Abstract
Background
Hepatic encephalopathy (HE) is a major cause of mortality and morbidity in patients with cirrhosis. Lactulose non-adherence is one of the most frequently reported precipitants of hospital admission for HE.
Aims
We aimed to identify which factors contribute most to lactulose non-adherence and propose strategies to promote greater adherence and utilization of lactulose.
Methods
Participants in this study consisted of patients with cirrhosis who were taking lactulose for prevention of HE. Subjects were administered the Morisky Adherence Scale 8 (MAS-8) and a customized 16-question survey that assessed barriers to lactulose adherence. Results from the MAS-8 were used to stratify subjects into “adherent” and “non-adherent” groups. Survey responses were compared between groups.
Results
We enrolled 129 patients in our study, of whom 45 were categorized as “adherent and 72 were categorized as “non-adherent.” Barriers to adherence included large volumes of lactulose, high frequency of dosing, difficulty remembering to take the medication, unpleasant taste, and medication side-effects. Most patients (97%) expressed understanding of the importance of lactulose, and 71% of patients felt that lactulose was working to manage their HE. Hospital admission rates for HE was higher in non-adherent patients, although this difference was not statistically significant.
Conclusion
We identified several factors that contribute to lactulose non-adherence among patients treated for HE. Many of these factors are potentially modifiable. Patient and care-giver education are critical to assure adherence. Pharmacists and nurses are an essential but underutilized aspect of education regarding proper medication use.
Keywords: Lactulose, Adherence, Hepatic, Encephalopathy
Introduction
Hepatic encephalopathy (HE) is a major cause of morbidity and mortality in patients with cirrhosis [1, 2] and is associated with decreased quality of life for both patients and their caregivers [3, 4]. It arises from hepatic insufficiency and portosystemic shunting, leading to accumulation of neurotoxic metabolites such as ammonia that cross the blood–brain barrier and cause neurological deterioration. Lactulose is a nonabsorbable disaccharide that is metabolized into short-chain organic acids by colonic microbiota. The subsequent increase in intestinal acidity allows for conversion of ammonia into ammonium, which can be excreted in the feces.
Lactulose is an effective first-line medication for both treatment and secondary prophylaxis for HE. It is prescribed as either monotherapy or in conjunction with an antibiotic such as rifaximin. Lactulose therapy requires self-titration by the patient: an initial regimen of 15–30 mL of lactulose syrup taken 2–4 times per day is adjusted until 2–3 soft bowel movements per day is achieved [5]. When taken correctly, lactulose has been shown to significantly reduce the risk of non-improvement in neuropsychiatric tests, prevent progression to overt HE, and improve health-related quality of life [6, 7].
Despite its effectiveness, adherence to lactulose is a challenge for many patients. This is in part due to difficulty titrating the dose, the medication’s sweet taste, and its diverse side-effect profile which includes diarrhea, bloating, and dehydration. Notably, non-adherence to lactulose is one of the most frequently reported factors to precipitate hospital admission for HE [8, 9]. In fact, lactulose non-adherence was associated with 6 months shorter time-to-recurrence of HE compared to lactulose-adherent patients [9]. Lactulose overuse and underuse was found to precipitate 21% of hospital admissions for HE [10]. The precise factors that contribute to lactulose non-adherence are unclear but have been postulated to involve lack of patient insight into their disease process, ability to self-titrate, and patient understanding of the consequences of non-adherence [9, 11]. Given the high economic burden that HE places on the healthcare system [12], as well as the relatively low cost and ubiquity of lactulose, the barriers preventing adequate lactulose utilization must be reexamined. The purpose of this study was to determine which factors contribute most to lactulose non-adherence and to propose strategies to promote greater adherence and utilization of lactulose.
Methods
Study Population and Data Collection
Participants in this study consisted of patients with cirrhosis who were taking lactulose for prevention of HE. All subjects were patients at the University of California, Los Angeles (UCLA) Pfleger Liver Institute, and were invited by investigators to participate in the study during their clinic visit. Recruitment began in October 2021 and ended in September 2022. Surveys and informed consent were administered in both English and Spanish, and translation services were provided for patients whose native language was neither English nor Spanish.
Following a short verbal description of the study, informed consent was obtained, and participants were administered a 24-question questionnaire (see below) that inquired about medication side-effects and factors that contributed to medication adherence. Participation in this study was completely voluntary and there was no compensation offered. Demographic and clinical information was also collected for each subject by a member of the research team. Data was obtained through the electronic health record and included age, gender, race/ethnicity, body mass index, smoking and alcohol status, education history, pertinent comorbidities, laboratory values, and medication use. This study was approved by the UCLA Institutional Review Board.
Questionnaire
The questionnaire consisted of 24 questions that took approximately 10 min to complete. The first 8 questions were derived from the Morisky Adherence Scale 8 (MAS-8), a validated instrument for measuring self-reported medication adherence [13]. The MAS-8 was originally developed to measure medication adherence in patients with hypertension and has since been adapted to study adherence in diseases such as diabetes and glaucoma [14–16]. We modified the questions to be specific to lactulose utilization. “Adherent” was defined as a MAS-8 score of 0 or 1, and “non-adherent” was defined as a MAS-8 score of 2 or greater as described by Newman-Casey et al. [15]
The remaining 16 questions, used to investigate barriers to lactulose adherence, were developed from expert opinion and hepatology prior experience (see Supplement). These included questions inquiring regarding the duration of lactulose treatment, medication adverse-effects, and instructions given. Social support was assessed with questions “Who do you live with?” and “Which of the following helps or reminds you to take lactulose?” Patients were also asked if they took the same dose of lactulose every day; and, if they were consuming the same lactulose dosage that was recommended by their healthcare provider to characterize the lability of the dosing changes. Patient insight into lactulose utilization was assessed with the question “Do you understand why you are taking lactulose?” The question “On a scale from 1 to 5, how important do you think taking lactulose is to prevent HE?” assessed the participant’s understanding of the importance and necessity of lactulose use. Perceived effectiveness of lactulose was measured with the question “Do you feel that lactulose is helping manage your HE?” One of the 16 question specifically asked patients to rank factors that may affect lactulose adherence: large lactulose volume, frequent doses, difficulty remembering to take the medication, difficulty understanding how to dose the medication, unpleasant taste, and the gastrointestinal adverse-effects. Response options were recorded on a 5-point Likert scale that ranged from “very easy,” “somewhat easy,” “neutral,” “somewhat difficult,” and “very difficult.”
Statistical Analysis
Results from the MAS-8 were used to stratify subjects into “adherent” and “non-adherent” groups. Survey responses were compared between groups. Categorical comparisons used Fisher exact tests and continuous comparisons used one-tailed Welch’s T-tests.
Results
We enrolled 129 patients with cirrhosis who take lactulose in our study, of whom 45 patients were categorized as “adherent” and 72 were categorized as “non-adherent” via the MAS-8 questionnaire. The adherence rate of our study population was 34.9%. The duration of lactulose treatment was shorter in the adherent group compared to the non-adherent group (27.9 months vs 46.8 months, p = 0.021).
There were no significant between-group differences in age, gender, ethnicity, education levels, or type of insurance. (Table 1) The comorbidities analyzed included hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, hepatocellular carcinoma, history of ascites, and history of variceal bleeding. Diabetes was more common in the non-adherent group (22% vs 44%, p-0.018), as was hypertension (18% vs 31%, p = 0.135), although the latter was not statistically significant. There were no differences in the other aforementioned comorbidities, nor was there a difference between rifaximin usage. Alcohol was the most common etiology of liver disease (51%), followed by non-alcoholic steatohepatitis (25%) and hepatitis C (23%). Alcohol-related etiology of liver disease was more common in the adherent group (67% vs 46%, p = 0.036). There were no between-group differences between the other listed etiologies of liver disease. (Table 2) There were also no significant differences between the most recently documented laboratory values, which included white blood cell count, hemoglobin, international normalized ratio (INR), aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin, albumin, or MELD-Na scores. (Table 3).
Table 1.
Demographics and background information
| Total N = 129 | Adherent N = 45 | Non-adherent N = 72_ | p-value | |
|---|---|---|---|---|
|
| ||||
| Age (mean, SD) | 58.5 (11.0) | 55.7 (11.2) | 59.8 (10.3) | 0.052 |
| Gender | ||||
| Male | 65 (50.4%) | 27 (60.0%) | 35 (48.6%) | 0.258 |
| Female | 64 (49.6%) | 18 (40.0%) | 37 (51.4%) | 0.258 |
| Race/Ethnicity | ||||
| Asian | 5 (3.9%) | 0 (0.0%) | 4 (5.6%) | 0.297 |
| Black | 3 (02.4%) | 1 (2.2%) | 2 (2.8%) | 1.000 |
| Hispanic or Latino | 52 (40.9%) | 18 (40.0%) | 27 (37.5%) | 0.846 |
| White | 50 (39.4%) | 18 (40.0%) | 30 (41.7%) | 1.000 |
| Other | 17 (13.4%) | 8 (17.8%) | 9 (12.5%) | 0.434 |
| Education | ||||
| Did not complete high school | 20 (19.0%) | 11 (25.0%) | 9 (14.8%) | 0.130 |
| High school graduate | 28 (26.7%) | 11 (25.0%) | 17 (27.9%) | 1.000 |
| Trade or vocational training | 27 (25.7%) | 12 (27.3%) | 15 (24.6%) | 0.504 |
| Associate degree or higher | 30 (28.6%) | 10 (22.7%) | 20 (32.8%) | 0.664 |
| Insurance | ||||
| HMO | 52 (40.3%) | 14 (31.1%) | 36 (50.0%) | 0.055 |
| PPO | 28 (21.7%) | 12 (26.7%) | 15 (20.8%) | 0.504 |
| MediCal | 27 (20.9%) | 14 (31.1%) | 12 (16.7%) | 0.108 |
| Other | 12 (9.3%) | 5 (11.1%) | 7 (9.7%) | 1.000 |
Categorical comparisons used Fisher exact tests and continuous comparisons used Welch’s two-tailed t-test
Table 2.
Medical history and medication use
| Total N = 129 | Adherent N = 45 | Non-adherent N = 72 | p-value | |
|---|---|---|---|---|
|
| ||||
| Comorbidities | ||||
| Coronary artery disease | 6 (4.7%) | 3 (6.7%) | 3 (4.2%) | 0.674 |
| Diabetes Mellitus | 46 (35.7%) | 10 (22.2%) | 32 (44.4%) | 0.018 |
| Hepatocellular carcinoma | 16 (12.4%) | 5 (11.1%) | 10 (13.9%) | 0.781 |
| History of ascites | 110 (85.2%) | 38 (84.4%) | 63 (87.5%) | 0.783 |
| History of variceal bleeding | 41 (31.8%) | 15 (33.3%) | 24 (33.3%) | 1.000 |
| Hyperlipidemia | 18 (14.0%) | 6 (13.3%) | 9 (12.5%) | 1.000 |
| Hypertension | 35 (27.1%) | 8 (17.8%) | 22 (30.6%) | 0.135 |
| Medication use | ||||
| Lactulose alone | 31 (26.5%) | 16 (35.6%) | 15 (20.8%) | 0.089 |
| Lactulose + Rifaximin | 86 (73.5%) | 29 (64.4%) | 57 (79.2%) | 0.089 |
| Etiology of liver disease | ||||
| Alcohol | 66 (51.2%) | 30 (66.6%) | 33 (45.8%) | 0.036 |
| Autoimmune liver disease | 2 (1.6%) | 1 (2.2%) | 0 (0.0%) | 0.385 |
| Hepatitis B | 6 (4.7%) | 1 (2.2%) | 5 (6.9%) | 0.404 |
| Hepatitis C | 29 (22.5%) | 7 (15.6%) | 18 (25.0%) | 0.255 |
| NASH | 32 (24.8%) | 9 (20.0%) | 20 (27.8%) | 0.386 |
| Other | 7 (5.4%) | 3 (6.7%) | 3 (4.2%) | 0.674 |
Comparisons used Fisher exact tests. Statistically significant values in which P < 0.05 are noted in bold
Table 3.
Most recent laboratory test values
| Total N = 129 | Adherent N = 45 | Non-adherent N = 72 | p-value | |
|---|---|---|---|---|
|
| ||||
| AST (IU/L) | 59.2 (45.1) | 60.6 (54.7) | 57 (32.6) | p = 0.695 |
| ALT (IU/L) | 38.9 (46.1) | 44.0 (71.3) | 34 (19.0) | p = 0.395 |
| Alkaline phosphatase(U/L) | 152.4 (73.4) | 152.2 (75.7) | 148.2 (65.5) | p = 0.772 |
| Total bilirubin (mg/dL) | 3.1 (4.5) | 3.2 (4.0) | 3.0 (4.8) | p = 0.800 |
| Hemoglobin (mm3) | 11.7 (6.8) | 11.1 (2.3) | 12.3 (8.9) | p = 0.254 |
| White blood cell (mm3) | 5.0 (2.6) | 5.5 (2.3) | 4.8 (2.9) | p = 0.153 |
| Platelet (mm3) | 100.2 (56.7) | 107.1 (58.2) | 94.4 (52.0) | p = 0.238 |
| Albumin (g/dL) | 3.3 (0.6) | 3.4 (0.7) | 3.2 (0.6) | p = 0.365 |
| INR | 1.4 (0.4) | 1.4 (0.5) | 1.4 (0.3) | p = 0.988 |
| Creatinine (mg/dL) | 1.4 (1.9) | 1.2 (1.0) | 1.5 (2.3) | p = 0.452 |
| Sodium (mEq/L) | 136.8 (4.0) | 136.5 (4.4) | 136.8 (3.5) | p = 0.742 |
| MELD-Na | 15.8 (6.4) | 15.9 (7.0) | 15.5 (5.8) | p = 0.312 |
Comparisons used Welch’s two-tailed T-test
Of our previously identified 6 barriers to adherence, 5 were more frequently reported as “difficult” or “very difficult” in the non-adherent group compared to the adherent group. These barriers were large volumes of lactulose (16% vs 42%, p = 0.004), high frequency of dosing (20% vs 47%, p = 0.003), difficulty remembering to take the medication (4% vs 20%, p = 0.015), unpleasant taste (40% vs 61%, p = 0.036), and medication side-effects (24% vs 46%, p = 0.030). Patients in the non-adherent group more frequently reported difficulty understanding the lactulose instructions compared to patients in the adherent group, although this difference was not statistically significant (7% vs 15%, p = 0.243) (Table 4; Fig. 1).
Table 4.
Survey responses
| Total N = 129 | Adherent N = 45 | Non-adherent N = 72 | p-value | |
|---|---|---|---|---|
|
| ||||
| Duration in months of lactulose treatment; mean (SD) | 39.3 (47.6) | 27.9 (28.8) | 46.8 (55.6) | p = 0.021 |
| Barriers to adherence | ||||
| Large volume | 42 (32.6%) | 7 (15.6%) | 30 (41.6%) | p = 0.004 |
| Frequent dosing | 46 (35.7%) | 9 (20.0%) | 34 (47.2%) | p = 0.003 |
| Difficulty remembering | 19 (14.7%) | 2 (4.4%) | 15 (20.8%) | p = 0.015 |
| Difficult instructions | 14 (10.9%) | 3 (6.7%) | 11 (15.3%) | p = 0.243 |
| Unpleasant taste | 69 (53.5%) | 18 (40.0%) | 44 (61.1%) | p = 0.036 |
| Side-effects | 49 (38.0%) | 11 (24.4%) | 33 (45.8%) | p = 0.030 |
| Side-effects | ||||
| Diarrhea | 90 (69.8%) | 29 (64.4%) | 54 (75.0%) | p = 0.295 |
| Nausea | 53 (41.1%) | 14 (31.1%) | 33 (45.8%) | p = 0.453 |
| Vomiting | 22 (17.1%) | 5 (11.1%) | 14 (19.4%) | p = 0.306 |
| Bloating | 49 (38.0%) | 10 (22.2%) | 32 (44.4%) | p = 0.018 |
| Gas | 81 (62.8%) | 30 (66.7%) | 45 (62.5%) | p = 0.695 |
| Belching | 32 (24.8%) | 7 (15.6%) | 21 (29.2%) | p = 0.120 |
| Stomach pain or discomfort | 61 (47.3%) | 14 (31.1%) | 41 (56.9%) | p = 0.007 |
| Dehydration | 40 (31.0%) | 14 (31.1%) | 20 (27.8%) | p = 0.834 |
| Excessive bowel movements | 56 (43.4%) | 18 (40.0%) | 33 (45.8%) | p = 0.570 |
| Abnormal sodium level | 33 (25.6%) | 8 (17.8%) | 21 (29.2%) | p = 0.192 |
| None | 11 (8.5%) | 6 (13.3%) | 4 (5.6%) | p = 0.180 |
| Other | 8 (6.2%) | 3 (6.7%) | 5 (6.9%) | p = 1.000 |
| Medication instruction-giver | ||||
| Primary care physician | 26 (20.2%) | 9 (20.0%) | 15 (20.8%) | p = 0.649 |
| Gastroenterologist | 77 (59.7%) | 25 (55.6%) | 43 (59.7%) | p = 0.703 |
| Nurse | 13 (10.1%) | 4 (8.9%) | 8 (11.1%) | p = 0.765 |
| Pharmacist | 16 (12.4%) | 5 (11.1%) | 8 (11.1%) | p = 1.000 |
| No one | 13 (10.1%) | 7 (15.6%) | 6 (8.3%) | p = 0.242 |
| Medication assistance | ||||
| Family member or caregiver | 52 (40.3%) | 17 (37.8%) | 30 (41.7%) | p = 0.703 |
| Electronic (alarm, calendar) | 11 (8.5%) | 5 (11.1%) | 6 (8.3%) | p = 0.747 |
| Myself | 91 (70.5%) | 32 (71.1%) | 50 (69.4%) | p = 1.000 |
| Other | 1 (0.8%) | 1 (2.2%) | 0 (0.0%) | p = 0.385 |
| Same dose of lactulose everyday | ||||
| Yes | 94 (72.9%) | 36 (80.0%) | 48 (66.7%) | p = 0.142 |
| How many BMs per day | ||||
| 0–1 | 9 (7.0%) | 4 (8.9%) | 4 (5.6%) | p = 0.482 |
| 2–4 | 101 (78.3%) | 36 (80.0%) | 56 (77.8%) | p = 0.821 |
| 5 or more | 19 (14.7%) | 5 (11.1%) | 12 (16.7%) | p = 0.591 |
| Understanding of why lactulose? | ||||
| Yes | 125 (96.9%) | 43 (95.6%) | 70 (97.2%) | p = 0.638 |
| Do you feel that lactulose is helping manage your hepatic encephalopathy? | ||||
| Yes | 91 (70.5%) | 31 (68.9%) | 49 (68.1%) | p = 1.000 |
| Hospital admission for hepatic encephalopathy | ||||
| Yes | 46 (35.7%) | 11 (24.4%) | 30 (41.7%) | p = 0.074 |
Comparisons used Fisher exact tests. Statistically significant values in which P < 0.05 are noted in bold
Fig. 1.
Comparison of barriers to lactulose adherence in the adherent versus the non-adherent groups. The y-axis represents the percentage of patients who reported the barrier as “difficult” or “very difficult.”
Study participants reported medication side-effects of diarrhea (70%), gas (63%), stomach pain or discomfort (47%), excessive bowel movements (43%), nausea (41%), bloating (38%), dehydration (31%), abnormal sodium levels (26%), belching (25%), vomiting (17%), and other unspecified side-effects (6%). Eleven respondents (9%) reported no side-effects. The non-adherent group reported higher rates of belching (22% vs 44%, p = 0.018) and stomach pain or discomfort (31% vs 57%, p = 0.007) compared to the adherent group (Table 4).
There were no differences in the primary medication instruction-giver between the adherent and non-adherent groups. Gastroenterologists were the most common instruction-giver overall (60%), followed by primary care physicians (20%), pharmacists (12%), and nurses (10%). Thirteen respondents (10%) reported that no one had given them instructions on how to take their lactulose (Table 4).
There were also no differences in medication administration assistance between the adherent and non-adherent groups. When asked who helps or reminds them to take lactulose, 71% reported “myself,” 40% reported relying on a family member or caregiver, and 9% reported using an electronic reminder system such as an alarm or calendar. Compared to patients in the non-adherent group, patients in the adherent group tended to take the same dose of lactulose every day, although this difference was not statistically significant (80% vs 67%, p = 0.142). Most patients (78%) reported having 2–4 bowel movements per day, while 7% reported having 0–1 bowel movements per day and 15% reported having 5 or more bowel movements per day. There were no between-group differences in bowel movement frequency per day (Table 4).
Most patients (97%) expressed understanding of the importance of lactulose, and 71% of patients felt that lactulose was working to manage their HE. These rates were similar between adherent and non-adherent groups. Hospital admission rates for HE was higher in non-adherent patients, although this difference was not statistically significant (24% vs 42%, p = 0.074) (Table 4).
Discussion
In our study we identified multiple barriers to proper lactulose utilization that were more frequently reported in patients who were non-adherent to lactulose. These barriers were large volume of the lactulose syrup, frequent dosing of the medication, difficulty remembering to take their medication, unpleasant taste, and the associated side-effects. Many of these barriers are potentially modifiable. Although there are no easy solutions to mitigate the frequent dosing and large volumes of lactulose syrup, several strategies can be trialed to improve the excessively sweet taste of lactulose. Lactulose is currently only available in a liquid syrup formulation. A jelly formulation of lactulose (SK-1202) has been tested in Japan and had improved palatability compared to the commercially available syrup formulation. However, this formulation is not widely available in the United States [17]. While we await the development of more tolerable formulations of lactulose, patients can try mixing or chasing the lactulose syrup with water, juice, milk, or other more palatable fluids. Patients should be encouraged to experiment with different flavor profiles to identify a concoction that is most tolerable for them.
Most patients reported good understanding of lactulose instructions, with only 11% of respondents reporting the instructions as “difficult” or “very difficult” to understand. Nevertheless, the adherence rate in our study population was only 35%. Although this may suggest that difficulty understanding of lactulose instructions is not a driver for non-adherence, it is possible that patients may think that they understand how to take lactulose when in reality they may not. Anecdotally, many patients believe that they should take the same dose of lactulose every day, when instead they should titrate their dose to achieve a goal bowel movement frequency of 2–3 bowel movements per day. Of the patients who reported finding lactulose instructions “easy” or “very easy” to understand, 76% reported taking the same dose of lactulose every day and 77% of patients report having 2–4 bowel movements per day. One strategy to assure understanding would be to frame lactulose as an anti-constipation medication in addition to preventing HE. If patients report symptoms of diarrhea and gas, patients should be encouraged to view this as signs that the lactulose is working. This positive framework may also mitigate the negative reinforcement that patients may experience when they associate lactulose use with diarrhea and gas.
Another strategy to promote adherence would be to start lactulose at a lower dose and slowly titrate upward. This reinforces the idea that the lactulose dose does not have to be fixed; rather, it should be titrated to achieve a goal bowel movement frequency. Additionally, this strategy may also avoid disenchanting the patient from using lactulose, as starting a patient on full-dose lactulose could result in severe diarrhea which could discourage patients from wanting to take it. Of course, this strategy should be limited to patients with mild HE for which aggressive management of HE is not as urgently needed.
Difficulty remembering to take their medication was reported in 4.4% of the adherent group and 20.8% of the non-adherent group. Forgetfulness can be multifactorial in nature but could potentially be mitigated by caregiver support and/or electronic reminder systems. Interventions targeted at patients’ social support systems should be performed. Caregivers and family members of patients should be encouraged to accompany the patient to their clinic appointments, and lactulose education should also be provided to them. For patients that do not have strong social support, electronic reminder systems (i.e., phone alarm, calendar) should be implemented to reduce medication errors due to forgetfulness. Another potential intervention could be for trained staff members to periodically reach out to patients taking lactulose by phone and remind them to take their lactulose as prescribed.
In our study, lactulose non-adherence was not associated with gender, race or ethnicity, education level, or insurance status. Patients in the non-adherent group were more likely to have concomitant diagnoses of diabetes and hypertension, although the latter was not statistically significant. One explanation could be that pill burden from comorbid disease is a driver of non-adherence. Alternatively, patients in the non-adherent group may have been non-adherent to all of their medications, not just lactulose. The duration of lactulose treatment was higher in the non-adherent group, suggesting that chronic long-term lactulose use and its associated side-effects could lead to burn-out and thus foster non-adherence. Most patients (97%) demonstrated good understanding of why they need to take lactulose, suggesting that most patients in our study possessed insight into their disease and treatment course. Most patients (73%) believed that lactulose was working to prevent their HE.
There is ample room for improvement in patient education regarding lactulose use. In our study, most patients received lactulose instruction from their gastroenterologists, followed by their primary care physicians, pharmacists, and nurses. Pharmacists and nurses are an essential but underutilized resource of education regarding proper medication use, reported in 10.1 and 12.4 percent respectively in our patient population. Multiple studies have demonstrated that both nursing and pharmacy interventions improve medication adherence in various patient populations [18–20]. Teaching a patient to properly dose lactulose takes a considerable amount of time, and patient education is non-reimbursable. Thus, proper guidance on lactulose use may not be a high priority in certain institutions. If physicians are limited in their time spent with the patient, a trained staff member (i.e., nurse, pharmacist) should spend additional time explaining the importance of lactulose adherence and working with the patient to develop personalized strategies to maximize adherence. Educational videos explaining how lactulose works and why it is important in preventing HE would also be beneficial. Personalized counseling should be performed to increase patient motivation. Continuous re-education and reminders of the importance of lactulose adherence is essential and should be reinforced during all follow-up visits.
Fatigue may also contribute to non-adherence. Fatigue is defined as difficulty performing physical or mental tasks and is the most frequently reported symptom in patients with liver disease [21]. It is frequently unresponsive to rest, making it challenging to treat [11]. Chronic fatigue produces a state of increased discomfort and lower capacity for work and may lead to confusion and difficulty comprehending and adhering to complex medication regimens. Furthermore, HE is associated with deficits in attention and memory, although the association between HE and memory impairment is questionable [22, 23].
Addition of rifaximin should be considered in patients who are at high risk for nonadherence. Rifaximin is a nonabsorbable oral antibiotic that reduces the number of ammonia-producing bacteria in the intestinal tract. It is prescribed as 400 mg three times per day, or 550 mg twice per day [24]. Compared to lactulose, it is well-tolerated [25, 26] with a gentler side-effect profile, and does not require dose titration. A meta-analysis by Wang, et al., demonstrated that the combination of rifaximin and lactulose was associated with increased clinical efficacy and decreased mortality in HE [27]. Similarly, Sharma et. Al. demonstrated in their randomized controlled trial that the combination of rifaximin and lactulose showed greater efficacy in preventing overt HE compared to lactulose alone [28]. However, no prospective trials have directly compared the efficacy of rifaximin monotherapy to lactulose monotherapy. Greater cost of rifaximin compared to lactulose may also pose a barrier to combination therapy, although some studies have suggested that the economic savings from decreased hospitalizations for HE due to greater efficacy of lactulose and rifaximin combination therapy may justify its increased cost [29–32].
There are several limitations to this study. This was a cross-sectional survey administered at a single academic medical center in southern California, and thus our study population may not be representative of patient populations located elsewhere in the country. Although we invited all patients with a history of cirrhosis who take lactulose to participate in this study, it is possible that non-adherent patients may have felt less inclined to participate, thus underestimating the rate of non-adherence in our population. Although patients were told that their responses would not affect their clinical care in any way, it is possible that some patients may have felt pressure to report adherence as to not disappoint the healthcare staff.
In conclusion, our study highlighted the many barriers that prevent proper lactulose utilization and adherence in patients with cirrhosis. These barriers are multifactorial and are unique to each patient. A tailored approach with easy-to-understand patient instructions, the use of reminder systems to prevent forgetfulness, and continuous re-education should be encouraged. Addition of rifaximin should be considered in patients at high-risk for non-adherence. Future research should evaluate whether patient-centered educational modules and individualized counseling plans can increase motivation to prevent HE and improve adherence.
Supplementary Material
Funding
The research described was supported by NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.
Footnotes
Competing interests All the authors declared that they have no conflict of interest.
Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s10620-023-07935-z.
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