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Both hydromorphone and morphine are administered as part of spinal anesthesia to help improve pain control after cesarean delivery. In this study, the investigators are going to determine the doses of each of those medicines that provides optimal pain control to women undergoing cesarean delivery while limiting side effects related to those medicines. The investigators hypothesize that the doses of hydromorphone and morphine that provide optimal pain control without significant side effects will be 100 micrograms and 150 micrograms, respectively. The investigators further hypothesize that at each respective optimal dose, side effects will be less in the hydromorphone group.
Spinal anesthesia is the most common anesthetic technique used for Cesarean delivery in the United States and across the world. Intrathecal opioids are administered along with a local anesthetic during spinal anesthesia for Cesarean delivery to provide postoperative analgesia. The effectiveness of intrathecal morphine for post-Cesarean pain control is well established, but the effectiveness of intrathecal hydromorphone in this patient population is limited to case reports and small retrospective studies. No prospective studies have been conducted to establish the effectiveness of intrathecal hydromorphone for post-Cesarean pain.
Hydromorphone has been studied extensively as a substitute for intrathecal morphine in patients with chronic noncancer pain. In fact, a recent consensus article placed hydromorphone as a first line therapy along with morphine for intrathecal pain management. Its ability to treat post-Cesarean pain when administered in the epidural space has been known for quite some time, but its effects in the intrathecal space are less established. In patients undergoing Cesarean delivery, intrathecal doses of 40 to 100 micrograms have been reported to provide good pain scores postoperatively with only minimal side effects. Doses of up to 300 micrograms have been used, leading to excellent pain control without out respiratory depression, but with significant pruritus and nausea.
Although reducing pain, intrathecal opioids are associated with side effects including pruritus, nausea, and respiratory depression. A meta-analysis reviewing twenty-eight studies which investigated intrathecal morphine versus placebo demonstrated moderate increases in the incidences of pruritus, nausea and vomiting. In fact the incidence of nausea with IT morphine has been reported to be 33%. While hydromorphone is similar chemically to morphine, it is metabolized differently. Differences in pharmacokinetics may allow for differences in side effect profiles. Hydromorphone is more lipid soluble than morphine. This decreases its spread within the intrathecal space and enhances its penetration into the dorsal horn of the spinal cord where interactions with opioid receptors occur. Some studies have found that hydromorphone causes less nausea and pruritus than morphine, while others have not. Although opioid-induced respiratory depression is a rare event, studies evaluating intrathecal hydromorphone for post-Cesarean delivery pain have not reported any cases of respiratory depression.
The optimal dose of intrathecal morphine for analgesia following Cesarean delivery is still debated and the efficacy of intrathecal hydromorphone has not been studied extensively in this patient population. The investigators aim to identify the dose of each medication that provides good pain relief without causing significant side effects. The investigators will then perform a comparative analysis of each drug at their optimal dose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intrathecal hydromorphone | Active Comparator | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. |
|
| Intrathecal morphine | Active Comparator | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Morphine | Drug | Duramorph is administered as part of spinal anesthesia for post-operative pain relief. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients | Each patient will be interviewed by a member of the study team 12 hours after receiving their spinal anesthetic (which will include either hydromorphone or morphine). Patients will be asked to rate their current level of pain on a scale of 0 (no pain) to 10 (worst pain imaginable). A pain score <4 will be considered a success. The up-down sequential allocation method will be used to determine the dose (mcg) of IT hydromorphone and IT morphine for subsequent patients | 12 hours after administration of spinal anesthesia |
| Measure | Description | Time Frame |
|---|---|---|
| Side Effects: Pruritus | Patients will be evaluated by a member of the study team at 6 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | 6 hours after spinal administration |
| Side Effects: Nausea |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hans P Sviggum, M.D. | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rochester Methodist Hospital, Mayo Clinic | Rochester | Minnesota | 55902 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23965210 | Background | Beatty NC, Arendt KW, Niesen AD, Wittwer ED, Jacob AK. Analgesia after Cesarean delivery: a retrospective comparison of intrathecal hydromorphone and morphine. J Clin Anesth. 2013 Aug;25(5):379-383. doi: 10.1016/j.jclinane.2013.01.014. Epub 2013 Aug 17. | |
| 9952150 | Background | Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology. 1999 Feb;90(2):437-44. doi: 10.1097/00000542-199902000-00018. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Intrathecal Hydromorphone | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Hydromorphone: Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control |
| FG001 | Intrathecal Morphine | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Morphine: Duramorph is administered as part of spinal anesthesia for post-operative pain relief. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Intrathecal Hydromorphone | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Hydromorphone: Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Dose of IT Morphine and IT Hydromorphone for Adequate Analgesia (Pain Score Less Than or Equal to 3) in 90% of Patients | Each patient will be interviewed by a member of the study team 12 hours after receiving their spinal anesthetic (which will include either hydromorphone or morphine). Patients will be asked to rate their current level of pain on a scale of 0 (no pain) to 10 (worst pain imaginable). A pain score <4 will be considered a success. The up-down sequential allocation method will be used to determine the dose (mcg) of IT hydromorphone and IT morphine for subsequent patients | The primary outcome was determining the optimal dose of IT morphine and IT hydromorphone for patients undergoing cesarean delivery. Study was designed to determine the ED90 (effective dose in 90% patients; effective dose meaning a VAS score for pain of 3 or less at 12 hours after spinal placement). | Posted | Number | micrograms | 12 hours after administration of spinal anesthesia |
|
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Hydromorphone arm: 41 patients received the intervention, 40 were analyzed
Morphine arm: 43 patients were randomized to this arm, 42 received the intervention (thus the denominator for adverse events) and 40 were analyzed
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intrathecal Hydromorphone | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Hydromorphone: Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Moderate to Severe Pruritus | Skin and subcutaneous tissue disorders | Pruritus | Systematic Assessment | Patients experiencing moderate to severe pruritus (self-reported) within 24 hours of spinal administration |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Hans Sviggum | Mayo Clinic | 507-581-6083 | sviggum.hans@mayo.edu |
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| ID | Term |
|---|---|
| D000377 | Agnosia |
| ID | Term |
|---|---|
| D010468 | Perceptual Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D009020 | Morphine |
| D004091 | Hydromorphone |
| ID | Term |
|---|---|
| D009022 | Morphine Derivatives |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
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| Hydromorphone | Drug | Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control |
|
|
Patients will be evaluated by a member of the study team at 6 hours after spinal administration. Patients with moderate or severe nausea will be recorded. |
| 6 hours after spinal |
| Side Effects: Sedation | Patients will be evaluated by a member of the study team at 6, 12, and 24 hours after spinal administration. The presence of sedation will be graded by the Richmond Agitation Sedation Scale. Patients with a score of (-)2 or lower on the Richmond were classified as being positive for sedation. | 6, 12, and 24 hours after spinal administration |
| Pruritus | Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | 12 hours after spinal |
| Pruritus | Patients will be evaluated by a member of the study team at 24 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | 24 hours after spinal |
| Nausea | Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded. | 12 hours after spinal |
| Nausea | Patients will be evaluated by a member of the study team at 24 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded. | 24 hours after spinal |
| Treatment for Nausea | number of patients needing medication treatment for nausea in first 24 hours | First 24 hours |
| Treatment for Pruritus | The number of patients needing medical treatment for pruritus in first 24 hours after surgery | First 24 hours after spinal |
| 23248827 | Background | Rauch E. Intrathecal hydromorphone for postoperative analgesia after cesarean delivery: a retrospective study. AANA J. 2012 Aug;80(4 Suppl):S25-32. |
| 23256273 | Background | Rauch E. Intrathecal hydromorphone for cesarean delivery: in search of improved postoperative pain management: a case report. AANA J. 2011 Oct;79(5):427-32. |
| 12928713 | Background | Terajima K, Onodera H, Kobayashi M, Yamanaka H, Ohno T, Konuma S, Ogawa R. Efficacy of intrathecal morphine for analgesia following elective cesarean section: comparison with previous delivery. J Nippon Med Sch. 2003 Aug;70(4):327-33. doi: 10.1272/jnms.70.327. |
| 19462494 | Background | Gehling M, Tryba M. Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: a meta-analysis. Anaesthesia. 2009 Jun;64(6):643-51. doi: 10.1111/j.1365-2044.2008.05817.x. |
| 2465709 | Background | Dougherty TB, Baysinger CL, Henenberger JC, Gooding DJ. Epidural hydromorphone with and without epinephrine for post-operative analgesia after cesarean delivery. Anesth Analg. 1989 Mar;68(3):318-22. |
| 17585226 | Background | Pace NL, Stylianou MP. Advances in and limitations of up-and-down methodology: a precis of clinical use, study design, and dose estimation in anesthesia research. Anesthesiology. 2007 Jul;107(1):144-52. doi: 10.1097/01.anes.0000267514.42592.2a. |
| 9972754 | Background | Gerancher JC, Floyd H, Eisenach J. Determination of an effective dose of intrathecal morphine for pain relief after cesarean delivery. Anesth Analg. 1999 Feb;88(2):346-51. doi: 10.1097/00000539-199902000-00023. |
| BG001 | Intrathecal Morphine | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Morphine: Duramorph is administered as part of spinal anesthesia for post-operative pain relief. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal hydromorphone will be 40 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Hydromorphone: Hydromorphone (Dilaudid) is administered in the intrathecal space for post-operative pain control |
| OG001 | Intrathecal Morphine | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Morphine: Duramorph is administered as part of spinal anesthesia for post-operative pain relief. |
|
|
| Secondary | Side Effects: Pruritus | Patients will be evaluated by a member of the study team at 6 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 6 hours after spinal administration |
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|
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| Secondary | Side Effects: Nausea | Patients will be evaluated by a member of the study team at 6 hours after spinal administration. Patients with moderate or severe nausea will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 6 hours after spinal |
|
|
|
| Secondary | Side Effects: Sedation | Patients will be evaluated by a member of the study team at 6, 12, and 24 hours after spinal administration. The presence of sedation will be graded by the Richmond Agitation Sedation Scale. Patients with a score of (-)2 or lower on the Richmond were classified as being positive for sedation. | Posted | Number | participants | 6, 12, and 24 hours after spinal administration |
|
|
|
| Secondary | Pruritus | Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 12 hours after spinal |
|
|
|
| Secondary | Pruritus | Patients will be evaluated by a member of the study team at 24 hours after spinal administration. The number of patients with moderate or severe pruritus will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 24 hours after spinal |
|
|
|
| Secondary | Nausea | Patients will be evaluated by a member of the study team at 12 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 12 hours after spinal |
|
|
|
| Secondary | Nausea | Patients will be evaluated by a member of the study team at 24 hours after spinal administration. The number of patients with moderate or severe nausea will be recorded. | The number of patients at the most commonly used doses of IT medication (50, 75, 100 mcg for hydromorphone) and (100, 150 mcg) for morphine were used in analysis | Posted | Number | participants | 24 hours after spinal |
|
|
|
| Secondary | Treatment for Nausea | number of patients needing medication treatment for nausea in first 24 hours | patients receiving most commonly used doses of IT medication (50,75,100 mcg for hydromorphone; 100, 150 mcg for morphine) | Posted | Number | participants | First 24 hours |
|
|
|
| Secondary | Treatment for Pruritus | The number of patients needing medical treatment for pruritus in first 24 hours after surgery | only patients receiving most commonly used doses of IT hydromorphone (50,75,100 mcg) and morphine (100,150 mcg) | Posted | Number | participants | First 24 hours after spinal |
|
|
|
| 0 |
| 41 |
| 29 |
| 41 |
| EG001 | Intrathecal Morphine | Patients will be randomized to receive a one-time dose of intrathecal hydromorphone or intrathecal morphine as part of their spinal anesthesia. The starting dose of intrathecal morphine will be 100 micrograms. This will be adjusted in subsequent patients based on the previous patient's success or failure according to an up-and-down methodology utilizing a biased coin design. Morphine: Duramorph is administered as part of spinal anesthesia for post-operative pain relief. | 0 | 42 | 26 | 42 |
|
| Moderate to Severe Nausea | Gastrointestinal disorders | Nausea | Systematic Assessment | Patients experiencing moderate to severe nausea (self-reported) within 24 hours of spinal administration |
|
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| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 |
| Heterocyclic Compounds |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |