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Zinc deficiency: A cause of opioid-induced physical dependence and addiction in post-operative total hip arthroplasty patients

Tyler J. Tantillo, DO, Manoj R. Jagtiani, DO, Eric R. Silverman, MD, Adam D. Bitterman, DO, Giles R. Scuderi, MD


Objectives: Recently, opioid abuse and related overdoses have increased warranting the need for research directed against the opioid epidemic. Previous studies identified that patients on opioid therapy may become zinc deficient and that zinc, in a murine model, may antagonistically affect the opioid receptor.13 Further understanding the relationship between opioid use and zinc deficiency may mitigate the opioid epidemic.

Methods: A retrospective study was conducted to identify zinc (Zn2+) deficiencies among post-operative total hip arthroplasty (THA) patients. On post-operative day one, patients had routine blood tests, including Zn2+ plasma levels. Patients were considered Zn2+-deficient if their Zn2+ plasma was < 56 μg/dL (Reference: 56-134 μg/dL). Upon discharge from the hospital, the patients’ inpatient opioid medication consumption per day was determined by dividing total morphine milligram equivalents (MMEs) by length of stay. A Student's t-test was performed to compare the total MMEs for Zn2+-deficient patients versus Zn2+-normal patients. A univariate analysis followed by multiple linear regression was performed to identify demographic or surgical predictors of MMEs/day.

Results: For Zn2+-deficient patients, the total MMEs/day was 33.62 ( ± 27.06), as compared to Zn2+-normal patients who consumed 16.22 ( ±16.01) MMEs/day (p = 0.031). The univariate analysis and multiple linear regression showed that patients’ Zn2+ status had a significant contribution toward predicting MMEs/day, with p = 0.022 and p = 0.04, respectively.

Conclusion: The results of this study suggest that Zn2+ deficiency may potentiate opioid consumption. Thus, Zn2+ supplementation may be a simple approach to reducing opioid addiction and dependence.


zinc, zinc deficiency, opioid dependence, addiction, orthopedics, total hip arthroplasty

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Centers for Disease Control and Prevention: Wide-Ranging Online Data for Epidemiologic Research (WONDER). Atlanta, GA: CDC, National Center for Health Statistics, 2016.

Muhuri PK, Gfroerer JC, Davies MC: Associations of nonmedical pain reliever use and initiation of heroin use in the United States. Center for Behavioral Health Statistics and Quality Data Review. Available at Accessed August, 2013.

Cicero TJ, Ellis MS, Kasper ZA: Psychoactive substance use prior to the development of iatrogenic opioid abuse: A descriptive analysis of treatment-seeking opioid abusers. Addict Behav. 2016; 65: 242-244.

Chang H-Y, Daubresse M, Kruszewski SP, et al.: Prevalence and treatment of pain in EDs in the United States, 2000 to 2010. Am J Emerg Med. 2014; 32(5): 421-431.

Frenk SM, Porter KS, Paulozzi LJ: Prescription opioid analgesic use among adults: United States, 1999–2012. NCHS Data Brief No. 189, 2015. Available at

Daubresse M, Chang H-Y, Yu Y, et al.: Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000–2010. Med Care. 2013; 51(10): 870-878.

Goesling J, Moser S, Zaidi B, et al.: Trends and predictors of opioid use after total knee and total hip arthroplasty. Pain. 2016; 157(6): 1259-1265.

Longo DL, Compton WM, Jones CM, et al.: Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med. 2016; 374(2): 154-163.

Volkow N, McLellan T: Opioid abuse in chronic pain: Misconceptions and mitigation strategies. N Engl J Med. 2016; 374(13): 1253-1263.

Chartoff EH, Connery HS: It's MORe exciting than mu: Crosstalk between mu opioid receptors and glutamatergic transmission in the mesolimbic dopamine system. Front Pharmacol. 2014; 5(116): 1-21.

Frederickson, CJ: Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol. 1989; 31: 145-238.

Lowe NM, Fekete K, Decsi T: Methods of assessment of zinc status in humans: A systematic review. Am J Clin Nutr. 2009; 89: 2040S-2051S.

Ciubotariu D, Mihaela Ghiciuc C, Elena Lupus¸oru C: Zinc involvement in opioid addiction and analgesia—Should zinc supplementation be recommended for opioid-treated persons? Subst Abuse Treat Prev Policy. 2015; 10(29): 1-14.

Wester PO: Urinary zinc excretion during treatment with different diuretics. Acta Med Scand. 1980; 208: 209-212.

Office of Dietary Supplements-Zinc. (n.d.). Available at

Thybo KH, Hägi-Pedersen D, Dahl JB, et al: Effect of combination of paracetamol (acetaminophen) and ibuprofen vs either alone on patient-controlled morphine consumption in the first 24 hours after total hip arthroplasty: The PANSAID randomized clinical trial. JAMA. 2019; 321(6): 562-571.

Han C, Li X, Jiang H, et al.: The use of gabapentin in the management of postoperative pain after total hip arthroplasty: A meta-analysis of randomised controlled trials. J Orthop Surg Res. 2016; 11: 79.

Prasad AS: Biochemistry of Zinc. New York: Plenum Press, 1993, pp. 155-156.

Contet C, Kieffer BL, Befort K: Mu opioid receptor: A gateway to drug addiction. Curr Opin Neurobiol. 2004; 14(3): 370-378.

Rodríguez-Muñoz M, Garzón J: Nitric oxide and zinc-mediated protein assemblies involved in mu opioid receptor signaling. Mol Neurobiol. 2013; 48(3): 769-782.

Rodríguez-Muñoz M, Torre-Madrid EDL, Sánchez-Blázquez P, et al.: NMDAR-nNOS generated zinc recruits PKCγ to the HINT1–RGS17 complex bound to the C terminus of Mu-opioid receptors. Cell Signal. 2008; 20(10): 1855-1864.

Ronan MV, Herzig SJ: Hospitalizations related to opioid abuse/dependence and associated serious infections increased sharply, 2002–12. Health Aff. 2016; 35(5): 832-837.

Zhao S, Chen F, Feng A, et al.: Risk factors and prevention strategies for postoperative opioid abuse. Pain Res Manag. 2019; 2019: 7490801.



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