Effects of 2 Mu-opiates on Gastrointestinal Transit
Conditions
Keywords
tapentadol, oxycodone, mu-opiate, stomach, small intestine, colon, motility, nausea, constipation
Brief summary
Tapentadol is FDA approved for the treatment of moderate to severe acute pain. Due to the dual mechanism of action as an opioid agonist and norepinephrine reuptake inhibitor, there is potential for off label use in chronic pain. Tapentadol is a new molecular entity that is structurally similar to tramadol. Tapentadol is a centrally-acting analgesic with a dual mode of action as an agonist at the mu-opioid receptor and as a norepinephrine reuptake inhibitor. These two actions are synergistic in pain relief. While its action reflects aspects of tramadol and morphine, its ability to control pain is more on the order of hydrocodone and oxycodone. Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and meperidine with a more tolerable side effect profile. Clinical studies showed that tapentadol effectively relieves moderate to severe pain in various pain care settings. In addition, it was reported to be associated with significantly fewer treatment discontinuations due to a significantly lower incidence of gastrointestinal-related adverse events compared with equivalent doses of oxycodone. The combination of these reduced treatment discontinuation rates and tapentadol efficacy for the relief of moderate to severe nociceptive and neuropathic pain may offer an improvement in pain therapy by increasing patient compliance with their treatment regimen.
Detailed description
Single center, parallel group, randomized controlled trial of tapentadol, oxycodone and placebo effects on gastrointestinal and colonic transit in healthy human volunteers
Interventions
DRUGTapentadol
Subjects received tapentadol immediate release formulation, 75 mg three times per day (tid) for 48 hours.
DRUGOxycodone
Subjects received oxycodone immediate release formulation, 5 mg three times per day (tid) for 48 hours.
DRUGPlacebo
Subjects received placebo three times per day (tid) for 48 hours.
Sponsors
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy volunteers Inclusion criteria 1. Males and non-pregnant, non-breastfeeding females 2. 18-65 years old
Exclusion criteria
1. Use of any mu-opioid agent in the last 3 months 2. Structural or metabolic diseases/conditions that affect the gastrointestinal system, or functional gastrointestinal disorders. For screening the shortened screening version of the Bowel Disease Questionnaire (Appendix) will be used to exclude subjects with dyspepsia, irritable bowel syndrome or significant gastrointestinal symptoms. Of 19 questions, participants have to have three or less positives to be eligible to participate. 3. Unable to withdraw medications 48 hours prior to the study : * Alter GI transit including laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and newer antidepressants. * Analgesic drugs including opiates, nonsteroidal anti-inflammatory drugs (NSAIDs), COX 2 inhibitors * SSRI NOTE: Low stable doses of thyroid replacement, estrogen replacement, low dose aspirin for cardioprotection and birth control pills or depot injections are permissible. 4. Female subjects who are pregnant or breast feeding. 5. Clinical evidence (including physical exam, ECG, hemoglobin level and review of the medical history) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study. 6. Subjects who are considered by the investigator to be alcoholics not in remission or known substance abusers. 7. Subjects who have participated in another clinical study within the past 30 days 8. History of porphyria, renal (creatinine \> 1.5mg/dL) or significant liver impairment (transaminases, alkaline phosphatase of gamma-glutamyl transpeptidase (GGT) \>2 times upper limit of normal)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Transit, Geometric Center at 24 Hours | 24 hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
| Gastric Emptying Half-time (t1/2) at 24 Hours | 24 hours | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Geometric Center at 8 and 48 Hours | 8 hours, 48 hours | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
| Colonic Filling at 6 Hours | 6 hours | Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time. |
| Ascending Colon Emptying (AC t1/2) | Over the first 24 hours after ingestion of the radioisotopically labeled charcoal particles | Ascending colon emptying t1/2 will be estimated by power exponential analysis of the proportionate emptying over time of counts from the colon. The primary data for this analysis will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly scans on the first day of transit measurement and the 24 hour data. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tapentadol 75 mg tapentadol tid | 13 |
| Oxycodone 5 mg oxycodone tid | 12 |
| Placebo Placebo tid | 13 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 2 | 0 |
Baseline characteristics
| Characteristic | Tapentadol | Oxycodone | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 34.99 years STANDARD_DEVIATION 7.82 | 33.26 years STANDARD_DEVIATION 12.94 | 39.48 years STANDARD_DEVIATION 12 | 35.98 years STANDARD_DEVIATION 11.11 |
| Body Mass Index (BMI) | 26.27 kg/m^2 STANDARD_DEVIATION 4.88 | 27.36 kg/m^2 STANDARD_DEVIATION 6.11 | 25.16 kg/m^2 STANDARD_DEVIATION 4.88 | 26.23 kg/m^2 STANDARD_DEVIATION 5.23 |
| Region of Enrollment United States | 13 participants | 12 participants | 13 participants | 38 participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 10 Participants | 28 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 13 | 4 / 12 | 1 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 | 0 / 13 |
Outcome results
Primary
Colonic Transit, Geometric Center at 24 Hours
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Colonic Transit, Geometric Center at 24 Hours | 2.06 units on a scale | Standard Deviation 0.67 |
| Oxycodone | Colonic Transit, Geometric Center at 24 Hours | 2.07 units on a scale | Standard Deviation 0.6 |
| Placebo | Colonic Transit, Geometric Center at 24 Hours | 2.17 units on a scale | Standard Deviation 0.739 |
Primary
Gastric Emptying Half-time (t1/2) at 24 Hours
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Gastric Emptying Half-time (t1/2) at 24 Hours | 159.2 minutes | Standard Deviation 46.45 |
| Oxycodone | Gastric Emptying Half-time (t1/2) at 24 Hours | 155.2 minutes | Standard Deviation 38.44 |
| Placebo | Gastric Emptying Half-time (t1/2) at 24 Hours | 124.7 minutes | Standard Deviation 39.08 |
Secondary
Ascending Colon Emptying (AC t1/2)
Ascending colon emptying t1/2 will be estimated by power exponential analysis of the proportionate emptying over time of counts from the colon. The primary data for this analysis will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly scans on the first day of transit measurement and the 24 hour data.
Time frame: Over the first 24 hours after ingestion of the radioisotopically labeled charcoal particles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Ascending Colon Emptying (AC t1/2) | 21.92 hours | Standard Deviation 9.89 |
| Oxycodone | Ascending Colon Emptying (AC t1/2) | 19.3 hours | Standard Deviation 6.27 |
| Placebo | Ascending Colon Emptying (AC t1/2) | 17.88 hours | Standard Deviation 6.21 |
Secondary
Colonic Filling at 6 Hours
Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time.
Time frame: 6 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tapentadol | Colonic Filling at 6 Hours | 35.55 percentage of radio-labeled meal | Standard Deviation 32.3 |
| Oxycodone | Colonic Filling at 6 Hours | 38.6 percentage of radio-labeled meal | Standard Deviation 19.5 |
| Placebo | Colonic Filling at 6 Hours | 65.54 percentage of radio-labeled meal | Standard Deviation 26.1 |
Secondary
Colonic Geometric Center at 8 and 48 Hours
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: 8 hours, 48 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tapentadol | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 8 hr | 0.78 units on a scale | Standard Deviation 0.589 |
| Tapentadol | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 48 hr | 3.59 units on a scale | Standard Deviation 1.16 |
| Oxycodone | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 8 hr | 0.75 units on a scale | Standard Deviation 0.54 |
| Oxycodone | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 48 hr | 3.51 units on a scale | Standard Deviation 0.82 |
| Placebo | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 8 hr | 0.79 units on a scale | Standard Deviation 0.98 |
| Placebo | Colonic Geometric Center at 8 and 48 Hours | Colonic geometric center at 48 hr | 3.742 units on a scale | Standard Deviation 0.83 |