Intranasal Esketamine-dexmedetomidine Combination in Patients With Postherpetic Neuralgia
Efficacy of Intranasal Esketamine-dexmedetomidine Combination in Patients With Postherpetic Neuralgia: a Randomized, Double-blind, Active Drug-controlled Trial
Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome suffered by patients with herpes zoster and often adversely affect patients' normal lives, leading to declines in sleep and quality of life. Ketamine/esketamine has been used for treatment of chronic pain but may produce adverse psychiatric reactions at slightly higher doses, including dissociative symptoms, hallucinations, and nightmares; the sedative effect of dexmedetomidine helps mitigate its psychiatric side effects. A previous study in orthopedic surgery patients also showed that dexmedetomidine combined with esketamine can significantly improve perioperative analgesia and sleep quality. The investigators hypothesize that intranasal administration of dexmedetomidine combined with esketamine in patients with postherpetic neuralgia can improve analgesic efficacy.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Postherpetic neuralgia (PHN) is a chronic neuropathic pain syndrome suffered by patients with herpes zoster. The typical feature of PHN is deep burning pain in the affected unilateral dermatome, often accompanied by stabbing pain and itching, persisting for more than 3 months after the initial onset of herpes zoster. The incidence of PHN among patients with herpes zoster is approximately 10-20%. The chronic pain symptoms of PHN often adversely affect patients' normal lives, leading to declines in sleep and quality of life. Approximately 50% of PHN patients have sleep disturbances. These ultimately affect cognitive function and mental health.
Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and has long been used as a dissociative anesthetic. At subanesthetic doses, ketamine exhibits analgesic and antihyperalgesic effects. Guidelines recommend low-dose ketamine infusion for the treatment of chronic pain. Esketamine is the more potent right-handed enantiomer of ketamine, with stronger affinity for the NMDA receptor; its potency is approximately twice that of ketamine, and the incidence of adverse psychiatric reactions is lower in clinical use. Intranasal esketamine has been approved by the FDA for the treatment of adults with treatment-resistant depression and represents a more non-invasive route of administration.
Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. Dexmedetomidine acts on the locus coeruleus, inhibiting the release of norepinephrine from neurons in the locus coeruleus and the activity of the medullary-spinal descending neural pathways, thereby producing sedative and analgesic effects. In perioperative management, dexmedetomidine is widely used for postoperative adjuvant analgesia; it can also improve patients' sleep, producing a state resembling non-rapid eye movement sleep. Intranasal dexmedetomidine can be safely used in adults and children and is currently widely used for pediatric procedural sedation and preoperative medication.
Ketamine/esketamine can produce adverse psychiatric reactions at slightly higher doses, including dissociative symptoms, hallucinations, and nightmares; the sedative effect of dexmedetomidine helps mitigate its psychiatric side effects. A previous study in orthopedic surgery patients also showed that dexmedetomidine combined with esketamine can significantly improve perioperative analgesia and sleep quality. The investigators hypothesize that intranasal administration of dexmedetomidine combined with esketamine in patients with postherpetic neuralgia can improve analgesic efficacy.
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 4
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Zeng-Mao Lin
- Número de teléfono: +86 010-83572784
- Correo electrónico: linzengmao@163.com
Ubicaciones de estudio
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Beijing Municipality
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Beijing, Beijing Municipality, Porcelana, 100034
- Peking University First Hospital
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Contacto:
- Dong-Xin Wang
- Número de teléfono: +86 010-83572784
- Correo electrónico: wangdongxin@hotmail.com
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
- Age ≥ 50 years.
- Diagnosis of postherpetic neuralgia (PHN) requiring pharmacological analgesia, with a pain score ≥ 4 on the numerical rating scale (NRS).
- Provision of written informed consent.
Exclusion Criteria:
- Unsuitability for intranasal administration due to nasal disorders (e.g., rhinitis, nasal polyps, or nasal obstruction from any cause).
- Inability to communicate owing to severe dementia, coma, or a language barrier.
- History of schizophrenia, epilepsy, Parkinson's disease, or myasthenia gravis.
- Previous diagnosis of sleep apnoea, or high risk of moderate-to-severe sleep apnoea on the STOP-Bang assessment, or body mass index > 30 kg/m².
- History of hyperthyroidism or phaeochromocytoma.
- Left ventricular ejection fraction (LVEF) < 30%; or sick sinus syndrome, severe sinus bradycardia (heart rate < 50 bpm), or second-degree or higher atrioventricular block without an implanted pacemaker; or systolic blood pressure < 90 mmHg before enrolment.
- Severe hepatic impairment (Child-Pugh class C); severe renal impairment requiring dialysis; or any ongoing life-threatening condition (e.g., myocardial infarction, cerebrovascular accident, transient ischaemic attack, or coronary stenting within the previous 3 months; active myocardial ischaemia; severe valvular disease; or end-stage renal disease not receiving dialysis).
- Hypersensitivity to dexmedetomidine and/or esketamine.
- Participation in another clinical trial, or any other condition that, in the investigator's opinion, makes the patient unsuitable for inclusion.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: DEX-ESK group
For each administration: dexmedetomidine (1 spray = 0.05 ml = 25 μg) is administered as one spray into each nostril; after 1 minute, esketamine (1 spray = 0.05 ml = 1.25 mg) is administered alternately into each nostril, 4 sprays per nostril. Esketamine administration is repeated every 5 minutes until a total dose of 0.3 mg/kg is reached (using the number of sprays closest to the predetermined dose). If a dose is not tolerated, one administration may be omitted. Administer once daily for 4 consecutive days, with the same administration method as above. |
For each administration: dexmedetomidine (1 spray = 0.05 ml = 25 μg) is administered as one spray into each nostril; after 1 minute, esketamine (1 spray = 0.05 ml = 1.25 mg) is administered alternately into each nostril, 4 sprays per nostril. Esketamine administration is repeated every 5 minutes until a total dose of 0.3 mg/kg is reached (using the number of sprays closest to the predetermined dose). If a dose is not tolerated, one administration may be omitted. Administer once daily for 4 consecutive days, with the same administration method as above.
Otros nombres:
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Comparador activo: ESK group
For each administration: placebo (0.9% saline; 1 spray = 0.05 ml) is administered as one spray into each nostril; after 1 minute, esketamine (1 spray = 0.05 ml = 1.25 mg) is administered alternately into each nostril, 4 sprays per nostril. Esketamine administration is repeated every 5 minutes until a total dose of 0.3 mg/kg is reached (using the number of sprays closest to the predetermined dose). If a dose is not tolerated, one administration may be omitted. Administer once daily for 4 consecutive days, with the same administration method as above. |
For each administration: placebo (0.9% saline; 1 spray = 0.05 ml) is administered as one spray into each nostril; after 1 minute, esketamine (1 spray = 0.05 ml = 1.25 mg) is administered alternately into each nostril, 4 sprays per nostril. Esketamine administration is repeated every 5 minutes until a total dose of 0.3 mg/kg is reached (using the number of sprays closest to the predetermined dose). If a dose is not tolerated, one administration may be omitted. Administer once daily for 4 consecutive days, with the same administration method as above.
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Sum of pain intensity difference (SPID) within 7 days after the first administration
Periodo de tiempo: Within 7 days after the first administration
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Follow-up time points: before each administration (Days 1, 2, 3, and 4 of enrollment; face-to-face follow-up); on Days 1, 2, and 3 after the last administration (Days 5, 6, and 7 of enrollment; telephone follow-up at the same time of day as drug administration). Pain intensity: the patient's NRS pain score over the past 24 hours is recorded (0-10; 0 = no pain at all, 10 = the worst pain imaginable). Sum of pain intensity difference (SPID): calculated as the sum of (baseline NRS score - NRS score at each scheduled daily follow-up) within 7 days after the first administration (i.e., 3 days after the last treatment). |
Within 7 days after the first administration
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Sum of pain intensity difference (SPID) during Weeks 2 to 12 after the first administration
Periodo de tiempo: During Weeks 2 to 12 after the first administration
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Follow-up time points: once weekly after the last administration until Week 12 of enrollment (Days 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84 of enrollment; telephone follow-up). Pain intensity: the patient's NRS pain score over the past 24 hours is recorded (0-10; 0 = no pain at all, 10 = the worst pain imaginable). Sum of pain intensity difference (SPID): calculated as the sum of (baseline NRS score - NRS score at each scheduled weekly follow-up) during Weeks 2 to 12 after the first administration. |
During Weeks 2 to 12 after the first administration
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Change from baseline in ZBPI chronic pain and impact scores within 3 months after treatment
Periodo de tiempo: Up to 3 months after the first administration
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Follow-up time points: Days 7 and 14 after the first administration (telephone follow-up); Months 1, 2, and 3 after the first administration (Days 28, 56, and 84 of enrollment; telephone follow-up). Severity of chronic pain and its impact on patients: assessed using the Zoster Brief Pain Inventory (ZBPI, Appendix 7). Pain severity is rated from 0 to 10, with higher scores indicating greater pain severity; pain interference is rated from 0 to 10 across 7 domains, with higher scores indicating greater interference with daily functioning. Within 3 months after the first dose |
Up to 3 months after the first administration
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Dong-Xin Wang, MD, PhD, Peking University First Hospital
Publicaciones y enlaces útiles
Publicaciones Generales
- 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 Jul;43(5):521-546. doi: 10.1097/AAP.0000000000000808.
- Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.
- Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects. Anesthesiology. 2003 Feb;98(2):428-36. doi: 10.1097/00000542-200302000-00024.
- Grewal A. Dexmedetomidine: New avenues. J Anaesthesiol Clin Pharmacol. 2011 Jul;27(3):297-302. doi: 10.4103/0970-9185.83670. No abstract available.
- De Kock MF, Lavand'homme PM. The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Pract Res Clin Anaesthesiol. 2007 Mar;21(1):85-98. doi: 10.1016/j.bpa.2006.12.006.
- Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med. 2014 Oct 16;371(16):1526-33. doi: 10.1056/NEJMcp1403062. No abstract available.
- Jun JH, Kim KN, Kim JY, Song SM. The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis. Can J Anaesth. 2017 Sep;64(9):947-961. doi: 10.1007/s12630-017-0917-x. Epub 2017 Jun 21.
- Bartova L, Papageorgiou K, Milenkovic I, Dold M, Weidenauer A, Willeit M, Winkler D, Kasper S. Rapid antidepressant effect of S-ketamine in schizophrenia. Eur Neuropsychopharmacol. 2018 Aug;28(8):980-982. doi: 10.1016/j.euroneuro.2018.05.007. Epub 2018 Jul 2.
- Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sanchez E, Gutierrez-Rojas L, Meana JJ. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs. 2018 May;32(5):411-420. doi: 10.1007/s40263-018-0519-3.
- Segmiller F, Ruther T, Linhardt A, Padberg F, Berger M, Pogarell O, Moller HJ, Kohler C, Schule C. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol. 2013 Sep;53(9):996-8. doi: 10.1002/jcph.122. Epub 2013 Jul 24. No abstract available.
- Persson J, Hasselstrom J, Maurset A, Oye I, Svensson JO, Almqvist O, Scheinin H, Gustafsson LL, Almqvist O. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol. 2002 Feb;57(12):869-75. doi: 10.1007/s002280100353.
- Bornemann-Cimenti H, Wejbora M, Michaeli K, Edler A, Sandner-Kiesling A. The effects of minimal-dose versus low-dose S-ketamine on opioid consumption, hyperalgesia, and postoperative delirium: a triple-blinded, randomized, active- and placebo-controlled clinical trial. Minerva Anestesiol. 2016 Oct;82(10):1069-1076. Epub 2016 Jun 21.
- Lee KH, Lee SJ, Park JH, Kim SH, Lee H, Oh DS, Kim YH, Park YH, Kim H, Lee SE. Analgesia for spinal anesthesia positioning in elderly patients with proximal femoral fractures: Dexmedetomidine-ketamine versus dexmedetomidine-fentanyl. Medicine (Baltimore). 2020 May;99(20):e20001. doi: 10.1097/MD.0000000000020001.
- Hu ZC, Xu G, Zhang XW, Ma K, Jin JJ, Li PS. [Meta-analysis of the effects of dexmedetomidine combined with ketamine during dressing changes in burn patients]. Zhonghua Shao Shang Za Zhi. 2020 Jun 20;36(6):458-464. doi: 10.3760/cma.j.cn501120-20190327-00145. Chinese.
- Canuso CM, Singh JB, Fedgchin M, Alphs L, Lane R, Lim P, Pinter C, Hough D, Sanacora G, Manji H, Drevets WC. Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study. Am J Psychiatry. 2018 Jul 1;175(7):620-630. doi: 10.1176/appi.ajp.2018.17060720. Epub 2018 Apr 16.
- Ratner V, Gao Y, Lee H, Elkin R, Nedergaard M, Benveniste H, Tannenbaum A. Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport. Neuroimage. 2017 May 15;152:530-537. doi: 10.1016/j.neuroimage.2017.03.021. Epub 2017 Mar 18.
- Irwin MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 2019 Nov;19(11):702-715. doi: 10.1038/s41577-019-0190-z.
- Yu J, Rawtaer I, Fam J, Jiang MJ, Feng L, Kua EH, Mahendran R. Sleep correlates of depression and anxiety in an elderly Asian population. Psychogeriatrics. 2016 May;16(3):191-5. doi: 10.1111/psyg.12138. Epub 2015 Jul 16.
- Dzierzewski JM, Dautovich N, Ravyts S. Sleep and Cognition in Older Adults. Sleep Med Clin. 2018 Mar;13(1):93-106. doi: 10.1016/j.jsmc.2017.09.009. Epub 2017 Dec 8.
- Fang H, Tu S, Sheng J, Shao A. Depression in sleep disturbance: A review on a bidirectional relationship, mechanisms and treatment. J Cell Mol Med. 2019 Apr;23(4):2324-2332. doi: 10.1111/jcmm.14170. Epub 2019 Feb 7.
- Wolff K, Winstock AR. Ketamine : from medicine to misuse. CNS Drugs. 2006;20(3):199-218. doi: 10.2165/00023210-200620030-00003.
- Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Sultan W, Alfonso M. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus. 2021 Aug 21;13(8):e17352. doi: 10.7759/cureus.17352. eCollection 2021 Aug.
- Guo TZ, Jiang JY, Buttermann AE, Maze M. Dexmedetomidine injection into the locus ceruleus produces antinociception. Anesthesiology. 1996 Apr;84(4):873-81. doi: 10.1097/00000542-199604000-00015.
- Gabriel RA, Swisher MW, Sztain JF, Furnish TJ, Ilfeld BM, Said ET. State of the art opioid-sparing strategies for post-operative pain in adult surgical patients. Expert Opin Pharmacother. 2019 Jun;20(8):949-961. doi: 10.1080/14656566.2019.1583743. Epub 2019 Feb 27.
- Zhang Y, Cui F, Ma JH, Wang DX. Mini-dose esketamine-dexmedetomidine combination to supplement analgesia for patients after scoliosis correction surgery: a double-blind randomised trial. Br J Anaesth. 2023 Aug;131(2):385-396. doi: 10.1016/j.bja.2023.05.001. Epub 2023 Jun 9.
- Dworkin RH, Gnann JW Jr, Oaklander AL, Raja SN, Schmader KE, Whitley RJ. Diagnosis and assessment of pain associated with herpes zoster and postherpetic neuralgia. J Pain. 2008 Jan;9(1 Suppl 1):S37-44. doi: 10.1016/j.jpain.2007.10.008.
- Gabutti G, Valente N, Kuhdari P, Lupi S, Stefanati A. Prevention of herpes zoster and its complications: from the clinic to the real-life experience with the vaccine. J Med Microbiol. 2016 Dec;65(12):1363-1369. doi: 10.1099/jmm.0.000386. Epub 2016 Nov 4.
- Gauthier A, Breuer J, Carrington D, Martin M, Remy V. Epidemiology and cost of herpes zoster and post-herpetic neuralgia in the United Kingdom. Epidemiol Infect. 2009 Jan;137(1):38-47. doi: 10.1017/S0950268808000678. Epub 2008 May 9.
- Drolet M, Brisson M, Schmader KE, Levin MJ, Johnson R, Oxman MN, Patrick D, Blanchette C, Mansi JA. The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. CMAJ. 2010 Nov 9;182(16):1731-6. doi: 10.1503/cmaj.091711. Epub 2010 Oct 4.
- Volpi A, Gatti A, Pica F, Bellino S, Marsella LT, Sabato AF. Clinical and psychosocial correlates of post-herpetic neuralgia. J Med Virol. 2008 Sep;80(9):1646-52. doi: 10.1002/jmv.21254.
- Mizukami A, Sato K, Adachi K, Matthews S, Holl K, Matsuki T, Kaise T, Curran D. Impact of Herpes Zoster and Post-Herpetic Neuralgia on Health-Related Quality of Life in Japanese Adults Aged 60 Years or Older: Results from a Prospective, Observational Cohort Study. Clin Drug Investig. 2018 Jan;38(1):29-37. doi: 10.1007/s40261-017-0581-5.
- Lee DH, Park JE, Yoon DM, Yoon KB, Kim K, Kim SH. Factors Associated with Increased Risk for Clinical Insomnia in Patients with Postherpetic Neuralgia: A Retrospective Cross-Sectional Study. Pain Med. 2016 Oct;17(10):1917-1922. doi: 10.1093/pm/pnw066. Epub 2016 Apr 12.
- Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther. 1999 May;289(2):1060-6.
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Finalización primaria (Estimado)
Finalización del estudio (Estimado)
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Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
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Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Dolor
- Manifestaciones neurológicas
- Enfermedades del Sistema Nervioso
- Enfermedades Neuromusculares
- Enfermedades del Sistema Nervioso Periférico
- Neuralgia
- Condiciones Patológicas, Signos y Síntomas
- Signos y síntomas
- Neuralgia Posherpética
- Preparaciones farmacéuticas
- Soluciones cristaloides
- Soluciones isotónicas
- Soluciones
- Esketamina
- Solución salina
Otros números de identificación del estudio
- 2026R0576
Plan de datos de participantes individuales (IPD)
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Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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