Adjuvant interventions with opioids for vaso-occlusive crisis in sickle cell disease: A mixed treatment network meta-analysis of randomized controlled clinical trials

Kannan Sridharan, MD, DM; Gowri Sivaramakrishnan, MDS

doi:10.5055/jom.2020.0580

Authors

Kannan Sridharan, MD, DM
Gowri Sivaramakrishnan, MDS

DOI:

https://doi.org/10.5055/jom.2020.0580

Keywords:

pain crisis, sickle cell anemia, hemoglobinopathies

Abstract

Objective: Vaso-occlusive crisis is the most common clinical feature requiring opioid analgesics in patients with sickle cell disease. We conducted a network meta-analysis to compare the drugs that can be used as add-on with opioids for vaso-occlusive crisis.

Design: Network meta-analysis of randomized clinical trials.

Patients: Sickle cell disease patients with vaso-occlusive crisis receiving adjuvants to opioids for pain management.

Main outcome measures: A number of patients with complete pain relief and pain scores assessed either by visual analog or by a numerical rating scale were the primary outcomes. Adverse events and dose of opioids (in morphine equivalents) for pain alleviation between the treatment arms were the secondary outcome measures.

Results: Eleven studies evaluating the addition of ketorolac, magnesium sulfate, ketoprofen, ibuprofen, methadone, inhalational nitric oxide, methylprednisolone, and arginine with morphine were obtained. The pooled analysis showed a favorable effect in the pain reduction for the additions of arginine {–2 [–3.39, –0.61]} and ibuprofen {–1.7 [–3.26, –0.14]} with morphine. Arginine has high probability of being the “best” in the pool followed by ibuprofen. No significant differences were observed in the risk of adverse events {ketoprofen—0.84 [0.42, 1.65]; magnesium sulfate—1.81 [0.64, 5.81]; and arginine—2.08 [0.18, 24.31]}. A significant lower dose of opioid was required when given adjunctive to arginine, inhalational nitric oxide, and methylprednisolone.

Conclusion: We observed that arginine and ibuprofen could produce additional analgesic effects when combined with morphine in vaso-occlusive crisis.

Author Biographies

Kannan Sridharan, MD, DM

Associate Professor, Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Manama, Bahrain

Gowri Sivaramakrishnan, MDS

Dental Specialist (Prosthodontist), Dental Training Department, Ministry of Health, Bahrain

References

Lervolino LG, Baldin PEA, Picado SM, et al.: Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev Bras Hematol Hemoter. 2011; 33: 49-54.

Ballas SK: Pathophysiology and principles of management of the many faces of the acute vaso-occlusive crisis in patients with sickle cell disease. Eur J Haematol. 2015; 95: 113-123.

Meremikwu MM, Okomo U: Sickle cell disease. BMJ Clin Evid 2011; 2: 2402.

Rasolofo J, Poncelet M, Rousseau V, et al.: Analgesic efficacy of topical lidocaine for vasoocclusive crisis in children with sickle cell disease. Arch Pediatr. 2013; 20: 762-767.

Nottage KA, Hankins JS, Faughnan LG, et al.: Addressing challenges of clinical trials in acute pain: The pain management of vaso-occlusive crisis in children and young adults with sickle cell disease study. Clin Trials. 2016; 13: 409-416.

Khansari M, Sohrabi M, Zamani F: The usage of opioids and their adverse effects in gastrointestinal practice: A review. Middle East J Dig Dis. 2013; 5: 5-16.

Baldini A, Von Korff M, Lin EHB: A review of potential adverse effects of long-term opioid therapy: A practitioner's guide. Prim Care Companion CNS Disord. 2012; 14: PCC.11m01326.

Hutton B, Salanti G, Caldwell DM, et al.: The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015; 162: 777-784.

Higgins JPT, Green S (eds.): Cochrane Handbook for Systematic Reviews of Interventions. 5.1.0 edition. Available at www.cochrane-handbook.org. Accessed May 1, 2017.

Higgins JPT, Thompson SG: Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21: 1539-1558.

Wright SW, Norris RL, Mitchell TR: Ketorolac for sickle cell vaso-occlusive crisis pain in the emergency department: Lack of a narcotic-sparing effect. Ann Emerg Med. 1992; 21: 925-928.

Hardwick WE Jr, Givens TG, Monroe KW, et al.: Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis. Pediatr Emerg Care. 1999; 15: 179-182.

Weiner DL, Hibberd PL, Betit P, et al.: Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA. 2003; 289(9): 1136-1142.

Perlin E, Finke H, Castro O, et al.: Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis. Am J Hematol. 1994; 46: 43-47.

Morris CR, Kuypers FA, Lavrisha L, et al.: A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica. 2013; 98: 1375-1382.

Horst J, Frei-Jones M, Deych E, et al.: Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease. Pediatr Blood Cancer. 2016; 63: 2123-2130.

Griffin TC, McIntire D, Buchanan GR: High-dose intravenous methylprednisolone therapy for pain in children and adolescents with sickle cell disease. N Engl J Med. 1994; 330: 733-737.

Bartolucci P, El Murr T, Roudot-Thoraval F, et al.: A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults. Blood. 2009; 114: 3742-3747.

Brousseau DC, Scott JP, Badaki-Makun O, et al.; Pediatric Emergency Care Applied Research Network (PECARN). A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood. 2015; 126: 1651-1657.

Cho G, Anie KA, Buckton J, et al.: SWIM (sickle with ibuprofen and morphine) randomised controlled trial fails to recruit: lessons learnt. BMJ Open. 2016; 6: e011276.

Goldman RD, Mounstephen W, Kirby-Allen M, et al.: Intravenous magnesium sulfate for vaso-occlusive episodes in sickle cell disease. Pediatrics. 2013; 132: e1634-1641.

Dampier CD, Smith WR, Wager CG, et al.: Sickle Cell Disease Clinical Research Network (SCDCRN). IMPROVE trial: A randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: Rationale, design challenges, initial experience, and recommendations for future studies. Clin Trials. 2013; 10: 319-331.

Li T, Puhan MA, Vedula SS, et al.: The adhoc network metaanalysis methods meeting working group. BMC Med. 2011; 9: 79.

Greco T, Biondi-Zoccai G, Saleh O, et al.: The attractiveness of network meta-analysis: A comprehensive systematic and narrative review. Heart Lung Vessel 2015; 7: 133-142.

Rees DC, Olujohungbe AD, Parker NE, et al.: British Committee for Standards in Haematology General Haematology Task Force by the Sickle Cell Working Party. Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol. 2003; 120: 744-752.

Blondell RD, Azadfard M, Wisniewski AM: Pharmacologic therapy for acute pain. Am Fam Physician. 2013; 87: 766-772.

Yale SH, Nagib N, Guthrie T: Approach to the vaso-occlusive crisis in adults with sickle cell disease. Am Fam Physician. 2000; 61: 1349-1356.

US FDA: The voice of the patient. Sickle cell disease. Available at https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM418430.pdf. Accessed June 1, 2017.