Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Dextromethorphan and memantine after ketamine analgesia: a randomized control trial This article was published in the following Dove Press journal: Drug Design, Development and Therapy Elodie Martin,1 Marc Sorel,2 Purpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N- 3 Véronique Morel, Fabienne methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the 4 4 Marcaillou, Pascale Picard, frequency of ketamine infusions and hospital admissions. This clinical trial aimed at asses- Noémie Delage,4 Florence sing whether oral dextromethorphan or memantine might prolong pain relief after intrave- Tiberghien,5 Marie-Christine 6 6 nous ketamine. Crosmary, Mitra Najjar, Renato Colamarino,6 Christelle Créach,7,8 Patients and methods: A multicenter randomized controlled clinical trial included 60 Béatrice Lietar,7 Géraldine Brumauld patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/ de Montgazon,9 Anne Margot- day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine 10 11,12 Duclot, Marie-Anne Loriot, infusion. The primary endpoint was pain intensity at one month. Secondary endpoints 11,12 13 Céline Narjoz, Céline Lambert, included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations 13 1,3 Bruno Pereira, Gisèle Pickering up to 12 weeks. 1Université Clermont Auvergne, Pharmacologie Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Fondamentale Et Clinique de la Douleur, Neuro- Dol, Inserm 1107, F-63000 Clermont-Ferrand, Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain France; 2Centre D’evaluation et de Traitement de intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain la Douleur/soins Palliatifs, Nemours, France; fi 3CHU Clermont-Ferrand, Centre de remained lower than at inclusion (p=0.001) and was not signi cantly different in the three Pharmacologie Clinique/Centre d’investigation groups. Significant benefits were observed on cognitive-affective domains and quality of life Clinique Inserm 1405, F-63003 Clermont- Ferrand cedex, France; 4Centre d’Evaluation et de for dextromethorphan and memantine (p<0.05). Traitement de la Douleur, CHU de Clermont- Conclusions: Oral dextromethorphan given after ketamine infusion extends pain relief Ferrand, France; 5Centre d’evaluation et de Traitement de la Douleur/soins Palliatifs, CHU during one month and could help patients to better cope with pain. Future studies should 6 ’ Jean Minjoz, Besançon, France; Centre d evalua- include larger populations stratified on pharmacogenetics screening. Optimization of an oral tion et de Traitement de la Douleur, CH Jacques Lacarin Vichy, France; 7Centre d’evaluation et de drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a Traitement de la Douleur, CHU de Saint-etienne, prime challenge in refractory neuropathic pain. France; 8Inserm U1028 & Umr 5292, Centre de Neurosciences de Lyon, Université Lyon & Jean- Keywords: N-methyl-D-aspartate antagonists, peripheral neuropathic pain, drug relay, 9 ’ monnet De Saint-etienne, France; Centre d eva- cognitive-affective status, health-related quality of life luation et de Traitement de la Douleur/soins Palliatifs, CH La Rochelle, France; 10Centre d’evaluation et de Traitement de la Douleur, Fondation A de Rothschild, Paris, France; 11Service de biochimie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France; 12Inserm UMR-S Introduction 1147, Université Paris Descartes, Paris, France; Chronic pain with neuropathic characteristics has a prevalence of 7–10% in the 13 CHU Clermont-Ferrand, Délégation 1 Recherche Clinique & Innovation - Villa annexe general population. Failure of neuropathic pain (NP) treatment with recommended IFSI, 58 Rue Montalembert, F-63003 Clermont- drugs is common in clinical practice,2 and antagonists of the N-methyl-D-aspartate Ferrand cedex, France receptor (NMDAR), a receptor known to play an important role in the development of central pain sensitization,3 have been studied with contradictory results.4–8 Correspondence: Gisèle Pickering 9 Centre de Pharmacologie Clinique, CHU Ketamine has been shown to be effective for the treatment of postoperative pain, Clermont-Ferrand, Bâtiment 3C, CIC post-herpetic neuralgia6 and phantom-limb pain,10 but displayed no analgesic effect Inserm 1405, BP 69, F-63003 Clermont- 11,12 Ferrand Cedex 1, France in other studies like surgery-induced NP. Ketamine is widely used in pain Tel +33 47 317 8416 clinics to treat NP and is reported to be effective in 30–65% patients.13–15 Pain Fax +33 47 317 8412 16,17 Email [email protected] alleviation diminishes however after a few weeks or months, requiring hospital submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2019:13 2677–2688 2677 DovePress © 2019 Martin et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the http://doi.org/10.2147/DDDT.S207350 work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Martin et al Dovepress readmission for another intravenous ketamine infusion. with an electric syringe at the dose of 0.4–0.5 mg/kg Furthermore, because of its psychodysleptic, cardiovascu- diluted in 45 mL of physiological saline (0.9% NaCl) for lar and hepatic side-effects, its use should be limited to 2 hrs according to the usual procedures of the pain clinic. short-term administration.18 After their ketamine infusion, patients were randomly Other NMDAR antagonists are available in oral form. assigned to oral dextromethorphan (n=20), memantine Dextromethorphan, a cough suppressant and memantine, (n=20) or placebo (n=20) for twelve weeks. A person not prescribed in Alzheimer’s disease to maintain cognitive involved in the study generated the randomization function, have minimal side-effects compared to ketamine sequence using random blocks with Stata Software at therapeutic doses. Memantine for NP alleviation was (Version 13, StataCorp, College Station, TX). preventive in human studies,7,19 but ineffective in the Dextromethorphan (Pulmodexane® 30 mg, Bailly-Creat treatment of postherpetic neuralgia.20 Dextromethorphan Laboratory) and memantine (Ebixa® 10 mg and 20 mg, alleviates NP in diabetes21,22 and trauma4,5 but has no Lundbeck SAS) were given in increasing doses: dextro- beneficial effect on NP in other clinical trials.8,23 Genetic methorphan: 30 mg/day (week 1); 60 mg/day (week 2); polymorphism has been identified as a variability factor of 90 mg/day (weeks 3 to 12); memantine: 5 mg/day (week dextromethorphan (CYP2D6, CYP3A4 and ABCB1) and 1); 10 mg/day (week 2); 15 mg/day (week 3); 20 mg/day memantine (NR1I2) metabolism, and may be involved in (weeks 4 to 12). Placebo (lactose tablet) was given once a the modulation of their analgesic effect.4,5,24 day for twelve weeks. Treatments were prepared and con- With the aim of limiting ketamine infusions (whose ditioned in the Central Hospital Pharmacy by a qualified long term repeated effects are poorly known) and hospital pharmacist according to good manufacturing principles. admissions, we hypothesized that oral NMDAR antago- Treatment compliance was assessed at the end of the trial nists could be a therapeutic option in patients relieved by by two persons independent of the protocol. ketamine. The objectives of the present trial were to assess Questionnaires and cognitive tests were carried out at whether one to three months treatment with oral dextro- the inclusion visit (pre ketamine infusion: preK or inclu- methorphan or memantine, that have similar chemical sion), 3 days after ketamine infusion (postK), at Month 1 structures and target receptors than ketamine but with (M1), Month 2 (M2) and Month 3 (M3). In order to fewer side effects, could be effective relays of ketamine maintain good compliance and safety, patients were con- for the management of refractory neuropathic pain and of tacted once a week by phone. A paper pain diary com- its cognitive-affective impact. pleted by patients included concomitant analgesic treatments, and adverse events. A blood sample was col- lected at the end of the trial to study the polymorphism of Materials and methods genes involved in the metabolism and bioavailability of Study design dextromethorphan (CYP2D6, CYP3A4 and ABCB1) and in This randomized, controlled, single-blind (patients blinded) the excretion of memantine (NR1I2). trial was conducted in seven French Pain Clinics with 60 patients suffering from severe NP. The study was coordi- Participants and setting nated by the Clinical Research Center, University Hospital All patients fulfilled the following inclusion criteria: of Clermont-Ferrand, France and has been approved by the ≥18 years of age, suffering from peripheral NP excluding regional Ethics