Systematic review: adherence issues in the treatment of ulcerative colitis


Dr S. V. Kane, Section of Gastroenterology, Department of Medicine, The University of Chicago, 5841 South Maryland Ave, MC 4076, Chicago, IL 60637, USA.


Ulcerative colitis is a chronic inflammatory and debilitating disease requiring lifelong treatment. First-line therapy for ulcerative colitis is 5-aminosalicylic acid, which suffers from poor patient adherence outside the clinical trial setting.

Formulations to deliver 5-aminosalicylic acid to the disease activity site, both orally and topically, are often inconvenient and require multiple daily dosing. Such regimens can interfere with normal life and reduce the overall quality of life, negatively impacting on treatment adherence and leading to poorer long-term outcomes. These include increased morbidity with an elevated risk of symptomatic relapse, possible greater risk of colorectal cancer and higher overall costs of care.

Ulcerative colitis patients cite treatment regimen complexity, tablet quantity and dose frequency as key negative influencers of adherence. Solutions to these issues include addressing patient concerns, simplifying daily regimens and utilizing new formulations such as micropellet and multimatrix oral formulations, rectal gel and once-daily suppository formulations.

This review examines the prevalence and impact of non-adherence to 5-aminosalicylic acid therapy among patients with ulcerative colitis, as well as drug delivery strategies that may enhance dosing regimens to improve patient acceptability, adherence and long-term clinical outcomes. It is a combination of understanding patient behaviour, recognizing signs of non-adherent behaviour and utilizing management strategies to change behaviour that will improve patient outcomes.


Ulcerative colitis (UC) is a chronic inflammatory disease that primarily affects the colonic mucosa. Ulcerative colitis is most commonly diagnosed in patients aged between 15 and 35 years although it can affect patients of any age and either sex.1 The annual incidence of UC in western European countries and the USA is estimated to be six to eight cases per 100 000 individuals, with the prevalence of UC reaching 70–150 cases per 100 000 individuals.1 The course of the disease is generally relapsing–remitting, with patients experiencing few or no gastrointestinal symptoms in between symptomatic flare-ups (relapses).

The cause of UC is unknown; however, over-stimulation of an inadequately regulated mucosal immune system appears to be a major pathophysiological pathway, perhaps in response to the colonic bacterial population itself.2–4 As the precise underlying cause of UC remains unclear, therapy is aimed at the treatment of symptoms and the maintenance of remission. 5-Aminosalicylic acid (5-ASA) is the current standard of care typically used as first-line treatment of mild-to-moderate UC and is efficacious and well tolerated for the treatment of active disease5 and the maintenance of remission.6

Both oral and topical formulations to deliver 5-ASA to the site of disease activity are inconvenient and, for oral formulations, require multiple daily dosing with many tablets per dose. Such demanding regimens can interfere with the normal life of the patient and reduce his or her overall quality of life. The additional burden of a complex and inconvenient dosing regimen has a negative impact on adherence to treatment in a variety of clinical settings and can lead to poorer long-term outcomes.7–12 This is particularly true in chronic medical conditions such as UC where patients may be required to take their medication throughout their life even during periods of symptomatic remission (quiescence). Indeed, ‘real-world’ compliance rates for patients with chronic medical conditions requiring long-term pharmacotherapy are generally estimated to be approximately 50%13 and may even be as low as 30% for certain conditions.14 This review will examine the prevalence and impact of non-adherence to 5-ASA therapy among patients with UC and examine ways in which making drug delivery methods and dosing regimens more acceptable and less intrusive for patients could improve adherence and long-term clinical outcomes. This review has focused on UC because there is a lack of data regarding medication adherence in Crohn's disease. Further studies are needed to investigate the impact of adherence on outcomes in these patients.

For this review, a Medline search was conducted for full publications in various languages using the search terms: ‘medication adherence’, ‘ulcerative colitis and adherence’, ‘ulcerative colitis and maintenance’, ‘non-compliance and ulcerative colitis’, ‘ulcerative colitis and quality of life’, ‘5-ASA and ulcerative colitis’. Only those citations that discussed the impact of adherence to ulcerative colitis management were included. The references of appropriate articles were then reviewed for additional papers not otherwise found during the search.

Patient non-compliance with 5-ASA treatment regimens

Compliance (a term often used interchangeably with adherence) can be defined as the extent to which a person's behaviour (in taking medication or otherwise) coincides with the advice of their physician or health adviser. While clinical trials report excellent rates of compliance with 5-ASA therapy, in the order of 80% of patients or more,15–17 participants are generally better motivated and under close medical supervision compared with those receiving therapy outside the clinical trial setting. Adherence rates in prospective, community-based studies are much lower (40–60%)13, 18 and are often particularly poor among patients in symptomatic remission18–21 with as many as 60% of patients failing to adhere to a prescribed dose regimen and taking less than 70% of their prescribed medication.18, 20, 21

In an early study of compliance with sulfasalazine therapy in patients with inflammatory bowel disease, van Hees and van Tongeren22 used serum concentrations of sulfapyradine (a sulfasalazine metabolite) as a proxy for measuring compliance to oral sulfasalazine treatment. A total of 51 patients prescribed a maintenance dose of sulfasalazine just prior to hospital discharge were followed up for 1–6 months. Of these, 21 patients (41%) had significantly lower levels of sulfapyradine (>25% lower) at follow-up compared with 24 in-patients whose medication was supervised. Furthermore, another 171 outpatients were followed up for between 1 and 4 years. Among this group of patients, 21 (12%) had no detectable serum sulfapyradine, despite claiming compliance, suggesting that they had in fact failed to take their medication as prescribed.22

Reasons for patient non-adherence differ widely, depending on patient characteristics, disease type and treatment regimen, making it difficult to characterize patients likely to be non-adherent. A variety of factors have been reported to be associated with non-adherence to 5-ASA therapy among patients with UC (Table 1). These include disease duration,23 male gender,18 single status,18 full-time employment and three times daily dosing.21 The reasons given by patients themselves for non-adherence are also varied and include forgetfulness, questioning the need for medication during periods of disease quiescence, inconvenient regimens and need for large numbers of tablets (Table 2).19, 20

Table 1.  Factors associated with non-adherence to 5-ASA medication among patients with ulcerative colitis18, 19, 21, 23
Diagnosis of left-sided disease
Disease duration
Full-time employment
History of >4 concomitant medications
Male gender
New patient status
Patient–physician discord
Single status
Three-times daily dosing
Table 2.  Reasons given for non-adherence to 5-ASA therapy among patients with ulcerative colitis19, 20
Patient beliefs and perceptions
 Denial of illness
 Unable to see the need for medication during periods of symptom quiescence
Health-care professional-driven
 Lack of a supportive relationship
 Lack of adequate information
 Costs of filling prescriptions
 Complicated dosing regimen
 Fear of side effects
 Impact of schedule on daily life
 Large number of tablets

In a study of 99 patients with quiescent UC whose adherence to 5-ASA medication was monitored for 2 years (Figure 1), 39 patients experienced a recurrence of their symptoms and 32 (82%) of these were non-adherent to their prescribed medication. Of the 59 patients who remained in symptomatic remission, 20 (34%) were not adherent to their prescribed medication (P = 0.01).19 By 6 months into this study, 12 patients (12%) had recurrence of their disease, all of whom were non-adherent. By 12 months, 19 of 86 patients relapsed, 13 (15%) of whom were non-adherent. By 24 months, eight of the remaining 66 patients had a recurrence of their disease, six (9%) of whom were non-adherent. Patients who did not adhere to their medication had more than a five-fold greater risk of disease recurrence than adherent patients (hazard ratio 5.5; 95% confidence interval 2.3–13.2, P < 0.001). When asked their reasons for non-adherence to their prescribed regimen, 21 (30%) patients who responded said there were too many pills, 14 (20%) did not think they needed that much medication and 35 (50%) said they ‘just forgot’.19 In some cases, ‘forgetting’ to take medication can be regarded as a form of illness denial since multiple daily dosing may make patients acutely aware of their chronic illness status.

Figure 1.

Frequency of symptomatic recurrence according to adherence with 5-ASA therapy among adult patients with ulcerative colitis followed for 6, 12 and 24 months.19

Inconvenient and intrusive drug delivery formulations can also be associated with reduced adherence. Rectal formulations of 5-ASA, for example, are associated with leakage, problems with retention and bloating.24 Using a large prescription pharmacy database, Kane and Hanauer25 showed that refill rates for rectal therapies were very low compared with those for oral therapies. Moreover, patients can be uncomfortable if others are aware of their medical condition, which may be emphasized by multiple daily dosing of oral medication or the use of rectal formulations, particularly those which require several daily applications.

Clinical impact of non-adherence to therapy for UC

The implications of non-adherence to 5-ASA therapy among patients with UC include increased morbidity with a greater risk of symptomatic relapse, reduced quality of life and a possible increased risk of colorectal cancer.

Prospective studies have shown that patients who adhere to their prescribed 5-ASA regimen have a reduced risk of symptomatic relapse compared with non-adherent patients. Among 95 patients with UC who were followed for up to 10 years after their initial diagnosis, all patients experienced at least one relapse during the follow-up period.26 Those patients with a diagnosis of pancolitis or left-sided colitis had the highest risk of relapse, typically experiencing their first recurrence within 2–3 years of diagnosis, while those with distal colitis experienced their first relapse within 9–10 years of diagnosis.26 Kane et al.19 found that those patients with quiescent UC who failed to adhere to their prescribed 5-ASA regimen had a 61% chance of relapse compared with just 11% among patients who did adhere to their prescribed therapy, a difference which was statistically significant (P = 0.001).

Several studies have highlighted the impact of symptomatic UC on the quality of life and established a direct relationship to disease severity.27–29 Using the Inflammatory Bowel Disease Questionnaire (IBDQ), the Medical Outcomes Study 36-Item Short-Form Survey and the Illness Perception Questionnaire, Han et al.27 found that symptom-related disease activity correlated with disease-specific quality of life. Further analysis using a multivariate regression modelling approach showed that disease activity was the major explanatory factor for decrements in each of the four subdomains of the IBDQ as well as the total score.27 Similar results have been reported in German populations of adult patients with UC.28, 30 Among 109 adults with UC, patients reported significant reductions in both general and health-related aspects of life satisfaction as measured using the Questions on Life Satisfaction (modules) compared with a control sample of the German population.30 A further study in 112 patients with UC confirmed these observations and showed that disease activity was a significant predictor of reduced health-related life satisfaction.28

The lifetime risk of colorectal cancer among patients with UC is estimated to be approximately 20%.31 Non-adherence to medication may significantly increase this risk. In a study of 175 patients with UC, the incidence of cancer over 10 years was significantly higher (P < 0.001) in patients who were either non-adherent or in whom medication (sulfasalazine) was discontinued upon the advice of a physician (31%), compared with those on maintenance therapy (3%). Moody et al.32 concluded that patients who did not adhere to sulfasalazine therapy, or whose treatment was stopped, were significantly more likely to develop colorectal cancer than those who adhered to the therapy. Epidemiological studies have taken the opposite approach to examine the impact of adherence to regular 5-ASA therapy on cancer risk.33–36 Results of a case-controlled study of 18 969 patients showed that the risk of developing colorectal cancer was reduced among patients who adhered to 5-ASA therapy compared with patients who did not (adjusted odds ratio = 0.60).35 In an earlier case–control study of patients with UC, Eaden et al.33 found that regular mesalazine (mesalamine) therapy reduced the risk of colorectal cancer risk by 81% compared with no treatment (P = 0.006). Similarly, a retrospective case–control study showed that a history of at least 3 months of pharmacological therapy for UC, especially with sulfasalazine, had a protective effect for colon cancer.34 A recent systematic review and meta-analysis of nine observational studies involving almost 2000 patients and 334 cases of colorectal cancer concluded that 5-ASA therapy is protective for colorectal cancer in patients with UC.36

Economic impacts of non-adherence to therapy for UC

In the USA, non-adherence to prescribed, long-term medical therapy has been estimated to cost as much as US$100 billion each year and accounts for 10% of all hospital admissions.37, 38 The largest proportion of this cost (70%) appears to be due to decreased productivity and premature death, with direct medical costs accounting for the remaining 30% (hospital admissions 25% and unnecessary nursing home admissions 5%).38

As failure to adhere to a prescribed 5-ASA regimen in patients with UC is associated with an increased risk of symptomatic relapse, non-adherence is likely to accrue significant additional costs for society in terms of increased utilization of healthcare services. The costs associated with the medical care of patients with UC are considerable, particularly for those who require hospitalization. In Canada, the mean cost of each hospital admission for UC was CAN$3726, with higher costs for those patients requiring surgical intervention.39 In a Swedish survey of healthcare costs in 1994, hospital admissions accounted for 58% of all direct costs associated with inflammatory bowel disease (IBD; UC and Crohn's disease together).40 In the USA, the total annual medical cost for UC patients was estimated to be between US$0.4 billion and US$0.6 billion, with an average annual medical cost of US$1488 per patient in 1990.41 Most recently, the cost of caring for patients with IBD, including 307 patients with UC and 172 with Crohn's disease, has been assessed in the UK.42 Over a 6-month period, the total direct cost of caring for patients with IBD ranged from UK£73 (approximately US$129) to UK£33 254 (US$58 980). The mean cost of care over 6 months for patients with UC was UK£1256 (US$2228) and, while only 67 (14%) patients with IBD required hospitalization during the 6-month assessment period, they accounted for 49% of the total secondary care costs (Figure 2).42 Among this group of patients, disease relapse was associated with a two- to three-fold increase in costs for those who did not require hospital care and a 20-fold increase for those who were hospitalized (Figure 3).42 Patients who experience symptomatic relapse will also accrue costs associated with additional diagnostics and treatment.43

Figure 2.

Proportion of total direct costs associated with the care of patients with ulcerative colitis in 1 year.42

Figure 3.

Direct costs associated with symptomatic relapse of ulcerative colitis.42

The personal economic cost to patients of non-adherence and subsequent symptomatic relapse may also be considerable. Prospective studies have suggested that patients with IBD, including those with UC, are likely to experience periods of unemployment or inability to work and subsequent loss of earnings at some point during their working life.44–46 Patients who pay for their own medication may accumulate increased medication costs as higher dose regimens are required more often to manage symptomatic episodes compared with lower doses during maintenance therapy.

Reducing the risk of symptomatic relapse by improving patient adherence to treatment is likely to offer considerable personal and societal economic benefits. For example, in a small-scale study of 42 patients with UC, intermittent combined oral and topical therapy significantly reduced the number of relapses and, while drug costs were increased, the overall costs of managing symptomatic relapse fell by 48%.47

Improving compliance

There are a variety of reasons why patients fail to adhere to a prescribed 5-ASA regimen, ranging from concerns about potential side effects and complicated dosing regimens to a belief that medication is not necessary during periods of symptom quiescence (Table 2). Therapeutic relationship can also influence adherence just as much as individual clinical and psychosocial characteristics.23 In a prospective study of 153 patients with IBD, 41% of patients were non-adherent to medication 2 weeks after a clinic visit. Eighty-one percent of these patients were not intentionally non-adherent; reasons for this included forgetfulness or carelessness in taking medication. Intentional non-adherence was associated with patient–physician discordance, disease duration, lack of certainty that treatment would help and failure to schedule of a follow-up appointment.

Addressing barriers to treatment adherence resulting from patient beliefs is a complex and controversial issue and a variety of interventions have been proposed, most of which appear to offer only limited long-term improvements in ‘real-world’ settings.48 Adherence can be encouraged by open communication between physician and patient. To establish a good therapeutic relationship, patients should be given time to discuss concerns and ask questions; physicians should use open questions, an appropriate tone and not under- or over-estimate the patient's level of understanding.

Providing patients with simpler, less intrusive drug delivery methods requiring more convenient dosing regimens has been proven to improve patient compliance in a range of clinical settings including hypertension,49 human immunodeficiency virus infection,50 angina pectoris51 and osteoporosis52 and should address some of the reasons given by patients for non-adherence with 5-ASA therapy.18,19 For example, patients have been reported to prefer once-daily oral dosing of 5-ASA to divided-daily dosing (two or three times per day)53 and a recent pilot study of a novel oral formulation of 5-ASA found that adherence to oral therapy was higher than adherence to a rectal formulation of 5-ASA (97 vs. 87.5%).17 In another small pilot study, patients were randomized to receive either once-daily or conventional (twice or three times daily) mesalazine for maintenance of UC.53 After 6 months, patients in the once-daily arm appeared more satisfied with their regimen and consumed more medication overall than those in the conventional arm (90% vs. 76%; P = 0.07). Similar numbers of patients experienced relapse in each group. Thus, once-daily oral formulations of 5-ASA are likely to become a viable therapeutic option due to their ability to offer comparable efficacy, improved adherence and long-term clinical outcomes.

New formulations of 5-ASA

A number of novel oral and rectal formulations of 5-ASA are in development which, it is hoped, will prove more acceptable to patients and so enhance their long-term adherence with treatment.

A novel oral formulation of 5-ASA that provides delayed and extended drug delivery, SPD476, has been shown to be efficacious for the induction of clinical remission and improvement in symptoms following once-daily dosing of 2.4 or 4.8 g.54, 55 SPD476 contains a high dose of 5-ASA (1.2 g) formulated in a multi-matrix system comprising lipophilic and hydrophilic coats to ensure constant, homogenous and timed release of the active drug throughout the colon.17 A preliminary clinical study in 79 patients with UC suggested that this novel oral formulation may prove more effective in achieving remission compared with a conventional 5-ASA enema formulation.17 The results of two large-scale, randomized, controlled clinical trials have extended these results and demonstrated a clear benefit for the novel oral formulation in terms of reducing symptoms and improving remission rates compared with placebo.54, 55 In both studies, a significantly greater percentage of patients given once-daily SPD476 for 8 weeks achieved remission compared with those given placebo [29.2% for SPD476 4.8 g vs. 12.9% for placebo (P < 0.01);54 40.5 and 41.2% for SPD476 2.4 and 4.8 g vs. 22.1% for placebo (P < 0.01)55].

Similarly, micropellet formulations may require less frequent dosing and appear to provide a slower, more prolonged release of active drug as indicated by plasma concentration data.56, 57 Gamma-scintigraphy studies have been conducted to determine the timing and site of release of active drug within the digestive tract.56, 57 In a study among 24 healthy volunteers, a single dose of a micropellet formulation (1.5 g sachet) provided comparable systemic exposure and released active drug at approximately the same time and same site (terminal ileum and ascending colon) as an equivalent single dose of Claversal (SmithKline French, Middlesex, UK) tablets (3 × 500 mg mesalazine tablets).57 A further study in 14 healthy male volunteers yielded similar results when a single dose of a micropellet formulation (500 mg sachet) was compared with a single Salofalk (Falk Pharma, Freiburg, Germany) tablet (500 mg mesalazine).56 The efficacy of the micropellet formulation was comparable to a conventional, prolonged-release tablet formulation in 227 patients with mild-to-moderate UC, offering similar improvements in the UC disease activity score, excellent compliance rates (97%) and no difference in terms of the incidence or nature of side effects.15 In this study, patients reported a preference for the twice daily dosing offered by the micropellet formulation compared with four times daily dosing.15

A once-daily, slow-release 5-ASA suppository inserted prior to bedtime has been developed and shown to be comparable to a twice-daily 5-ASA suppository in patients with ulcerative proctitis, whose disease was limited to within 15 cm of the anal margin, in terms of efficacy (disease activity index), safety and compliance (>95% in both groups) over 6 weeks.58

Conventional suspension and foam enema formulations for delivery of 5-ASA within the colon as far as the splenic flexure have proved particularly effective. However, they are often less than acceptable to patients and are often associated with side effects such as difficulty in retention, abdominal bloating and discomfort on administration.24 Rectal gels of 5-ASA are being developed and appear to be at least as effective as conventional enema formulations and more acceptable to patients.24, 59 In a randomized, multicenter, investigator-blind, parallel-group trial, 103 patients with mild-to-moderate left-sided colitis or proctosigmoiditis were randomly allocated to mesalazine 2 g gel enema (n = 50) and mesalazine 2 g foam enema (n = 53) for 4 weeks.24 Remission rates (clinical, endoscopic and histological) were comparable between the two groups. Patients in the foam group reported significantly more difficulty in retention (25 vs. 6%, P < 0.05), abdominal bloating (50 vs. 26%, P < 0.005) and discomfort during administration (48 vs. 26%, P < 0.05) compared with the gel formulation and that the new mesalazine gel preparation was significantly better tolerated than the foam enema.24

While several studies have demonstrated the efficacy and safety of these novel formulations, none have examined changes in adherence, patient quality of life and pharmaco-economic implications of less frequent dosing within the community practice environment. These programs, and many others, remain to be conducted upon approval of such once-daily formulations.


Ulcerative colitis is a chronic medical condition which requires patients to take prophylactic medication throughout their lives. Despite clinical trials reporting excellent compliance to 5-ASA therapy regimens, studies have shown that patient compliance is poor, outside of the clinical trial setting. Non-adherence to a prescribed regimen of 5-ASA has been shown to dramatically increase the risk of symptomatic relapse resulting in decreased quality of life and increased societal and personal costs, while adherence has long-term benefits. Adherence to 5-ASA therapy has also been associated with a reduced risk of colorectal cancer compared with non-adherence. The problem of treatment compliance is a complex, multifaceted problem that is not well understood. When questioned directly, patients with UC have cited the complexity of the treatment regimen, dose (number of tablets) and dose frequency (three to four times daily dosing) as key factors that negatively influence compliance. Simpler and more convenient dose regimens delivered via a practical, acceptable and minimally intrusive formulation should reduce this barrier to compliance with 5-ASA therapy, decreasing the risk of symptomatic relapse, maintaining patient quality of life and reducing the overall cost of care for this patient group. Several advances in drug delivery technology are now in development to provide simple and acceptable drug delivery, including micropellet and multi-matrix oral formulations as well as rectal gel and once-daily suppository formulations.


The author kindly acknowledges the contributions of Tracey Lonergan and Clare Baker for professional medical writing support and Karen Middleton for editorial assistance, with funding for professional writing services from Shire Pharmaceuticals Group plc.