Year: 2017
Type: editorial
Abstract: See Article on Page 305 This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The opioid epidemic has received significant attention because of the nearly quadrupling of prescription opioids in the past 15 years1 and the associated rise in unintentional overdoses and high‐profile deaths. Although a majority of these overdoses have resulted from illicit opioid abuse, the subsequent stricter regulation of pain medication prescriptions has brought these issues into focus for clinicians as well. Clinicians treating patients with chronic liver disease commonly encounter those with complaints of chronic pain,2 and the use of prescribed opioids in this population is high, including prescription prevalence estimates of 24%‐54% for patients with cirrhosis.3 The use of opioids for pain management is likely in part related to the lack of alternative analgesic options in this population, especially for the treatment of moderate to severe pain.4 However, liver disease is a primary risk factor for opioid‐related overdose and respiratory and central nervous system depression.5 These increased risks among patients with liver disease are partly attributable to altered opioid metabolism. In patients with cirrhosis, opioid use predicts hospital readmissions and can contribute to symptoms of hepatic encephalopathy and slow intestinal motility, reducing the effectiveness of treatments for encephalopathy.6 Despite the risks of opioid use in patients with cirrhosis and a high prevalence of pain among patients wait‐listed for liver transplantation,7 questions regarding the impact of opioids on outcomes of liver transplantation remain. Two earlier studies demonstrating an association between pretransplant opioid prescriptions and increased risk of complications after kidney transplant8 prompted Randall et al.10 in the current issue of Liver Transplantation to examine these issues in liver transplant patients, namely, whether opioid use prior to and following liver transplantation is associated with poorer posttransplant patient and graft survival. The authors linked Scientific Registry of Transplant Recipients records with aggregated pharmaceutical data among nearly 30,000 patients undergoing liver transplantation between 2008 and 2014. They found that all‐cause mortality was increased in the first 5 years after transplant among recipients with the highest levels of opioid use. Additional analyses indicated that the impact of pretransplant opioid use on mortality was observed only after the first year after transplant. The authors suggest that this may be related to postsurgical complications driving mortality in the first year or because the effect is due to sustained opioid use over time or return to illicit drug use after transplantation. The findings suggest our efforts should focus on increased monitoring of high pretransplant and early posttransplant dose opioid users—especially as they move beyond the first year after transplant—yet the findings do not inform us whether opioid reduction or discontinuation would improve their outcomes. To design interventions targeting such high‐risk groups requires better understanding of the mechanisms underlying the associations between opioid use and transplant outcomes. In animal models, direct hepatotoxic effects and increased skin graft rejection related to opioid use have been identified and may provide insights for human studies.11 However, death‐censored graft loss was rare in the study sample and was not associated with opioid use, suggesting that graft loss was driven by overall mortality rather than direct toxicity. Future investigations should consider the timing, duration of exposure, dosage of opioid use, and proximity to outcomes in order to establish the relevant connections. Future work should also assess whether the comorbidities associated with opioid use—beyond those considered by Randall et al.10—explain the apparent increases in mortality that they observed. For example, whether chronic pain (particularly pain requiring opioids) is associated with specific comorbidities that impact morbidity and survival in liver transplant patients such as depression and sarcopenia/frailty needs to be investigated. Readers are likely to be particularly interested in the authors’ finding that, among transplant recipients included in the analysis, only 9.3% had received opioids while wait‐listed and only 922 (3%) patients took the highest levels of opioids (level 3 opioid users > 10 to 70 morphine equivalents/day and level 4 opioid users > 70 morphine equivalents/day). In prior work, they had found 28% of kidney recipients filled an opioid prescription in the year prior to transplant.8 Opioid use is thus lower in the current study than in kidney recipients, and indeed, it might be lower than in past studies of patients with cirrhosis.3 However, the current study focuses on only the subset of wait‐listed patients who underwent transplantation. It may be that those taking opioids, and particularly those taking high‐dose opioids, did not survive to transplantation due to comorbidities or were delisted. Furthermore, the percentage of recipients who had received opioids was not considered in light of time on the waiting list—patients with a short wait time would have had less “opportunity” to have received opioids. Finally, the composition of the sample may have affected the observed opioid use rates. They were less likely to be publicly insured than excluded recipients, but they were otherwise similar to excluded recipients on sociodemographic and clinical characteristics (personal communication with authors). However, this difference, in combination with the authors’ finding that public insurance was associated with increased likelihood of opioid use, suggests that the prevalence of pretransplant opioid use in liver recipients may have been underestimated in the current study. Additionally, studies have shown that publically insured patients are more likely to have adverse outcomes related to prescription opioids,13 further suggesting that not only the prescription rates but the risks may be even higher than estimated in the current study. Nevertheless, consistent with a national trend of increasing opioid prescriptions, the authors found across all levels of morphine equivalents that opioid use was more likely to be observed in the later period of the current study (2011‐2014). Thus, their work may indicate that, despite increased awareness of the risks of opioid use, the trend in liver transplantation is toward a greater number of prescriptions. A key concern among clinicians with respect to opioid use is abusive use, but as the authors acknowledge, it is not possible to identify abusive use of opioids simply by the prescription refills. Although it may be tempting to assume the use of high‐dose opioids represent drug misuse/abuse, high opioid dosages—although perhaps seeming excessive—do not define actual abusive use. Abusive opioid use can only be defined by behaviors of misusing the provided prescription or the use of nonprescribed opioids. In fact, these specific data would be less likely to represent those who are either misusing their prescriptions or using illicit drugs because prescription drug monitoring programs require close monitoring of prescribed opioids and typically screening for other illicit drug use. Additionally, most liver transplant programs require candidates to undergo a psychosocial evaluation with resolution of any identified substance abuse issues prior to listing. Interestingly, although the majority of high‐dose opioid users remained on high dosages after transplant, Randall et al.10 found 25% of pretransplant level 4 opioid users and nearly 40% of level 3 users had discontinued opioid medications after the initial 90‐day postoperative recovery, suggesting that some patients’ pain may have been related to liver disease. However, these data support the notion that many patients with chronic liver disease have pain that is unrelated to the liver and unresolved after transplantation. Where does this leave clinicians caring for patients with end‐stage disease and significant chronic pain that impacts their quality of life and functioning? Patients being treated for chronic pain may be best served through pain specialists in collaboration with liver disease specialists who can advise on the degree of liver failure and associated complications (eg, hepatic encephalopathy). Specialty pain clinics can provide proper oversight of opioid medication use, routinely monitor for drugs of abuse, and can provide a range of pain therapies in addition to pharmacologic management. The Centers for Disease Control guidelines for prescribing opioids for chronic pain provide education, sensible recommendations, and clinical tools for initiating and maintaining opioid therapy.14 Importantly, the Centers for Disease Control guidelines recommend specific caution and careful reassessment of individual benefits and risks when considering increasing dosages to ≥50 morphine milligram equivalents/day, dosages represented by levels 3 and 4 opioid use in this study. Key among the authors’ recommendations is a need for multidisciplinary team management; perhaps including palliative care, pain management, addiction treatment, and collaborative care models that can longitudinally address these patients’ complex care needs. Additional work is required to understand how to best address pain in an opioid‐sparing manner in this high‐risk population. Future studies should also assess how attention to overall psychosocial needs in the peri‐transplant period may or may not mitigate the associations between opioid use and posttransplant outcomes. Until then, caution should be taken to avoid assuming patients are receiving pain medications they do not require, and to ensure that patients are neither forced to discontinue use or be denied transplant listing merely for reasons of pain medication usage.
Source: Liver Transplantation
DOI: 10.1002/lt.24731
Authors: Shari Rogal, Mary Amanda Dew, Andrea DiMartini
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2579962601