IS MEPERIDINE BETTER THAN MORPHINE FOR PANCREATIC OR BILIARY PAIN?
Many clinicians were taught to avoid
morphine (Astramorph/PF, Duramorph, Infumorph, generics) in the treatment of pancreatitis and biliary colic because it is associated with sphincter of Oddi spasm, which can exacerbate pain. Although meperidine (Demerol, generics) was originally thought not to have this adverse effect, it is now known that all opioids can cause biliary spasm.1 Therefore, there is no advantage to using meperidine in patients with biliary colic or pancreatitis, and some clinicians recommend avoiding it altogether.
Meperidine has the potential for drug interactions as well as serious neurotoxicity that has limited its use as an analgesic. Normeperidine, a neurotoxic metabolite of meperidine, can accumulate and cause seizures and neuromuscular agitation, particularly in patients with renal disease. In fact, many hospitals have restricted the use of meperidine or have completely removed it from formulary. Although meperidine may be beneficial for rigors and postoperative shivering, safer alternatives are available for analgesia. Morphine, hydromorphone (Dilaudid, generics), and fentanyl (Sublimaze, generics) are options for biliary or pancreatic pain. Additionally, each is available in patient-controlled analgesia pumps for severe pain.
DO PROTON PUMP INHIBITORS INTERACT WITH CLOPIDOGREL?
This is a hot and controversial topic. Studies have confirmed that proton pump inhibitors (PPIs) reduce the antiplatelet effect of clopidogrel (Plavix). However, data are conflicting on whether this is a clinically significant effect. The FDA has decided to err on the side of caution and changed the labeling of clopidogrel to include a warning statement to avoid the concomitant use of omeprazole/esomeprazole (Nexium, Prilosec, generics) and clopidogrel. However, some experts feel this warning is premature.
Clopidogrel is a prodrug that requires hepatic activation via the cytochrome P450 2C19 enzyme (CYP2C19) to exert its antiplatelet effects. The problem is that PPIs are also metabolized by CYP2C19 and compete with clopidogrel for this enzyme. Additionally, omeprazole and esomeprazole inhibit the CYP2C19 enzyme, which further reduces the conversion of clopidogrel to its active metabolite. This mechanism is theorized to be the etiology of the drug interaction.
The evidence regarding the clinical significance of this drug interaction is conflicting. A number of retrospective studies and database reviews have shown that patients taking clopidogrel plus a PPI have an increased risk of acute MI, revascularization, and an overall increased risk for major cardiovascular events compared to patients taking clopidogrel without a PPI.
Conversely, other retrospective studies have shown no impact of PPIs on cardiac outcomes when combined with clopidogrel. The issue was expected to be put to rest with the COGENT trial, which compared a combination pill of clopidogrel plus omeprazole versus clopidogrel alone (all patients received aspirin). Unfortunately, the trial was stopped prematurely because the sponsor declared bankruptcy. However, preliminary data showed that the addition of omeprazole did not increase cardiovascular events. The mixed and inconsistent data are confusing.
To further complicate the picture, approximately 30% of whites and African Americans and more than 50% of Asians are "poor metabolizers" of clopidogrel. This genetic polymorphism of the CYP2C19 allele diminishes the platelet response to clopidogrel and is also associated with worse cardiovascular outcomes.2 This variant allele may have confounded some of the aforementioned study results.
So what do we do? Until more prospective data help clarify this puzzle, it is best to use caution and common sense. Try H2 receptor antagonists in patients with gastroesophageal reflux disease (avoid cimetidine [Tagamet, generics], as it inhibits CYP2C19). Consider prasugrel (Effient) in patients who qualify (no history of stroke, younger than 75 years, and weighing more than 60 kg). In patients who require a PPI, consider pantoprazole (Protonix, generics) or rabeprazole (AcipHex) because some studies have shown these drugs to be less problematic than omeprazole. Additionally, keep an eye out for ticagrelor, a novel antiplatelet agent currently under review by the FDA that is not metabolized by CYP2C19. JAAPA
REFERENCES
1. Gutstein HB, Akil H. Chapter 21. Opioid analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: The McGraw-Hill Companies, Inc; 2006: chapter 21.
2. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;
302(8):849-857.