Elsevier

Clinical Therapeutics

Volume 43, Issue 6, June 2021, Pages 968-989
Clinical Therapeutics

Original Research
Characterization and Associated Costs of Constipation Relating to Exposure to Strong Opioids in England: An Observational Study

https://doi.org/10.1016/j.clinthera.2021.03.021Get rights and content

Abstract

Purpose

Opioid use is associated with gastrointestinal adverse events, including nausea and constipation. We used a real-world dataset to characterize the health care burden associated with opioid-induced constipation (OIC) with particular emphasis on strong opioids.

Methods

This retrospective cohort study was conducted using the Clinical Practice Research Datalink, a large UK primary care dataset linked to hospital data. Patients prescribed opioids during 2016 were selected and episodes of opioid therapy constructed. Episodes with ≥84 days of exposure were classified as chronic, with date of first prescription as the index date. The main analysis focused on patients prescribed strong opioids who were laxative naive. Constipation was defined by ≥2 laxative prescriptions during the opioid episode. Patients for whom initial laxative therapy escalated by switch, augmentation, or dose were defined as OIC unstable, and the first 3 lines of OIC escalation were classified. Health care costs accrued in the first 12 months of the opioid episode were aggregated and compared.

Findings

A total of 27,629 opioid episodes were identified; 5916 (21.4%) involved a strong opioid for patients who were previously laxative naive. Of these patients, 2886 (48.8%) were defined as the OIC population; 941 (33.26%) were classified as stable. Of the 1945 (67.4%) episodes classified as unstable, 849 (43.7%), 360 (18.5%), and 736 (37.8%) had 1, 2, and ≥3 changes of laxative prescription, respectively. Patients without OIC had lower costs per patient year (£3822 [US$5160/€4242]) compared with OIC (£4786 [US$6461/€5312]). Costs increased as patients had multiple changes in therapy: £4696 (US$6340/€5213), £4749 (US$6411/€5271), and £4981 (US$6724/€5529) for 1, 2, and ≥3 changes, respectively. The adjusted cost ratio relative to non-OIC was 1.14 (95% CI, 1.09–1.32) for those classified as stable and 1.19 (95% CI, 1.09–1.32) for those with ≥3 laxative changes. Similar patterns were observed for patients taking anyopioid, with costs increased for those classified as having OIC (£3727 [US$5031/€4137] vs £2379 [US$3212 /€2641),and for those patients classified as unstable versus stable (£3931 [US$5307/€4363] vs £3432 [US$4633/€3810). Costs increased with each additional line of therapy from £3701 (US$4996/€4108), £3916 (US$5287/€4347), and £4318 (US$5829/€4793).

Implications

OIC was a common adverse event of opioid treatment and was poorly controlled for a large number of patients. Poor control was associated with increased health care costs. The impact of OIC should be considered when prescribing opioids. These results should be interpreted with consideration of the caveats associated with the analysis of routine data.

Introduction

Since the early 1990s, opioid prescription rates have increased sharply in UK primary care,1, 2, 3 almost doubling for weak opioids and increasing 6-fold for strong opioids between 2005 and 2012.4 This increase has been ascribed to an escalation in the use of opioids for chronic noncancer pain.5, 6, 7 The increase in opioid use has raised concerns because of the risk of misuse, reduced effectiveness with long-term exposure, and impact of adverse events, including gastrointestinal disturbance.8, 9, 10 Although opioids therefore have a place in pain management, their use needs to be carefully considered by clinicians as part of an overall treatment strategy, and they should not be used without first trying other nonpharmacologic and nonopioid strategies.11,12

Constipation is a known adverse effect of opioid exposure, and opioid-induced constipation (OIC) describes a set of symptoms that reflect a change in bowel habits after initiation of opioid therapy, including reduced bowel movement frequency, sense of incomplete evacuation, hard stool consistency, and straining,13 which may cause patients to avoid or stop using opioids, thereby compromising effective pain relief and increasing the associated burden of care.14 OIC has a significant impact on the direct and indirect costs of patient care. It has a strong negative effect on patients’ quality of life and may lead to nonadherence to opioid therapy, impairing quality of life still further and increasing the associated costs of care. Several studies of health care resource use and cost in the United States in opioid-treated patients have found higher utilization and costs in those experiencing OIC.15, 16, 17, 18, 19

Despite the debilitating effects of OIC, there is little awareness of this complication on the part of medical practitioners and little or no precautionary discussion of its effects and management before prescribing opioids. Recent guidelines have recommended that first-line treatment options for OIC include dietary modifications (such as increased fluid and fiber intake), exercise and, laxatives, with the potential for laxatives to be prescribed prophylactically.20 Many physicians wrongly believe that OIC can be effectively treated by current laxatives (both over the counter and prescribed), although approximately 70% of patients will not respond satisfactorily to laxatives, even after rotating and changing products. Patients are often reluctant to discuss constipation and its symptoms with their physicians, partly because of embarrassment and partly because they worry that the opioid treatment will be withdrawn. This reluctance can result in patients adjusting their own opioid doses to attempt self-management of the condition, often affecting the successful management and intent of the primary prescriber. Thus, this serious complication remains underdiagnosed and undertreated and is a significant hidden burden to the health care system through ineffective use of opioids for pain relief in many patients, especially those being managed in primary care.

The aim of the study was to use a real-world dataset to characterize the health care burden associated with opioid use in the UK health service, in particular those prescribed laxatives with particular emphasis on strong opioids. These data will help inform treatment choices for this complex population.

Section snippets

Data Source

The study used a retrospective cohort design within the UK Clinical Practice Research Datalink (CPRD) GOLD primary care dataset. CPRD-GOLD is a longitudinal, anonymized research database derived from nearly 800 primary care practices in the United Kingdom Kingdomwith data collected as part of the day-to-day administration of the primary care practice. Approximately 60% of the practices participate in a linkage scheme by which their patient records are linked to other data sources, including the

Strong Opioid Episodes

During 2016, a total of 27,629 opioid episodes were identified (Figure 1). Of these, 25,091 (90.8%) were defined as chronic episodes based on our defined minimum opioid exposure threshold of 84 days. Mean (SD) follow-up was 347 (55.6) days. A total of 448 patients (1.8%) died during the 12-month follow-up period, and an additional 2618 patients (10.4%) had incomplete follow-up because they left their primary care practice or they were censored at the last date of data collection for their

Laxative-Naive Cohort

In the laxative-naive cohort, 2886 (48.8%) had multiple laxative prescriptions recorded subsequent to the index date and were defined as the OIC population. Of these, 941 (32.6%) were classified as stable and 1945 (67.4%) as unstable. Of the unstable patients, 849 (43.7%), 360 (18.5%), and 736 (37.8%) had 1, 2, and 3 changes of laxative prescription from first index laxative, respectively (Table I).

Of those patients defined as having OIC, the mean (SD) age at the index date was 63.0 (16.5)

Prior-Laxative-Exposed Cohort

Of the 781 patients with long-term strong laxative exposure and a prior history of laxative exposure, 92 (11.8%) had no subsequent multiple laxative prescriptions. These patients were different at baseline from those who developed MEC in terms of sex (53.3% vs 68.8% female), age (65.6 vs 72.5 years), and index cancer diagnosis (38.0% vs 24.1%) (Table II). Of the remaining 689, 183 (26.6%) were considered stable while receiving laxative therapy and 506 (73.4%) were considered unstable. A total

Discussion

This descriptive study considered health care costs associated with constipation status among patients exposed to long-term opioid therapy. We report that almost half of the patients previously naive to laxative who received a strong opioid developed OIC as determined by multiple laxative prescriptions and that of those classified with OIC only one-third were maintained with their initial laxative prescription, with most requiring multiple changes of either laxative type or dose.

Patients naive

DISCLOSURES

None.

Acknowledgments

C.Ll. Morgan was involved in the study design, data analysis, produced the first draft of the manuscript and contributed to subsequent versions. S. Jenkins-Jones. contributed to study design, data analysis and contributed to the interpretation of the results. R. Knaggs provided data interpretation and revised the first draft of the manuscript. C. Currie was involved in the concept of the study, study design, data interpretation and revision of the manuscript. P. Conway was involved in the

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