5mg Capsules | Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | 6 participants |