Background: Postoperative pain management remains a challenge for clinicians due to unpredictable patient responses to opioid therapy. Some of this variability may result from single nucleotide polymorphisms (SNPs) of the human opioid mu- 1 receptor (OPRM1) that modify receptor binding or signal transduction. The OPRM1 variant with the highest frequency is the A118G SNP. However, previous studies have produced inconsistent results regarding the clinical effects of A118G on opioid response. We hypothesized that measurement of serum opioid concentrations, in addition to determining total opioid consumption, may provide a more precise method of assessing the effects of A118G on analgesic response. The current study evaluated the relationship of analgesia, side effects, total hydrocodone consumption, quantitative serum hydrocodone and hydromorphone concentrations, and A118G SNP in postoperative patients following Cesarean section.Methods: 158 women scheduled for Cesarean section were enrolled prospectively in the study. The patients had bupivacaine spinal anesthesia for surgery and received intrathcal morphine with the spinal anesthetic or parenteral morphine for the first 24 hours after surgery. Thereafter, patients received hydrocodone/acetaminophen for postoperative pain control. On postoperative day 3, venous blood samples were obtained for OPRM1 A118G genotyping and serum opioid concentrations.Results: 131 (82.9%) of the subjects were homozygous for the 118A allele of OPRM1 (AA) and 27 (17.1%) carried the G allele (AG/GG). By regression analysis, pain relief was significantly associated with total hydrocodone dose in the AA group (P = 0.01), but not in the AG/GG group (P = 0.554). In contrast, there was no association between pain relief and serum hydrocodone concentration in either group. However, pain relief was significantly associated with serum hydromorphone concentration (a metabolite of hydrocodone) in the AA group (P = 0.004), but not in the AG/GG group (P = 0.724). Conversely, side effects were significantly higher (P < 0.04) in the AG/GG group (mean = 6.4) than in the AA group (mean = 4.4), regardless of adjustment for BMI, pain level, or total dose of hydrocodone.Conclusion: This study found a correlation between pain relief and total hydrocodone dose in patients homozygous for the 118A allele (AA) of the OPRM1 gene, but not in patients with the 118G allele (AG/GG). However, pain relief in 118A patients did not correlate with serum hydrocodone concentrations, but rather with serum hydromorphone levels, the active metabolite of hydrocodone. This suggests that pain relief with hydrocodone may be due primarily to hydromorphone. Although pain relief did not correlate with opioid dose in AG/GG patients, they had a higher incidence of opioid side effects. The correlations identified in this study may reflect the fact that serum opioid concentrations were measured directly, avoiding the inherent imprecision associated with relying solely on total opioid consumption as a determinant of opioid effectiveness. Thus, measurement of serum opioid concentrations is recommended when assessing the role of OPRM1 variants in pain relief. This study supports pharmacogenetic analysis of OPRM1 in conjunction with serum opioid concentrations when evaluating patient responses to opioid therapy.

TAKOTSUBO CARDIOMYOPATHY, also referred to as transient left ventricular ballooning syndrome or stress-induced cardiomyopathy, describes a rapid-onset, yet reversible systolic dysfunction that typically is triggered by an acute, stressful event. The pathophysiology is not completely understood, and similar presentations have been described as a result of the endocrine crisis of pheochromocytoma, 1 Iga K. Gen H. Tomonaga G. et al. Reversible left ventricular wall motion impairment caused by pheochromocytoma—A case report. Jpn Circ J. 1989; 53: 813-818 Crossref PubMed Scopus (42) Google Scholar subarachnoid hemorrhage, 2 Pollick C. Cujec B. Parker S. et al. Left ventricular wall motion abnormalities in subarachnoid hemorrhage: An echocardiographic study. J Am Coll Cardiol. 1988; 12: 600-605 Abstract Full Text PDF PubMed Scopus (192) Google Scholar and Guillain-Barré syndrome. 3 Iga K. Himura Y. Izumi C. et al. Reversible left ventricular dysfunction associated with Guillain-Barre syndrome—An expression of catecholamine cardiotoxicity?. Jpn Circ J. 1995; 59: 236-240 Crossref PubMed Scopus (73) Google Scholar A wide heterogeneity of presentation suggests that multiple overlapping mechanisms such as neurogenic catecholamine-induced myocardial stunning, 4 Wittstein I.S. Thiemann D.R. Lima J.A. et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005; 352: 539-548 Crossref PubMed Scopus (2324) Google Scholar microvascular dysfunction, 5 Bybee K.A. Prasad A. Barsness G.W. et al. Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol. 2004; 94: 343-346 Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar and multivessel epicardial spasm 6 Dote K. Sato H. Tateishi H. et al. Myocardial stunning due to simultaneous multivessel coronary spasms: A review of 5 cases. J Cardiol. 1991; 21: 203-214 PubMed Google Scholar , 7 Gianni M. Dentali F. Grandi A.M. et al. Apical ballooning syndrome or takotsubo cardiomyopathy: A systematic review. Eur Heart J. 2006; 27: 1523-1529 Crossref PubMed Scopus (1098) Google Scholar may play a role. Symptoms mimic an ST-segment elevation myocardial infarction. Patients present with ischemic electrocardiographic changes, reduced left ventricular ejection fraction, and a balloon-like contractility pattern that portrays a unique wall-motion abnormality that extends beyond the myocardial territory of a single coronary artery. The classic form presents as transient apical ballooning with basal hypercontractility. In more rare cases of reverse Takotsubo, the opposite is observed—transient dilatation of the basal segments of the heart with hyperkinesis of the apex.

University of Louisville School of Medicine, Louisville, Kentucky Reprints: Gary E. Loyd, MD, MMM, Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, 530 S Jackson Street, Louisville, KY 40202, E-mail: [email protected]