REVIEW

pISSN 1598-9100 • eISSN 2288-1956

https://doi.org/10.5217/ir.2017.15.4.434
Intest Res 2017;15(4):434-445

Medication adherence in inflammatory bowel disease

Webber Chan1,2, Andy Chen3, Darren Tiao4, Christian Selinger5, Rupert Leong1
1
Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney, Australia, 2Department of Gastroenterology and
Hepatology, Singapore General Hospital, Singapore, 3South Western Sydney Clinical School, University of New South Wales, Sydney, 4Sydney
Medical School, the University of Sydney, Sydney, Australia, 5IBD Unit, Leeds Gastroen­terology Institute, Leeds Teaching Hospitals NHS Trust, St
James University Hospital, Leeds, UK

Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory condition with intestinal and extraintestinal manifesta-
tions. Medications are the cornerstone of treatment of IBD. However, patients often adhere to medication poorly. Adherence
to medications is defined as the process by which patients take their medications as prescribed. Treatment non-adherence is
a common problem among chronic diseases, averaging 50% in developed countries and is even poorer in developing coun-
tries. In this review, we will examine the adherence data in IBD which vary greatly depending on the study population, route of
administration, and methods of adherence measurement used. We will also discuss the adverse clinical outcomes related to
non-adherence to medical treatment including increased disease activity, flares, loss of response to anti-tumor necrosis factor
therapy, and so forth. There are many methods to measure medication adherence namely direct and indirect methods, each
with their advantages and drawbacks. Finally, we will explore different intervention strategies to improve adherence to medica-
tions. (Intest Res 2017;15:434-445)

Key Words: Medication adherence; Colitis, ulcerative; Crohn disease; Inflammatory bowel disease

INTRODUCTION decades.1-3 Sackett and Haynes4 were the first to introduce

the term “compliance” to medicine in 1976. They defined
Inflammatory bowel disease (IBD), comprising UC and “compliance” as the extent to which the patient’s behavior
CD, a chronic idiopathic inflammatory condition possessing (in terms of taking medications, following diets or executing
intestinal and extra-intestinal features and is characterized other lifestyle changes) coincides with the clinical prescrip-
by periods of relapses and remission. Medications, includ- tion. Since then various adaptations of the original definition
ing 5-aminosalicylates, corticosteroids, immunomodulators took place, leading to misunderstanding and confusion, and
(thiopurines [azathioprine and mercaptopurine] and meth- hamper comparisons of results of medical research and ap-
otrexate), and biological agents (anti-tumor necrosis factor plication in practice. Hence, a new taxonomy for describing
[TNF; infliximab, adalimumab, and certolizumab pegol], and defining adherence to medications has been proposed
and anti-adhesion molecules [vedolizumab]), are the cor- to promote consistency in terminology and methods so
nerstone of treatment of IBD. However, patient adherence as to aid in the conduct, analysis and interpretation of sci-
to medication, like other chronic diseases, is often poor. The entific studies of medication adherence. 5 Today the word
definition of medication adherence evolved over the past 4 “adherence” is preferred by many health care professionals,
because “compliance,” implies patients’ passive obedience to
Received May 17, 2017. Revised May 28, 2017. the doctor’s orders and that the treatment plan is not based
Accepted May 29, 2017. Published online August 2, 2017
Correspondence to Webber Chan, Gastroenterology and Liver Services, on cooperation between physicians and patients.
Concord Repatriation General Hospital, ACE Unit, Level 1 West, Hospital
Road Concord NSW 2139, Australia. Tel: +61-2-9767-6111, Fax: +61-2-
9767-6767, E-mail: webber.chan.p.w@singhealth.com.sg
Financial support: None. Conflict of interest: None.

© Copyright 2017. Korean Association for the Study of Intestinal Diseases. All rights reserved.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 https://doi.org/10.5217/ir.2017.15.4.434 • Intest Res 2017;15(4):434-445

DEFINITION OF ADHERENCE patients (both adult and paediatric patients) were included
in the review. The pooled adherence rate to biologics in pa-
Adherence to medications is defined as the process by tients with IBD was 82.6%, ranging from 36.8% to 96.0%.
which patients take their medications as prescribed.5 It has
3 components: initiation (when the patient takes the first EFFECTS OF NON-ADHERENCE
dose of a prescribed medication), implementation (the ex-
tent to which a patient’s actual dosing corresponds to the Non-adherence in IBD is associated with an increase in
prescribed dosing regimen, from initiation until the last dose disease activity,13 relapse,13,14 loss of response (LOR) to anti-
is taken), and discontinuation (when the next dose to be TNF agents, 15 higher morbidity and mortality (e.g., with
taken is omitted and no more doses are taken thereafter). To colorectal cancer), increased health expenditure,16 poor
achieve the full benefit of the many effective medications, quality of life (QOL)17,18 and higher disability.19 Kane et al.13
patients have to follow prescribed treatment regimens rea- followed a cohort of 99 consecutive patients who had UC in
sonably closely. There is no consensus on the cutoff to de- remission for more than 6 months and were on maintenance
fine adequate adherence. Some clinical trials consider rates mesalamine. They found that those who were not adher-
of greater than 80% to be acceptable, while others consider ent with medication had more than a 5-fold greater risk of
rates of greater than 95% to be an absolute requirement for recurrence than adherent patients. In a United States-based
adequate adherence. 10-year retrospective study of 13,062 patients with UC with
Treatment non-adherence in chronic diseases averages a median follow-up of 6.1 years, low adherers to oral me-
50% in developed countries and is even poorer in develop- salazine had significantly increased the risk of flares in UC
ing countries.2 In IBD, adherence data vary greatly according compared with high adherers (hazard ratio, 2.8; P <0.001).14
to study population (adults versus paediatric patients), route Similarly, Robinson et al.20 observed from their retrospective
of administration, and methods of adherence measurement study that non-adherence to mesalazine maintenance ther-
(e.g., blood analysis, pharmacy refill, self-report [diaries, in- apy was associated with significant increases in the risk of
terviews, and questionnaires]), and so forth. A systematic relapse. Interestingly, they also found that adherent patients
review6 of 17 studies totalling 4,322 adult IBD subjects found who switched between mesalazine formulations had a 3.5-
non-adherence to oral medications ranging from 7% to fold greater risk of relapse than those who did not switch.
72%. The reported medication non-adherence rate in Asian Non-adherence to anti-TNF therapy may result in immu-
IBD patients ranged between 20% and 30%. For example, nogenicity and subsequent LOR to biological treatment. Few
Kawakami et al.7 found that 27.9% of their patients were non- studies have examined the association between adherence
adherent to aminosalicylate, whereas Kim et al.8 reported to anti-TNF and LOR. van der Have et al.15 demonstrated that
a 22.3% of non-adherence rate in their cohort of patients in of those 128 IBD patients who were on either infliximab or
Korea. Non-adherence to oral medications in adolescents adalimumab, adherence was negatively associated with LOR
with IBD has been found to range from 2% to 93%.9 Jegana- to anti-TNF.
than et al.10 recently observed that transition from paediatric The association between adherence to medication and
to adult IBD service did not affect medication adherence. In healthcare costs in IBD has also been evaluated. Kane and
that pilot study, non-adherence rates of young adults (age, Shaya16 reviewed a U.S. population-based insurance data-
18−25 years), and paediatric patients (age, 12−18 years) base and included patients who had a follow-up of more
were 17% and 5%, respectively (P =0.28). There were no than 1 month and were prescribed at least one 5-aminosali-
significant differences in Medication Adherence Reporting cylic acid (ASA) preparation. They demonstrated that adher-
Scale (MARS) scores between children, recently transitioned ence was associated with 62% lower costs for hospital ad-
adults, other post-transitional adults, and never-transitioned missions (P <0.001), 13% lower for outpatient visits (P <0.05),
adults. Adherence rate with biological therapy is higher. 45% lower for visits to the emergency department (P <0.001),
Selinger et al.11 (in abstract form only) reported an overall and 49.8% lower overall total health care costs compared
non-adherence rate of 30% to maintenance medication in an with non-adherence.
Australian cohort of IBD patients, with the highest adherent Data on the association between drug adherence and
rate among patients on biological therapies (94.7%). Lopez health-related QOL (HRQOL) in IBD patients is conflicting.
et al.12 performed a systematic review on the adherence rate Hommel et al.17 studied the relationship between medica-
to anti-TNF therapy in IBD. A total of 13 studies with 93,998 tion adherence and QOL in 36 adolescents with IBD. Medi-

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Webber Chan, et al. • Medication adherence in IBD

cation adherence was measured by the Medical Adherence

nondiscrete dosages or taken on an as-needed basis

Measure and pill counts. Paediatric QOL inventory was used

- Results could be easily manipulated by patients

- Not equivalent to consumption of medication
to measure the adolescents’ QOL. Non-adherence to 6-mer-

- Not suitable for medications administered in

captopurine (MP)/azathioprine was related to poorer pa-

- Could associate with overestimation or

tient-reported physical health QOL. In contrast, Horváth et

- Requires a closed pharmacy system

al.18 enrolled 592 IBD patients to evaluate whether HRQOL

- Requires return visits of patients

Weakness

underestimation of adherence
influences medication adherence and vice versa. The pa-
tients completed the Short Form-36 (SF-36) questionnaire

- White coat adherence

and a medication adherence report scale during their visits.

- Expensive system
It was concluded that there was no association between the

- Labor-intensive
sum of HRQOL and different subscores and non-adherence.

TGN, thioguanine nucleotides; MMAS, Morisky Medication Adherence Scale; VAS, Visual Analogue Scale; MARS, Medication Adherence Reporting Scale.
Disability, which might more objectively measure the ef-

- Costly
fects of IBD than QOL, was found to be significantly higher
in non-adherers.19 Perry et al.19 did the first study to examine
the relationship between non-adherence to medication and

secondary loss of response to biological agents

functional outcomes (using the IBD-disability index) in IBD

- Useful in case of primary nonresponse and

patients. Disability was strongly correlated with medication
non-adherence (r=0.366; median difference of IBD-disability
index, 13.5; P <0.01).

- Relatively easy to obtain data

- Results are easily quantified

Strength
METHODS OF ADHERENCE MEASUREMENTS

There are a number of ways of measuring drug adherence.

The available methods for measuring adherence can be

- Inexpensive

- Inexpensive
grouped into direct and indirect methods and no method is
- Objective

- Objective

Medication possession ratio, proportion - Objective

Medication Event Monitoring System - Accurate

- Simple

- Simple
considered the gold standard. Direct measures include bio-
chemical analysis such as checking drug metabolite levels in
blood or urine sample and directly observed therapy (such
as in tuberculosis treatment). Indirect methods include ob-
infliximab and vedolizumab trough
Measurement of the level of metabolite Measurement of serum 6-TGN level;

jective monitoring of medication usage (e.g., performing pill

counts, pharmacy refills, and electronic monitoring devices)
of days covered method

and subjective reports (e.g., patient-kept diaries, patient in-

Example

terviews, and self-report questionnaires) (Table 1).

-

MMAS-4, MMAS-8,
VAS, MARS-4
1. Drug Metabolites
Table 1. Summary of Methods of Measuring Adherence

levels

Thiopurines, including azathioprine or MP, have been

widely used as steroid-sparing agents and are indicated to
maintain remission in both UC and CD. Azathioprine is a
diaries, patient interviews, self-report
Patient self-report (e.g., patient-kept

prodrug that is rapidly cleaved to 6-MP in the liver. Subse-

quently, 6-MP is metabolized through a series of enzymatic
Electronic monitoring device

pathways into 6-methylmercaptopurine (6-MMP) and

the active metabolite, 6-thioguanine nucleotides (6-TGN).
Test

Several prospective studies have reported a significant cor-

in blood or urine

questionnaires)

relation between 6-TGN level of 235 to 450 pmol/8×10 8

Pharmacy refill
Indirect method
Direct method

red blood cell (RBC) and clinical response.21-23 Therapeutic

Pill count

drug monitoring (TDM) of thiopurine metabolites levels al-

lows identification of non-adherent and refractory patients.

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Thiopurine non-adherence was defined as 6-TGN levels patients obtain their medication from a centralized phar-
<100 pmol/8×108 RBC, in the absence of a metabolite profile macy in order to keep track of medicine refills. The major
suggesting hypermethylation of thiopurines to MMP (MMP, drawback of pharmacy refill records is their inability to
6-TGN >11) when patients were adequately dosed.24 determine if the patient actually takes the dispensed medi-
TDM is also a promising tool to increase the efficacy, pa- cation. At present, the 2 most commonly used methods for
tient safety and cost-effectiveness of biological agents. It is measuring medication adherence based on pharmacy data
useful in case of primary nonresponse and secondary LOR. are the medication possession ratio (MPR; defined as the
While infliximab, a monoclonal antibody against TNF-α, and proportion of days’ supply obtained over refill interval or
vedolizumab, a monoclonal antibody against α4 β7 integrin, fixed interval) and the proportion of days covered methods
are administered at infusion centres (where adherence (PDC; defined as the number of days covered over a time
could be monitored), the SC anti-TNF (e.g., adalimumab and interval).31 Patients with an MPR or PDC ≥80% are generally
golimumab) are self-administered. TDM may have a role in classified as adherent to their treatment.
monitoring adherence to these SC agents, but this indication
has not been explored in clinical trials. 4. Electronic Monitoring Devices
There are drawbacks associated with measuring drug me-
tabolites. Variation in drug metabolism among individuals, Electronic monitoring systems may provide a more reli-
and “white coat adherence,” defined as “improved patient ad- able means of assessing adherence to both oral and topical
herence to treatment around clinic visits,”25 make an assess- medications. The Medication Event Monitoring System
ment of adherence difficult. Moreover, direct methods are (MEMS ®) medication bottles contain a microelectronic
costly and labour intensive to carry out. Finally, not all drug chip that registers the date and time of every bottle opening.
metabolite levels could be tested easily in the clinical setting. Provided that each bottle openings represent medication in-
For methotrexate, there is limited and conflicting data on the take, MEMS give a detailed profile of the patient’s adherence
usefulness of methotrexate metabolites as a measure of clini- behavior. Electronic monitoring is considered approximate a
cal response in IBD patients.26-28 With regards to mesalazine, gold standard due to the high correlation between electronic
although measurement of 5-ASA and n-acetyl-5-ASA , the estimates and clinical outcomes. However, it is expensive,
metabolites of mesalazine, could be performed with gas or and there is no guarantee that the medicine which is re-
liquid chromatography−mass spectrometry (GC-MS or LC- moved is actually consumed or administered correctly.
MS),29 they are costly and not widely available.
5. Self-Reporting
2. Pill Counts
The most common method to measure medication ad-
Pill count of dosage units (e.g., capsules, tablets) that herence is the use of self-report measures. These methods
the patient has not taken by the scheduled clinic visit can include: (1) patient-kept diaries, (2) patient interviews, and
be compared against the number of units received by the (3) standardized, validated questionnaires. The advantages
patient in the most recent prescription and the time since of these measures are that they are simple, easy, inexpen-
dispensing. Pill count adherence rate is calculated as the sive, and have a high degree of specificity for non-adherence.
([number of pills dispensed−number of pill returned]/num- However, they are subject to recall bias and the potential that
ber of pills prescribed)×100.30 This method is simple, objec- participants give answers that suit the perceived expecta-
tive and inexpensive but could associate with overestimation tions of their interviewer.
or underestimation of adherence, as when patients remove
excess doses or refill medicines respectively before pill count 1) Patient-Kept Diaries
is conducted. Moreover, pill counts are not suitable for medi- Diaries can track any prescribed behavior including medi-
cations administered in nondiscrete dosages or taken on an cation consumption and diet and are supposed to be com-
as-needed basis. pleted on a daily basis, soon after the medication or diet is
taken. Studies on using patient diaries have confirmed their
3. Pharmacy Refill Data role as a reliable method for securing data. Unfortunately,
diaries are cumbersome for patients to complete. Therefore,
For pharmacy refill data to be valid, it is necessary that all there are often significant missing data or the diaries are

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Webber Chan, et al. • Medication adherence in IBD

completed just prior to a clinic visit. Moreover, overestima-

tion of compliance is common with patient diaries. Straka 3) Questionnaires
et al.32 assessed the accuracy of patient-kept diaries relative There are a large number of self-report medication ad-
to electronic monitoring of compliance. The study indicated herence questionnaires that are suitable for use in clinical
that 67% of patients overestimated their compliance when or research settings. In a systematic review, Nguyen et al.33
using a self-recording tool. An average of 30% of diary entries identified 43 adherence scales that had been validated and
was in error compared with the MEMS vial recordings. compared against an objective measure of medication ad-
herence. The identified adherence scales elicit information
2) Patient Interviews regarding different aspects of adherence including medica-
Patient interview by physicians is an easy and inexpensive tion-taking behavior, barriers to and determinants of adher-
method to assess adherence. Interviewer’s skill and the con- ence and beliefs associated with adherence. Some of the
struction of the questions can affect the accuracy and valid- commonly used questionnaires in IBD are described below.
ity of the interview. Open-ended, nonjudgmental questions
are recommended; negative questions that seem to blame (1) Four-item Morisky Medication Adherence Scale
the patient for noncompliant will bias the answers given by The original 4-item self-reported Medication Taking Scale
patients. Examples that may encourage honest, open an- was developed by Morisky et al.34 to assesses the reasons
swers on medication adherence include: “People often have why people might fail to adhere to antihypertensive medica-
difficulty taking their medicine for 1 reason or another… tions−forgetting to take medicine, carelessness, and stopping
Have you had any difficulty taking your medicine?,” or “About the drug when feeling better or starting the drug when feeling
how often would you say you miss taking your medicine?” worse. Despite fair psychometric properties (Cronbach’s α

Table 2. Four-Item Morisky Medication Adherence Scale

Question Scoring
1. Do you ever forget to take your (name of health condition) medicine? 1, Yes; 0, no
2. Do you ever have problems remembering to take your (name of health condition) medication?
3. When you feel better, do you sometimes stop taking your (name of health condition) medicine?
4. Sometimes if you feel worse when you take your (name of health condition) medicine, do you stop taking it?

Table 3. Eight-Item Morisky Adherence Scale for IBD Patients

Question Scoring
1. Do you sometimes forget to take your IBD pills? 1, No; 0, yes
2. People sometimes miss taking their medications for reasons other than forgetting. Thinking over the past 2 weeks, were there any 1, No; 0, yes
days when you did not take your medication?
3. Have you ever cut back or stopped taking your medication without telling your doctor because you felt worse when you took it? 1, No; 0, yes
4. When you travel or leave home, do you sometimes forget to bring along your IBD medication? 1, No; 0, yes
5. Did you take your IBD medicine yesterday? 1, No; 0, yes
6. When you feel like your IBD symptoms are under control, do you sometimes stop taking your medication? 1, No; 0, yes
7. Taking medication everyday is a real inconvenience for some people. Do you ever feel hassled about sticking to your IBD 1, No; 0, yes
treatment plan?
8. How often do you have difficulty remembering to take your IBD medications?
Rarely/never 1.00
Once in a while 0.75
Sometimes 0.50
Usually 0.25
Always 0

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reliability, 0.61), this scale has been used to measure medica- ability in patients with other chronic diseases. This was also
tion adherence with asthma, hypertension, and other chron- the first adherence scale to be validated in IBD38 although
ic diseases. The sensitivity and specificity of the scale were conflicting data exist on its performance in patients with IBD.
81% and 44%, respectively. The scale was later revised based In the validation study, Trindade et al.38 correlated continu-
on focus group discussions among patients being treated ous single-interval medication availability (CSA) and MPR
for active tuberculosis. The item asking: “Are you careless at to the MMAS-8 scale. Of the 110 IBD patients in the study,
times about taking your (name of health condition) medi- MMAS-8 identified 54 patients as low adherers to their IBD
cine?” was replaced by a nonintentional, non-blaming item medication and 56 patients as medium or high adherers.
“Do you ever have problems remembering to take your Eighty-five percent of low adherers had non-persistent fill
(name of health condition) medication?” This version of the rates, as per CSA, compared with 11% of medium or high ad-
original scale became known as the 4-item Morisky Medica- herers. In contrast, Kane et al.39 administered the MMAS-8 to
tion Adherence Scale (MMAS-4)35 which demonstrated high 150 IBD patients. The median survey adherence score was
criterion validity and discriminant validity. 36 Each of the 4 7. The MPR ranged from 0% (injectable biologic) to 75% (in-
questions is given the dichotomous response of “yes” or “no” fliximab) by drug class. Only those on an immunomodulator
with the sum of “yes” answers providing a composite mea- had a survey score that positively correlated with adherence.
sure of non-adherence (Table 2). Patients score 1 point for Variation in study designs and inclusion criteria may have
every “yes” answer. A score of 0 indicates high adherence; a accounted for the differences in results from the 2 studies.
score of 1 or 2 indicates intermediate adherence; and a score
of 3 or 4 indicates low adherence. (3) Visual Analogue Scale
The Visual Analogue Scale (VAS) is a single item within
(2) Eight-item Morisky Medication Adherence Scale the questionnaire, wherein subjects are asked, “What per-
In 2008, Morisky et al. 37 supplemented the validated centage of time do you take your daily prescribed medica-
MMAS-4 with additional items addressing the circum- tion?” The subjects are instructed to place an “×” on a hori-
stances surrounding adherence behavior to develop the zontal line that is marked by 0% and 100 in 10% intervals,
8-item MMAS (MMAS-8). Each item measures a specific with 100% indicating a perfect adherence (Fig. 1). Patients
medication-taking behavior and not a determinant of adher- whose VAS is less than 80% are classified as poorly adherent,
ence behavior. Response categories are dichotomous with whereas patients with a VAS of 80% or greater are classified
yes/no for the first 7 items and a 5-point Likert response for as highly adherent.
the last item. The scale is scored by assigning a single point
to each question answered “no” in questions 1−4 and 6−7. A (4) Medication Adherence Reporting Scale-4
point is given in question 5 for an answer of “yes.” Question 8 There are a few versions of the Medication adherence
is scored as per Table 3. As mentioned in Morisky’s previous Reporting Scale (MARS) which include a 9-item,40 5-item
report, fewer than 6 points are interpreted as low adherence; and 4-item scale.41-43 The 4-item MARS is commonly used
6−7 points as medium adherence; and 8 points as high ad- in IBD. 42,43 The MARS measures adherence by assessing
herence. The 8-item medication adherence scale has much agreement with statements including “I alter the dose of
better psychometric properties: Cronbach’s α reliability was these medicines,” “I forget to take these medicines,” “I decide
0.83; using a cutpoint of <6, the sensitivity of the measure to to miss a dose of these medicines,” and “I stop taking these
identify patients with poor blood pressure control was es- medicines altogether” on 5-point Likert scales, ranging from
timated to be 93%, and the specificity was 53%. MMAS was always “1” to never “5.” Scores for each of the 4 items are
subsequently validated with outstanding validity and reli- summed to give a total score ranging from 4 to 20, with high-

Visual Analogue Scale

On the line below, please indicate by marking on the line which number corresponds to the
degree you consider how well you take your IBD medication. The far left means that you hardly
take your medication and the far right means that you are taking your medication very well (always).

0% 100%
Very bad Very good
0 10 20 30 40 50 60 70 80 90 100 Fig. 1. Visual Analogue Scale.

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Webber Chan, et al. • Medication adherence in IBD

er scores indicating higher levels of adherence. Participants influenced their adherence to mesalamine over time.
with scores between 4 and 16 are classified as low adherers, Recognizing that traditional ways of identifying and ad-
and those who score 17 to 20 are classified as high adherers. dressing non-adherence in IBD failed led to a paradigm shift
In a recent study comparing 3 different tools to measure in approaching the problem. Emerging concepts in the iden-
self-assessed medication adherence of patients with IBD, tification and prediction of non-adherence were the com-
Severs et al. 44 found that the VAS most optimally repre- bination of “practicalities and perceptions approach” and
sented the quantitative variability of adherence, whereas the the necessity−concerns framework. Horne et al.42 suggested
MMAS-8 and the Forget Medicine Scale might have resulted that interventions to facilitate medication adherence would
in overestimation or underestimation of adherence due to be more effective if they address both the practical factors
unequal differences in outcome possibilities. It was conclud- (e.g., capacity and resources) influencing patients’ ability to
ed that VAS seems to be the most appropriate tool for quan- implement instructions to follow the agreed treatment plan
tifying medication adherence in clinical practice and that the and the perceptual factors (e.g., beliefs and preferences)
MMAS-8 may be used additionally to provide insight into influencing motivation to start and continue with treatment.
specific reasons for non-adherence. The Necessity Concerns Framework46 assists clinicians to
conceptualise and understand the key beliefs influencing
FACTORS ASSOCIATED WITH NON-ADHERENCE adherence. It states that treatment adherence is associated
with the way in which patients judge their personal need for
Identifying risk factors for non-adherence helps planning a prescribed treatment relative to their concerns about its
of intervention to improve adherence and clinical outcomes. potential adverse effects. A further development to the Ne-
In a recent systematic review, Jackson et al.6 acknowledged cessity Concerns Framework was the addition of attitudinal
that existing literature had identified some significant as- analysis based on patients’ beliefs about medication using
sociations between demographic, clinical, and psychosocial the Beliefs about Medicines Questionnaire.47 There are 4 at-
factors and non-adherence in IBD. However, heterogene- titude categories (Fig. 2): (1) accepting (high necessity, low
ity in the inclusion criteria of articles may bias the results concerns), (2) ambivalent (high necessity, high concerns),
of systematic reviews. Based on their analysis, they found (3) skeptical (low necessity, high concerns), and (4) indiffer-
that none of the frequently measured demographic, clinical ent (low necessity, low concerns).
and treatment variables were consistently associated with Horne et al.42 performed an attitudinal analysis on IBD
non-adherence. Non-adherence to oral medication in IBD patients and showed that compared to those who were “ac-
was more likely in younger patients, employed patients, un- cepting” of maintenance therapies prescribed for IBD, par-
married patients, and those with shorter disease duration. ticipants in all 3 other attitudinal groups were significantly
Prescription of concomitant medications was generally as-
sociated with lower adherence. The relationship between
psychological factors (depression and anxiety) and non-
High necessity
adherence remains to be determined. In Jackson et al.’s sys-
tematic review, psychological distress (depression, anxiety,
psychiatric diagnosis, or chronic perceived stress), patients’
Accepting Ambivalent
beliefs about medications, and doctor-patient discordance
were associated with non-adherence. In contrast, a later
Low concerns High concerns
study by Selinger et al.43 showed that non-adherence in IBD
was not associated with anxiety and depression. In addition,
membership of an IBD patient organization was associated Indifferent Skeptical

with better adherence.

In addition, recognizing that poor adherence to mesala-
Low necessity
mine is common, Moss et al.45 developed a 10-item survey
to assesses UC patient-reported barriers to mesalamine ad-
Fig. 2. Attitudinal analysis. Horne et al.42 showed that compared to
herence and predict those at risk for future non-adherence. those who were “accepting” of maintenance therapies prescribed for
They found that patients’ beliefs about the need for main- IBD, participants in all 3 other attitudinal groups were significantly
tenance mesalamine and their concerns about side effects more likely to be non-adherent.

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more likely to be non-adherent. simplification, and assessment of adherence with feedback

to the patient (rewards and reinforcement), and so forth.
INTERVENTIONS TO IMPROVE ADHERENCE Simplifying dosing schedule of mesalazine to once daily for
maintenance of UC improves adherence. In a randomized
There are various interventions to improve adherence in pilot trial, Kane et al.51 randomized adults with UC to either
chronic diseases. However, the literature on interventions once daily dosing (QD) or a conventional regimen (2 or 3
to enhance medication adherence in IBD is scarce and the times daily dosing). At 3 months after initiation of the trial, all
reported studies varied widely with regards to patient popu- patients in the QD group were adherent, whereas only 70%
lation, intervention strategies, methods of adherence assess- of patients in the conventional dosing group were adherent.
ment, and clinical outcome measure, therefore making a The adherence rate in the QD group remained significantly
comparison of results inappropriate. Moreover, they mainly higher in the QD group at 6 months. In a subsequent multi-
concentrated on adult patients with UC and on promoting center, randomized, single blind, noninferiority trial, Dignass
adherence to oral maintenance medications. They can be et al.52 demonstrated that patients with UC given prolonged-
grouped into education, behavioral intervention, cognitive- release oral mesalamine 2 g once daily had better remission
behavioral intervention, and multifaceted approach. rates, acceptability, and self-reported adherence to therapy
(measured by VAS score) compared with those given oral
1. Education mesalamine 1 g twice daily. Similarly, Suzuki et al. 53 also
showed that once-daily dosing of a pH-dependent release
Educational interventions involve teaching patients about mesalamine is as effective and safe as 3-times-daily dosing
IBD aetiology, pathology, anatomy, investigations, medical for maintenance of remission in Japanese patients with UC.
and surgical treatment, mechanisms of action of the medi- Use of audio-visual reminder systems (e.g., phone text re-
cation regimen, dosing schedule, potential side effects of minder, pager text reminder, programmed electronic voice
treatment, consequences of non-adherence, disease course, reminder device, etc.), and pill boxes are other practical
nutrition, and complications of IBD. In the randomized ways to improve medication adherence. A meta-analysis
controlled trial on effects of formal education for adult IBD of randomized controlled trials54 of reminder interventions
patients, Waters et al.48 demonstrated a lower, though statisti- revealed a statistically significant increase in adherence in
cally nonsignificant, rate of medication non-adherence and groups receiving a reminder intervention compared to con-
health care use for the education group compared with stan- trols, whereas the type of reminder system did not seem to
dard care group. In another study, Tiao et al.49 (in abstract affect the adherence rate.
form only) investigated the effects and durability of IBD
pharmacist targeted counselling intervention on adherence 3. Cognitive-Behavioral Therapy
rates. Non-adherers were targeted for a structured personal-
ized counselling session with an IBD pharmacist addressing Cognitive behavioral interventions combine psychologi-
misperceptions, concerns, risk and other queries. The study cal and behavioral therapy aiming to promote adherence.
showed that targeted pharmacist counselling intervention Cognitive-Behavioral therapy (CBT) works on the principle
on non-adherers effectively increased medication accep- that negative thoughts (e.g., not believing medications could
tance rates to be equivalent to adherers at 3 months and was alleviate symptoms) can block the abilities to act and learn
durable to at least 15 months. Education however is rarely new behaviors (e.g., consume medications at the prescribed
used alone in promoting medication adherence and always time or refill medicines). CBT vary widely in content such as
forms part of the multifaceted intervention. problem solving and increasing motivation to adhere. CBT
alone has not been assessed in adult IBD patients. Problem
2. Behavioral Intervention solving skills training (PSST) has been evaluated as a stand-
alone intervention to enhance adherence in paediatric IBD.
Behavioral interventions are strategies designed to in- Greenley et al.55 recruited 76 youth (age, 11−18 years) on an
fluence behavior through shaping, reminding (cues), or oral IBD maintenance medication to participate in the study.
rewarding desired behavior (reinforcement). 50 Such inter- Families randomized to a treatment group received either 2
ventions include the use of visual or auditory reminder sys- or 4 PSST sessions. Modest increases in adherence occurred
tems, use of weekly or daily pill box organisers (cues), dose after 2 PSST sessions among those with imperfect baseline

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Webber Chan, et al. • Medication adherence in IBD

adherence and significant increases in adherence after 2

PSST sessions were documented for older adolescents.

among studies; it does not allow isolation

of individual methods contributing to the
uncertain if the result could generalize to

Different sample size, patient population,

it does not allow isolation of individual
Benefit is small as a standalone strategy

It is part of multifaceted intervention so

methods make it difficult to compare

Data on oral mesalazine therapy only;

methods contributing to the benefit

4. Multifaceted Approach

Small sample size in the RCT limits

Weakness
In this approach, different strategies such as education,

other treatment regimens

behavioral modification, CBT, motivational interviewing,
telemedicine (with subtypes including telemonitoring, tele-

generalizability
education, teleconsultation, and telecare), and so forth are
employed in different combinations. The majority of the in-

benefit
tervention studies to improve medication adherence in IBD
used a multifaceted approach and proved useful in enhanc-
ing adherence in both adult and youth patients with IBD on

adherence, which results from misunderstanding

oral treatment.56-60 Motivational interviewing is a patient-

Improve adherence and HRQOL in youth with IBD

Most beneficial in addressing accidental non-
centred counselling method used to elicit/strengthen moti-
vation towards change.

- No additional staff or equipment cost

Most beneficial in improving adherence

Over the past 2 decades, advances in systems and informa-
tion and communication technologies have influenced the

of the regimen requirements

Strength
practice of medicine. Telemedicine, simply defined as the
application of information and communication technologies
for providing health care services at a distance without the

- Easy to implement

- Easy to implement
need for direct contact with the patient,61 is a promising tool
in IBD management because they are safe and feasible ap-

- Low costs
plications with excellent patient acceptance. However, there
are few robust data on many eHealth interventions outcome
such as disease activity, medication adherence, cost-efficacy,
and so forth, in comparison with the best available clinical
Meta-analysis of RCT54

care. In particular, the reported rates of adherence have been

Evidence

inconsistent between studies. Pedersen et al.62 performed

a prospective, open-label, web-guided study with 3 months
mesalazine therapy among patients with mild-to-moderate RCT56-60,62,63
RCT51-53
RCT48

RCT55
Table 4. Summary of Interventions to Improve Medication Adherence

RCT, randomized controlled trial; HRQOL, health-related quality of life.

UC. Comparing week 0 with week 12, a statistically signifi-
cant difference in adherence by VAS (P <0.001) and MARS
Cognitive behavioral therapy Problem-solving skill training
Audiovisual reminder system

(P <0.001) was observed. In the randomized controlled trial motivational interviewing,

of web-based patient management, Elkjaer et al.57 did not
modification, cognitive
Education, behavioral

behavioral therapy,

find statistically significant difference in adherence rates

Example

Dose simplification

between the web and control groups at 12 months, although

-

telemedicine

short-term adherence with acute treatment up to 4 weeks

did improve significantly in the intervention group. In con-
trast, in another randomized, controlled trial of home tele-
management in patients with UC, the intervention did not
improve disease activity, QOL, or adherence compared to
Multifaceted intervention

best available care after 1 year.63 It seems therefore that web-

Behavioral intervention
Intervention

based therapy can help to improve adherence in an acute

flare of UC.
Telemedicine (telecare) has been used for adolescent
Education

patients with IBD. Hommel et al.64 developed an uncon-

trolled clinical pilot study to assess a telehealth behavioral

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 https://doi.org/10.5217/ir.2017.15.4.434 • Intest Res 2017;15(4):434-445

treatment for medication non-adherence in that group of AUTHOR CONTRIBUTION

patients. The program consisted of 4 weekly sessions, each
lasting 60 to 90 minutes. The video sessions were conducted W.C. wrote the initial draft which was then extensively ed-
via Skype between patients and providers and psychologists. ited by A.C., D.T., C.S., and R.L. All authors approved the final
Although this program produced a slight decrease in adher- draft. The manuscript, including related data, figures, and
ence to thiopurine therapy from 61% at baseline to 53% after tables has not been previously published and that the manu-
treatment (without different statistical differences due to the script is not under consideration elsewhere.
small sample size), it led to a meaningful increase in adher-
ence to mesalamine therapy from 62% at baseline to 91%. REFERENCES
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