Meperidine (pethidine, Demerol) is a well known opioid analgesic that has been used in practice since the early 1940's.  Unfortunately, meperidine is also known to induce seizures from the accumulation of meperidine's metabolite, normeperidine (also called norpethidine).1-3  When meperidine is administered, it undergoes extensive hepatic metabolism via N-demethylation to produce normeperidine.2  Normeperidine has a half-life of 15-20 hours which is 5-10 times greater than the half-life of the parent compound, meperidine.2,3  Therefore, when meperidine is administered on a scheduled basis, normeperidine can easily accumulate.  This is especially true in patients with renal impairment since normeperidine is primarily renally eliminated.4  In addition, meperidine rapidly appears in the cerebrospinal fluid (CSF) while normeperidine appears gradually and erratically in the CSF.5  The CSF penetration is important because normeperidine has half the analgesic potency as compared to meperidine but produces twice the potency as a proconvulsant compared with meperidine.6  See the figure below for the basic metabolism of meperidine.7 

How does a patient exhibit signs of normeperidine toxicity? 
Accumulation of normeperidine will produce central nervous system (CNS) effects such as mood alterations, anxiety, tremor, myoclonus, and seizures.8   The tremors, myoclonus, and seizures correlate with the plasma normeperidine concentrations rather than meperidine plasma concentrations.3 Patients experiencing myoclonus and/or seizures display a mean normeperidine plasma concentration of 814ng/mL, which is approximately twice the level in those experiencing only tremors, shaking, or twitching sensations.3Electroencephalograms in patients exhibiting CNS effects also demonstrate a diffuse, slow-wave activity with sporadic paroxysmal activity.3  In addition, the development of agitated delirium generally precedes the development of seizures.3  Unfortunately, in some reports of patients receiving patient controlled analgesia with meperidine, seizures occurred without the classic warning signs of myoclonus and agitation.9  For example, one study found that in over 400 samples, the median normeperidine concentrations were 303, 519, and 640 ng/mL for those patients exhibiting no symptoms, mild symptoms, and seizures, respectively.9  However there is a wide interpatient variability in the presence of symptoms and the levels.  It has been suggested that if a patient exhibits signs or symptoms of normeperidine toxicity, it can be assumed that the plasma normeperidine level will be elevated > 50 ng/mL and meperidine should be discontinued.9  Since the normeperidine half-life is 15-20 hours, the neurological signs will slowly resolve (up to 5 days after the meperidine is stopped) and do not correlate with any other chemistry blood values.2,3 

We have reviewed the causative role of normeperidine and seizures, but what is the exact mechanism? The exact mechanism of how normeperidine induces seizures is unknown.  It has been determined from a rat model study that the seizures are not dopaminergic or cholinergic in nature.10  However, meperidine has the ability to increase serotonin by blocking its neuronal uptake.2,11 The use of meperidine in combination with other agents known to increase serotonin has been linked with the development of serotonin syndrome.12-14  Serotonin syndrome is characterized by the excitatory effects (e.g., delirium, rigidity, convulsions) similar to normeperidine toxicity.14  Since meperidine is considered to be a weak serotonin reuptake inhibitor, its potential to induce a serotonin syndrome alone is uncommon.14

What patients are at risk for meperidine induced seizures?
Due to the above information, many well known professional societies and accrediting bodies have taken positions against the general use of meperidine.  For example, the authors of the 2008 National Comprehensive Cancer Network (NCCN) guidelines on cancer pain management  do not recommend the use of meperidine in cancer patients with pain.18  In addition, the American College of Surgeons (ACS) distinctively cautions against meperidine.19  Several national health care organizations such as the Centers for Medicare and Medicaid Services (CMS), Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and Agency for Health Care Policy and Research or currently named the Agency for Healthcare Research and Quality (AHRQ) also do not recommend meperidine for pain management.20-22

References:

1. Beckwith SK Hospice, cancer pain management, and symptom control. In:Weiner's Pain Management: A Practical Guide for Clinicians, 7th ed. Taylor & Francis Group, LLC, Boca Raton, FL, 2006:1327-1352.
2. Gutstein HB, Akil H. Opioid analgesics.  In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. McGraw-Hill. New York, NY, 2001: 569-619.
3. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1983;13(2):180-5.
4. Szeto HH, Inturrisi CE, Houde R, et al. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med 1977;86(6):738-41. 
5. Boréus LO, Sköldefors E, Ehrnebo M. Appearance of pethidine and norpethidine in cerebrospinal fluid of man following intramuscular injection of pethidine. Acta Anaesthesiol Scand 1983;27(3):222-5. 
   
6. Kornitzer BS, Manace LC, Fischberg DJ, Leipzig RM. Prevalence of meperidine use in older surgical patients. Arch Surg 2006;141(1):76-81.
7. Mather LE, Gourlay GK. Biotransformation of opioids: significance for pain therapy. In: Nimmo WS, Smith G, eds. Opioid Agonist/Antagonist Drugs in Clinical Practice. Amsterdam: Excerpta Medica, 1984;31-46.
8. Seifert CF, Kennedy S. Meperidine is alive and well in the new millennium: evaluation of meperidine usage patterns and frequency of adverse drug reactions. Pharmacotherapy 2004;24(6):776-83. 
9. Plummer JL, Gourlay GK, Cherry DA. Norpethidine toxicity. Pain Reviews 2001;8(3-4):159-70.
10. Plummer JL, Gourlay GK, Cmielewski PL, Odontiadis J, Harvey I. Behavioural effects of norpethidine, a metabolite of pethidine, in rats. Toxicology 1995;95(1-3):37-44. 
11. Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther 2002;9(1):53-68. 
12. Altman EM, Manos GH. Serotonin syndrome associated with citalopram and meperidine. Psychosomatics 2007;48(4):361-3. 
13. Huang SS, Jou SH, Chiu NY. Catatonia associated with coadministration of tramadol and meperidine. J Formos Med Assoc 2007;106(4):323-6. 
14. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 2005;95(4):434-41. 
15. Danziger LH, Martin SJ, Blum RA. Central nervous system toxicity associated with meperidine use in hepatic disease. Pharmacotherapy 1994;14(2):235-8. 
16. Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS. Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Arch Surg 2002;137(1):84-8. 
17. Umans JG, Inturrisi CE. Antinociceptive activity and toxicity of meperidine and normeperidine in mice. J Pharmacol Exp Ther 1982;223(1):203-6.PubMed
18. NCCN Guidelines.http://www.nccn.org/professionals/physician_gls/PDF/pain.pdf. Accessed 11/30/2008.
19. Wilmore DW, Cheung LY, Harken AH, Holcroft JW, Meakins JL, Soper NJ, eds. In: ACS Surgery: Principles and Practice. New York, NY: WebMD Corp; 2002.
20. Joint Commission on Accreditation of Healthcare Organizations. Improving the Quality of Pain Management through Measurement and Action. Oakbrook Terrace, Ill: Joint Commission Resources; 2003.
21. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med 2003; 163(22):2716-24. 
22. Clinical Practice Guideline Number 1: Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guideline. Rockville, Md: Agency for Health Care Policy and Research, US Dept of Health and Human Services;1992. AHCPR publication 92-0032.

• Pharmacology: Tramadol (Ultram) and SSRI Interaction and Risk of Serotonin Syndrome
• Pharmacology: Mechanism of Action of Opioid Analgesics
• EBM Focused Topic: The Mechanism of Naloxone (Narcan) Associated Non-Cardiogenic Pulmonary Edema
  
• Drug Monograph: Naloxone (Narcan)
  

Meperidine, Demerol, Normeperidine, Norpethidine, Demerol Induced Seizures