EDITORS, We appreciate the letter from Li et al about our recently pub-lished article on the association between opioids and hepatic en-cephalopathy (HE). The letter raises interesting points deserving additional clarification

Barritt, A.S., IV

Jiang, Y.

Lieber, S.R.

Moon, A.M.

Rogal, S.S.

Tapper, E.B.

Carolina Digital Repository

DOI: 10.1111/apt.15669  Letter: are opioid prescriptions associated with hepatic encephalopathy in patients with compensated cirrhosis? Authors' replyEDITORS,We appreciate the letter from Li et al about our recently pub-lished article on the association between opioids and hepatic en-cephalopathy (HE).1,2 The letter raises interesting points deserving additional clarification.While physicians worldwide may be cautious prescribing opioids, recent studies from the US demonstrate that opioids are prescribed at alarming rates for patients with cirrhosis.3,4 We found that opi-oid prescriptions are independently associated with incident HE in younger patients with well compensated cirrhosis,2 validating sim-ilar findings from the US Medicare population.5 This adds to many other potential harms of opioids in cirrhosis, including hospital re-admissions,6 overdose7 and decreased health-related quality of life.8 Furthermore, in a recent randomized trial of treatments for osteoar-thritis and back pain, patients receiving opioids reported increased pain compared to the non-opioid group9 and, in cirrhosis, opioid use is associated with greater pain-related disability, even when adjust-ing for the severity of pain.10 Based on opioids’ demonstrated risks, uncertain benefits and widespread use in the US, we feel justified in our conclusion that, when possible, opioids should be avoided in cirrhosis.Without question, pain control is challenging in patients with cir-rhosis given contraindications to commonly used analgesics like non-steroidal anti-inflammatory drugs. There are some situations when short-term opioids are indicated (e.g. post-operative pain). However, with a well-reasoned approach, we believe that opioid-sparing strat-egies are possible for most patients with cirrhosis. Clinicians should first identify and treat contributors to pain including comorbid sleep disturbances, anxiety/depression and substance use disorders.10 First-line pharmacologic options, including low-dose acetaminophen (<2 g/day) and topical analgesics, should be routinely offered. For pain not responsive to first-line treatments, clinicians should pursue a multidisciplinary treatment approach including physical, behavioural, procedural and pharmacological aspects (Figure 1).11 When patients do require opioids, clinicians should be vigilant to detect and prevent HE, including use of empiric lactulose and/or rifaximin.Lastly, Li et al state that we did not account for the severity of liver disease or indications for opioid prescriptions. We used a national insurance claims database that does not contain labora-tory data, thus precluding assessment of model for end-stage liver disease. However, we did account for liver disease severity by carefully controlling for decompensation events. We failed to find evidence that opioid prescriptions were associated with incident non-HE decompensation events, suggesting that our results were not confounded by the severity of the liver disease. In fact, the annual incidence of non-HE decompensation events was nearly identical in patients with no opioid prescriptions (12.0%), short-term opioids (12.0%) and chronic opioids (11.6%). Similarly, this database includes the type and duration of opioid prescriptions, but does not include information on the indication of opioids, precluding assessment of the ‘appropriateness’ of prescriptions. Nevertheless, this does not affect our conclusion that opioids, regardless of indication, were associated with an increased risk of HE.In summary, given risks of opioids in patients with cirrhosis, we think their use should be limited. Broad employment of a multidis-ciplinary approach to pain in cirrhosis could reduce the high preva-lence of opioid use and decrease the incidence of HE.ACKNOWLEDG EMENTThe authors' declarations of personal and financial interests are un-changed from those in the original article.2F I G U R E  1   Multidisciplinary approach to pain management in patients with cirrhosis. TENS, transcutaneous electrical nerve stimulation. *Caution in patients with coagulopathy [Colour figure can be viewed at wileyonlinelibrary.com]Multidisciplinary approach to pain management in patients with cirrhosisTENS: transcutaneous electrical nerve stimulation; *caution in patients with coagulopathyPhysicalPhysical therapyWeight lossTENS unitsMeditationPain self-management programsCognitive behavioral therapyNerve blocks*Acupuncture*Topical analgesicsAcetaminophenBehavioural interventions Procedural interventionsNon-opioidpharmacotherapiesLINKED CONTENTThis article is linked to Moon et al and Li et al papers. To view these articles, visit https://doi.org/10.1111/apt.15639 and https://doi.org/10.1111/apt.15661.Andrew M. Moon1Yue Jiang2Shari S. Rogal3Elliot B. Tapper4,5Sarah R. Lieber1A. Sidney Barritt IV11Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA2Department of Statistical Science, Duke University, Durham, NC, USA3Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA4Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA5Gastroenterology Section, VA Ann Arbor Healthcare System, Ann Arbor, MI, USAEmail: andrew.moon@unchealth.unc.eduORCIDAndrew M. Moon  https://orcid.org/0000-0001-7163-2062 Shari S. Rogal  https://orcid.org/0000-0001-8184-1546 Elliot B. Tapper  https://orcid.org/0000-0002-0839-1515 R E FE R E N C E S1. Li C, Liang L, Jia H-D, Diao Y-K, Yang T. Letter: are opioid prescrip-tions associated with hepatic encephalopathy in patients with com-pensated cirrhosis? Aliment Pharmacol Ther. 2020;51:742.2. Moon AM, Jiang Y, Rogal SS, Tapper EB, Lieber SR, Barritt AS.Opioid prescriptions are associated with hepatic encephalopathy in a national cohort of patients with compensated cirrhosis. AlimentPharmacol Ther. 2020;51:652-660.3. Konerman MA, Rogers M, Kenney B, et al. Opioid and benzodiaze-pine prescription among patients with cirrhosis compared to otherforms of chronic disease. BMJ Open Gastroenterol. 2019;6:e000271.4. Rogal SS, Beste LA, Youk A, et al. Characteristics of opioid pre-scriptions to Veterans with cirrhosis. Clin Gastroenterol Hepatol2019;17:1165–1174 e1163.5. Tapper EB, Henderson JB, Parikh ND, Ioannou GN, Lok AS.Incidence of and risk factors for hepatic encephalopathy in a pop-ulation-based cohort of Americans with cirrhosis. Hepatol Commun 2019;3:1510–1519.6. Acharya C, Betrapally NS, Gillevet PM, et al. Chronic opioiduse is associated with altered gut microbiota and predicts re-admissions in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45:319–331.7. Zedler B, Xie L, Wang LI, et al. Development of a risk index forserious prescription opioid-induced respiratory depression oroverdose in Veterans' health administration patients. Pain Med. 2015;16:1566–1579.8. Tapper EB, Baki J, Parikh ND, Lok AS. Frailty, psychoactivemedications, and cognitive dysfunction are associated withpoor patient-reported outcomes in cirrhosis. Hepatology. 2019;69:1676–1685.9. Krebs EE, Gravely A, Nugent S, et al. Effect of opioid vs nonopioidmedications on pain-related function in patients with chronic backpain or hip or knee osteoarthritis pain: the SPACE randomized clin-ical trial. JAMA. 2018;319:872–882. 10. Rogal SS, Bielefeldt K, Wasan AD, et al. Inflammation, psychi-atric symptoms, and opioid use are associated with pain anddisability in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13:1009–1016. 11. Klinge M, Coppler T, Liebschutz JM, et al. The assessment and man-agement of pain in cirrhosis. Curr Hepatol Rep. 2018;17:42–51.

Letter: are opioid prescriptions associated with hepatic encephalopathy in patients with compensated cirrhosis? Authors' reply

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Letter: are opioid prescriptions associated with hepatic encephalopathy in patients with compensated cirrhosis? Authors' reply

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