E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic pain patients/ mhealthy volunteers |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049475 |
E.1.2 | Term | Chronic pain |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To study the effectivess of tepantadol vs morphien vs placebo on endogenous pain modulation |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient inclusion criteria. (i) Patients diagnosed with small-fiber neuropathy or according to the guidelines of the IASP or other professional pain societies (eg., Netherlands Society of Anesthesiologists); (ii) a pain score of 5 or higher; (iii) age between 18 and 75 years; (iv) being able to give written informed consent. Volunteer inclusion criteria. Healthy volunteers in the age range 18-75 years of either sex.
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E.4 | Principal exclusion criteria |
Patient and volunteer exclusion criteria. (i) Unable to give written informed consent; (ii) medical disease such as pulmonary, renal, liver, cardiac, gastro-intestinal, vascular (incl. hypertension) disease; (iii) allergy to study medication; (iv) use of strong opioids; (v) use of benzodiazepines; (vi) history of illicit drug abuse or alcohol abuse; (vii) history of psychosis; (viii) epilepsy; (ix) raised intracranial pressure;(x) pregnancy and/or lactation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Endogenous modulation of pain. Pain perception is modulated via facilitatory and inhibitory control systems. Inhibitory control is most important to chronic pain patients as there are strong indications that failed inhibition constitutes a predisposition to acquired chronic pain. Various systems involved in inhibitory control have been demonstrated over the years. Two systems seem important: (1) top-down inhibition of afferent noxious information by endogenous analgesia originating in the periaquaductal grey (PAG) and affecting pain perception via descending pathways; (2) bottom-up activation of pain modulatory systems via activation of spino-bulbo-spinal loops originating in the dorsal horn of the spinal cord. The effect that the latter system has on pain perception is called Diffuse Noxious Inhibitory Control (DNIC). The two systems are interconnected and DNIC is considered a bottom-up activation of the pain modulatory mechanism, as part of the descending endogenous analgesia system. DNIC dysfunctions or is less efficacious in various complex chronic pain states, such as irritable bowel syndrome, chronic headache, fibromyalgia and temporomandibular disorder.
Offset analgesia (OA) is another expression of the endogenous analgesia system and is evoked by noxious stimulation, in order to reduce (or control) the perception of the noxious event. Offset analgesia becomes apart when an even more painful stimulus occurs briefly during prolonged painful stimulation. Due to activation of the endogenous opioid system the prolonged stimulation is perceived less painful after the intense noxious stimulus than therefore. In a current study (P09.107) we observed that patients with neuropathic pain have a delayed OA or sometimes even absent OA, suggesting a crucial role of pain pathways involved in OA in the development of chronic pain.
Neuropathic pain. Neuropathic pain is a form of chronic pain due to an evident nerve lesion from trauma (incl. surgical trauma), diabetes (small fiber neuropathy), infection (incl. HIV), chemotherapy, etc. The primary sensation is a burning pain coinciding with areas of hyperalgesia and allodynia. In the current study we will focus on patients with chronic neuropathic pain caused by diabetes.
Tapentadol and endogenous modulation of pain. Tapentadol is a centrally acting analgesic with two mechanisms of action: a μ-opioid receptor agonism and noradrenaline (NA) reuptake inhibition. Although the binding of tapentadol to the μ-opioid receptor is weaker than that of morphine its analgesic action is similar to that of morphine due to the (synergistic) effect of the second mechanism (i.e., NA reuptake inhibition). NA plays a role in the endogenous descending pain inhibitory system. Especially at descending pathways NA reuptake inhibition plays a crucial role at the spinal level to reduce chronic neuropathic pain. Hence it is to be expected that tapentadol has a modulatory role on DNIC and OA and consequently will ameliorate pain in chronic neuropathic pain patients. This is the main focus of our current study.
The aims of our study are: 1. Measure DNIC and offset analgesia in neuropathic pain patients;
2. Compare DNIC and offset analgesia in chronic pain patients with DNIC and offset analgesia in healthy volunteers;
3. Assess the effect of oral tapentadol on DNIC and offset analgesia relative to placebo and morphine.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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In case of severe adverse events, inccluding allergies |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |