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. 2019 Aug 28;9(1):12490.
doi: 10.1038/s41598-019-48955-y.

Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids

Tigran Makunts  1 , Andrew U  1 , Rabia S Atayee  1   2 , Ruben Abagyan  3
Affiliations

Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids

Tigran Makunts et al. Sci Rep. .

Abstract

Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild μ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Inclusion, exclusion and analysis cohort selection for adverse event rate comparison between tramadol, non-tramadol opioid, SNRI and NMDAR antagonist cohorts.
Figure 2
Figure 2
(a) Frequencies of hypoglycemia events for patients on tramadol (n = 6,355), opioids (n = 83,662), SNRIs (n = 45,201), and NMDAR antagonists (n = 16,541). (b) Odds ratios were calculated comparing frequencies of hypoglycemia reports from the tramadol cohort and each of the opioid, SNRI and NMDAR antagonist cohorts. Ranges represent 95% confidence intervals (95% CI) (see Methods). X-axis is presented in log scale. Abbreviations: TRA-tramadol, SNRI-serotonin norepinephrine reuptake inhibitor, NMDAR-N-methyl-D-aspartate receptor.
Figure 3
Figure 3
Frequencies of hypoglycemia events for patients on codeine (n = 1,030), dextropropoxyphene (n = 256), fentanyl (n = 28,538), hydrocodone (n = 5,641), hydromorphone (n = 2,103), methadone (n = 4,234), morphine (n = 11,431), oxycodone (n = 19,824), oxymorphone (n = 1,984), tapentadol (n = 2,265), tramadol (n = 6,355), desvenlafaxine (n = 8,688), duloxetine (n = 22,892), milnacipran (n = 969), venlafaxine (n = 12,652), atomoxetine (n = 8,417), dextromethorphan (n = 2,939), ketamine (n = 620), memantine (n = 2,120), and minocycline (n = 2,445).
Figure 4
Figure 4
Reporting odds ratios were calculated comparing frequencies of hypoglycemia reports from the tramadol cohort and each of the opioid, SNRI and NMDAR antagonist cohorts. Ranges represent 95% confidence intervals (95% CI) (see Methods). X-axis is presented in log scale. Abbreviations: TRA-tramadol, SNRI-serotonin norepinephrine reuptake inhibitor, NMDAR-N-methyl-D-aspartate receptor.
Figure 5
Figure 5
Reporting Odds ratios were calculated comparing frequencies of hypoglycemia reports from the methadone cohort and each of the opioid and NMDAR antagonist cohorts. Ranges represent 95% confidence intervals (95% CI) (see Methods). X-axis is presented in log scale. Abbreviations: MTD-methadone, NMDAR-N-methyl-D-aspartate receptor.
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References

    1. Vickers MD, O’Flaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia. 1992;47:291–296. doi: 10.1111/j.1365-2044.1992.tb02166.x. - DOI - PubMed
    1. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol. 1998;15:64–68. doi: 10.1097/00003643-199801000-00013. - DOI - PubMed
    1. Fuentes Andrea, Pineda Moises, Venkata Kalyan. Comprehension of Top 200 Prescribed Drugs in the US as a Resource for Pharmacy Teaching, Training and Practice. Pharmacy. 2018;6(2):43. doi: 10.3390/pharmacy6020043. - DOI - PMC - PubMed
    1. Hedegaard, H., Warner, M. & Miniño, A. M. Drug Overdose Deaths in the United States, 1999–2016. NCHS Data Brief, 1–8 (2017). - PubMed
    1. Drug Enforcement Administration, Office of Diversion Control. (2014, July). Tramadol (trade names: Ultram®, Ultracet® 7 Retrieved from, http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf (2014).