Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)

Jacob Juel; Søren Schou Olesen; Anne Estrup Olesen; Jakob Lykke Poulsen; Albert Dahan; Oliver Wilder-Smith; Adnan Madzak; Jens Brøndum Frøkjær; Asbjørn Mohr Drewes

doi:10.1136/bmjopen-2014-007087

Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)

Jacob Juel, Søren Schou Olesen, Anne Estrup Olesen, Jakob Lykke Poulsen, Albert Dahan, Oliver Wilder-Smith, Adnan Madzak, Jens Brøndum Frøkjær, Asbjørn Mohr Drewes

8 Citations (Scopus)

Abstract

INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP.

METHODS AND ANALYSIS: 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.

ETHICS AND DISSEMINATION: The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences.

TRIAL REGISTRATION NUMBER: The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

Original language	English
Article number	e007087
Journal	B M J Open
Volume	5
Pages (from-to)	1-8
Number of pages	8
ISSN	2044-6055
DOIs	https://doi.org/10.1136/bmjopen-2014-007087
Publication status	Published - 2015

Keywords

Administration, Oral
Analgesics
Analgesics, Opioid
Chronic Pain
Double-Blind Method
Humans
Hyperalgesia
Infusions, Intravenous
Ketamine
Pain Measurement
Pancreatitis, Chronic
Receptors, N-Methyl-D-Aspartate
Research Design

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10.1136/bmjopen-2014-007087

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Juel, J., Olesen, S. S., Olesen, A. E., Poulsen, J. L., Dahan, A., Wilder-Smith, O., Madzak, A., Frøkjær, J. B., & Drewes, A. M. (2015). Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial). B M J Open, 5, 1-8. Article e007087. https://doi.org/10.1136/bmjopen-2014-007087

Juel, J, Olesen, SS, Olesen, AE, Poulsen, JL, Dahan, A, Wilder-Smith, O, Madzak, A, Frøkjær, JB & Drewes, AM 2015, 'Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)', B M J Open, vol. 5, e007087, pp. 1-8. https://doi.org/10.1136/bmjopen-2014-007087

@article{fd537aafffa4438489f044ffabb3ef30,

title = "Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)",

abstract = "INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP.METHODS AND ANALYSIS: 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.ETHICS AND DISSEMINATION: The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences.TRIAL REGISTRATION NUMBER: The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).",

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author = "Jacob Juel and Olesen, {S{\o}ren Schou} and Olesen, {Anne Estrup} and Poulsen, {Jakob Lykke} and Albert Dahan and Oliver Wilder-Smith and Adnan Madzak and Fr{\o}kj{\ae}r, {Jens Br{\o}ndum} and Drewes, {Asbj{\o}rn Mohr}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2015",

doi = "10.1136/bmjopen-2014-007087",

language = "English",

volume = "5",

pages = "1--8",

journal = "B M J Open",

issn = "2044-6055",

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T1 - Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)

AU - Juel, Jacob

AU - Olesen, Søren Schou

AU - Olesen, Anne Estrup

AU - Poulsen, Jakob Lykke

AU - Dahan, Albert

AU - Wilder-Smith, Oliver

AU - Madzak, Adnan

AU - Frøkjær, Jens Brøndum

AU - Drewes, Asbjørn Mohr

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015

Y1 - 2015

N2 - INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP.METHODS AND ANALYSIS: 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.ETHICS AND DISSEMINATION: The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences.TRIAL REGISTRATION NUMBER: The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

AB - INTRODUCTION: Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP.METHODS AND ANALYSIS: 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP.ETHICS AND DISSEMINATION: The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences.TRIAL REGISTRATION NUMBER: The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

KW - Administration, Oral

KW - Analgesics

KW - Analgesics, Opioid

KW - Chronic Pain

KW - Double-Blind Method

KW - Humans

KW - Hyperalgesia

KW - Infusions, Intravenous

KW - Ketamine

KW - Pain Measurement

KW - Pancreatitis, Chronic

KW - Receptors, N-Methyl-D-Aspartate

KW - Research Design

U2 - 10.1136/bmjopen-2014-007087

DO - 10.1136/bmjopen-2014-007087

M3 - Journal article

C2 - 25757947

SN - 2044-6055

VL - 5

SP - 1

EP - 8

JO - B M J Open

JF - B M J Open

M1 - e007087

ER -

Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)

Abstract

Keywords

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