Background and aims:
Acute pain episodes associated with sickle cell disease (SCD) are very difficult to manage effectively. Opioid tolerance and side effects have been major roadblocks in our ability to provide these patients with adequate pain relief. Ketamine is cheap, widely safe, readily available drug, with analgesic effects at sub-anesthetic doses and has been used in wide range of surgeries, pediatric burns dressing change and cancer related pain however, literature concerning its use in sickle cell crises is still limited in our setting. This study aimed to establish if 1 mg/kg of intravenous ketamine is non inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain.
We performed an institutional review board-approved randomized, prospective, double-blinded, active-control, non-inferiority trial at the national referral sickle cell center. Children between 7 and 18 years of age with severe painful sickle cell crisis, defined by numerical rating scale score of greater or equal to 7 were enrolled. Patients were consented and randomized to receive, either IV ketamine (LDK) 1 mg/kg or IV morphine (MOR) 0.1 mg/kg as an infusion over 10 min. The primary endpoint is maximal change in Numerical Rating Scale (NRS) pain score. Secondary outcomes were, incidence of adverse effects, optimal time to and duration of action of ketamine and incidence of treatment failures by treatment group. A clinically meaningful difference in validated pain scores was defined as 1.3 units. Assuming both treatments are on average equal, a sample size of 240 patients (120 per group) provided 95% power to demonstrate that IV LDK is non-inferior to IV morphine with a 0.05 level of significance and a 10% non-inferiority margin. All analyses were based on a modified intention to treat. This trial was registered with clinicaltrials.gov NCT02434939.
Two hundred and forty patients were enrolled (LDK120, MOR120). Demographic variables and baseline NRS scores (8.9 vs. 9.2) were similar. LDK was comparable to MOR in the maximum change in NRS scores, 66.4% vs. 61.3% (MD 5.5; 95% CI −2.2 to −13.2). Time to achieve maximum reduction in NRS pain scores was at 19.8 min for LDK and 34.1 min for MOR. The average duration of action for LDK was 60 min. MOR had more patients still at maximum effect at 120 min (45.8% vs. 37.5%; RR 1.2; 95% CI 0.9–1.7). LDK patients were 11.3 times more likely to develop side effects, though were transient, anticipated and non-life threatening (37.5% vs. 3.3%). MOR had significantly more treatment failures 40% vs. 28.3% (RR 0.7; 95% CI 0.5–1.03, p=0.07) Vital signs and sedation scores were similar in both groups.
Intravenous LDK at 1 mg/kg provides comparable analgesic effectiveness as IV MOR in the acute treatment of severe painful sickle cell crisis in children in the day care sickle cell center. However, it is associated with a high incidence of several transient, non-life threatening mild side effects.
Intravenous ketamine at 1 mg/kg can be a reliable alternative to morphine in the management of severe painful sickle cell crisis especially in a resource limited area where morphine is not readily available.
We would not be able to complete this trial without the contributions of Nakato Winfred MD, Nabulya Ruth, AO and the team of nurses at the SCC day care centre. We thank Prof. Karamagi and Sam Kizito MD for the statistical support. Lastly our partners in education i.e. Association of Anesthesiologists’ of Great Britain and Ireland (AAGBI) and Global Partners of Anesthesia and Surgery (GPAS).
Research funding: This research did not receive any specific grant from funding agencies in public, commercial or not- for- profit sectors.
Conflict of interest: No conflict of interest to declare.
Informed consent: Parental consent and child assent for children above 8 years was obtained from all participants.
Ethical approval: This study was approved by the Makerere University, School of Medicine Research and Ethics Committee (SOMREC) and was registered to the clinical trials.gov registry with identifier number NCT02434939.
Dr. Lubega hand in hand with his supervisors developed this idea from conceptualization to final proposal. Dr. MSD primarily assisted in data collection and training research assistants. Drs. LTS and MD supervised proposal development, oversaw study design, data analysis plus results review through to dissertation completion. Drs. JT, PKA, RN, FB & LTN were involved in final manuscript writing.
 Benjamin LJ, Dampier CD, Jacox A, Odesina V, Phoenix D, Shapiro B, Strafford M, Treadwell M. Guideline for the management of acute and chronic pain in sickle cell disease. APS Clinical Practice Guidelines Series, No. 1. Glenview, II.: American Pain Society, 1999:12–3.Search in Google Scholar
 Dampier C. The management of pain from sickle cell disease. In: Benzon H, Rathmell J, Wu C, Turk DC, Argoff C, Hurley R, editors. Practical Management of Pain. Philadelphia, PA: Mosby, 2014:997–1002.10.1016/B978-0-323-08340-9.00073-6Search in Google Scholar
 Frenette PS. Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol 2002;9:101–6.10.1097/00062752-200203000-00003Search in Google Scholar PubMed
 Elander J, Lusher J, Bevan D, Telfer P, Burton B. Understanding the causes of problematic pain management in sickle cell disease: evidence that pseudoaddiction plays a more important role than genuine analgesia dependence. J Pain Symptom Manage 2004;27:156–9.10.1016/j.jpainsymman.2003.12.001Search in Google Scholar PubMed
 Zempsky WT, Loiselle KA, McKay K, Blake GL, Hagstrom JN, Schechter NL, Kain ZN. Retrospective evaluation of pain assessment and treatment for vasoocclusive episodes in children with sickle cell disease. Pediatr Blood Cancer 2008;51:265–8.10.1002/pbc.21572Search in Google Scholar PubMed
 Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood 2012;120:3647–56.10.1182/blood-2012-04-383430Search in Google Scholar PubMed
 Jacob E, Mueller BU. Pain experience of children with sickle cell disease who had prolonged hospitalizations for acute painful episodes. Pain Med 2008;9:13–21.10.1111/j.1526-4637.2006.00252.xSearch in Google Scholar PubMed
 Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease – life expectancy and risk factors for early death. N Engl J Med 1994;330:1639–44.10.1056/NEJM199406093302303Search in Google Scholar PubMed
 Panepinto JA, Brousseau DC, Hillery CA, Scott JP. Variation in hospitalizations and hospital length of stay in children with vaso-occlusive crises in sickle cell disease. Pediatr Blood Cancer 2005;44:182–6.10.1002/pbc.20180Search in Google Scholar PubMed
 Yang YM, Shah AK, Watson M, Mankad VN. Comparison of costs to the health sector of comprehensive and episodic health care for sickle cell disease patients. Pub Health Rep 1995;110:80–6.Search in Google Scholar
 Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev 2006:CD003350.10.1016/j.acpain.2006.08.005Search in Google Scholar
 Yoon SL, Black S. Comprehensive, integrative management of pain for patients with sickle cell disease. J Altern Complement Med 2006;12:995–1001.10.1089/acm.2006.12.995Search in Google Scholar PubMed
 Campbell CM, Moscou-Jackson G, Carroll CP, Kiley K, Haywood C, Lanzkron S, Hand M, Edwards RR, Haythornthwaite JA. An evaluation of central sensitization in patients with sickle cell disease. J Pain 2016;17:617–27.10.1016/j.jpain.2016.01.475Search in Google Scholar
 Mitra S. Opioid-induced hyperalgesia: pathophysiology and clinical implications. J Opioid Manag 2007;4:123–30.10.5055/jom.2008.0017Search in Google Scholar
 Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011;14:145–61.10.36076/ppj.2011/14/145Search in Google Scholar
 Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations. Clin J Pain 2008;24:479–96.10.1097/AJP.0b013e31816b2f43Search in Google Scholar
 DuPen A, Shen D, Ersek M. Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Manag Nurs 2007;8:113–21.10.1016/j.pmn.2007.02.004Search in Google Scholar
 Darbari DS, Neely M, VandenAnker J, Rana SR. Morphine pharmacokinetics in sickle cell disease: implications for pain management. Blood 2009;114:2574.10.1182/blood.V114.22.2574.2574Search in Google Scholar
 Dampier CD, Setty B, Logan J, Ioli JG, Dean R. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.10.1016/S0022-3476(95)70472-8Search in Google Scholar
 Joubert K. Ketamine hydrochloride-an adjunct for analgesia in dogs with burn wounds. J S Afr Vet Ass 1998;69:95–7.10.4102/jsava.v69i3.825Search in Google Scholar
 Fisher K, Coderre TJ, Hagen NA. Targeting the NMDA receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000;20:358–73.10.1016/S0885-3924(00)00213-XSearch in Google Scholar
 Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Pediatr Anesth 2013;23:684–9.10.1111/pan.12172Search in Google Scholar PubMed
 Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain 2010;26:163–7.10.1097/AJP.0b013e3181b511abSearch in Google Scholar
 Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother 2013;27:150–4.10.3109/15360288.2013.788599Search in Google Scholar
 Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol 2014;93:769–71.10.1007/s00277-013-1954-3Search in Google Scholar
 Finkel JC, Pestieau SR, Quexado ZMN. Ketamine as an adjuvant for the treatment of cancer pain in children and adolescents. J Pain 2007;8:515–21.10.1016/j.jpain.2007.02.429Search in Google Scholar
 Fine PG. Low-dose ketamine in the management of opiod nonresponsive terminal cancer pain. J Pain Symptom Manage 1999;17:296–300.10.1016/S0885-3924(98)00144-4Search in Google Scholar
 Tsui BC, Davies D, Desai S, Malherbe S. Intravenous ketamine infusion as an adjuvant to morphine in a 2-year-old with severe cancer pain from metastatic neuroblastoma. J Pediatr Hematol Oncol 2004;26:678–80.10.1097/01.mph.0000140656.96085.2cSearch in Google Scholar
 Bartoc C, Frumento RJ, Jalbout M, Bennet-Guerrero E, Du E, Nishanian E. A randomised, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J Cardiothorac Vasc Anesth 2006;20:217–22.10.1053/j.jvca.2005.12.005Search in Google Scholar
 Luggya TS, Roche T, Ssemogerere L, Kintu A, Kasumba JM, Kwizera A, Tindimwebwa JV. Effect of low-dose ketamine on post-operative serum IL-6 production among elective surgical patients: a randomized clinical trial. Afr Health Sci 2017;17:500–7.10.4314/ahs.v17i2.25Search in Google Scholar
 Green SM, Krauss B. Ketamine is safe, effective and appropriate technique for emergency department pediatric procedural sedation. Emerg Med J 2004;21:271–3.10.1136/emj.2004.015370Search in Google Scholar
 Green SM, Rothrock SG, Lynch EL, Ho M, Harris T, Hestdalen R, Hopkins GA, Garrett W, Westcott K. Intravenous ketamine for pediatric sedation in the emergency department: safety profile in 1022 cases. Ann Emerg Med 1998;31:688–97.10.1016/S0196-0644(98)70226-4Search in Google Scholar
 Meals CG, Mullican BD, Shaffer CM, Dangerfield PF, Ramirez RP. Ketamine infusion for sickle cell crisis pain in an adult. J Pain Symptom Manage 2011;42:7–9.10.1016/j.jpainsymman.2011.06.003Search in Google Scholar PubMed
 Neri CM, Pestieau SR, Young H, Elmi A, Finkel JC, Darbari DS. Low-dose ketamine for children and adolescents with acute sickle cell disease related pain: a single center experience. J Anesth Clin Res 2014;5:394.10.4172/2155-6148.1000394Search in Google Scholar
 Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage 2014;47:334–40.10.1016/j.jpainsymman.2013.03.012Search in Google Scholar PubMed
 Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med 2015;33:197–201.10.1016/j.ajem.2014.11.010Search in Google Scholar PubMed
 Neri CM, Pestieau S, Young H, Elmi A, Darbari DS. Safety and efficacy of adjuvant low-dose ketamine therapy for patients with sickle cell disease. Blood 2012;120:3226.10.1182/blood.V120.21.3226.3226Search in Google Scholar
 Motov S, Rockoff B, Cohen V, Pushkar I, Likourezos A, McKay C, Soleyman-Zomalan E, Homel P, Terentiev V, Fromm C. Intravenous subdissociative-dose ketamine versus morphine for analgesia in the emergency department: a randomized controlled trial. Ann Emerg Med 2015;66:222–9.e221.10.1016/j.annemergmed.2015.03.004Search in Google Scholar PubMed
 Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med 2015;33:402–8.10.1016/j.ajem.2014.12.058Search in Google Scholar PubMed
©2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.