Trial record 1 of 1 for:
NCT00983385
Evaluation of Effectiveness and Tolerability of Tapentadol Hydrochloride in Subjects With Severe Chronic Low Back Pain Taking Either WHO Step I or Step II Analgesics or no Regular Analgesics
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT00983385 |
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Recruitment Status :
Completed
First Posted : September 24, 2009
Results First Posted : April 17, 2012
Last Update Posted : January 15, 2019
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Sponsor:
Grünenthal GmbH
Information provided by (Responsible Party):
Grünenthal GmbH
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Brief Summary:
The main objective of the study is to evaluate the effectiveness, tolerability, and safety of tapentadol hydrochloride prolonged release in subjects suffering from severe chronic low back pain (LBP) who are taking either WHO Step I or Step II analgesics or no regular analgesics. This is a clinical effectiveness trial designed to establish a link between anticipated clinical outcomes and the clinical practice by means of selected measures of clinical and subject-reported outcome.
The trial will compare the effectiveness of previous analgesic treatment (either WHO Step I or Step II analgesics or no regular analgesics) with that of tapentadol hydrochloride prolonged release (PR) treatment during defined periods of evaluation.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Chronic Pain Low Back Pain | Drug: Tapentadol PR Other: Observation period | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 208 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | An Evaluation of the Effectiveness and Tolerability of Tapentadol Hydrochloride Prolonged Release, and Tapentadol Hydrochloride Immediate Release on Demand, in Subjects With Uncontrolled Severe Chronic Nociceptive, Mixed or Neuropathic Low Back Pain Taking Either WHO Step I or Step II Analgesics or no Regular Analgesics. |
| Actual Study Start Date : | September 30, 2009 |
| Actual Primary Completion Date : | May 2010 |
| Actual Study Completion Date : | July 6, 2010 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Tapentadol
Tapentadol PR was given orally twice a day. A maximum of 2 oral Tapentadol immediate release (IR) tablets per day, with a minimum of a 4 hour interval between doses, were taken if there were acute pain episodes. The total daily dose of Tapentadol PR and IR were not permitted to exceed 500 mg per day.
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Drug: Tapentadol PR
Tapentadol Prolonged Release (PR) Titration and Optimal Dose Period: Starting at 50 mg Tapentadol PR twice daily, adjusted with 50 mg PR steps (upwards or downwards) as necessary to achieve a balance between pain relief and a satisfactory level of tolerability. Participants were not permitted to exceed a dose of 500 mg of Tapentadol per day.
Other Names:
Other: Observation period Eligibility assessment period to characterize the baseline over a one week period (week -1). Participants continued their previous treatment prior to allocation to tapentadol, if eligible. Drug: Tapentadol PR Maintenance Period: In this period participants continued Tapentadol Prolonged Release (PR) on the dose established in the Titration and Optimal Dose Period. Tapentadol IR participants were not permitted to exceed a total daily tapentadol dose of 500 mg.
Other Names:
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Primary Outcome Measures :
- The Primary Endpoint is Defined as the Change of the Average Pain Intensity Score on an 11-point NRS-3 at Week 6 From Week -1 (Baseline). [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value indicates the change from the baseline participant assessment on the 0 to 10 scale. A negative value indicates a reduction in pain intensity.
Secondary Outcome Measures :
- Patient Global Impression of Change at End of Titration and Optimal Dose Period [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.
- Patient Global Impression of Change at End of the Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 weeks) ]In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.
- Change in the Health Survey Scores Form (SF-36) at End of Titration and Optimal Dose Period [ Time Frame: Baseline; End of Week 6 (6 weeks) ]The Scores Form 36 (SF-36) includes several brief board questions on 8 aspects, (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. A higher score indicates an improvement in health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. A positive mean value indicates an improvement from baseline.
- Change in the Health Survey Scores Form (SF-36) at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 weeks) ]The Scores Form 36 (SF-36) includes several brief board questions on 8 aspects, (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a participant was asked to score over the last week. A higher score indicates an improvement in health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. A positive mean value indicates an improvement from baseline.
- painDETECT Assessment at Baseline [ Time Frame: Baseline ]The painDETECT questionnaire was used to determine the possibility of the presence of a neuropathic pain component. It is a participant completed questionnaire. A total score is calculated. Participants with a score between 0 and 12 are scored as being "negative" (no neuropathic pain component). Value between 19 and 38 as being "positive" (presence of neuropathic component)". Values from 13 to 18 are scored as being "unclear".
- painDETECT Assessment for Participants at End of Titration and Optimal Dose Period [ Time Frame: End of Week 6 ]
The baseline painDETECT score was reassessed at the end of Week 6.
It is a participant completed questionnaire. A total score is calculated. Participants with a score between 0 and 12 are scored as being "negative" (no neuropathic pain component). Value between 19 and 38 as being "positive" (presence of neuropathic component)". Values from 13 to 18 are scored as being "unclear".
- painDETECT Assessment for Participants at End of the Maintenance Period [ Time Frame: End of Week 12 ]
The baseline painDETECT score was reassessed at the end of Week 12.
It is a participant completed questionnaire. A total score is calculated. Participants with a score between 0 and 12 are scored as being "negative" (no neuropathic pain component). Value between 19 and 38 as being "positive" (presence of neuropathic component)". Values from 13 to 18 are scored as being "unclear".
- Neuropathic Pain Symptom Inventory (NPSI) Subscores and Overall Score Assessment at Baseline [ Time Frame: Baseline Visit ]Mean score NPSI (Neuropathic Pain Symptom Inventory). The participant rates their symptoms of neuropathic pain. Ten pain questions are answered on an 11-point scale 0 (no pain) to 10 (most intense pain imaginable). Two items related to temporal pain assessed on 5-point scales.
- Neuropathic Pain Symptom Inventory (NPSI) Subscores and Overall Score at End of Titration and Optimal Dose Period [ Time Frame: End of Week 6 ]Mean score NPSI (Neuropathic Pain Symptom Inventory). The participant rates their symptoms of neuropathic pain. Ten pain questions are answered on an 11-point scale 0 (no pain) to 10 (most intense pain imaginable). Two items related to temporal pain assessed on 5-point scales.
- Neuropathic Pain Symptom Inventory (NPSI) Subscores and Overall Score Assessment at End of the Maintenance Period [ Time Frame: End of Week 12 ]Mean score NPSI (Neuropathic Pain Symptom Inventory). The participant rates their symptoms of neuropathic pain. Ten pain questions are answered on an 11-point scale 0 (no pain) to 10 (most intense pain imaginable). Two items related to temporal pain assessed on 5-point scales.
- Change in Neuropathic Pain Symptom Inventory (NPSI) Final Score Assessment at End of Titration and Optimal Dose Period [ Time Frame: Baseline; End of Week 6 (6 Weeks) ]Change in mean score NPSI, questionnaire evaluates symptoms of neuropathic pain. Ten pain descriptors questions are answered on an 11-point scale 0 (no pain)-10 (most intense pain imaginable). The NPSI derives a total intensity score calculated from the subscores. A negative value indicates improvement in neuropathic symptoms.
- Change in Neuropathic Pain Symptom Inventory (NPSI) Final Score Assessment at End of the Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 Weeks) ]Change in mean score NPSI, questionnaire evaluates symptoms of neuropathic pain. Ten pain descriptors questions are answered on an 11-point scale 0 (no pain)-10 (most intense pain imaginable). The NPSI derives a total intensity score calculated from the subscores. A negative value indicates improvement in neuropathic symptoms.
- EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time at End of Titration and Optimal Dose Period. [ Time Frame: Baseline; End of Week 6 (6 weeks) ]The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.
- Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS)at End of Titration and Optimal Dose Period. [ Time Frame: Baseline; End of Week 6 (6 weeks) ]EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.
- EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 weeks) ]The participant scored the EuroQol-5. This is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. The positive values indicate that during the study the health status improved.
- Change in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 weeks) ]EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from the baseline, a positive value indicates an improvement.
- Clinical Global Impression of Change (All Participants) at End of Titration and Optimal Dose Period [ Time Frame: Baseline; End of Week 6 (6 weeks) ]In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.
- Clinical Global Impression of Change (All Participants) at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 weeks) ]In the Clinical Global Impression of Change (CGIC) the clinician indicates the perceived change over the treatment period. The clinician is requested to choose one of seven categories. Scores range from very much improved to very much worse.
- Hospital Anxiety Depression Scale (HADS): Anxiety Score at Baseline [ Time Frame: Baseline ]
Anxiety Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Hospital Anxiety Depression Scale: Change in Anxiety Score at End of Titration and Optimal Dose Period [ Time Frame: Baseline; End of Week 6 (6 weeks) ]
Anxiety Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Hospital Anxiety Depression Scale: Change in Anxiety Score at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 Weeks) ]
Anxiety Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Hospital Anxiety Depression Scale: Depression Score at Baseline [ Time Frame: Baseline ]
Depression Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Hospital Anxiety Depression Scale: Change in Depression Score at End of Titration and Optimal Dose Period. [ Time Frame: Baseline; End of Week 6 (6 weeks) ]
Depression Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Hospital Anxiety Depression Scale: Change in Depression Score at End of Maintenance Period [ Time Frame: Baseline; End of Week 12 (12 Weeks) ]
Depression Scale - 7 items scored for each individual question from 0 = best and 3 = worst.
HADS is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises of 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points.
A negative value indicates that there has been an improvement.
- Final Stable Tapentadol PR Dose in Opioid Naive Participants at End of Titration and Optimal Dose Period. [ Time Frame: Week 6 ]Tapentadol hydrochloride PR dose after 5 weeks of titration which was to be kept stable during the remained of the trial.
- Participant's Satisfaction With Previous Analgesic Treatment at Baseline [ Time Frame: Baseline ]Participants were requested to rate their previous analgesic medication on a 5-point scale. Previous analgesic medication was rated as excellent, very good, good, fair and poor.
- Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol, at the End of Titration and Optimal Dose Period. [ Time Frame: End of Week 6 ]Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.
- Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol, in the Maintenance Period. [ Time Frame: End of Week 8 ]Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.
- Participant's Satisfaction With New Analgesic Treatment, i.e Tapentadol, at End of the Maintenance Period. [ Time Frame: End of Week 12 ]Participants were requested to rate their tapentadol (new) analgesic medication on a 5-point scale. The medication was rated as excellent, very good, good, fair and poor.
- Baseline NRS-3 Pain Intensity in Participants With No Prior Opioid Treatment, at Baseline. [ Time Frame: Baseline ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
- NRS-3 Pain Intensity in Participants With No Prior Opioid Treatment at the End of the Titration and Optimal Dose Period. [ Time Frame: End of Week 6 ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
- NRS-3 Pain Intensity in Participants With No Prior Opioid Treatment at the End of the Maintenance Period. [ Time Frame: End of Week 12 ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
- Baseline NRS-3 Pain Intensity in Participants With Prior Opioid Treatment, at Baseline. [ Time Frame: Baseline ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
- NRS-3 Pain Intensity Assessment in Participants With Prior Opioid Treatment at the End of the Titration and Optimal Dose Period. [ Time Frame: End of Week 6 ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
- NRS-3 Pain Intensity Assessment in Participants With Prior Opioid Treatment at the End of the Maintenance Period. [ Time Frame: End of Week 12 ]For this pain assessment, the participant was to indicate the level of average pain experienced over the previous 3 days on an 11-point Numerical Rating Scale(NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Participants must have signed an Informed Consent Form.
- Participants were men or non-pregnant, non-lactating women. Female participants must be postmenopausal, surgically sterile, or practicing an effective method of birth control. Women of childbearing potential must have a negative pregnancy test at screening.
- Participants must be appropriately communicative to verbalize and to differentiate with regard to location and intensity of the pain.
- Participants must be at least 18 years of age.
- Participants must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months.
- If the participant has radicular pain, this must have been present for at least 3 months and stable for the 4 weeks before enrollment.
- Participants's pain must require a strong analgesic (defined as WHO Step III) as judged by the Investigator.
- Participants must report a rate of satisfaction with their previous analgesic regimen not exceeding "fair" on a subject satisfaction with treatment scale (5-point VRS).
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If under regular, daily pretreatment:
- Participants must be taking a WHO Step I or Step II analgesic medication on a daily basis for at least 2 weeks prior to the Screening Visit.
- The Investigator considers dose increase of WHO Step I analgesics (as mono- or combination therapy) and/or continuation with or dose increase of WHO Step II analgesics inadequate for the individual participant, whatever applicable.
- Participants must have an average pain intensity score (NRS 3) greater than 5 points during the last 3 days prior to the Screening Visit. or
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If no regular analgesic pretreatment is reported:
- Participants must have an average pain intensity score (NRS-3) greater than 6 points in the last 3 days prior to the Screening Visit and related to low back pain.
Exclusion Criteria:
- Presence of a clinically significant disease or laboratory findings that in the Investigator's opinion may affect efficacy or safety assessments.
- Presence of active systemic or local infection that may, in the opinion of the Investigator, affect the efficacy, quality of life/function or safety assessments.
- History of alcohol or drug abuse, or suspicion of in Investigator's judgement.
- Presence of concomitant autoimmune inflammatory conditions.
- Known history of or laboratory values reflecting severe renal impairment.
- Known history of moderately or severely impaired hepatic function.
- History of or active hepatitis B or C within the past 3 months or history of HIV infection
- History of seizure disorder or epilepsy.
- Any of the following within 1 year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm. Severe traumatic brain injury within 15 years (consisting of 1 or more of the following: brain contusion, intracranial hematoma, either unconsciousness or post-traumatic amnesia lasting more than 24 h) or residual sequelae suggesting transient changes in consciousness.
- Pregnant or breast-feeding.
- History of allergy to, or hypersensitivity to tapentadol hydrochloride or its excipients, or contraindications related to tapentadol hydrochloride including:
- Participants with acute or severe bronchial asthma or hypercapnia.
- Participants who have or are suspected of having paralytic ileus.
- Employees of the Investigator or trial site, with direct involvement in this trial or other trials under the direction of the Investigator or trial site, as well as family members of employees of the Investigator.
- Participation in another trial concurrently or within 4 weeks prior to the Screening Visit.
- Known to or suspected of not being able to comply with the protocol and the use of the investigational medicinal product.
- Use of monoamine oxidase inhibitors within 14 days before the Screening Visit.
- Non-stable dosing of selective serotonin reuptake inhibitors within 30 days before the Screening Visit (the doses must remain stable during the trial).
- Presence of conditions other than low back pain that could confound the assessment or self evaluation of pain, e.g., anatomical deformities, significant skin conditions such as abscess or syndromes with widespread pain such as fibromyalgia.
- Any concomitant painful condition that could interfere with the subject's trial assessments or with their ability to differentiate low back pain from other painful conditions.
- Any painful procedures during the trial (e.g., major surgery) that may, in the opinion of the Investigator, affect the efficacy or safety assessments.
- Pending litigation due to chronic pain or disability.
- Intake of Step III analgesics within the 30 days prior to the Screening Visit.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00983385
Locations
Show 46 study locations
Sponsors and Collaborators
Grünenthal GmbH
Investigators
| Principal Investigator: | Hans Kress, Prof. MD | Medical University / AKH Vienna |
Publications of Results:
| Responsible Party: | Grünenthal GmbH |
| ClinicalTrials.gov Identifier: | NCT00983385 |
| Other Study ID Numbers: |
787579 2009-010427-12 ( EudraCT Number ) KF5503/44 ( Other Identifier: Sponsor ) |
| First Posted: | September 24, 2009 Key Record Dates |
| Results First Posted: | April 17, 2012 |
| Last Update Posted: | January 15, 2019 |
| Last Verified: | December 2018 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Information available on the Grünenthal Web Site |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| URL: | http://www.grunenthal.com/r-d-vision-mission/clinical-trials/data-sharing-clinical-trials |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Grünenthal GmbH:
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low back pain pain assessment tapentadol centrally acting analgesic |
Additional relevant MeSH terms:
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Back Pain Low Back Pain Chronic Pain Pain Neurologic Manifestations Tapentadol Analgesics, Opioid Narcotics Central Nervous System Depressants Physiological Effects of Drugs |
Analgesics Sensory System Agents Peripheral Nervous System Agents Adrenergic Uptake Inhibitors Neurotransmitter Uptake Inhibitors Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Adrenergic Agents Neurotransmitter Agents |