INTRODUCTION

Cirrhosis patients have high rates of chronic pain, yet providers often struggle to manage pain in this population due to risks associated with multiple classes of analgesics.1 Opioids, in particular, are thought to exacerbate hepatic encephalopathy, and experts typically recommend dose reduction or complete avoidance in this population.2 Despite these recommendations, we found that cirrhosis inpatients were more likely to receive opioids than inpatients without cirrhosis.3 In the present study, we analyzed detailed clinical data from a large contemporary cohort of Veterans on long-term opioid therapy (LTOT), with and without cirrhosis, in an effort to better understand patient characteristics and analgesic prescribing patterns among cirrhosis patients on LTOT.

METHODS

Our cohort includes all Veterans on long-term opioid therapy (LTOT) in 2014–2018, excluding those at the end of life (e.g., hospice). We identified patients with a urine drug screen (UDS) positive for opioids, and then limited our cohort to those with a VA prescription for opioids for ≥ 84 of 90 days before the UDS. Validated International Classification of Diseases (ICD) codes in the 2 years prior to UDS were used to define cirrhosis, decompensation, and comorbidities.4, 5 Pharmacy records identified concurrent medication use and average morphine equivalent daily dose (MEDD), with high-dose opioids defined as MEDD ≥ 50 mg. Multivariable logistic regression models determined predictors of high-dose opioid use.

RESULTS

Among Veterans on LTOT (n=112,843), 3% had cirrhosis. Compared to patients without cirrhosis, cirrhosis patients were older (p<0.001) and had more medical and psychiatric comorbidities (Table 1). Cirrhosis patients were twice as likely to have common types of chronic pain (p<0.001 for all), >3 times more likely to use alcohol (p<0.001), and more likely to have had falls or functional impairment (p<0.001). Mean MEDD was 53 mg in patients with cirrhosis compared to 45 mg in those without cirrhosis (p<0.001). Concurrent cannabis and gabapentinoid use was more common in patients with cirrhosis (p ≤ 0.001). On multivariable logistic regression, patients with cirrhosis prescribed LTOT were 40% more likely to receive high-dose opioids (OR 1.37, 95% CI 1.26–1.48, p<0.001), after adjustment for demographics, comorbidities, and other substance/medication use (Table 2).

Table 1 Demographic, Clinical, and Pain-Related Characteristics by Cirrhosis and Decompensation Status Among Veterans on LTOT, 2014–2018
Table 2 Risk Factors for High-Dose Opioid Use (≥ 50 MEDD) Among Veterans on LTOT, 2014–2018 (N = 112,843)

Similar patterns were observed in the 25% (n=787) of cirrhosis patients with decompensated disease: these patients were older and had more functional impairment and substance use than compensated patients (all p<0.001; Table 1). Mean MEDD was similar (p=0.52), though decompensated patients were less likely to use other psychoactive medications, such as muscle relaxants (p<0.001).

DISCUSSION

Although there are limited data on real-world harms of prescribed opioids in cirrhosis patients, the primary metabolic pathways for most opioids are impaired in cirrhosis, with malnutrition and renal failure further impacting susceptibility to toxicity. As a result, lower opioid doses are recommended in this population. In the present study of Veterans on LTOT, however, we found the opposite to be true: cirrhosis patients were more likely to receive high-dose opioids than patients without cirrhosis.

What explains these findings? We found that cirrhosis patients were more likely to have most types of pain, suggesting that they may have higher rates of pain and/or opioid dependence than patients without cirrhosis, perhaps related to concurrent psychiatric comorbidities and substance use disorders. Additionally, providers may feel handcuffed regarding analgesic use in this population due to concerns and about medication-related risks of nonopioid agents, resulting in higher rates of prescription opioid use. For example, we found that muscle relaxants and benzodiazepines were less commonly used in patients with decompensated cirrhosis, possibly reflecting concerns regarding fall risk or deliriogenic effects of such medications.

Unfortunately, the same comorbidities that likely lead to increased rates of pain and opioid dependence in cirrhosis patients (e.g., psychiatric disease, substance use, functional impairment) may further increase the risk of opioid-related adverse events in this population, on top of risk related to hepatic impairment and demographic characteristics (e.g., older age). Interestingly, patients with these high-risk characteristics were the precise target for the VA’s 2013 opioid safety initiative,6 so these patterns may be even more pronounced in non-VA healthcare settings. It remains unknown, however, whether high-dose LTOT in this population truly leads to feared adverse events, such as hepatic encephalopathy, falls, or hospital admission. Future pharmacoepidemiologic studies answering these questions will be essential to developing evidence-based recommendations for providers treating the large proportion of cirrhosis patients living with chronic pain.