Effects of Tapentadol Versus Oxycodone After Hysterectomy.

Study Overview
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Brief Summary
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Opioids remain the first-line drugs for the treatment of moderate to severe postoperative pain, but the use is limited by well-known side-effects, most of which are dose-dependent. The opioid oxycodone is standard therapeutic treatment for acute postoperative pain, either in immediate-release formulation, OxyNorm®, or as extended-release formulation, OxyContin®. Oxycodone provides analgesic effects through µ-opioid receptors in the central nervous system. Tapentadol hydrochloride/depot (Palexia/depot®) is a novel, centrally acting, strong analgesic with a dual mechanism of action on µ-opioid receptors and noradrenaline reuptake in the central nervous system. Tapentadol is an active compound, devoid of active metabolites and not reliant on enzyme systems. For these reasons, it has a low drug interaction potential. This dual mechanism also translates clinically into less adverse effects than with pure opioid agonists like oxycodone. This is probably due to less µ-opioid receptor stimulation. Tapentadol has been shown effective in models of acute, osteoarthritic, neuropathic and cancer pain. There is now an increasing use of tapentadol in postoperative pain treatment in Norway. However, there is a lack of broad-based evidence for the use of tapentadol in the post-surgical setting. So far, to our knowledge, there are only published studies on postoperative pain treatment after orthopedic and dental surgery, but none related to deep abdominal pain. Tapentadol is shown in several studies on chronic pain patients to have comparable analgesic effects to traditional opioid pain medications like oxycodone and morphine, but with a more tolerable side-effect profile. In the postoperative setting after dental or orthopedic surgery, studies have shown less nausea and constipation. It has also been suggested a lower frequency of pruritus compared with oxycodone, but no difference in central nervous system symptoms such as sleepiness or dizziness. The most dangerous side-effect from opioids is respiratory depression with the potential of fatal outcome. The investigators have not found any publications from short-term postoperative pain management comparing the respiratory effect of tapentadol to the traditional opioids. The aim of the study is to compare the analgesic effect and side-effects of this new analgesic, tapentadol, to the standard treatment to day, oxycodone, in the acute postoperative period after hysterectomy.

Detailed Description
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Postoperative pain is a major cause of postoperative suffering, prolonged hospitalization, complications and increased costs. It has been shown that postoperative pain is a frequent and unresolved problem in Norwegian hospitals, and so also internationally. Building knowledge on pain prophylaxis and treatment of postoperative pain is an area with substantial potential for improvement and affecting many patients. Opioids remain as first-line drugs for the treatment of moderate to severe postoperative pain, but the use is limited by well-known side-effects, most of which are dose-dependent. The opioid oxycodone is used as standard therapeutic treatment for acute postoperative pain, either in immediate-release formulation, OxyNorm®, or as extended-release formulation, OxyContin®. Oxycodone is a pure opioid receptor agonist with central and peripheral effects. Tapentadol hydrochloride/depot (Palexia/depot®) is a novel, centrally acting, strong analgesic with a dual mechanism of action. It is a µ-opioid receptor agonist with central and peripheral effects, and it also inhibits noradrenaline reuptake in the central nervous system. Tapentadol is an active compound, devoid of active metabolites and not reliant on enzyme systems. For these reasons, it has a low drug interaction potential. Opioid receptors are usually not well expressed in non-inflamed peripheral tissue and they have limited effect on the peripheral pathophysiology and origin of acute wound pain. While postoperative pain basically is induced by relevant nociceptive pain nerve stimulation, there is also a neuropathic component in most cases. Opioids are not very effective in blocking neuropathic pain in low to moderate doses. Also, opioids do not have the potential to block the wind-up of pain when given before the start of surgical trauma. The noradrenaline re-uptake inhibition (NRI) component of tapentadol is believed to have effect on descending pathways in the spinal cord. Such excitatory and inhibitory pathways act through monoamine systems mediated by noradrenaline and 5-hydroxytryptamine (5-HT). The inhibition of noradrenaline reuptake increases monoaminergic transmission in the descending pain inhibitory pathways, leading to reduced pain sensation. It seems like tapentadol produce not simply additive, but synergistic anti-nociceptive action by inhibitory actions in µ-opioid receptor agonism and NRI. While the effect on µ-opioid receptors is important in nociceptive pain, the NRI component seems to be especially relevant for both acute and persistent neuropathic pain. Tapentadol has been shown effective in models of acute, osteoarthritic, neuropathic and cancer-induced bone pain. There is now an increasing use of tapentadol in postoperative pain treatment in Norwegian hospitals. However, there is a lack of broad-based evidence for the use of tapentadol in the post-surgical setting. So far, to our study group's knowledge, there are only published studies on postoperative pain treatment after orthopedic and dental surgery, but none related to visceral pain. Most studies have so far been initiated by the industry. The standard treatment today, oxycodone, on the other hand is shown in several studies to have a preferable analgesic effect on pain of visceral origin compared to morphine. The synergistic effect of µ-opioid receptor agonism and NRI translates clinically into less adverse effects than with pure opioid agonists. This is probably due to less µ-opioid receptor stimulation. Tapentadol is shown in several studies on chronic pain patients to have comparable analgesic effects to traditional opioid pain medications like oxycodone and morphine, but with a more tolerable side-effect profile. In the postoperative setting after dental or orthopedic surgery, studies have shown less nausea and constipation. It has also been suggested a lower frequency of pruritus compared with oxycodone, but no difference in central nervous system symptoms such as somnolence or dizziness. The most dangerous side-effect from opioids is respiratory depression with the potential of fatal outcome. Intravenous oxycodone is shown to have dose dependent effect on respiratory depression decreasing the mean minute volume with a more rapid onset than morphine. One study has attempted to study respiratory depression after tapentadol administration, but failed due to technical failure of the pulse oximetry device. The investigators have not found any other publications from short-term postoperative pain management comparing any respiratory effect of tapentadol to the traditional opioids. The aim of the study is to compare the analgesic effect and side-effects of this new analgesic, tapentadol, to the standard treatment to day, oxycodone, in the acute postoperative period in patients with visceral pain. Patients scheduled for elective hysterectomy are chosen as the study population, as this is a group of patients with significant visceral pain after surgery. The study will be performed as a randomized, double-blind, prospective, parallel-group, single-center study on patients scheduled for laparoscopic sub-/total hysterectomy, as this is a classic study comparing effects from two different medications on two groups in a population.

Official Title
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A Comparison of Analgesic and Respiratory Effects From Tapentadol Versus Oxycodone After Laparoscopic Hysterectomy.

Conditions
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Pain, Postoperative, Pain Uterus, Pain, Acute, Opioid Use, Analgesics, Antipyretics, and Antirheumatics Causing Adverse Effects in Therapeutic Use, Visceral Pain

Intervention / Treatment
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* Drug: Tapentadol
* Drug: Oxycodone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women diagnosed with a benign gynecological condition, undergoing laparoscopic, supra-cervical or total hysterectomy in general anesthesia. Age 18-64 years. ASA (American Society of Anesthesiologists) classification I-III. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to International Conference on Harmonisation GCP, and national/local regulations. The patients will be recruited from the patient population at the Department of Gynaecology. Exclusion Criteria: Age under 18 or over 65. BMI > 31 and/or weight <55 kg, >85 kg. Chronic pain syndromes related to organ systems other than the female reproductive system. Chronic opioid therapy (codeine medication allowed up to 60 mg/day) or enteral steroid therapy. Alcohol or medical abuse/addiction. Chronic obstructive pulmonary disease (spirometry with postbronchodilator FEV1/FVC ratio less than 0.7), untreated asthma (FEV1/FVC is reduced to less than 0.70), obstructive sleep apnea or other conditions known to predispose for respiratory depression. Neurological diagnosis with affection of respiratory system or prone to seizures. Previously diagnosed kidney (glomerular filtration rate <60 mL/min/1.73 m2 over 3 months) or liver impairment (ALAT > 45 U/L; ASAT > 35 U/L; ALP > 105 U/L; GT > 45 U/L age 18-39 or GT > 75 U/L age over 39; LD > 205 U/L). Biliary tract disease. Paralytic ileus. Heart failure (NYHA III-IV). Malignancy of any kind under treatment. Malignancy during last 5 years. HIV infection. Infections of any kind affecting the patient's clinical status, i.e. upper or lower airway infection, urinary tract infection, deep wound infection. Infections not affecting the patient's clinical status, i.e. conjunctivitis, is not an exclusion criteria. Untreated depression, severe anxiety or other psychiatric disorders independent of treatment. Nursing mothers. Cognitive failure, language barriers, hearing/visual disability or other factors which make follow-up difficult. Allergy or contraindication to any of the medications used in the study. Lactose intolerance. Monoamine oxidase inhibitors or SNRI (serotonin norepinephrine reuptake inhibitors) within 14 days prior to randomization. SSRI (selective serotonin reuptake inhibitors) use is not an exclusion criterion if stable dose for at least 30 days before screening. H1-antihistamine is not an exclusion criterion unless the patient experiences somnolence as a side-effect. The concurrent use of benzodiazepines, barbiturates, neuroleptics, phenytoin tricyclic antidepressants, gabapentinoids, tramadol, clonidine, cimetidine, rifampicin, protease inhibitors, St John's wort (Hypericum perforatum), macrolides and antimycotics such as ketoconazole and fluconazole is not allowed. Known complications to anesthesia or difficult airway (Definition of difficult airway: The clinical situation in which a conventionally trained anesthesiologist experiences difficulty with mask ventilation, difficulty with tracheal intubation, or both.). Patients who have participated in other clinical trials during the last 6 months are excluded to avoid confounders to the current study and for patient safety reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oxycodone<br>Active comparator drug administrated. | Drug: Oxycodone<br>* OxyContin 10 mg® (oxycodone extended-release 10 mg): Administered by the patient as oral premedication 1 hour before scheduled start of surgery. OxyContin is repeated once after 12 hours. OxyNorm 10 mg® (oxycodone immediate-release 10 mg): Administered as oral rescue medicine. First possible administration in postoperative ward when the patient is awake and available for oral medication. Maximum 4 capsules/24-hour study period. Minimum 1 hour 15 minutes between capsules. The patient is instructed to take 1 tablet if pain is increasing and the minimum period since last tablet is exceeded.<br>|
| Experimental: Tapentadol<br>Experimental drug administrated. | Drug: Tapentadol<br>* Palexia depot 50 mg® (tapentadol depot 50 mg): Administered by the patient as oral premedication 1 hour before scheduled start of surgery. Palexia depot is repeated once after 12 hours. Palexia 50 mg® (tapentadol 50 mg): Administered as oral rescue medicine. First possible administration in postoperative ward when the patient is awake and available for oral medication. Maximum 4 tablets/24-hour study period. Minimum 1 hour 15 minutes between tablets. The patient is instructed to take 1 tablet if pain is increasing and the minimum period since last tablet is exceeded.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain 1 hour postoperatively. | Difference in scoring of pain at rest using the numerical rating scale for pain between the two intervention groups, tapentadol and oxycodone. | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain 2 hours postoperatively. | Difference in scoring of pain at rest using the numerical rating scale for pain between the two intervention groups, tapentadol and oxycodone. | 2 hours | 
| Pain 3 hours postoperatively. | Difference in scoring of pain at rest using the numerical rating scale for pain between the two intervention groups, tapentadol and oxycodone. | 3 hours | 
| Pain 24 hours postoperatively. | Difference in scoring of pain at rest using the numerical rating scale for pain between the two intervention groups, tapentadol and oxycodone. | 24 hours | 
| Pain relief 30 minutes | Pain relief, measured with categorical scale none, slight, moderate, good or complete, comparing pain at 30 minutes postoperatively to the previous measurement point. The measure total pain relief (TOTPAR) will be calculated from these values. | 30 minutes | 
| Pain relief 1 hour | Pain relief, measured with categorical scale none, slight, moderate, good or complete, comparing pain at 1 hour postoperatively to the previous measurement point. The measure total pain relief (TOTPAR) will be calculated from these values. | 1 hours | 
| Pain relief 2 hours | Pain relief, measured with categorical scale none, slight, moderate, good or complete, comparing pain at 2 hours postoperatively to the previous measurement point. The measure total pain relief (TOTPAR) will be calculated from these values. | 2 hours | 
| Pain relief 3 hours | Pain relief, measured with categorical scale none, slight, moderate, good or complete, comparing pain at 3 hours postoperatively to the previous measurement point. The measure total pain relief (TOTPAR) will be calculated from these values. | 3 hours | 
| Pain relief 24 hours | Pain relief, measured with categorical scale none, slight, moderate, good or complete, comparing pain at 24 hours postoperatively to the previous measurement point. The measure total pain relief (TOTPAR) will be calculated from these values. | 24 hours | 
| Global medication performance | The measure Global medication performance after 24 hours: the patient evaluates the overall satisfaction with the pain treatment on a scale (poor, fair, good, very good, excellent). | 24 hours | 
| Time to first rescue medicine | Time to first intravenous and/or per oral rescue medicine. | 24 hours | 
| Total rescue analgesic consumption | Total intravenous and per oral rescue analgesic consumption over 24 hours. | 24 hours | 
| Respiratory depression | Continuous measurement of end-tidal carbon dioxide (ETCO2) with Smart CapnoLine® Plus (Microstream®), data are collected at postoperatively. | 24 hours | 
| Respiratory rate | Respiratory rate at rest is measured postoperatively. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, analgesia, postoperative pain, postoperative pain management, opioid, oxycodone, tapentadol, hysterectomy, respiratory depression