Effects of Tapentadol Versus Oxycodone After Hysterectomy.
Condition: Pain, Postoperative; Pain Uterus; Pain, Acute; Opioid Use; Analgesics, Antipyretics, and Antirheumatics Causing Adverse Effects in Therapeutic Use; Visceral Pain
MeSH terms: Pain, Postoperative; Acute Pain; Visceral Pain
Study type: Interventional
Phase: Phase 4

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.

      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.
    

Intervention name(s): Tapentadol; Oxycodone
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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.
Intervention MeSH terms: Oxycodone; Tapentadol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: pain; postoperative pain; postoperative pain management; opioid; analgesia; oxycodone; tapentadol; hysterectomy; respiratory depression