Low-dose ketamine adjuvant treatment for refractory pain in children, adolescents and young adults with cancer: a pilot study

Objectives Ketamine, an N-methyl-D-aspartate receptor antagonist, is effective at relieving adult cancer pain, although there have been very few reports to date regarding its use in children and in adolescents and young adults (AYA). This study assessed the efficacy, safety and opioid-sparing effects of low doses of ketamine added to opioid analgesics to alleviate persistent cancer pain. Methods This prospective, multicentre, observational trial collected data regarding demographics, pain characteristics, pain score assessment within the first 48 hours of ketamine administration, tolerance and satisfaction from 38 patients aged 2–24 years prescribed with ketamine as an adjuvant antalgic for refractory cancer pain in 10 French paediatric oncology centres. Results The mean visual analogue scale pain score decreased from 6.7 to 4.3 out of 10 (n=39, p<0.001) from day 1 to day 3 and by at least 2 points in 56% of the patients (n=22) 48 hours after initiation of ketamine. Nine patients experienced poor tolerance (≥2 side effects), all with infusion rates lower than 0.05 mg/kg/hour. None had limiting toxicities. An opioid-sparing effect was highlighted in four patients. Fifty-four per cent of the prescribers and 47% of the patients found the addition of ketamine ‘very helpful’. Conclusions Low doses of ketamine as an adjuvant to opioids significantly reduced the intensity of pain in half of the study population. A tendency towards better pain control is shown, although a lack of statistical power somewhat limits our conclusions, especially in children. Nevertheless, ketamine may be a useful option for improving the treatment of refractory pain in children and AYA with cancer.

[1]  Jonathan M. Hagedorn,et al.  Ketamine Infusion for Pain Control in Acute Pediatric Sickle Cell Painful Crises , 2016, Pediatric emergency care.

[2]  Z. Quezado,et al.  Subanesthetic ketamine for pain management in hospitalized children, adolescents, and young adults: a single-center cohort study , 2017, Journal of pain research.

[3]  D. Michelet,et al.  Opioid-Sparing Effect of Ketamine in Children: A Meta-Analysis and Trial Sequential Analysis of Published Studies , 2016, Pediatric Drugs.

[4]  E. Bruera,et al.  Randomized Trial of Low-Dose Morphine Versus Weak Opioids in Moderate Cancer Pain. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  P. Thibault,et al.  HEDEN Pain Scale: A Shortened Behavioral Scale for Assessment of Prolonged Cancer or Postsurgical Pain in Children Aged 2 to 6 Years , 2015, Pediatric hematology and oncology.

[6]  D. Caraway,et al.  A Definition of Refractory Pain to Help Determine Suitability for Device Implantation , 2014, Neuromodulation : journal of the International Neuromodulation Society.

[7]  R. Dworkin,et al.  Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature. , 2013, Pain medicine.

[8]  D. Darbari,et al.  Low‐dose ketamine as a potential adjuvant therapy for painful vaso‐occlusive crises in sickle cell disease , 2013, Paediatric anaesthesia.

[9]  J. Dolan,et al.  Oral ketamine for children with chronic pain: a pilot phase 1 study. , 2013, Jornal de Pediatria.

[10]  J. Plummer,et al.  Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  E. Prommer Ketamine for pain: an update of uses in palliative care. , 2012, Journal of palliative medicine.

[12]  K. Baumstarck,et al.  Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. , 2012, Journal of palliative medicine.

[13]  S. Bhatnagar,et al.  Cancer Pain Management: Basic Information for the Young Pain Physicians , 2011, Indian journal of palliative care.

[14]  C. Woolf Central sensitization: Implications for the diagnosis and treatment of pain , 2011, PAIN.

[15]  R. Bell Ketamine for chronic non-cancer pain , 2009, PAIN.

[16]  B. Bulloch,et al.  Clinically significant changes in acute pain in a pediatric ED using the Color Analog Scale. , 2007, The American journal of emergency medicine.

[17]  Z. Quezado,et al.  Ketamine as an adjuvant for treatment of cancer pain in children and adolescents. , 2007, The journal of pain : official journal of the American Pain Society.

[18]  Martin S. Angst,et al.  Opioid-induced Hyperalgesia: A Qualitative Systematic Review , 2006, Anesthesiology.

[19]  J. Mao Opioid-induced abnormal pain sensitivity , 2006, Current pain and headache reports.

[20]  L. Oakes,et al.  Ketamine use for reduction of opioid tolerance in a 5-year-old girl with end-stage abdominal neuroblastoma. , 2005, Journal of pain and symptom management.

[21]  M. Durieux,et al.  Ketamine and kids: an update , 2005, Paediatric anaesthesia.

[22]  J. Body,et al.  Successful use of ketamine for intractable cancer pain , 2005, Supportive Care in Cancer.

[23]  S. Malherbe,et al.  Intravenous Ketamine Infusion as an Adjuvant to Morphine in a 2-Year-Old With Severe Cancer Pain From Metastatic Neuroblastoma. , 2004, Journal of pediatric hematology/oncology.

[24]  R. Drake,et al.  Opioid rotation in children with cancer. , 2004, Journal of palliative medicine.

[25]  E. Kalso,et al.  Ketamine as an adjuvant to opioids for cancer pain. , 2017, The Cochrane database of systematic reviews.

[26]  Michael J. Cousins,et al.  Ketamine in Chronic Pain Management: An Evidence-Based Review , 2003, Anesthesia and analgesia.

[27]  S. Kaasa,et al.  Long-term treatment with ketamine in a 12-year-old girl with severe neuropathic pain caused by a cervical spinal tumor. , 2001, Journal of pediatric hematology/oncology.

[28]  A. Mayor,et al.  A prospective randomized controlled study of the efficacy of ketamine for postoperative pain relief in children after adenotonsillectomy , 2001, Paediatric anaesthesia.

[29]  R. A’Hern Sample size tables for exact single‐stage phase II designs , 2001, Statistics in medicine.

[30]  S. Mercadante,et al.  Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. , 2000, Journal of pain and symptom management.

[31]  D. Price,et al.  NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. , 2000, Journal of pain and symptom management.

[32]  G. Lauretti,et al.  Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. , 1999, Anesthesiology.

[33]  S. Rothrock,et al.  Intramuscular ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases. , 1998, Annals of emergency medicine.

[34]  D. Price,et al.  Mechanisms of hyperalgesian and morphine tolerance: a current view of their possible interactions , 1995, Pain.

[35]  Clifford J. Woolf,et al.  The induction and maintenance of central sensitization is dependent on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states , 1991, Pain.