Meperidine for Acute Sickle Cell Pain in the Emergency Department: Revisited Controversy

Abstract

Meperidine used to be the most commonly administered opioid analgesic for treating pain due to sickle cell disease in emergency departments (EDs) and hospitals. Its widespread use unmasked serious effects that appear to be related to the accumulation of a toxic metabolite, normeperidine. While the half-life of meperidine is only 3 hours, the half-life of normeperidine is 18 hours. Normeperidine can cause anxiety, tremors, myoclonus, and generalized seizures that occur almost exclusively in the setting of massive doses repeated every 1-2 hours for several days, and invariably occurs in patients with impaired renal function. Seizure prevalence among sickle cell disease patients receiving meperidine varies between 1 and 12%,1Tobin D.L. Holroyd K.A. Reynolds R.V. et al.The hierarchical factor structure of the Coping Strategies Inventory.Cognitive Therapy and Research. 1989; 13: 343-361Crossref Scopus (569) Google Scholar, 2Nadvi S. Sarnaik S. Ravindranath Y. Association of seizures with meperidine in sickle cell disease.in: Book of Abstracts, 20th Meeting of the National Sickle Cell Disease Program. 1995: 210Google Scholar and is associated with the following factors: 1) doses greater than 100 mg every 2 hours, 2) alkaline urine, 3) co-administration of phenobarbital and other enzyme-inducing drugs, 4) co-administration of phenothiazines, and 5) prior seizures. Renal impairment places patients at particular risk. Neurotoxic concerns prompted many hospitals to remove meperidine from their formulary or ban its use in sickle cell disease pain, allowing morphine to emerge as a gold standard analgesic. This switch overlooks two important issues that I wish to emphasize. The first pertains to seizures, which are automatically attributed to utilization of meperidine, despite the fact that there are other causes of seizures in patients with sickle cell disease, including emergent conditions such as stroke. In fact, many patients who discontinue meperidine continue to have seizures. Moreover, serotonin syndrome may easily be mistaken for seizure activity. Thus, patients with sickle cell disease who experience seizure activity should undergo a thorough workup to identify the true nature of their disorder. Secondly, morphine is not a panacea. Meperidine was used for 50 years before its neurotoxic potential was recognized, while morphine has been used to treat sickle cell disease for only the last 20 years. During this time, reports have emerged documenting problems associated with morphine use, including increased risk of acute coronary syndrome, accelerated renal injury, and increased retinopathy.3Kopecky E.A. Jacobson S. Joshi P. et al.Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease.Clinical Pharmacology and Therapeutics. 2004; 75: 140-146Crossref PubMed Scopus (66) Google Scholar, 4Buchanan I.D. Woodward M. Reed G.W. Opioid selection during sickle cell pain crisis and its impact on the development of acute chest syndrome.Pediatr Blood Cancer. 2005; 45: 716-724Crossref PubMed Scopus (66) Google Scholar, 5Weber M.L. Hebbel R.P. Gupta K. Morphine induces kidney injury in transgenic sickle cell mice.Blood. 2005; 106: 884a-885aGoogle Scholar, 6Gupta K. Chen C. Lutty G.A. et al.Morphine exaggerates retinopathy in transgenic sickle mice.Blood. 2005; 106: 64a-65aGoogle Scholar These early reports are still inconclusive, but must be taken seriously in view of the fact that morphine-6-glucuronide, a toxic metabolite of morphine, accumulates in plasma in the presence of renal disease. Morphine also causes seizures with a reported prevalence of 1.2% if given in sufficiently large doses.7Winkelmuller M. Winkelmuller W. Long-term effects of continuous intrathecal opioids treatment in chronic pain of nonmalignant etiology.J Neurosurg. 1996; 85: 458-476Crossref PubMed Scopus (288) Google Scholar While no controlled trials compare the efficacy and safety of different opioids in the management of acute sickle cell painful crises, patient safety can be maximized by obtaining a detailed history, understanding opioid pharmacology, mechanism of action and side effects, carefully monitoring patients, and individualizing care. Renal failure and history of seizure are contraindications for meperidine, and this agent should not be used to treat acute sickle cell disease pain in patients who have impaired renal function, history of seizure disorders, or who are taking other serotoninergic medications, especially the elderly. Renal failure and history of acute chest syndrome appear to be contraindications for morphine. Meperidine or morphine doses should be modified in patients who have a history of renal disease but no history of seizure or acute coronary syndrome.