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For peer review onlyProtocol for a randomised, double-blind, placebo controlled trial to assess the effectiveness of perioperative s-ketamine

on new-onset headache after resective epilepsy surgery (ESPAIN-trial)

Journal: BMJ Open

Manuscript ID bmjopen-2019-030580

Article Type: Protocol

Date Submitted by the Author: 25-Mar-2019

Complete List of Authors: Sloekers, Jiske; Maastricht Universitair Medisch Centrum+, Bos, Michael; Maastricht Universitair Medisch Centrum+, AnaesthesiologyHoogland, Govert; Maastricht Universitair Medisch Centrum+, Neurosurgery; Maastricht University MHeNS School for Mental Health and NeuroscienceBastiaenen, Caroline; Maastricht University, Epidemiologyvan Kuijk, Sander; Maastricht Universitair Medisch Centrum+, Clinical Epidemiology and Medical Technology AssessmentTheunissen, Maurice; Maastricht Universitair Medisch Centrum+, Rijkers, Kim; Maastricht Universitair Medisch Centrum+, NeurosurgeryDings, Jim; Maastricht Universitair Medisch Centrum+, NeurosurgeryColon, Albert; Maastricht Universitair Medisch Centrum+, Academic Centre for Epileptology; KempenhaegheRouhl, Rob; Maastricht Universitair Medisch Centrum+, NeurologySchijns, Olaf; Maastricht Universitair Medisch Centrum+, Neurosurgery; Maastricht University, School for Mental Health and Neuroscience

Keywords: drug-resistant epilepsy, epilepsy surgery, opioids, post-craniotomy headache, s-ketamine, temporal lobe epilepsy

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Protocol for a randomised, double-blind, placebo controlled trial to assess the effectiveness of perioperative s-ketamine on new-onset headache after resective epilepsy surgery (ESPAIN-trial)

Jiske C.T. Sloekers*1, Michael Bos2, Govert Hoogland1,4, Caroline H.G. Bastiaenen5, Sander M.J. van Kuijk6, Maurice Theunissen2, Kim Rijkers1,3,4, Jim T.A. Dings1,3, Albert Colon3, Rob Rouhl7, Olaf E.M.G. Schijns1,3,4

1 Department of Neurosurgery, Maastricht University Medical Centre+, Maastricht, the Netherlands. 2 Department of Anaesthesiology, Maastricht University Medical Centre+, Maastricht, the Netherlands. 3 Academic Centre for Epileptology, Maastricht University Medical Centre+ and Kempenhaeghe, Maastricht / Heeze, the Netherlands. 4 School for Mental Health and Neuroscience (MHeNS), University Maastricht, Maastricht, the Netherlands5 Department of Epidemiology, Maastricht University, Maastricht, the Netherlands6 Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, the Netherlands7 Department of Neurology, Maastricht University Medical Centre+, Maastricht, the Netherlands

*Corresponding authorJiske C.T. Sloekers, Maastricht University Medical Centre+, Department of Neurosurgery, PO box 5800, 6202 AZ Maastricht, the Netherlands; [email protected]

Running title ESPAIN trialKeywords drug-resistant epilepsy, epilepsy surgery, opioids, post-craniotomy headache, s-ketamine, temporal lobe epilepsyWord count abstract 287Word count manuscript 3216 Protocol version: Issue date: 29-05-2018Protocol amendment number: 01Authors: JS, MB, OS Revision chronology: Version 00, 2018-Feb-07, OriginalVersion 01, 2018-May-29, Amendment 01:Reason for amendment: addition of clarification of action in case that patients experience persisting pain or hallucinations.

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ABSTRACTIntroduction Effective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy.AimA randomised parallel group design in which s-ketamine is compared with a placebo as add on medication to a multimodal pain approach.Methods and analysisIn total 62 adult participants, undergoing anterior temporal lobectomy for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg.kg-1 bolus followed by a continuous infusion of 0.1 mg.kg-1.h-1 of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression.Ethics and disseminationEthical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal.Registration detailsThis study has been registered in the Dutch National Trial Register (NTR6480).

STRENGTHS AND LIMITATIONS OF THIS STUDY First randomised controlled trial to evaluate the effect of s-ketamine as add-on analgesic

therapy in treating new-onset headache after craniotomy in a strict uniform study-group: patients with temporal lobe epilepsy undergoing anterior temporal lobectomy under general anaesthesia.

The surgical technique and the anaesthesiologic procedure are the same in all patients and performed by the same surgeons (OS and JD) and a small group of neuro-anaesthesiologists.

Extensive measurement at baseline and follow-up of relevant factors that influence pain perception enables more precise interpretation of pain intensity scores.

The finding of a positive effect of s-ketamine as add-on analgesic therapy will contribute to the conceptualisation of a standardised guideline for the treatment of post-craniotomy headache.

A limitation is that opioid consumption, though an objective and quantifiable measure, does not necessarily reflect a clinically relevant effect in the treatment of post-craniotomy headache.

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ABBREVIATIONSATL Anterior Temporal LobectomyMUMC+ Maastricht University Medical Centre+ NRS Numeric Rating ScalePCA Patient Controlled AnalgesiaSAE Serious Adverse EventsTLE Temporal Lobe EpilepsyVAS Visual Analogue Score

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INTRODUCTION

Until recently, clinicians strongly believed that patients had minimal pain and discomfort following craniotomy, based on low average pain intensity scores in a frequently cited retrospective study. However, their results were based only on a short (90 minutes) post-operative observation of patients who received substantial intra-operative analgesics.1 Contrarily, post-craniotomy headache is the most common adverse event following craniotomy. The reported incidence is highly variable, rising up to 91% depending on the criteria used for the definition of post-craniotomy headache.2-5 According to the International Classification of Headache Disorders (3rd edition) by the International Headache Society, post-craniotomy headache is defined as a headache that develops within 7 days after craniotomy. Acute post-craniotomy headache resolves within 3 months, whereas the chronic form persists for more than 3 months.6 Accordingly to this definition, the reported incidence of post-craniotomy headache is 40%, whereby 10.7% was limited to the acute stage and 29.3% developed into a chronic form.7 When the definition is broadened to onset within 30 days, the reported incidence rises to 62% and when including headache anytime during follow-up, the incidence reported is 91%.3 The incidence of post-craniotomy headache after temporal lobectomy for focal drug-resistant epilepsy is reported as 17.5% for headaches that persist for more than 2 months and 11.9% for more than 1 year.8 This is unfavourable as chronic headaches are often associated with symptoms of depression and anxiety that in turn interfere with quality of life.7 9 Since the pathophysiology of post-craniotomy headache is not well understood, it is generally poorly managed.2 10 Acetaminophen is often not sufficient and the use of non-steroidal anti-inflammatory drugs in neurosurgical procedures is controversial due to their effect on bleeding time.11 The current practice is opioids combined with acetaminophen, yet there still is continuing controversy regarding the choice of the “best” regimen.10 12 13 The use of potent analgesic opioid drugs, administered by a patient controlled analgesia (PCA) pump, may cause serious side effects such as respiratory depression, vomiting, nausea, ileus, and may lead to deterioration of consciousness, which interferes with the assessment of the neurologic status and post-craniotomy pain.10 The addition of other non-opioid analgesics, such as s-ketamine, might be effective in reducing the need for opioid analgesics. The analgesic effects of s-ketamine are mediated by an N-methyl-D-aspartate-receptor antagonist mechanism, which improves the efficacy of opioids and reduces the development of chronic pain syndromes.14 15 When used in high doses, this drug is known for its reversible neuropsychiatric side effects such as hallucinations, nightmares and blurred vision. However, when s-ketamine is administered in low doses, these side effects are well tolerated, reversible and occur in a minority of patients.14 Benefits of s-ketamine in postoperative pain management and its opioid sparing effects have already been reported in abdominal, thoracic and orthopaedic surgeries.14 16 The most recent systematic review on the use of s-ketamine in craniotomies showed an overall opioid sparing effect of 40%. However, the effect on pain intensity scores was very diverse, whereby only 8 of 34 studies showed a significant reduction. The majority of the studies used was underpowered for pain intensity scores, the assessment of pain intensity scores differed largely and factors that influence pain perception, such as anxiety and depression, were poorly documented.17

To date, no studies have been performed to evaluate the beneficial effects of s-ketamine as part of a multimodal pain approach after anterior temporal lobectomy (ATL) for drug-resistant temporal lobe epilepsy (TLE). The primary objective of this randomised parallel group trial is to investigate the effect of perioperative s-ketamine, compared to placebo, as addition to a routine multimodal pain approach of acetaminophen and opioids, on the total opioid consumption after craniotomy in patients with drug-resistant temporal lobe epilepsy. In this paper, we present the study protocol according to SPIRIT protocol guidelines for randomised controlled trial protocols.

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PATIENTS AND METHODS

Design and settingThe ESPAIN trial is a randomised, placebo controlled, double-blind, single centre trial with two parallel groups. Patients with drug-resistant TLE scheduled for elective ATL with or without amygdalohippocampectomy under general anaesthesia are suitable candidates for study participation. The surgical technique is the same in all included patients and the surgery is performed by either of two neurosurgeons (OS and JD) from the department of Neurosurgery of the Maastricht University Medical Centre+ (MUMC+), Maastricht, the Netherlands.

Recruitment, eligibility criteria and informed consentApproximately 21 TLE patients are scheduled for surgery every year in the neurosurgical outpatient clinic of the MUMC+. All patients scheduled for elective ATL with or without amygdalohippocampectomy will be considered for eligibility. Prior to their visit to the outpatient clinic, these patients will be informed about their up-coming operation by one of the three epileptologists at Kempenhaeghe Academic Centre for Epileptology, Heeze, rhe Netherlands. The epileptologist will ask patient’s permission for a phone interview by the GCP-certified coordinating investigator (JS). In this phone call the patient will receive detailed study information and will be asked for permission to send a patient information brochure by mail. The patient will have a minimum of 14 days to consider participation, starting from the moment of receiving the patient information brochure at home. During the visit at the neurosurgical outpatient clinic of the MUMC+, the patient will be informed about the surgery by one of the two neurosurgeons who perform the epilepsy surgery. Afterwards, the coordinating investigator (JS) will answer any remaining questions about the trial. When it is clear that the patient has understood all the provided information and wants to participate in the trial, both the patient and the coordinating investigator will sign the informed consent sheet, after which the patient will be included in the randomization procedure. Patients eligible for the trial must comply with all of the inclusion criteria and are not allowed to have any of the exclusion criteria, as listed in table 1. The general practitioner will be informed by letter about the patient’s participation in the ESPAIN trial.

Table 1. Overview of inclusion and exclusion criteriaInclusion criteria Exclusion criteria Age > 18 years Declined informed consent Elective resective surgery for drug-resistant temporal lobe epilepsy

Allergy to any of the trial medications

Current chronic pain, such as, but not limiting to, migraine or other headaches. Chronic pain treatment with use of different kinds of pain medication.

Drug-resistant epilepsy, based on: - chronic, focal epilepsy- not seizure free with

antiepileptic medication - no medication options due to

adverse effectsAlcohol, hard- or soft drug abuses

Signed informed consent for trial participation

Inability to complete questionnaires or language barrier

History of psychiatric complaints for which treatment was performed History of craniotomy or subdural electrode implantation

Interventions Patients will be randomly allocated to either of the two study arms. The intervention group receives s-ketamine (Ketanest-S®, Pfizer, Dun Laoghaire, Ireland) and the control group receives a placebo (0.9% NaCl). The operation consists of an ATL with or without an amygdalohippocampectomy performed with a standard surgical technique for all patients by either of two neurosurgeons (OS and JD). The trial

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medication will start perioperatively after induction, but before incision, and will be continued for 48 hours in total. All patients will receive general anaesthesia as part of the routine medical treatment as further specified in the overview of interventions in figure 1. No premedication will be given, except for the patient’s own antiepileptic medication. In case the potential side effects of s-ketamine cause too much discomfort for patients, this will be registered as an adverse event. In case of severe hallucinations, the study medication will be terminated and the PCA-pump and acetaminophen will be continued. The patient will not be deblinded or withdrawn from the study. Data collection will continue according to the protocol. In case a patient experiences severe pain, the study medication and the PCA-pump will be discontinued and regular s-ketamine protocol will be started, whereby the patient will receive morphine in a PCA-pump, acetaminophen and s-ketamine. The patient will not be deblinded and data collection will continue according to protocol. Severe pain will be defined as unsatisfactory pain treatment despite receiving the maximum amount of morphine with the highest possible PCA-pump dosage for at least one hour. When the trial medication is discontinued and regular s-ketamine protocol is started, the time, pain score (NRS and VAS) and the reason for discontinuation of trial medication will be registered.

OutcomesThe primary study outcome is the total postoperative opioid consumption (mg) in both study arms, measured at the 7th postoperative day, with interim measurements at 24, 48, 72 and 96 hours postoperatively. Secondary study outcomes are length of hospital stay (days), postoperative pain intensity scores from day 0 until 4 and at day 7 postoperatively, and the occurrence of several potential adverse events. Pain intensity is quantified in scores using the Visual Analogue Scale (VAS), range 0-100mm, and Numeric Rating Scale (NRS), range 0-10. Specifically the occurrence of delirium as adverse event is assessed every day for the first seven postoperative days using the Delirium Observation Screening (DOS) scale. Other potential adverse events that will be registered are: hallucinations, nausea, vomiting, dizziness, vivid dreams or nightmares, diplopia, blurred vision, nystagmus, and elevated blood pressure or heart rate. Furthermore, patient health-related quality of life, surgical fear, depression, pain catastrophizing, severity of pain, neuropathic pain and characteristics of the headache will be assessed using standardised and validated questionnaires as presented in table 2.

Table 2. Abbreviations and timing of questionnaires RAND-36 Research and Development-36-item Health Survey

SFQ Surgical Fear QuestionnaireCES-D Centre for Epidemiologic Studies Depression scale

PCS Pain Catastrophizing ScaleBPI-SF Brief Pain Inventory-Short Form

DN4-interview Douleur Neuropathique (7 self-report items)T0 – preoperatively

T1 – 3 months postoperatively


RAND-36 X X XSFQ XCES-D X X XPCS XBPI-SF X X XDN4-interview X X XSelf-compiled questionnaire characteristics headache X X X

The reliability and validity of the NRS and VAS scoring systems is high and both scores are recommended as sensitive and responsive in measuring pain intensity18. The DN4-interview is a

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diagnostic tool that enables physicians to make a distinction between nociceptive and neuropathic pain and is linguistically validated for usage in Dutch19, whereby only the 7 self-report items will be used (DN4-interview)20. The CES-D is a screening tool for depression with excellent validity21. Furthermore, the SFQ, PCS, RAND-36, BPI-SF and DOS have also been proven valid and reliable22-26. The self-compiled questionnaire inquiring the characteristics of the headache was compiled by a headache neurologist, based on the International Classification of Headache Disorders-3rd edition by the International Headache Society. Other study parameters which will be documented are baseline values such as gender, age, weight, type of antiepileptic drugs, epilepsy duration, details of the surgery, duration of surgery, side of surgery and seizure outcome according to International League Against Epilepsy and Engel class.

Participant timelineThe study duration for each single patient is 6 months, starting at the moment of trial inclusion until the last questionnaire has been completed 6 months later, as can be seen in figure 2. The baseline questionnaires will be provided web-based to the surgical candidates before hospital admission and will take approximately 45 minutes to complete. After surgery, at day 1 until 4 and at day 7, patients will complete a pain diary and anaesthesiologic nurse practitioners and nurses on the neurosurgical ward will report VAS and NRS scores and presence of delirium using the DOS questionnaire. Completing the pain diary will take approximately 15 minutes each day. The last two follow-up questionnaires will be completed web-based after 3 and 6 months. The total burden of study participation for the patient will be 3 hours.

Sample sizeA minimum of 62 patients is needed for the study sample, with 31 patients in each study arm. A 5% dropout rate has been included in the calculation. The sample size calculation is based on clinical data from previous patients who underwent resective epilepsy surgery for TLE and were administered s-ketamine as pain medication. It is performed with Gpower based on longitudinal analysis of the data with 5 measurements, and based on the primary outcome: a difference of standards of opioid consumption. Expected means and standard deviations (SD) for each group (intervention group 32 and control group 42 standards of opioid consumption (SD 24 standards)), with an effect size based on Cohen d of 0.29, lead to a sample size of n=58. Presuming a level of significance below 5% and a power of 0.80, a minimum of 58 patients is needed, with the addition of 4 people for an expected drop out of 5%, 62 people have to be included in the trial. With an expectation of 21 eligible trial participants every year, the duration of the period of inclusion will be 3 years.

Randomisation, allocation and blinding Allocation of study participants will be done by randomisation by use of a computerised randomisation system at the Department of Epidemiology, Maastricht University. Block randomisation with random permuted block sizes of 4 and 6 will be used. The randomisation scheme will be handed over by an independent member of the Department of Epidemiology to the hospital pharmacist. The surgeon, the attending anaesthesiologist, the nurse, the patient, and all investigators will be blinded to the allocated study treatment. The hospital pharmacist, the single not-blinded trial staff member, will prepare the medication according to the allocated protocol either for s-ketamine or NaCl 0.9% in the correct dosage for the correct patient and will ensure that the study medication is labelled and can be administered by nursing staff in a blind manner. In case emergency unblinding is required, the investigator will contact the hospital pharmacist, who is the only trial staff member authorised to trace back to which procedure the patients were allocated through a scheme provided by the computer program.

Data collectionOpioid consumption peroperatively and during a patient’s stay at the recovery is registered by the anaesthesiologist in the patients file. The PCA pump is managed by dedicated anaesthesiologic nurse practitioners, who register the opioid consumption from the PCA pump in the patients file.

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Furthermore every gift of medication, amongst which are oral opioids, at the regular ward is also registered by nurses in the patients file. Pain and DOS scores will be taken by nurses, after which they will be registered in the patients file. All perioperative complications and adverse events will be registered daily in the patients file. Therefore the primary outcome measure, opioid consumption, will be collected from the patients file. The secondary outcomes, pain and DOS scores, perioperative complications, adverse events and baseline demographic values such as gender, age, weight, details regarding the surgery, the duration of surgery and the length of hospital stay will also be collected from the patients file. All questionnaires and the pain diary will be filled in web-based through the electronic data capture system Castor EDC, after which data will automatically be stored. All data will be recorded using an electronic case report form, web-based, in Castor EDC. Data will be stored coded, which warrants privacy of participants.

Statistics At baseline, normally distributed variables will be presented as mean values and standard deviations. Non normally distributed variables will be presented as median and range. Categorical data will be presented as frequencies percentages. All collected variables will be presented as a total for the entire study population and stratified by randomised subgroup. There will be no formal testing for statistical differences between the randomised groups.We will perform all analyses on the intention to treat sample. Linear mixed-effects regression will be used to test for statistical differences between the groups, taking the longitudinal nature of the data into account (5 measurements). This will be performed based on the primary outcome measure: standards of opioid consumption. In case of clinically meaningful imbalance in baseline characteristics between groups, these variables will be regarded as potential confounders, and will be taken into account using multivariable linear mixed-effects regression. The assumption of a multivariate normally distributed outcome will be checked by visually assessing the histogram of residuals and Q-Q plots. In case of clear violation the outcome variable will be transformed using a transformation that solves the non-normality of residuals. Differences are considered to be statistically significant when p ≤ 0.05. Missing data will not be replaced. Analyses will be performed using SPSS 23 for Windows (SPSS Inc., Chicago , IL, USA). We will consider performing a post hoc subgroup analysis on the difference in opioid consumption between patients that underwent a standard anterior temporal resection or a maximal temporal resection. Results of these analyses will be considered preliminary as the sample size calculation was performed on the main analysis and power is likely to be insufficient.

Interim analysis and preterm terminationNo interim analyses will be performed. Due to the small size of the study sample and the required large difference in primary outcome measure, interim analysis is expected to show no significant difference in the primary outcome measure prior to 3-years termination of the study. S-ketamine is a registered drug administered in daily practice, hence, preterm termination of the study due to unwanted side effects of s-ketamine is not expected.

Monitoring and auditingMonitoring will be performed by a member of the local data monitoring committee, from the Clinical Trial Centre Maastricht. Prior to the start of the trial, the study has been classified as low risk. Monitoring will be performed at least three times during the study. Once after the first three patients have been included, once 1,5 year after trial onset and one last time at the end of the inclusion period. Monitoring visits include control of data collection, informed consent forms, compliance to the protocol and applicable laws and regulations and the control of general rights and well-being of trial participants. A monitoring visit report will be sent to the local medical ethical committee and the principal investigator. Unannounced audits can be performed by the audit team of the Clinical Trial Centre Maastricht.

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HarmsAny adverse events reported spontaneously by the subject or observed by the hospital staff will be registered. The most important potential expected adverse event due to s-ketamine is the occurrence of hallucinations. All serious adverse events (SAEs) will be registered and reported through ToetsingOnline to the local medical ethical committee. Life threatening SAEs or SAEs resulting in death of the patient will be reported within 7 days of first knowledge, followed by a period of maximum 8 days to complete the initial preliminary report. All other SAEs will be reported within a period of maximum 15 days after the sponsor has first knowledge of the serious adverse event. Liability and subject insurances are provided.

ETHICS AND DISSEMINATION

Research ethics approval and amendmentsEthical approval has been given by the local medical ethical committee academisch ziekenhuis Maastricht/Maastricht University (METC azM/UM) on March 14th, 2018. The study had been given the following ID: NL61666.068.17. Institutional approval has been given by the MUMC+ Board of Directors on April 3rd, 2018. A significant modification in the study protocol has been submitted as a substantial amendment to the local medical ethical committee, which has given approval on June 6th, 2018. Participants will be included from August 2018 until 2021. Any further significant modifications in the study protocol or significant modifications in other study documents will be submitted for approval to the local medical ethical committee. Subsequently, all study participants will be notified and informed consent will be requested again when necessary. This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act (Wet Medisch-wetenschappelijk Onderzoek met mensen) and the Declaration of Helsinki.

Confidentiality and access to dataPatient information will be coded and the key to the code that makes traceability possible is saved in a password-locked file and only accessible to the principal investigators. All patient data will be recorded using Castor EDC. Recorded data will be stored using a secured database and safeguarded. Informed consent forms are stored in a locked closet in a locked room (principal investigators room). All research related data and forms will be saved for 15 years and nihilated after this period. Research related data and forms are accessible to the investigators, monitors and auditors of the Clinical Trial Centre Maastricht, the Dutch Healthcare authority (Inspectie voor de Gezondheidszorg), and the local medical ethical committee.

Dissemination policyThe study has been registered with the Dutch National Trial Register (NTR) and been assigned the following ID: NTR6480. Furthermore, the results of this trial will be publicly disclosed and submitted for publication in international peer-reviewed scientific journals.

Figure legendsFigure 1. Interventions overview peroperativelyFigure 2. Participant timeline

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AUTHORS’ CONTRIBUTIONSJ.C.T. Sloekers: coordinating investigator, concept, drafting, and critically revising of protocol O.E.M.G. Schijns: principal investigator, performing surgery, concept, drafting, and critically revising of protocolM. Bos: principal investigator, concept, drafting, and critically revising of protocolG. Hoogland: drafting, and critically revising of protocolS.M.J. van Kuijk: drafting, and critically revising of protocolC.H.G. Bastiaenen: concept, drafting, and critically revising of protocol H.M.S. Theunissen: critically revising of protocolK.Rijkers: critically revising of protocolA.Colon: critically revising of protocolR.Rouhl: critically revising of protocolJ.Dings: performing surgery, and critically revising of protocol

FUNDING STATEMENTThis research received no specific grant from any funding agency in the public, commercial, or non-profit sector.

COMPETING INTERESTS STATEMENT We have read and understood BMJ policy on declaration of interests and declare that we have no competing interests.

PATIENT AND PUBLIC INVOLVEMENT STATEMENTThis research protocol was developed without the involvement of patients or the public. Patients were not invited to contribute to the design of the research methods, material and design or to the writing and editing of any documents.

TRIAL REGISTRATION DATA SETData Category InformationPrimary registry and trial identifying number NTR6480Date of registration in primary registry 4 July, 2017Secondary identifying numbers 2017-002616-13Source(s) of monetary or material support Maastricht Universitair Medisch Centrum +Primary sponsor Maastricht Universitair Medisch Centrum +Secondary sponsor -Contact for public queries JS, [email protected] Contact for scientific queries JS, [email protected] title S-ketamine for acute and chronic headache

after brainsurgeryScientific title The effect of perioperative intravenous s-

ketamine on acute and chronic postoperative craniotomy pain compared to placebo

Countries of recruitment The Netherlands Health condition(s) or problem(s) studied Post-craniotomy pain

Active comparator: s-ketamineInterventionPlacebo comparator: NaCl 0.9%Ages eligible for study: ≥18 years; Sexes eligible for study: both; Accepts healthy volunteers: no

Key inclusion and exclusion criteria

Inclusion criteria: age >18 years, elective resective surgery for drug-resistant temporal lobe epilepsy, drug-resistant epilepsy, based on:

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(1) chronic, focal epilepsy; (2) not seizure free with antiepileptic medication; (3) no medication options due to adverse effects, signed informed consent for trial participationExclusion criteria: declined informed consent, allergy to any of the trial medications, current chronic pain, such as, but not limiting to, migraine or other headaches, chronic pain treatment with use of different kinds of pain medication, alcohol, hard- or soft drug abuses, inability to complete questionnaires or language barrier, history of psychiatric complaints for which treatment was performed, history of craniotomy or subdural electrode implantationInterventional Allocation: randomizedIntervention model: parallel assignment Masking: double blind Primary purpose: treatment

Study type

Phase IVDate of first enrolment 14-08-2018Target sample size 62Recruitment status RecruitingPrimary outcome(s) Total postoperative opioid consumption at the

7th postoperative day with interim measurements at 24, 48, 72 and 96 hours

Key secondary outcome(s) Postoperative pain intensity scores (VAS+NRS), patient health-related quality of life, psychological parameters, length of hospital stay and adverse events

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References

1. Dunbar PJ, Visco E, Lam AM. Craniotomy procedures are associated with less analgesic requirements than other surgical procedures. Anesth Analg 1999;88(2):335-40.

2. de Oliveira Ribeiro Mdo C, Pereira CU, Sallum AM, et al. Immediate post-craniotomy headache. Cephalalgia 2013;33(11):897-905. doi: 10.1177/0333102413479833

3. Rocha-Filho PA, Gherpelli JL, de Siqueira JT, et al. Post-craniotomy headache: a proposed revision of IHS diagnostic criteria. Cephalalgia 2010;30(5):560-6. doi: 10.1111/j.1468-2982.2009.02010.x

4. Gee JR, Ishaq Y, Vijayan N. Postcraniotomy headache. Headache 2003;43(3):276-8.5. Molnar L, Simon E, Nemes R, et al. Postcraniotomy headache. J Anesth 2014;28(1):102-11. doi:

10.1007/s00540-013-1671-z6. Headache Classification Committee of the International Headache S. The International

Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808. doi: 10.1177/0333102413485658

7. Rocha-Filho PA, Gherpelli JL, de Siqueira JT, et al. Post-craniotomy headache: characteristics, behaviour and effect on quality of life in patients operated for treatment of supratentorial intracranial aneurysms. Cephalalgia 2008;28(1):41-8. doi: 10.1111/j.1468-2982.2007.01465.x

8. Kaur A, Selwa L, Fromes G, et al. Persistent headache after supratentorial craniotomy. Neurosurgery 2000;47(3):633-6.

9. Rocha Filho PAS. Post-craniotomy headache after surgery for treatment of cerebral aneurysms. Arquivos de Neuro-Psiquiatria 2007;65:921-22.

10. Nemergut EC, Durieux ME, Missaghi NB, et al. Pain management after craniotomy. Best Pract Res Clin Anaesthesiol 2007;21(4):557-73.

11. Umamaheswara Rao GS, Gelb AW. To use or not to use: the dilemma of NSAIDs and craniotomy. Eur J Anaesthesiol 2009;26(8):625-6. doi: 10.1097/EJA.0b013e32832a21ad

12. Williams DL, Pemberton E, Leslie K. Effect of intravenous parecoxib on post-craniotomy pain. Br J Anaesth 2011;107(3):398-403. doi: 10.1093/bja/aer223

13. Jellish WS, Leonetti JP, Sawicki K, et al. Morphine/ondansetron PCA for postoperative pain, nausea, and vomiting after skull base surgery. Otolaryngol Head Neck Surg 2006;135(2):175-81. doi: 10.1016/j.otohns.2006.02.027

14. Laskowski K, Stirling A, McKay WP, et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011;58(10):911-23. doi: 10.1007/s12630-011-9560-0

15. Hayashi Y, Kawaji K, Sun L, et al. Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. J Neurosci 2011;31(48):17370-82. doi: 10.1523/JNEUROSCI.4152-11.2011

16. Karcioglu M, Davarci I, Tuzcu K, et al. Addition of ketamine to propofol-alfentanil anesthesia may reduce postoperative pain in laparoscopic cholecystectomy. Surg Laparosc Endosc Percutan Tech 2013;23(2):197-202. doi: 10.1097/SLE.0b013e3182827f09

17. Jouguelet-Lacoste J, La Colla L, Schilling D, et al. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med 2015;16(2):383-403. doi: 10.1111/pme.12619

18. Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. PAIN® 2011;152(10):2399-404.

19. van Seventer R, Vos C, Giezeman M, et al. Validation of the Dutch version of the DN4 diagnostic questionnaire for neuropathic pain. Pain Pract 2013;13(5):390-8. doi: 10.1111/papr.12006

20. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114(1-2):29-36. doi: 10.1016/j.pain.2004.12.010

21. Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Applied psychological measurement 1977;1(3):385-401.

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22. Theunissen M, Peters ML, Schouten EG, et al. Correction: Validation of the Surgical Fear Questionnaire in Adult Patients Waiting for Elective Surgery. PLoS One 2016;11(9):e0162737. doi: 10.1371/journal.pone.0162737

23. Sullivan MJ, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychological assessment 1995;7(4):524.

24. Vander Zee KI, Sanderman R, Heyink JW, et al. Psychometric qualities of the RAND 36-Item Health Survey 1.0: a multidimensional measure of general health status. International journal of behavioral medicine 1996;3(2):104.

25. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23(2):129-38.

26. Schuurmans MJ, Shortridge-Baggett LM, Duursma SA. The Delirium Observation Screening Scale: a screening instrument for delirium. Res Theory Nurs Pract 2003;17(1):31-50.

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Postoperative: - Acetaminophen 1000mg 4 times a day - PCA-pump: bolus morphine 1mg,

lockout 5 minutes. Continued 48 hours.

30 minutes before end of surgery: loading dose morphine 0.1mg/kg iv

Blood pressure: in range of 20% from baseline: - Hypotension: noradrenaline 0.05-0.1

µg/kg/min - Hypertension: nicardipine 3-5 mg/h,

maximum 15 mg/h

Trial medication: after induction, before incision. Continued 48 hours postoperatively.

Bolus s-ketamine 0.25 mg/kg, with continuous s-ketamine

infusion of 0.1mg/kg/h.

Bolus 0.9% NaCl, with continuous 0.9% NaCl

infusion, both in the same packaging and volume as s-

ketamine

Figure 1. Interventions overview peroperatively

Application of standard monitoring First 18G iv to start crystalloid infusion

Second 18G iv for anaesthetics

Induction: - Bolus sufentanil 0.2-0.4 µg/kg iv - Propofol 2 mg/kg iv - Rocuronium 0.6 mg/kg iv - Dexamethasone 10mg iv

Oral intubation and ventilation: - Male tube size 8.0, female tube size

7.5 - Tidal volumes 6-8 mL/kg, frequency

12-15 per minute, 5 cm H2O positive end-expiratory pressure [PEEP])

Maintenance: - Propofol 5-7 mg/kg/h iv - Remifentanil 0.25-0.5 µg/kg/min iv

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Telephonic provision of study details by investigator and assessment of candidate's

eligibility and interest

Informed consent by investigator after visit to outpatient clinic MUMC+

Assessment of permission for telephonic approach at results appointment

Kempenhaeghe

Non-eligible or non-interested participants

excluded

Randomisation process (n=62)

Participants declining informed consent excluded

Pre-operative: completion of baseline questionnaires

S-ketamine group (n=31) Placebo group (n=31)

Surgery: perioperative start administration of study medication

Provision of surgical details at visit to outpatient clinic MUMC+

Directly postoperative: completion of headache diary and assessment of pain scores

(VAS+NRS) and delirium (DOS) by nurse

Postoperative 3 months: completion of first follow-up questionnaires

Postoperative 6 months: completion of last follow-up questionnaires

End of study participation

Figure 2. Participant timeline

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Reporting checklist for protocol of a clinical trial.

Based on the SPIRIT guidelines.

Instructions to authors

Complete this checklist by entering the page numbers from your manuscript where readers will find

each of the items listed below.

Your article may not currently address all the items on the checklist. Please modify your text to

include the missing information. If you are certain that an item does not apply, please write "n/a" and

provide a short explanation.

Upload your completed checklist as an extra file when you submit to a journal.

In your methods section, say that you used the SPIRIT reporting guidelines, and cite them as:

Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, Hróbjartsson A, Mann

H, Dickersin K, Berlin J, Doré C, Parulekar W, Summerskill W, Groves T, Schulz K, Sox H, Rockhold

FW, Rennie D, Moher D. SPIRIT 2013 Statement: Defining standard protocol items for clinical trials.

Ann Intern Med. 2013;158(3):200-207

Reporting Item

Page

Number

Title #1 Descriptive title identifying the study design, population,

interventions, and, if applicable, trial acronym

1

Trial registration #2a Trial identifier and registry name. If not yet registered, name

of intended registry

2,9

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https://www.goodreports.org/spirit/info/#1

https://www.goodreports.org/spirit/info/#2a



Trial registration:

data set

#2b All items from the World Health Organization Trial

Registration Data Set

10

Protocol version #3 Date and version identifier 1

Funding #4 Sources and types of financial, material, and other support 10

Roles and

responsibilities:

contributorship

#5a Names, affiliations, and roles of protocol contributors 10

Roles and

responsibilities:

sponsor contact

information

#5b Name and contact information for the trial sponsor 10

Roles and

responsibilities:

sponsor and funder

#5c Role of study sponsor and funders, if any, in study design;

collection, management, analysis, and interpretation of

data; writing of the report; and the decision to submit the

report for publication, including whether they will have

ultimate authority over any of these activities

10

Roles and

responsibilities:

committees

#5d Composition, roles, and responsibilities of the coordinating

centre, steering committee, endpoint adjudication

committee, data management team, and other individuals or

groups overseeing the trial, if applicable (see Item 21a for

data monitoring committee)

n/a

Background and

rationale

#6a Description of research question and justification for

undertaking the trial, including summary of relevant studies

4

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https://www.goodreports.org/spirit/info/#5c

https://www.goodreports.org/spirit/info/#5d




(published and unpublished) examining benefits and harms

for each intervention

Background and

rationale: choice of

comparators

#6b Explanation for choice of comparators 4

Objectives #7 Specific objectives or hypotheses 4

Trial design #8 Description of trial design including type of trial (eg, parallel

group, crossover, factorial, single group), allocation ratio,

and framework (eg, superiority, equivalence, non-inferiority,

exploratory)

5

Study setting #9 Description of study settings (eg, community clinic,

academic hospital) and list of countries where data will be

collected. Reference to where list of study sites can be

obtained

5

Eligibility criteria #10 Inclusion and exclusion criteria for participants. If applicable,

eligibility criteria for study centres and individuals who will

perform the interventions (eg, surgeons, psychotherapists)

5

Interventions:

description

#11a Interventions for each group with sufficient detail to allow

replication, including how and when they will be

administered

5,6

Interventions:

modifications

#11b Criteria for discontinuing or modifying allocated

interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or

6

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improving / worsening disease)

Interventions:

adherance

#11c Strategies to improve adherence to intervention protocols,

and any procedures for monitoring adherence (eg, drug

tablet return; laboratory tests)

5,6

Interventions:

concomitant care

#11d Relevant concomitant care and interventions that are

permitted or prohibited during the trial

n/a

Outcomes #12 Primary, secondary, and other outcomes, including the

specific measurement variable (eg, systolic blood pressure),

analysis metric (eg, change from baseline, final value, time

to event), method of aggregation (eg, median, proportion),

and time point for each outcome. Explanation of the clinical

relevance of chosen efficacy and harm outcomes is strongly

recommended

6

Participant timeline #13 Time schedule of enrolment, interventions (including any

run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended

(see Figure)

7

Sample size #14 Estimated number of participants needed to achieve study

objectives and how it was determined, including clinical and

statistical assumptions supporting any sample size

calculations

7

Recruitment #15 Strategies for achieving adequate participant enrolment to

reach target sample size

5

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Allocation: sequence

generation

#16a Method of generating the allocation sequence (eg,

computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random

sequence, details of any planned restriction (eg, blocking)

should be provided in a separate document that is

unavailable to those who enrol participants or assign

interventions

7

Allocation

concealment

mechanism

#16b Mechanism of implementing the allocation sequence (eg,

central telephone; sequentially numbered, opaque, sealed

envelopes), describing any steps to conceal the sequence

until interventions are assigned

7

Allocation:

implementation

#16c Who will generate the allocation sequence, who will enrol

participants, and who will assign participants to

interventions

7

Blinding (masking) #17a Who will be blinded after assignment to interventions (eg,

trial participants, care providers, outcome assessors, data

analysts), and how

7

Blinding (masking):

emergency

unblinding

#17b If blinded, circumstances under which unblinding is

permissible, and procedure for revealing a participant’s

allocated intervention during the trial

6,7

Data collection plan #18a Plans for assessment and collection of outcome, baseline,

and other trial data, including any related processes to

promote data quality (eg, duplicate measurements, training

of assessors) and a description of study instruments (eg,

8

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questionnaires, laboratory tests) along with their reliability

and validity, if known. Reference to where data collection

forms can be found, if not in the protocol

Data collection plan:

retention

#18b Plans to promote participant retention and complete follow-

up, including list of any outcome data to be collected for

participants who discontinue or deviate from intervention

protocols

8

Data management #19 Plans for data entry, coding, security, and storage, including

any related processes to promote data quality (eg, double

data entry; range checks for data values). Reference to

where details of data management procedures can be

found, if not in the protocol

8

Statistics: outcomes #20a Statistical methods for analysing primary and secondary

outcomes. Reference to where other details of the statistical

analysis plan can be found, if not in the protocol

8

Statistics: additional

analyses

#20b Methods for any additional analyses (eg, subgroup and

adjusted analyses)

8

Statistics: analysis

population and

missing data

#20c Definition of analysis population relating to protocol non-

adherence (eg, as randomised analysis), and any statistical

methods to handle missing data (eg, multiple imputation)

8

Data monitoring:

formal committee

#21a Composition of data monitoring committee (DMC); summary

of its role and reporting structure; statement of whether it is

independent from the sponsor and competing interests; and

reference to where further details about its charter can be

n/a

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found, if not in the protocol. Alternatively, an explanation of

why a DMC is not needed

Data monitoring:

interim analysis

#21b Description of any interim analyses and stopping guidelines,

including who will have access to these interim results and

make the final decision to terminate the trial

8

Harms #22 Plans for collecting, assessing, reporting, and managing

solicited and spontaneously reported adverse events and

other unintended effects of trial interventions or trial conduct

9

Auditing #23 Frequency and procedures for auditing trial conduct, if any,

and whether the process will be independent from

investigators and the sponsor

8

Research ethics

approval

#24 Plans for seeking research ethics committee / institutional

review board (REC / IRB) approval

9

Protocol

amendments

#25 Plans for communicating important protocol modifications

(eg, changes to eligibility criteria, outcomes, analyses) to

relevant parties (eg, investigators, REC / IRBs, trial

participants, trial registries, journals, regulators)

9

Consent or assent #26a Who will obtain informed consent or assent from potential

trial participants or authorised surrogates, and how (see

Item 32)

5

Consent or assent:

ancillary studies

#26b Additional consent provisions for collection and use of

participant data and biological specimens in ancillary

studies, if applicable

n/a

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Confidentiality #27 How personal information about potential and enrolled

participants will be collected, shared, and maintained in

order to protect confidentiality before, during, and after the

trial

7,8

Declaration of

interests

#28 Financial and other competing interests for principal

investigators for the overall trial and each study site

10

Data access #29 Statement of who will have access to the final trial dataset,

and disclosure of contractual agreements that limit such

access for investigators

9

Ancillary and post

trial care

#30 Provisions, if any, for ancillary and post-trial care, and for

compensation to those who suffer harm from trial

participation

9

Dissemination policy:

trial results

#31a Plans for investigators and sponsor to communicate trial

results to participants, healthcare professionals, the public,

and other relevant groups (eg, via publication, reporting in

results databases, or other data sharing arrangements),

including any publication restrictions

9


authorship

#31b Authorship eligibility guidelines and any intended use of

professional writers

n/a


reproducible

research

#31c Plans, if any, for granting public access to the full protocol,

participant-level dataset, and statistical code

9

Informed consent #32 Model consent form and other related documentation given n/a

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materials to participants and authorised surrogates

Biological specimens #33 Plans for collection, laboratory evaluation, and storage of

biological specimens for genetic or molecular analysis in the

current trial and for future use in ancillary studies, if

applicable

n/a

The SPIRIT checklist is distributed under the terms of the Creative Commons Attribution License CC-

BY-ND 3.0. This checklist can be completed online using https://www.goodreports.org/, a tool made

by the EQUATOR Network in collaboration with Penelope.ai

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https://www.goodreports.org/

https://www.equator-network.org

https://www.penelope.ai




Journal: BMJ Open

Manuscript ID bmjopen-2019-030580.R1


Date Submitted by the Author: 11-Jun-2019


<b>Primary Subject Heading</b>: Anaesthesia

Secondary Subject Heading: Evidence based practice





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Jiske C.T. Sloekers*1, Michael Bos2, Govert Hoogland1,4, Caroline H.G. Bastiaenen5, Sander M.J. van Kuijk6, Maurice Theunissen2, Kim Rijkers1,3,4, Jim T.A. Dings1,3, Albert Colon3, Rob Rouhl7, Olaf E.M.G. Schijns1,3,4



Running title ESPAIN trialKeywords drug-resistant epilepsy, epilepsy surgery, opioids, post-craniotomy headache, s-ketamine, temporal lobe epilepsyWord count abstract 284Word count manuscript 3260 Protocol version: Issue date: 29-05-2018Protocol amendment number: 01Authors: JS, MB, OS Revision chronology: Version 00, 2018-Feb-07, OriginalVersion 01, 2018-May-29, Amendment 01:Reason for amendment: addition of clarification of action in case that patients experience persisting pain or hallucinations.

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ABSTRACTIntroduction Effective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy. This randomised parallel group design trial compares s-ketamine with a placebo as add on medication to a multimodal pain approach.Methods and analysisIn total 62 adult participants, undergoing anterior temporal lobectomy for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg.kg-1 bolus followed by a continuous infusion of 0.1 mg.kg-1.h-1 of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression.Ethics and disseminationEthical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal.Registration detailsThis study has been registered in the Dutch National Trial Register (NTR6480).







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INTRODUCTION

Until recently, clinicians strongly believed that patients had minimal pain and discomfort following craniotomy, based on low average pain intensity scores in a frequently cited retrospective study. However, their results were based only on a short (90 minutes) post-operative observation of patients who received substantial intra-operative analgesics.1 Contrarily, post-craniotomy headache is the most common adverse event following craniotomy. The reported incidence is highly variable, rising up to 91% depending on the criteria used for the definition of post-craniotomy headache.2-5 According to the International Classification of Headache Disorders (3rd edition) by the International Headache Society, post-craniotomy headache is defined as a headache that develops within 7 days after craniotomy. Acute post-craniotomy headache resolves within 3 months, whereas the chronic form persists for more than 3 months.6 Accordingly to this definition, the reported incidence of post-craniotomy headache is 40%, whereby 10.7% was limited to the acute stage and 29.3% developed into a chronic form.7 When the definition is broadened to onset within 30 days, the reported incidence rises to 62% and when including headache anytime during follow-up, the incidence reported is 91%.3 The incidence of post-craniotomy headache after temporal lobectomy for focal drug-resistant epilepsy is reported as 17.5% for headaches that persist for more than 2 months and 11.9% for more than 1 year.8 This is unfavourable as chronic headaches are often associated with symptoms of depression and anxiety that in turn interfere with quality of life.7 9 Since the pathophysiology of post-craniotomy headache is not well understood, it is generally poorly managed.2 10 Acetaminophen is often not sufficient and the use of non-steroidal anti-inflammatory drugs in neurosurgical procedures is controversial due to their effect on bleeding time.11 The current practice is opioids combined with acetaminophen, yet there still is continuing controversy regarding the choice of the “best” regimen.10 12 13 The use of potent analgesic opioid drugs, administered by a patient controlled analgesia (PCA) pump, may cause serious side effects such as respiratory depression, vomiting, nausea, ileus, and may lead to deterioration of consciousness, which interferes with the assessment of the neurologic status and post-craniotomy pain.10 The addition of other non-opioid analgesics, such as s-ketamine, might be effective in reducing the need for opioid analgesics. The analgesic effects of s-ketamine are mediated by an N-methyl-D-aspartate-receptor antagonist mechanism, which improves the efficacy of opioids and reduces the development of chronic pain syndromes.14-17 When used in high doses, this drug is known for its reversible neuropsychiatric side effects such as hallucinations, nightmares and blurred vision. However, when s-ketamine is administered in low doses, these side effects are well tolerated, reversible and occur in a minority of patients.14 Benefits of s-ketamine in postoperative pain management and its opioid sparing effects have already been reported in abdominal, thoracic and orthopaedic surgeries.14 18 The most recent systematic review on the use of s-ketamine in craniotomies showed an overall opioid sparing effect of 40%. However, the effect on pain intensity scores was very diverse, whereby only 8 of 34 studies showed a significant reduction. The majority of the studies used was underpowered for pain intensity scores, the assessment of pain intensity scores differed largely and factors that influence pain perception, such as anxiety and depression, were poorly documented.19


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Recruitment, eligibility criteria and informed consentApproximately 21 TLE patients are scheduled for surgery every year in the neurosurgical outpatient clinic of the MUMC+. All patients scheduled for elective ATL with or without amygdalohippocampectomy will be considered for eligibility. Prior to their visit to the outpatient clinic, these patients will be informed about their up-coming operation by one of the three epileptologists at Kempenhaeghe Academic Centre for Epileptology, Heeze, rhe Netherlands. The epileptologist will ask patient’s permission for a phone interview by the GCP-certified coordinating investigator (JS). In this phone call the patient will receive detailed study information and will be asked for permission to send a patient information brochure by mail. The patient will have a minimum of 14 days to consider participation, starting from the moment of receiving the patient information brochure at home. During the visit at the neurosurgical outpatient clinic of the MUMC+, the patient will be informed about the surgery by one of the two neurosurgeons who perform the epilepsy surgery. Afterwards, the coordinating investigator (JS) will answer any remaining questions about the trial. When it is clear that the patient has understood all the provided information and wants to participate in the trial, both the patient and the coordinating investigator will sign the informed consent sheet, after which the patient will be included in the randomization procedure. Patients eligible for the trial must comply with all of the inclusion criteria and are not allowed to have any of the exclusion criteria, as listed in table 1. The general practitioner will be informed by letter about the patient’s participation in the ESPAIN trial.










Interventions Patients will be randomly allocated to either of the two study arms. The intervention group receives s-ketamine (Ketanest-S®, Pfizer, Dun Laoghaire, Ireland) and the control group receives a placebo (0.9% NaCl). The operation consists of an ATL with or without an amygdalohippocampectomy performed with a standard surgical technique for all patients by either of two neurosurgeons (OS and JD). The trial

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medication will start perioperatively after induction, but before incision, and will be continued for 48 hours in total. All patients will receive general anaesthesia as part of the routine medical treatment as further specified in the overview of interventions in figure 1. No premedication will be given, except for the patient’s own antiepileptic medication. In case the potential side effects of s-ketamine cause too much discomfort for patients, this will be registered as an adverse event. In case of severe hallucinations, the study medication will be terminated and the PCA-pump and acetaminophen will be continued. The patient will not be deblinded or withdrawn from the study. Data collection will continue according to the protocol. In case a patient experiences severe pain, the study medication will be discontinued and regular s-ketamine protocol will be started. This consists of morphine in a PCA-pump, acetaminophen and s-ketamine. Since the patient already receives morphine in a PCA-pump and acetaminophen, only the study medication will be discontinued and replaced with s-ketamine. The patient will not be deblinded and data collection will continue according to protocol. Severe pain will be defined as unsatisfactory pain treatment despite receiving the maximum amount of morphine with the highest possible PCA-pump dosage for at least one hour. When the trial medication is discontinued and regular s-ketamine protocol is started, the time, pain score (NRS and VAS) and the reason for discontinuation of trial medication will be registered.

OutcomesThe primary study outcome is the total postoperative opioid consumption (mg) in both study arms, measured at the 7th postoperative day, with interim measurements at 24, 48, 72 and 96 hours postoperatively. Secondary study outcomes are length of hospital stay (days), postoperative pain intensity scores from day 0 until 4 and at day 7 postoperatively, and the occurrence of several potential adverse events. Pain intensity is quantified in scores using the Visual Analogue Scale (VAS), range 0-100mm, and Numeric Rating Scale (NRS), range 0-10. Specifically the occurrence of delirium as adverse event is assessed every day for the first seven postoperative days using the Delirium Observation Screening (DOS) scale. Other potential adverse events that will be registered are: hallucinations, nausea, vomiting, dizziness, vivid dreams or nightmares, diplopia, blurred vision, nystagmus, and elevated blood pressure or heart rate. Furthermore, patient health-related quality of life, surgical fear, depression, pain catastrophizing, severity of pain, neuropathic pain and characteristics of the headache will be assessed using standardised and validated questionnaires as presented in table 2.


SFQ Surgical Fear QuestionnaireCES-D Centre for Epidemiologic Studies Depression scale

PCS Pain Catastrophizing ScaleBPI-SF Brief Pain Inventory-Short Form

DN4-interview Douleur Neuropathique (7 self-report items)T0 – preoperatively




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The reliability and validity of the NRS and VAS scoring systems is high and both scores are recommended as sensitive and responsive in measuring pain intensity20. The DN4-interview is a diagnostic tool that enables physicians to make a distinction between nociceptive and neuropathic pain and is linguistically validated for usage in Dutch21, whereby only the 7 self-report items will be used (DN4-interview)22. The CES-D is a screening tool for depression with excellent validity23. Furthermore, the SFQ, PCS, RAND-36, BPI-SF and DOS have also been proven valid and reliable24-28. The self-compiled questionnaire inquiring the characteristics of the headache was compiled by a headache neurologist, based on the International Classification of Headache Disorders-3rd edition by the International Headache Society. Other study parameters which will be documented are baseline values such as gender, age, weight, type of antiepileptic drugs, epilepsy duration, details of the surgery, duration of surgery, side of surgery and seizure outcome according to International League Against Epilepsy and Engel class.


Sample sizeA minimum of 62 patients is needed for the study sample, with 31 patients in each study arm. A 5% dropout rate has been included in the calculation. The sample size calculation is based on clinical data from previous patients who underwent resective epilepsy surgery for TLE and were administered s-ketamine as pain medication. It is performed with Gpower based on longitudinal analysis of the data with 5 measurements, and based on the primary outcome: a difference of standards of opioid consumption. Expected means and standard deviations (SD) for each group (intervention group 32mg and control group 42mg of opioid consumption (SD 24mg)), with an effect size based on Cohen d of 0.29, lead to a sample size of n=58. Presuming a level of significance below 5% and a power of 0.80, a minimum of 58 patients is needed, with the addition of 4 people for an expected drop out of 5%, 62 people have to be included in the trial. With an expectation of 21 eligible trial participants every year, the duration of the period of inclusion will be 3 years.


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Data collectionOpioid consumption peroperatively and during a patient’s stay at the recovery is registered by the anaesthesiologist in the patients file. The PCA pump is managed by dedicated anaesthesiologic nurse practitioners, who register the opioid consumption from the PCA pump in the patients file. Furthermore all medication administered at the regular ward, amongst which are oral opioids, is registered by nurses in the patients file. Pain and DOS scores will be taken by nurses, after which they will be registered in the patients file. All perioperative complications and adverse events will be registered daily in the patients file. Therefore the primary outcome measure, opioid consumption, will be collected from the patients file. The secondary outcomes, pain and DOS scores, perioperative complications, adverse events and baseline demographic values such as gender, age, weight, details regarding the surgery, the duration of surgery and the length of hospital stay will also be collected from the patients file. All questionnaires and the pain diary will be filled in web-based through the electronic data capture system Castor EDC, after which data will automatically be stored. All data will be recorded using an electronic case report form, web-based, in Castor EDC. Data will be stored coded, which warrants privacy of participants.

Statistics At baseline, normally distributed variables will be presented as mean values and standard deviations. Non normally distributed variables will be presented as median and range. Categorical data will be presented as frequencies percentages. All collected variables will be presented as a total for the entire study population and stratified by randomised subgroup. There will be no formal testing for statistical differences between the randomised groups.We will perform all analyses on the intention to treat sample. In case study medication has to be terminated and regular s-ketamine protocol will be started, this will have no effect on the intention to treat analysis and will be regarded as cointervention. Linear mixed-effects regression will be used to test for statistical differences between the groups, taking the longitudinal nature of the data into account (5 measurements). This will be performed based on the primary outcome measure: standards of opioid consumption. In case of clinically meaningful imbalance in baseline characteristics between groups, these variables will be regarded as potential confounders, and will be taken into account using multivariable linear mixed-effects regression. The assumption of a multivariate normally distributed outcome will be checked by visually assessing the histogram of residuals and Q-Q plots. In case of clear violation the outcome variable will be transformed using a transformation that solves the non-normality of residuals. Differences are considered to be statistically significant when p ≤ 0.05. Missing data will not be replaced. Analyses will be performed using SPSS 23 for Windows (SPSS Inc., Chicago , IL, USA). We will consider performing a post hoc subgroup analysis on the difference in opioid consumption between patients that underwent a standard anterior temporal resection or a maximal temporal resection. Results of these analyses will be considered preliminary as the sample size calculation was performed on the main analysis and power is likely to be insufficient.


Monitoring and auditingMonitoring will be performed by a member of the local data monitoring committee, from the Clinical Trial Centre Maastricht. Prior to the start of the trial, the study has been classified as low risk. Monitoring will be performed at least three times during the study. Once after the first three patients have been included, once 1,5 year after trial onset and one last time at the end of the inclusion period. Monitoring visits include control of data collection, informed consent forms, compliance to the

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protocol and applicable laws and regulations and the control of general rights and well-being of trial participants. A monitoring visit report will be sent to the local medical ethical committee and the principal investigator. Unannounced audits can be performed by the audit team of the Clinical Trial Centre Maastricht.


Patient and public involvement statementThis research protocol was developed without the involvement of patients or the public. Patients were not invited to contribute to the design of the research methods, material and design or to the writing and editing of any documents.





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TRIAL REGISTRATION DATA SETPrimary registry and trial identifying number: NTR6480Date of registration in primary registry: 4 July, 2017Secondary identifying numbers: 2017-002616-13Source(s) of monetary or material support: Maastricht Universitair Medisch Centrum +Primary sponsor: Maastricht Universitair Medisch Centrum +Secondary sponsor: not applicableContact for public and scientific queries: JS, [email protected] Public title: S-ketamine for acute and chronic headache after brainsurgeryScientific title: The effect of perioperative intravenous s-ketamine on acute and chronic

postoperative craniotomy pain compared to placeboCountries of recruitment: The Netherlands Health condition(s) or problem(s) studied: Post-craniotomy painIntervention: Active comparator: s-ketamine

Placebo comparator: NaCl 0.9%Key inclusion and exclusion criteria: Ages eligible for study: ≥18 years; Sexes eligible for study: both;

Accepts healthy volunteers: noInclusion criteria: age >18 years, elective resective surgery for drug-resistant temporal lobe epilepsy,

drug-resistant epilepsy, based on: (1) chronic, focal epilepsy; (2) not seizure free with antiepileptic medication; (3) no medication options due to adverse effects, signed informed consent for trial participation

Exclusion criteria: declined informed consent, allergy to any of the trial medications, current chronic pain, such as, but not limiting to, migraine or other headaches, chronic pain treatment with use of different kinds of pain medication, alcohol, hard- or soft drug abuses, inability to complete questionnaires or language barrier, history of psychiatric complaints for which treatment was performed, history of craniotomy or subdural electrode implantation

Study type: Interventional; Allocation: randomized; Intervention model: parallel assignment Masking: double blind; Primary purpose: treatment; Phase IV

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Date of first enrolment: 14-08-2018Target sample size: 62Recruitment status: RecruitingPrimary outcome(s): Total postoperative opioid consumption at the 7th postoperative day with

interim measurements at 24, 48, 72 and 96 hoursKey secondary outcome(s): Postoperative pain intensity scores (VAS+NRS), patient health-related

quality of life, psychological parameters, length of hospital stay and adverse events

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References
















16. Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med 2018;43(5):521-46. doi: 10.1097/AAP.0000000000000808

17. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand 2014;58(10):1199-213. doi: 10.1111/aas.12377



20. Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. PAIN® 2011;152(10):2399-404. doi: 10.1016/j.pain.2011.07.005

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maximum 15 mg/h






ketamine









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Kempenhaeghe


excluded













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Ann Intern Med. 2013;158(3):200-207

Reporting Item

Page

Number



1



2,9

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Trial registration:

data set



10



Roles and

responsibilities:

contributorship


Roles and

responsibilities:

sponsor contact

information


Roles and

responsibilities:

sponsor and funder






10

Roles and

responsibilities:

committees






n/a

Background and

rationale



4

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Background and


comparators






exploratory)

5




obtained

5




5

Interventions:

description



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5,6

Interventions:

modifications




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Interventions:

adherance




5,6

Interventions:

concomitant care



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recommended

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(see Figure)

7




calculations

7



5

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generation







interventions

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Allocation

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implementation



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analysts), and how

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retention




protocols

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analyses


adjusted analyses)

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population and

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Data monitoring:

interim analysis




8




9




8

Research ethics

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Protocol

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ancillary studies




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trial

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trial results






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applicable

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Journal: BMJ Open

Manuscript ID bmjopen-2019-030580.R2


Date Submitted by the Author: 23-Jul-2019


<b>Primary Subject Heading</b>: Anaesthesia

Secondary Subject Heading: Evidence based practice





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Jiske C.T. Sloekers*1, Michael Bos2, Govert Hoogland1,4, Caroline H.G. Bastiaenen5, Sander M.J. van Kuijk6, Maurice Theunissen2, Kim Rijkers1,3,4, Jim T.A. Dings1,3, Albert Colon3, Rob P.W. Rouhl7, Olaf E.M.G. Schijns1,3,4



Running title ESPAIN trialKeywords drug-resistant epilepsy, epilepsy surgery, opioids, post-craniotomy headache, s-ketamine, temporal lobe epilepsyWord count abstract 284Word count manuscript 3990Protocol version: Issue date: 29-05-2018Protocol amendment number: 01Authors: JS, MB, OS Revision chronology: Version 00, 2018-Feb-07, OriginalVersion 01, 2018-May-29, Amendment 01:Reason for amendment: addition of clarification of action in case that patients experience persisting pain or hallucinations.

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ABSTRACTIntroduction Effective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy. This randomised parallel group design trial compares s-ketamine with a placebo as add on medication to a multimodal pain approach.Methods and analysisIn total 62 adult participants, undergoing anterior temporal lobectomy for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg.kg-1 bolus followed by a continuous infusion of 0.1 mg.kg-1.h-1 of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression.Ethics and disseminationEthical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal.Registration detailsThis study has been registered in the Dutch National Trial Register (NTR6480).







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INTRODUCTION

Until recently, clinicians strongly believed that patients had minimal pain and discomfort following craniotomy, based on low average pain intensity scores in a frequently cited retrospective study. However, their results were based only on a short (90 minutes) post-operative observation of patients who received substantial intra-operative analgesics.1 Contrarily, post-craniotomy headache is the most common adverse event following craniotomy. The reported incidence is highly variable, rising up to 91% depending on the criteria used for the definition of post-craniotomy headache.2-5 According to the International Classification of Headache Disorders (3rd edition) by the International Headache Society, post-craniotomy headache is defined as a headache that develops within 7 days after craniotomy. Acute post-craniotomy headache resolves within 3 months, whereas the chronic form persists for more than 3 months.6 Accordingly to this definition, the reported incidence of post-craniotomy headache is 40%, whereby 10.7% was limited to the acute stage and 29.3% developed into a chronic form.7 When the definition is broadened to onset within 30 days, the reported incidence rises to 62% and when including headache anytime during follow-up, the incidence reported is 91%.3 The incidence of post-craniotomy headache after temporal lobectomy for focal drug-resistant epilepsy is reported as 17.5% for headaches that persist for more than 2 months and 11.9% for more than 1 year.8 This is unfavourable as chronic headaches are often associated with symptoms of depression and anxiety that in turn interfere with quality of life.7 9 Since the pathophysiology of post-craniotomy headache is not well understood, it is generally poorly managed.2 10 Acetaminophen is often not sufficient and the use of non-steroidal anti-inflammatory drugs in neurosurgical procedures is controversial due to their effect on bleeding time.11 The current practice is opioids combined with acetaminophen, yet there still is continuing controversy regarding the choice of the “best” regimen.10 12 13 The use of potent analgesic opioid drugs, administered by a patient controlled analgesia (PCA) pump, may cause serious side effects such as respiratory depression, vomiting, nausea, ileus, and may lead to deterioration of consciousness, which interferes with the assessment of the neurologic status and post-craniotomy pain.10 The addition of other non-opioid analgesics, such as s-ketamine, might be effective in reducing the need for opioid analgesics. The analgesic effects of s-ketamine are mediated by an N-methyl-D-aspartate-receptor antagonist mechanism, which improves the efficacy of opioids and reduces the development of chronic pain syndromes.14-17 When used in high doses, this drug is known for its reversible neuropsychiatric side effects such as hallucinations, nightmares and blurred vision. However, when s-ketamine is administered in low doses, these side effects are well tolerated, reversible and occur in a minority of patients.14 Benefits of s-ketamine in postoperative pain management and its opioid sparing effects have already been reported in abdominal, thoracic and orthopaedic surgeries.14 18 The most recent systematic review on the use of s-ketamine in craniotomies showed an overall opioid sparing effect of 40%. However, the effect on pain intensity scores was very diverse, whereby only 8 of 34 studies showed a significant reduction. The majority of the studies used was underpowered for pain intensity scores, the assessment of pain intensity scores differed largely and factors that influence pain perception, such as anxiety and depression, were poorly documented.19


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Recruitment, eligibility criteria and informed consentApproximately 21 TLE patients are scheduled for surgery every year in the neurosurgical outpatient clinic of the MUMC+. All patients scheduled for elective ATL with or without amygdalohippocampectomy will be considered for eligibility. Prior to their visit to the outpatient clinic, these patients will be informed about their up-coming operation by one of the three epileptologists at Kempenhaeghe Academic Centre for Epileptology, Heeze, the Netherlands. The epileptologist will ask patient’s permission for a phone interview by the GCP-certified coordinating investigator (JS). In this phone call the patient will receive detailed study information and will be asked for permission to send a patient information brochure by mail. The patient will have a minimum of 14 days to consider participation, starting from the moment of receiving the patient information brochure at home. During the visit at the neurosurgical outpatient clinic of the MUMC+, the patient will be informed about the surgery by one of the two neurosurgeons who perform the epilepsy surgery. Afterwards, the coordinating investigator (JS) will answer any remaining questions about the trial. When it is clear that the patient has understood all the provided information and wants to participate in the trial, both the patient and the coordinating investigator will sign the informed consent sheet, after which the patient will be included in the randomization procedure. Patients eligible for the trial must comply with all of the inclusion criteria and are not allowed to have any of the exclusion criteria, as listed in table 1. The general practitioner will be informed by letter about the patient’s participation in the ESPAIN trial.Resective temporal lobe surgery is the golden standard curative therapy for drug-resistant temporal lobe epilepsy. Novel methods such as MRI guided laser institutional thermal therapy (LITT) are not yet available in the Netherlands, only stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation is applied for highly selected patients. Therefore we do not expect a drop in participant recruitment.










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Interventions Patients will be randomly allocated to either of the two study arms. The intervention group receives s-ketamine (Ketanest-S®, Pfizer, Dun Laoghaire, Ireland) and the control group receives a placebo (0.9% NaCl). The operation consists of an ATL with or without an amygdalohippocampectomy performed with a standard surgical technique for all patients by either of two neurosurgeons (OS and JD). The trial medication will start perioperatively after induction, but before incision, and will be continued for 48 hours in total. The intervention group will receive a bolus of 0.25mg/kg s-ketamine, followed by a continuous infusion of 0.1mg/kg. This dosage is based on the Dutch Association of Anaesthesiology guidelines on postoperative pain The placebo (NaCl 0.9%) will be administered in the same dosage and packaging as s-ketamine. All patients will receive general anaesthesia as part of the routine medical treatment as further specified in the overview of interventions in figure 1. No premedication will be given, except for the patient’s own antiepileptic medication. In case the potential side effects of s-ketamine cause too much discomfort for patients, this will be registered as an adverse event. In case of severe hallucinations, the study medication will be terminated and the PCA-pump and acetaminophen will be continued. The patient will not be deblinded or withdrawn from the study. Data collection will continue according to the protocol. In case a patient experiences severe pain, the study medication will be discontinued and regular s-ketamine protocol will be started. This consists of morphine in a PCA-pump, acetaminophen and s-ketamine. Since the patient already receives morphine in a PCA-pump and acetaminophen, only the study medication will be discontinued and replaced with s-ketamine. S-ketamine is chosen as rescue medication, since it is a potent analgesic drug and the current practice for postoperative rescue pain management is already based on use of s-ketamine. Increasing the morphine dosage in the PCA pump is undesirable due to the subsequent increase in adverse events caused by opioids. Therefore we have chosen to apply the current practice of s-ketamine as rescue medication. The patient will not be deblinded and data collection will continue according to protocol. Severe pain will be defined as unsatisfactory pain treatment despite receiving the maximum amount of morphine with the highest possible PCA-pump dosage for at least one hour. When the trial medication is discontinued and regular s-ketamine protocol is started, the time, pain score (NRS and VAS) and the reason for discontinuation of trial medication will be registered.

OutcomesThe primary study outcome is the total postoperative opioid consumption (mg) in both study arms, measured at the 7th postoperative day, with interim measurements at 24, 48, 72 and 96 hours postoperatively. Secondary study outcomes are length of hospital stay (days), postoperative pain intensity scores from day 0 until 4 and at day 7 postoperatively, and the occurrence of several potential adverse events. Pain intensity is quantified in scores using the Visual Analogue Scale (VAS), range 0-100mm, and Numeric Rating Scale (NRS), range 0-10. In case pain intensity scores and the accompanying opioid consumption achieve paradoxical results, implications of the effect of s-ketamine on postoperative headache will be based on the opioid consumption, since it is the main outcome measure. Specifically the occurrence of delirium as adverse event is assessed every day for the first seven postoperative days using the Delirium Observation Screening (DOS) scale. Other potential adverse events that will be registered are: hallucinations, nausea, vomiting, dizziness, vivid dreams or nightmares, diplopia, blurred vision, nystagmus, and elevated blood pressure or heart rate. Furthermore, patient health-related quality of life, surgical fear, depression, pain catastrophizing, severity of pain, neuropathic pain and characteristics of the headache will be assessed using standardised and validated questionnaires as presented in table 2.


SFQ Surgical Fear Questionnaire

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CES-D Centre for Epidemiologic Studies Depression scalePCS Pain Catastrophizing Scale

BPI-SF Brief Pain Inventory-Short FormDN4-interview Douleur Neuropathique (7 self-report items)

T0 – preoperatively




The reliability and validity of the NRS and VAS scoring systems is high and both scores are recommended as sensitive and responsive in measuring pain intensity20. The DN4-interview is a diagnostic tool that enables physicians to make a distinction between nociceptive and neuropathic pain and is linguistically validated for usage in Dutch21, whereby only the 7 self-report items will be used (DN4-interview)22. The CES-D is a screening tool for depression with excellent validity23. Furthermore, the SFQ, PCS, RAND-36, BPI-SF and DOS have also been proven valid and reliable24-28. The self-compiled questionnaire inquiring the characteristics of the headache was compiled by a headache neurologist, based on the International Classification of Headache Disorders-3rd edition by the International Headache Society. Other study parameters which will be documented are baseline values such as gender, age, weight, type of antiepileptic drugs, epilepsy duration, details of the surgery, duration of surgery, side of surgery and seizure outcome according to International League Against Epilepsy and Engel class.


Sample sizeA minimum of 62 patients is needed for the study sample, with 31 patients in each study arm. A 5% dropout rate has been included in the calculation. The sample size calculation is based on clinical data from previous patients who underwent resective epilepsy surgery for TLE and were administered s-ketamine as pain medication. It is performed with Gpower based on longitudinal analysis of the data with 5 measurements, and based on the primary outcome: a difference of standards of opioid consumption. Expected means and standard deviations (SD) for each group (intervention group 32mg and control group 42mg of opioid consumption (SD 24mg)), with an effect size based on Cohen d of 0.29, lead to a sample size of n=58. Presuming a level of significance below 5% and a power of 0.80, a minimum of 58 patients is needed, with the addition of 4 people for an expected drop out of 5%, 62 people have to be included in the trial. With an expectation of 21 eligible trial participants every year, the duration of the period of inclusion will be 3 years.

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Data collectionOpioid consumption peroperatively and during a patient’s stay at the recovery is registered by the anaesthesiologist in the patients file. The PCA pump is managed by dedicated anaesthesiologic nurse practitioners, who register the opioid consumption from the PCA pump in the patients file. Furthermore all medication administered at the regular ward, amongst which are oral opioids, is registered by nurses in the patients file. Pain and DOS scores will be taken by nurses, after which they will be registered in the patients file. All perioperative complications and adverse events will be registered daily in the patients file. Therefore the primary outcome measure, opioid consumption, will be collected from the patients file. The secondary outcomes, pain and DOS scores, perioperative complications, adverse events and baseline demographic values such as gender, age, weight, details regarding the surgery, the duration of surgery and the length of hospital stay will also be collected from the patients file. All questionnaires and the pain diary will be filled in web-based through the electronic data capture system Castor EDC, after which data will automatically be stored. All data will be recorded using an electronic case report form, web-based, in Castor EDC. Data will be stored coded, which warrants privacy of participants.

Statistics At baseline, normally distributed variables will be presented as mean values and standard deviations. Non normally distributed variables will be presented as median and range. Categorical data will be presented as frequencies percentages. All collected variables will be presented as a total for the entire study population and stratified by randomised subgroup. There will be no formal testing for statistical differences between the randomised groups.We will perform all analyses on the intention to treat sample. In case study medication has to be terminated and regular s-ketamine protocol will be started, this will have no effect on the intention to treat analysis and will be regarded as cointervention. Linear mixed-effects regression will be used to test for statistical differences between the groups, taking the longitudinal nature of the data into account (5 measurements). This will be performed based on the primary outcome measure: standards of opioid consumption. In case of clinically meaningful imbalance in baseline characteristics between groups, these variables will be regarded as potential confounders, and will be taken into account using multivariable linear mixed-effects regression. The assumption of a multivariate normally distributed outcome will be checked by visually assessing the histogram of residuals and Q-Q plots. In case of clear violation the outcome variable will be transformed using a transformation that solves the non-normality of residuals. Differences are considered to be statistically significant when p ≤ 0.05. Missing data will not be replaced. Analyses will be performed using SPSS 23 for Windows (SPSS Inc., Chicago , IL, USA). We will consider performing a post hoc subgroup analysis on the difference in opioid consumption between patients that underwent a standard anterior temporal resection or a maximal temporal resection. Results of these analyses will be considered preliminary as the sample size calculation was performed on the main analysis and power is likely to be insufficient.

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Monitoring and auditingMonitoring will be performed by a member of the local data monitoring committee, from the Clinical Trial Centre Maastricht. Prior to the start of the trial, the study has been classified as low risk. Monitoring will be performed at least three times during the study. Once after the first three patients have been included, once 1,5 year after trial onset and one last time at the end of the inclusion period. Monitoring visits include control of data collection, informed consent forms, compliance to the protocol and applicable laws and regulations and the control of general rights and well-being of trial participants. A monitoring visit report will be sent to the local medical ethical committee and the principal investigator. Unannounced audits can be performed by the audit team of the Clinical Trial Centre Maastricht.


Patient and public involvement statementThis research protocol was developed without the involvement of patients or the public. Patients were not invited to contribute to the design of the research methods, material and design or to the writing and editing of any documents.



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