Pain, PostoperativePhase 4NCT03314792
Effects of Tapentadol Versus Oxycodone After Hysterectomy.
A Phase 4 study testing Tapentadol and Oxycodone in people with Pain, Postoperative and Pain Uterus, run by Oslo University Hospital at 1 site in Norway.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years, women only
- Conditions the study is for
- Pain, Postoperative, Pain Uterus, Pain, Acute
- What is being tested?
- Tapentadol and Oxycodone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 86 participants
- Where
- 1 siteNorway
- Study dates
- 4 Dec 2017to 28 Feb 2019
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Comparison of Analgesic and Respiratory Effects From Tapentadol Versus Oxycodone After Laparoscopic Hysterectomy.
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Pain, Postoperative, Pain Uterus, Pain, Acute, Opioid Use, Analgesics, Antipyretics, and Antirheumatics Causing Adverse Effects in Therapeutic Use, Visceral Pain
- Being tested
- Tapentadol, Oxycodone
- Keywords
- pain, postoperative pain, postoperative pain management, opioid, analgesia, oxycodone, tapentadol, hysterectomy, respiratory depression
- Medical subject headings
- Pain, Postoperative, Acute Pain, Visceral Pain, Pain, Agnosia, Respiratory Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TapentadolDrug
- 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.
OxycodoneDrug
- 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.
| Study group | Role | What they receive |
|---|---|---|
| Oxycodone | Active comparator | Active comparator drug administrated. Receives: Drug: Oxycodone |
| Tapentadol | Experimental | Experimental drug administrated. Receives: Drug: Tapentadol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 1 hour
Secondary outcomes (13)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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").
Measured: 24 hours
Time to first rescue medicine
Time to first intravenous and/or per oral rescue medicine.
Measured: 24 hours
Total rescue analgesic consumption
Total intravenous and per oral rescue analgesic consumption over 24 hours.
Measured: 24 hours
Respiratory depression
Continuous measurement of end-tidal carbon dioxide (ETCO2) with Smart CapnoLine® Plus (Microstream®), data are collected at postoperatively.
Measured: 24 hours
Respiratory rate
Respiratory rate at rest is measured postoperatively.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2017
- Study start4 Dec 2017
- Primary completion28 Feb 2019
- Study completion28 Feb 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Pain, PostoperativeStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 86 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Harald Lenz, Oslo University Hospital
- Investigators
- Harald Lenz, MD, PhD, Principal investigator, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03314792
- Sponsor's protocol ID
- 2017/776
- Status last verified
- Apr 2019
- First submitted
- 25 Sep 2017
- Last updated
- 4 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The study has no collaborators outside Oslo University Hospital and individual participant data (IPD) is not planned shared with other researchers during the study periode. The database with IPD will be stored in a secure research server at Oslo University Hospital according to the policy for secure storage.
Publications
Langford RM, Knaggs R, Farquhar-Smith P, Dickenson AH. Is tapentadol different from classical opioids? A review of the evidence. Br J Pain. 2016 Nov;10(4):217-221. doi: 10.1177/2049463716657363. Epub 2016 Jul 25.
PubMed 27867511Raeder J. Opioids in the treatment of postoperative pain: old drugs with new options? Expert Opin Pharmacother. 2014 Mar;15(4):449-52. doi: 10.1517/14656566.2014.879292. Epub 2014 Jan 17.
PubMed 24437530Schroder W, Vry JD, Tzschentke TM, Jahnel U, Christoph T. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 2010 Sep;14(8):814-21. doi: 10.1016/j.ejpain.2010.05.005. Epub 2010 Jun 11.
PubMed 20541444Riley J, Eisenberg E, Muller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin. 2008 Jan;24(1):175-92. doi: 10.1185/030079908x253708.
PubMed 18039433Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesth Analg. 2008 Dec;107(6):2048-55. doi: 10.1213/ane.0b013e31818881ca.
PubMed 19020157Stegmann JU, Weber H, Steup A, Okamoto A, Upmalis D, Daniels S. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunionectomy) surgery. Curr Med Res Opin. 2008 Nov;24(11):3185-96. doi: 10.1185/03007990802448056. Epub 2008 Oct 15.
PubMed 18851776Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009 Mar;25(3):765-76. doi: 10.1185/03007990902728183.
PubMed 19203298Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009 May;25(5):1095-104. doi: 10.1185/03007990902816970.
PubMed 19301989Lee LA, Caplan RA, Stephens LS, Posner KL, Terman GW, Voepel-Lewis T, Domino KB. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015 Mar;122(3):659-65. doi: 10.1097/ALN.0000000000000564.
PubMed 25536092Chang SH, Maney KM, Phillips JP, Langford RM, Mehta V. A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation. Anaesthesia. 2010 Oct;65(10):1007-12. doi: 10.1111/j.1365-2044.2010.06498.x.
PubMed 20712805Ramaswamy S, Chang S, Mehta V. Tapentadol--the evidence so far. Anaesthesia. 2015 May;70(5):518-22. doi: 10.1111/anae.13080. No abstract available.
PubMed 25866038Comelon M, Raeder J, Draegni T, Lieng M, Lenz H. Tapentadol versus oxycodone analgesia and side effects after laparoscopic hysterectomy: A randomised controlled trial. Eur J Anaesthesiol. 2021 Sep 1;38(9):995-1002. doi: 10.1097/EJA.0000000000001425.
PubMed 33428347
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Comparison of Analgesic and Respiratory Effects From Tapentadol Versus Oxycodone After Laparoscopic Hysterectomy.
- ClinicalTrials.gov ID
- NCT03314792
- Acronym / sponsor ID
- 2017/776
- Conditions
- Pain, Postoperative, Pain Uterus, Pain, Acute, Opioid Use, Analgesics, Antipyretics, and Antirheumatics Causing Adverse Effects in Therapeutic Use, Visceral Pain
- Keywords
- pain, postoperative pain, postoperative pain management, opioid, analgesia, oxycodone, tapentadol, hysterectomy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 86 participants (actual)
- Lead sponsor
- Oslo University HospitalUniversity, hospital or other
- Study start
- 4 Dec 2017 (actual)
- Primary completion
- 28 Feb 2019 (actual)
- Study completion
- 28 Feb 2019 (actual)
- First posted
- 19 Oct 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Oxycodone | Active comparator | Drug: OxycodoneActive comparator drug administrated. |
| Tapentadol | Experimental | Drug: TapentadolExperimental drug administrated. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tapentadol* 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. | Drug | Tapentadol |
| Oxycodone* 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. | Drug | Oxycodone |
Primary outcome
Pain 1 hour postoperatively.
Time frame: 1 hour
Difference in scoring of pain at rest using the numerical rating scale for pain between the two intervention groups, tapentadol and oxycodone.
13 secondary outcomes
Pain 2 hours postoperatively.
Time frame: 2 hours
Pain 3 hours postoperatively.
Time frame: 3 hours
Pain 24 hours postoperatively.
Time frame: 24 hours
Pain relief 30 minutes
Time frame: 30 minutes
Pain relief 1 hour
Time frame: 1 hours
Pain relief 2 hours
Time frame: 2 hours
Pain relief 3 hours
Time frame: 3 hours
Pain relief 24 hours
Time frame: 24 hours
Global medication performance
Time frame: 24 hours
Time to first rescue medicine
Time frame: 24 hours
Total rescue analgesic consumption
Time frame: 24 hours
Respiratory depression
Time frame: 24 hours
Respiratory rate
Time frame: 24 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Apr 2019.
- Background: PubMed 27867511Langford RM, Knaggs R, Farquhar-Smith P, Dickenson AH. Is tapentadol different from classical opioids? A review of the evidence. Br J Pain. 2016 Nov;10(4):217-221. doi: 10.1177/2049463716657363. Epub 2016 Jul 25.
- Background: PubMed 24437530Raeder J. Opioids in the treatment of postoperative pain: old drugs with new options? Expert Opin Pharmacother. 2014 Mar;15(4):449-52. doi: 10.1517/14656566.2014.879292. Epub 2014 Jan 17.
- Background: PubMed 20541444Schroder W, Vry JD, Tzschentke TM, Jahnel U, Christoph T. Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain. Eur J Pain. 2010 Sep;14(8):814-21. doi: 10.1016/j.ejpain.2010.05.005. Epub 2010 Jun 11.
- Background: PubMed 18039433Riley J, Eisenberg E, Muller-Schwefe G, Drewes AM, Arendt-Nielsen L. Oxycodone: a review of its use in the management of pain. Curr Med Res Opin. 2008 Jan;24(1):175-92. doi: 10.1185/030079908x253708.
- Background: PubMed 19020157Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesth Analg. 2008 Dec;107(6):2048-55. doi: 10.1213/ane.0b013e31818881ca.
- Background: PubMed 18851776Stegmann JU, Weber H, Steup A, Okamoto A, Upmalis D, Daniels S. The efficacy and tolerability of multiple-dose tapentadol immediate release for the relief of acute pain following orthopedic (bunionectomy) surgery. Curr Med Res Opin. 2008 Nov;24(11):3185-96. doi: 10.1185/03007990802448056. Epub 2008 Oct 15.
- Background: PubMed 19203298Daniels SE, Upmalis D, Okamoto A, Lange C, Haeussler J. A randomized, double-blind, phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for postoperative (bunionectomy) pain. Curr Med Res Opin. 2009 Mar;25(3):765-76. doi: 10.1185/03007990902728183.
- Background: PubMed 19301989Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009 May;25(5):1095-104. doi: 10.1185/03007990902816970.
- Background: PubMed 25536092Lee LA, Caplan RA, Stephens LS, Posner KL, Terman GW, Voepel-Lewis T, Domino KB. Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology. 2015 Mar;122(3):659-65. doi: 10.1097/ALN.0000000000000564.
- Background: PubMed 20712805Chang SH, Maney KM, Phillips JP, Langford RM, Mehta V. A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation. Anaesthesia. 2010 Oct;65(10):1007-12. doi: 10.1111/j.1365-2044.2010.06498.x.
- Background: PubMed 25866038Ramaswamy S, Chang S, Mehta V. Tapentadol--the evidence so far. Anaesthesia. 2015 May;70(5):518-22. doi: 10.1111/anae.13080. No abstract available.
- Derived from this study: PubMed 33428347Comelon M, Raeder J, Draegni T, Lieng M, Lenz H. Tapentadol versus oxycodone analgesia and side effects after laparoscopic hysterectomy: A randomised controlled trial. Eur J Anaesthesiol. 2021 Sep 1;38(9):995-1002. doi: 10.1097/EJA.0000000000001425.
- Individual participant dataSharing planned: Yes. The study has no collaborators outside Oslo University Hospital and individual participant data (IPD) is not planned shared with other researchers during the study periode. The database with IPD will be stored in a secure research server at Oslo University Hospital according to the policy for secure storage.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Harald Lenz, MD, PhD principal investigator
Oslo University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tapentadol and Oxycodone in people with Pain, Postoperative and Pain Uterus, run by Oslo University Hospital at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pain 1 hour postoperatively. (time frame: 1 hour). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03314792, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2019.