Long-term Pain Modulation by Intravenous Esketamine in CRPS

Официальное название

Long-term Pain Modulation by Intravenous Esketamine in Complex Regional Pain Syndrome: a Non-inferiority Study

Обзор

Intravenous administration of esketamine is an effective recognized therapeutic option in refractory pain in CRPS, which sometimes in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. Inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective. The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days. The end of study is at 6 months after the start of the study/treatment.

Подробное описание

Rationale: Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition of one or more limbs. Its diagnosis is based on (combinations of) underlying pathophysiological mechanisms. Achieving relevant pain relief fails in a significant proportion of CRPS patients. Intravenous administration of esketamine is an effective therapeutic option in refractory pain in CRPS, which in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration; however, logistical boundaries limit this therapy. Esketamine infusions in an outpatient setting might increase flexibility and availability of esketamine treatment. However, inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective.

Objective: The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days at 3 months after the start of the study/treatment. The secondary objective is to assess pain scores till 6 months follow-up, logistical problems, adverse effects, questionnaires, thermography and quantitative sensory testing in both treatment groups.

Study design: Prospective, randomized, non-inferiority study in 60 patients

Study population: Sixty adult patients with chronic pain due to CRPS

Intervention: All patients will receive intravenous esketamine. The standard treatment group receives intravenous esketamine for 6 consecutive days (in hospital). The experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.

Main study parameters/endpoints: The main study parameter is pain intensity, measured by means of Numerical Rating Scale (NRS), to demonstrate non-inferiority of the experimental treatment after three months.

Вмешательства

• Препарат S-ketamine infusion inpatient setting
  S-ketamine is administered intravenously for six consecutive days. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.
• Препарат S-ketamine infusion outpatient setting
  S-ketamine is administered intravenously for six hours. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.

Первичные конечные точки

• Change from baseline pain scores [Срок оценки: Baseline (week 0), During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11), Follow-up (3 months), End of study (6 months)]

Вторичные конечные точки (11)

• Change from baseline Quantitative Sensory Testing [Срок оценки: Baseline (week 0) and follow-up visit (week 12)]
• Change from baseline Thermography [Срок оценки: Baseline (week 0) and follow-up visit (week 12)]
• Adverse events due to S-ketamine infusion [Срок оценки: During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11)]
• Change from baseline pain medication dose [Срок оценки: Baseline (week 0), follow-up visit (3 months) and end of study (6 months)]
• Change from baseline Complex Regional Pain Syndrome severity score [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]
• Global Perceived Effect [Срок оценки: During telephone consultation (week 1, 3, 5, 7, 9, 11), follow-up visit (3 months) and end of study (6 months)]
• Patient-Reported Outcomes Measurement Information System (PROMIS) -29 Profile [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]
• Short-form McGill Pain Questionnaire-2 [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]
• Pain Catastrophizing Scale [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]
• EQ-5D-5L. [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]
• Pain Self-Efficacy Questionnaire [Срок оценки: Baseline (week 0) and follow-up visit (3 months)]

Критерии участия

Критерии включения

• Meeting the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS ("the Budapest Criteria) (Harden et al., 2010) or having met the new IASP diagnostic criteria of CRPS ("CRPS with Remission of Some features") (Goebel et al., 2021).
• Willing and capable to participate in the study.
• CRPS in one upper extremity and/or CRPS in one lower extremity
• Treatment in an elective setting.
• Adequate comprehension of the Dutch language
• Age ≥ 18 years

Критерии исключения

• Severe liver disease
• Psychiatric (schizophrenia, psychosis, delirium, manic depression)
• Active substance abuse
• Intoxication with alcohol or other substances
• Poorly controlled hypertension
• Unstable angina
• High-risk coronary vascular disease
• Heart failure
• Elevated intracranial pressure
• Elevated intraocular pressure
• Thyrotoxicosis
• Pregnancy
• Combination with derivates of xanthines (theophylline) or ergometrine

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Нидерланды · 1 центр

• Erasmus MC — Rotterdam

Публикации

• Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14. PMID 19604642
• Mangnus TJP, Bharwani KD, Stronks DL, Dirckx M, Huygen FJPM. Ketamine therapy for chronic pain in The Netherlands: a nationwide survey. Scand J Pain. 2021 Aug 24;22(1):97-105. doi: 10.1515/sjpain-2021-0079. Print 2022 Jan 27. PMID 34432970
• Mangnus TJP, Dirckx M, Bharwani KD, de Vos CC, Frankema SPG, Stronks DL, Huygen FJPM. Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study. Pain Pract. 2021 Nov;21(8):890-897. doi: 10.1111/papr.13056. Epub 2021 Jul 24. PMID 34233070
• Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Chont M, Vatine JJ. Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268-274. doi: 10.1016/j.pain.2010.04.030. Epub 2010 May 20. PMID 20493633
• Grieve S, Perez RSGM, Birklein F, Brunner F, Bruehl S, Harden RN, Packham T, Gobeil F, Haigh R, Holly J, Terkelsen A, Davies L, Lewis J, Thomassen I, Connett R, Worth T, Vatine JJ, McCabe CS. Recommendations for a first Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies (COMPACT). Pain. 2017 Jun;158(6):1083-1090. doi: 10.1097/j.pain.0000000000000866. PMID 28178071
• Goebel A, Birklein F, Brunner F, Clark JD, Gierthmuhlen J, Harden N, Huygen F, Knudsen L, McCabe C, Lewis J, Maihofner C, Magerl W, Moseley GL, Terkelsen A, Thomassen I, Bruehl S. The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria. Pain. 2021 Sep 1;162(9):2346-2348. doi: 10.1097/j.pain.0000000000002245. No abstract available. PMID 33729210
• Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. 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 J PMID 29870458
• Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018-0664-x. PMID 29404715

Идентификаторы

NCT: NCT05212571 · NL77785.078.21 · 2021-000640-21 · MEC-2021-0426

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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