Constipation, Neoplasms, Opioid-Related Disorders
Conditions
Keywords
Methylnaltrexone, Constipation, Narcotic Antagonists, Analgesics, Opioid, Neoplasms
Brief summary
The purpose of this study is to evaluate the efficacy of methylnaltrexone in relieving opioid-induced constipation in cancer patients at various stages of disease.
Detailed description
Pain is one of the most common and important symptoms of cancer, often requiring opioid analgesics for control. However constipation is one of the most frequent and debilitating side effects of opioids, occurring in 40%-70% of patients being treated for chronic pain. Although laxatives are commonly used to manage opioid-induced constipation, these agents are not always effective or satisfactory. Methylnaltrexone bromide is a peripherally acting antagonist of the mu-opioid receptor. As a quaternary amine, the ability of methylnaltrexone to cross the blood-brain barrier is limited. This allows methylnaltrexone to function as a peripherally-acting antagonist in the gastrointestinal tract without impacting opioid-mediated analgesic effects in the central nervous system. The efficacy and safety of methylnaltrexone in treating opioid-induced constipation in patients with advanced disease receiving palliative care has been demonstrated. However the efficacy of this agent has not been evaluated in more active patients who are earlier in their disease course. The present study will evaluate the efficacy and safety of methylnaltrexone for the relief of severe opioid-induced constipation in this population and will attempt to identify factors predictive of methylnaltrexone response.
Interventions
Methylnaltrexone bromide, dosage based on weight (0.15 mg/kg (round dose up to nearest 0.1 mL of volume) for weight less than 38 kg or greater than 114 kg; 8 mg (0.4 mL) for weight 38 kg to less than 62 kg; and 12 mg (0.6 mL) for weight 62 kg to 114 kg), single dose
Sponsors
University of Vermont
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed neoplasm * 18 years of age or older * Have received opioids for analgesia for at least 2 weeks and been on a stable regimen of opioids and laxatives for 3 or more days before study entry * Fewer than three laxation during the preceding week and no laxation within 24 hours before study entry, or no laxation within 48 hours before study entry * Life expectancy of at least 6 months * World Health Organization Performance Status 0-3 * Women of childbearing potential must have a negative pregnancy test * Breastfeeding should be discontinued prior to study entry * Ability to understand and the willingness to sign a written informed consent document. * Laboratory values within a week of study entry: Absolute neutrophil count \> 1,500/microliter Hemoglobin \> 7 g/dL Platelet count \> 100,000/microliter Calculated calcium \< 10.5 mg/dL Calculated creatinine clearance \> 30 mg.min Alanine aminotransferase \< 3 x upper limit of normal (ULN) Aspartate aminotransferase \< 3 x ULN Alkaline phosphatase \< 2.5 x ULN Bilirubin \< 1.5 x ULN
Exclusion criteria
* Constipation not primarily caused by opioids, such as mechanical gastrointestinal obstruction or ongoing vinca alkaloid administration * Indwelling peritoneal catheter * Clinically active diverticular disease * Fecal impaction * Acute surgical abdomen * Fecal ostomy * Peritoneal carcinomatosis * Known hypersensitivity to methylnaltrexone, naltrexone, or naloxone * Administration of any investigational drug or experimental product within the previous 30 days * Initiation of a new bowel regimen or prokinetic agents within a week of study entry
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Rescue-free Laxation After Administration of Subcutaneous Methylnaltrexone | 4 hours after the dose of subcutaneous methylnaltrexone |
Secondary
| Measure | Time frame |
|---|---|
| Time to Laxation After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
| Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
| Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
| Laxation After Administration of Subcutaneous Methylnaltrexone | 24 and 48 hours after the dose of subcutaneous methylnaltrexone |
| Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
| Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
| Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | 48 hours after the dose of subcutaneous methylnaltrexone |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methylnaltrexone Methylnaltrexone bromide: Methylnaltrexone bromide, dosage based on weight (0.15 mg/kg (round dose up to nearest 0.1 mL of volume) for weight less than 38 kg or greater than 114 kg; 8 mg (0.4 mL) for weight 38 kg to less than 62 kg; and 12 mg (0.6 mL) for weight 62 kg to 114 kg), single dose | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Methylnaltrexone |
|---|---|
| Age, Continuous | 52 years |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Rescue-free Laxation After Administration of Subcutaneous Methylnaltrexone
Time frame: 4 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylnaltrexone | Rescue-free Laxation After Administration of Subcutaneous Methylnaltrexone | 33 percentage of participants |
Secondary
Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Frequency of ≥ 1 laxation (0-4 hours) (n=12) | 33 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Frequency of ≥ 1 laxation (4-24 hours) (n=12) | 42 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Frequency of ≥ 1 laxation (24-48 hours) (n=11) | 73 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Consistency (slight-very hard) (0-4 hours) (n=12) | 8 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Consistency (slight-very hard) (4-24 hours) (n=12) | 8 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Consistency (slight-very hard)(24-48 hours) (n=11) | 9 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Difficulty (severe-very severe) (0-4 hours) (n=12) | 42 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Difficulty (severe-very severe)(4-24 hours) (n=12) | 42 percentage of participants |
| Methylnaltrexone | Bowel Movement Assessment (Frequency, Consistency and Difficulty) After Administration of Subcutaneous Methylnaltrexone | Difficulty (severe-very severe)(24-48hours) (n=11) | 18 percentage of participants |
Secondary
Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Severity (severe-very severe) (0-4 hours) (n=12) | 42 percentage of participants |
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Severity (severe-very severe) (4-24 hours) (n=12) | 50 percentage of participants |
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Severity (severe-very severe) (24-48 hours) (n=11) | 27 percentage of participants |
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Distress (severe-very severe) (0-4 hours) (n=12) | 25 percentage of participants |
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Distress (severe-very severe) (4-24 hours) (n=12) | 25 percentage of participants |
| Methylnaltrexone | Constipation Assessment (Severity and Distress) After Administration of Subcutaneous Methylnaltrexone | Distress (severe-very severe) (24-48 hours) (n=11) | 0 percentage of participants |
Secondary
Laxation After Administration of Subcutaneous Methylnaltrexone
Time frame: 24 and 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methylnaltrexone | Laxation After Administration of Subcutaneous Methylnaltrexone | Rescue-free Laxation within 24 hours (n=12) | 42 percentage of participants |
| Methylnaltrexone | Laxation After Administration of Subcutaneous Methylnaltrexone | Laxation within 48 hours (n=12) | 83 percentage of participants |
Secondary
Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylnaltrexone | Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone | Average pain (0-4 hours) (n=12) | 2.9 units on a scale | Standard Deviation 2.7 |
| Methylnaltrexone | Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone | Average pain (4-24 hours) (n=12) | 2.4 units on a scale | Standard Deviation 3 |
| Methylnaltrexone | Overall Pain Scores (0-10; 0=no Pain, 10=Worst Pain) After Administration of Subcutaneous Methylnaltrexone | Average pain (24-48 hours) (n=12) | 2.3 units on a scale | Standard Deviation 3.1 |
Secondary
Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methylnaltrexone | Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone | Satisfied-very satisfied (0-4 hours) (n=12) | 33 percentage of participants |
| Methylnaltrexone | Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone | Satisfied-very satisfied (4-24 hours) (n=12) | 58 percentage of participants |
| Methylnaltrexone | Patient Satisfaction With the Study Medication After Administration of Subcutaneous Methylnaltrexone | Satisfied-very satisfied (24-48 hours) (n=11) | 64 percentage of participants |
p-value: 0.161ANOVA
Secondary
Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylnaltrexone | Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone | 0-4 hours (n=12) | 8.8 units on a scale | Standard Deviation 1.1 |
| Methylnaltrexone | Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone | 4-24 hours (n=12) | 9.2 units on a scale | Standard Deviation 2.2 |
| Methylnaltrexone | Symptoms of Opioid Withdrawal (Modified Himmelsbach Withdrawal Scales (Ranging 7-28 in Total; 1=None - 4=Severe for 7 Items)) After Administration of Subcutaneous Methylnaltrexone | 24-48 hours (n=11) | 8.8 units on a scale | Standard Deviation 1.8 |
Secondary
Time to Laxation After Administration of Subcutaneous Methylnaltrexone
Time frame: 48 hours after the dose of subcutaneous methylnaltrexone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylnaltrexone | Time to Laxation After Administration of Subcutaneous Methylnaltrexone | Mean time to laxation ≤48 hours (n=11) | 20 hours | Standard Error 0.087 |
| Methylnaltrexone | Time to Laxation After Administration of Subcutaneous Methylnaltrexone | Mean time to rescue-free laxation ≤4 hours (n=11) | 3.3 hours | Standard Error 0.134 |
| Methylnaltrexone | Time to Laxation After Administration of Subcutaneous Methylnaltrexone | Mean time to rescue-free laxation ≤24 hours (n=11) | 16 hours | Standard Error 0.155 |