Efficacy and safety of laxatives for chronic constipation in longterm care settings: A systematic review

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1 Received: 6 January 2018 Accepted: 14 May 2018 DOI: /jcpt REVIEW ARTICLE Efficacy and safety of laxatives for chronic constipation in longterm care settings: A systematic review N. Alsalimy PharmD 1,2 L. Madi PharmD 3 A. Awaisu PhD 4 1 Geriatric Medicine, Rumailah Hospital, Hamad Medical Corporation, Doha, Qatar 2 Faculty of Pharmacology and Physiology, College of Medicine, University of Montreal, Montreal, QC, Canada 3 Qatar Rehabilitation Institute, Hamad Medical Corporation, Doha, Qatar 4 College of Pharmacy, Qatar University, Doha, Qatar Correspondence A. Awaisu, College of Pharmacy, Qatar University, Doha, Qatar. aawaisu@qu.edu.qa Funding information This research did not receive any specific grant from funding agencies in the public, commercial or not- for- profit sectors. Summary What is known and objective: Constipation is a common disorder among long- term care (LTC) patients due to several factors. However, there are no systematic reviews investigating the use of laxatives for chronic constipation in LTC settings. This study aims to explore the safety and efficacy of laxatives in LTC patients. Methods: A systematic review of randomized controlled trials (RCTs) describing the efficacy and safety of laxatives for chronic constipation in LTC patients was conducted using the following databases and search engines: MEDLINE, Cochrane Database of Systematic Reviews, ScienceDirect, ProQuest and Google Scholar. Two of the investigators independently performed the searches, and the data were extracted using a standardized data abstraction tool. Results and discussion: Seven RCTs involving 444 patients were included in the review. These studies included senna (with or without fibre, ie Plantago ovata), lactulose, sodium picosulphate, docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol and Chinese herbal medicine. Senna and lactulose were the most studied laxatives in LTC patients, and senna was found to be superior to or as effective as other laxatives. Generally, the frequency and severity of adverse drug reactions (ADRs) were similar between the arms of the studies, and no serious ADRs were reported. What is new and conclusion: Considering the short duration of the trials, the lack of trials including newer laxatives and the low quality of some of the included trials, the long- term efficacy and safety of these laxatives are not conclusive. There is a need to conduct more robust RCTs that include newer agents to evaluate long- term outcomes. KEYWORDS chronic constipation, laxatives, laxatives, long-term care settings, nursing homes The authors whose names are listed certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers bureaus; membership, employment, consultancies, stock ownership or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. J Clin Pharm Ther. 2018;43: wileyonlinelibrary.com/journal/jcpt 2018 John Wiley & Sons Ltd 595

2 596 1 WHAT IS KNOWN AND OBJECTIVE Constipation is a common disorder that can develop from several causes. Generally, constipation can be defined as a functional bowel disorder that is characterized by persistently difficult, infrequent or incomplete defecation which does not meet irritable bowel syndrome criteria. 1 The reported prevalence of chronic constipation in adults ranged from 2.6% to 26.9%. 2 However, the prevalence of constipation appears to increase with age, 3 and it ranges from 24% to 50% in older adult patients above the age of 65 years. 4,5 Therefore, laxatives are used regularly by 50%- 75% of the elderly individuals residing in nursing homes. 6,7 Constipation is considered a common side effect of several medications such as analgesics, anticholinergics and cationcontaining agents. 8 Phillips et al 9 conducted a study to evaluate the prevalence of diagnosed constipation in long- term care (LTC) patients, which revealed that approximately 70% of LTC patients had at least one condition that precipitated constipation, and more than 75% of patients had at least one medication that caused it. Loop diuretics, opioids, iron supplements and calcium channel blockers were among the most frequently reported medications that caused constipation in LTC patients, with percentages reaching up to 15%. 9 Although constipation is usually considered a mild condition, it can lead to several serious complications and impaired healthrelated quality of life (HR- QoL) and is an economic burden if left untreated. 10 The most common complications of chronic constipation are faecal impaction and the development of a sigmoid volvulus and stercoral ulcer, and if complications are severe and left untreated, they can lead to colonic perforation. 11 Knowing that elderly individuals are more prone to constipation due to their lower sensory perception and other dietary factors, it is not a surprise that constipation and faecal impaction are common in elderly and institutionalized adults. 12,13 The chronic constipation in LTC residents results in diminished HR- QoL as well. 14 Whitehead et al 14 reported that mental status was lower and physiological distress was worse in constipated than in non- constipated older adults. In addition, LTC facilities require high costs of $2253 annually per resident for the management of constipation. 15 Lifestyle and dietary modifications are considered the first steps in the treatment of chronic constipation. 16 Laxatives, which work by influencing bowel movements and facilitating defecation through different mechanisms of action, are reserved for patients who do not respond to non- pharmacological approaches. 16 Many studies have reported the efficacy and safety of laxatives in adults and elderly populations. In 2004, Ramkumar et al 17 published a review on the effectiveness of laxatives in adults with chronic constipation, which showed that the use of polyethylene glycol and tegaserod was supported by good evidence (Grade A). Another literature review of laxatives in the elderly population was published by Fleming et al 18 in 2010, which concluded that more studies are needed to evaluate the treatment of constipation in this population. In addition, a review of treatments of constipation in older adults revealed that osmotic laxatives, such as polyethylene glycol and lactulose, increased stool frequency, but this review found no sufficient evidence for the efficacy of other laxatives, such as bulk agents, stool softeners, stimulants and prokinetic agents. 19 However, there are no systematic reviews investigating the efficacy and safety of laxatives for chronic constipation in LTC settings. Our systematic review will analyse and synthesize the findings of studies conducted in LTC settings, including nursing homes, LTC wards in hospitals and residential care settings, to explore the safety and effectiveness of laxatives in LTC patients. 2 METHODS 2.1 Selection criteria The methodological protocol of this review has been published in PROSPERO (International prospective register of systematic reviews) at the Center for Reviews and Dissemination, University of York, UK. 20 This review included randomized control trials (RCTs) and cost- effectiveness studies, which assessed the safety and efficacy of laxatives for chronic constipation in adults (18 years and above) in LTC settings. The laxatives included were pharmaceutical products or herbal preparations. However, animal studies, review articles, pharmacological studies, phase 1 and 2 clinical trial studies, studies with no documented results and observational studies were excluded. Moreover, trials that studied patients with acute constipation, irritable bowel syndrome, cancer, opioid- induced constipation, diabetes- induced constipation and neuropathy- induced constipation and trials that included only diet- based interventions (eg, increasing fibre or fruit intake) were excluded. Moreover, studies that combined LTC facility patients with others (eg, community- dwelling patients) without subgroup analysis were also excluded. 2.2 Outcome measures The review considered original studies that included, but were not limited to, the following outcome measures: the frequency of defecation, the number of spontaneous and complete bowel evacuations, the need for rescue medications and adverse drug reactions. 2.3 Search strategy A systematic review of original studies describing the efficacy and safety of laxatives for chronic constipation in LTC patients was carried out through the following databases and search engines: MEDLINE, Cochrane Database of Systematic Reviews, ScienceDirect, ProQuest and Google Scholar. There were no date restrictions placed on the electronic literature searches, and databases were searched from their inception to 30 August Furthermore, a manual search of relevant reviews and tertiary literature was also conducted to identify any additional studies not found in the electronic searches. The following search terms were used in connection: chronic constipation, laxatives, management, treatment, geriatrics, elderly,

3 597 FIGURE 1 Study selection process (PRISMA flowchart) senior adults, long- term care, institutionalized, therapy, nursing, hospitalized and residential care. Alternative terms were used according to the respective databases (eg, MeSH terms in MEDLINE). Boolean connectors were used as appropriate. Any two of the investigators (NA, LM or AA) independently performed the searches to improve the output (Figure 1). 2.4 Data extraction All investigators (NA, LM and AA) independently evaluated the titles and abstracts of the retrieved articles. Articles selected for inclusion were then subjected to full- text review by two investigators (NA and LM) to decide whether they met the inclusion criteria and did not meet any of the exclusion criteria. Any disagreements in the process were resolved through consensus among all authors. A standardized data abstraction tool was used for data collection for each included study. A checklist guided by the PRISMA statement, along with the authors knowledge of systematic review processes, helped in designing the data abstraction tool. 21 The data were summarized in a table that included the following elements: study design, population studied and number of participants, baseline characteristics, outcome measures and summary of the overall results. 2.5 Quality assessment Two reviewers (NA and LM) individually reviewed each of the retrieved studies qualitatively by critically appraising the methodological quality and internal and external validity. The Jadad scale 22 was employed to assess the quality of the selected studies; this scale included the following criteria: proper conduct of randomization; concealment of treatment allocation; proper description of eligibility criteria; and proportion of patients who completed the study follow- up. Any disagreements over the quality score of the reviewed studies were resolved by consensus among all the reviewers. 3 RESULTS 3.1 Characteristics of the included studies Of the 986 screened studies, seven studies met the inclusion criteria and were included in the systematic review (Figure 1). All of the studies were RCTs, four of which were double- blinded, 25,27-29 two of which used crossover design 25,26 and two of which were open- label trials. 23,26 The studies were conducted in the UK, USA, Finland and Taiwan. None of the seven studies included relatively large sample sizes. The mean study sample size (using the number of all patients who were enrolled and randomly allocated to treatment arms) was 63.4 (±22.9), ranging between 30 and 93 participants. The studies were published over four decades. Two studies were published in the 1970s, 23,24 two were published in the 1990s, 25,26 and the remaining studies were published in the 2000s, the latest of which was published in The characteristics of the included studies and main outcomes are summarized in Table 1. We did not conduct a meta- analysis in this systematic review due to the high heterogeneity of the included studies; the outcome measures were mostly diverse and measured at different time points among the included studies. 3.2 Participants A total of 444 long- term patients were randomized in the included RCTs. Participants were residing either in nursing homes or in hospitals. Their average age ranged from 68 to 85 years, with the majority of the participants being female (7 RCTs had more than

4 598 TABLE 1 Characteristics and main outcomes of the included studies (Continues) ADR, adverse drug reaction; BID, twice daily; CI, confidence interval; CVA, cerebrovascular accidents; DM, diabetes mellitus; EOD, every other day; h, hours; MgO, magnesium oxide; n, number; OD, once daily; PEG, polyethylene glycol; RCT, randomized controlled trial; RT, rectal treatment; SBM, spontaneous bowel movement; SD, standard deviation; SE, standard error; wk, week; y, years. 50% female participants). Most of the studies included elderly patients, whereas only two RCTs recruited adult participants. 23,29 Functional status was addressed in only three studies: in the studies by Kinnunen et al and Huang et al, 26,29 in which the participants were mainly bedridden; or in the trial by Seinelä et al, 28 which included mainly ambulatory patients. 3.3 Interventions The laxatives that had been evaluated for efficacy and safety in the included studies were senna (alone or in combination with fibre, ie, Plantago ovata), lactulose, sodium picosulphate (SPS), docusate sodium, docusate calcium, isotonic and hypotonic polyethylene glycol (PEG) and

5 599 TABLE 1 (Continued) (Continues) Chinese herbal medicine (CCH1; herbal formula modified from Wen-Pi Tang ). The most studied laxatives were senna and lactulose. Most of the studies had a run- in period between 3 and 14 days. The treatment duration was generally short and ranged between 2 and 8 weeks. 3.4 Efficacy of laxatives A summary of the included studies and their findings is presented in Table Studies including senna Senna was the most studied intervention in the included RCTs, 23,25-27 either as the main intervention or as the comparator. These trials were of different quality levels according to Jadad scale. Two of the RCTs were of high quality (Jadad score 4-5), 25,27 whereas one RCT scored as low as The efficacy and safety of senna was tested against lactulose, 25,26 SPS 23 or placebo. 27 These trials concluded that senna was equally as effective as SPS or more effective than

6 600 TABLE 1 (Continued) (Continues) lactulose or placebo. The longest duration of treatment with senna was 5 weeks Studies including lactulose Lactulose was studied in three RCTs. 25,26,29 Two of the studies were of high quality. 25,29 All trials studied lactulose as the comparator, and it was compared to senna 25,26 and to CCH1. 29 All the interventions were found to be significantly more effective than lactulose. The longest duration of treatment of lactulose was 8 weeks Studies including other laxatives Sodium picosulphate, docusate calcium, docusate sodium, CCH1 and hypotonic and isotonic PEG were studied in four RCTs, 23,24,28,29 which were of relatively high quality with a score range from three to five. Most of these laxatives were studied as the intervention, and they were compared to senna or lactulose or were studied against each other. Two of the trials concluded that SPS and hypotonic PEG were as effective as the comparators, 23,28 and the other two showed superiority to the comparators. 24,29 Specifically, CCH1 was

7 601 TABLE 1 (Continued) significantly more effective than lactulose, whereas docusate calcium was significantly better than docusate sodium in increasing the frequency of bowel motion. The treatment duration of the four RCTs ranged from 2 to 8 weeks. arms of the studies, and no serious ADRs were reported. Flatulence and abdominal pain were the most repeated ADRs. One trial evaluated the tolerability of the studied laxatives by assessing participants willingness to continue to use the study treatment Safety of laxatives Five of seven trials evaluated the safety of the laxatives, 23,25,26,28,29 of which senna and lactulose were the most studied. 23,25,26,29 The safety of PEG was evaluated as well. 28 Generally, the frequency and severity of adverse drug reactions (ADRs) were similar between the 3.6 Quality assessment Jadad scores were relatively high in four studies. 25,27-29 Two of the high- quality studies showed that senna was significantly better than the comparators (lactulose or placebo); however, the duration of the treatment was not reflective of the prolonged use of laxatives in LTC

8 602 TABLE 2 Quality assessment of included studies No. Author, year Strength Limitations Jadad score External validity (generalizability) 1 W. J. MacLennan et al, 1975 Study design; RCT Inclusion and exclusion criteria were not mentioned Lack of presentation of patients demographic characteristics Statistical analysis was not described Using high initial dose of study intervention that was not based on previous human studies, which exaggerated the effect of the intervention 3 Most participants (72%) were women 2 A. M. Fain et al, 1978 Study design; RCT Lack of presentation of patients demographic characteristics Blinding method not described 3 All the participants were Caucasians 3 A. P. Passmore et al, 1993 Study design; multicenter double- dummy RCT The use of computer- generated randomization code A standardized scoring system for all efficacy outcomes was used The study did not reach required sample size according to its power calculations No mention if rescue laxatives were used during the study or not Discontinuation of previously taken laxatives at baseline were not mentioned 4 Excluded diabetes mellitus and faecal incontinent patients, which could affect generalizability on majority of long- term care patients 4 O. Kinnunen et al, 1993 Study design; cross- over RCT The administration of a study questionnaire assessing the safety of interventions in patients with poor mental capabilities Small sample size (30 participants) 1 Most participants (83%) were women All participants were elderly bedridden on oral feeding 5 S. Bub et al, 2006 Study design; double- blinded RCT The use of matching placebo The clear bowel routine protocol Unclear representation of data (primary outcomes) Sponsored by the manufacturer of the investigational herbal tea One component of the herbal tea was licorice, which is known to increase BP and water retention, and thus, it was required to exclude patients with uncontrolled hypertension and heart failure patients Lack of study follow- up period 5 Excluded all renal failure patients, regardless of the stage Patients on feeding tube were excluded, which does not reflect long- term care residents 6 Lauri Seinela et al, 2009 Study design; double- blinded RCT Adequate follow- up duration Unspecified method of randomization The study excluded patients who were on other laxatives (rather than PEG), which could affect the response to treatment The study did not reach sample size according to power calculations Questionable effectiveness of blinding strategy due to differences in dosage forms though in identical packaging (granules vs. powder) Questionable acceptability assessment methods Not using a standardized scoring system for all efficacy outcomes 4 All participants were elderly conscious populations on oral feeding who were previously on isotonic PEG 7 C. Huang et al, 2012 Study design; double- blind, doubledummy RCT Chronic constipation was well- defined in the inclusion criteria Well- defined protocol for doses titration according to participants response The use of indistinguishable matching placebo Stratification of participants according to baseline severity of constipation The inclusion of some patients who were not fitting the definition of chronic constipation The inclusion of more cases of Parkinson s disease, depression and anxiety in lactulose arm (who were most likely on treatments with anticholinergic side effects) 5 The study excluded spinal cord injury patients, which reduces its generalizability to long- term care settings PEG, polyethylene glycol; RCT, randomized controlled trials.

9 603 settings. All the studies conducted in the 2000s were of high quality, whereas the Jadad score was as low as one in a Finnish study conducted in the 1990s. 26 However, a score of 5 was achieved in two RCTs 27,29 that studied senna and CCH1. Quality assessment of the included trials is presented in Table 2. 4 DISCUSSION Generally, there is insufficient data from RCTs to evaluate the safety and efficacy of laxatives in LTC patients with chronic constipation. The prevalence of chronic constipation increases with age. Choung et al 5 reported that the incidence of chronic constipation reached up to 18% among patients less than 50 years of age, whereas the incidence was 25% in those over 70 years. These findings comply with the current review that most participants were elderly patients with an average age ranging from 68 to 85 years, with the exception of two studies that involved adult patients. In addition to age, female gender could be a risk factor for chronic constipation, as reported in some studies. 5,30 Therefore, the majority of participants in our review were females. Based on published literature, physical activity was lower in nursing home residents compared to communitydwelling peers, which can have an effect on bowel function. 31 Given that there is a relation between physical activity and constipation and that LTC residents might have variable functional abilities, there is a need for trials to categorize patients based on their functionality, as it has an impact on the results of the studied interventions. The included studies, however, did not address the participants functionality, with the exception of two studies. 28,29 In the light of the above, specific population factors, such as older age, gender and physical activity, should be taken into consideration when approaching LTC patients with constipation. Based on the studies included in this review among LTC patients with chronic constipation, senna and lactulose were the most studied laxatives, which belong to the stimulant and osmotic laxative groups, respectively. Based on two included trials, senna in combination with bulking agents had better efficacy than lactulose. 25,26 The efficacy of combination agents (senna plus bulk laxative (Plantago ovata)) was difficult to assess, in terms of whether the efficacy was due to the stimulant laxative component or to the synergistic mechanism effect of the bulking agent. In one trial, senna with bulk laxative (psyllium) was found to be more effective in adult ambulatory patients than bulk laxative (psyllium) alone. 32 Generally, osmotic agents are considered a second- line therapy in patients not responding to bulk laxatives either as a regular or intermittent therapy. 16 Lactulose appeared to be less effective in the treatment of chronic constipation in LTC patients than senna and CCH1. Another osmotic laxative, PEG, appeared to be efficacious and well tolerated compared to lactulose in community- dwelling patients. 33 Recent meta- analyses in the treatment of functional constipation in adults have also concluded that PEG is more effective than lactulose in terms of increasing stool frequency. 34 Although the available evidence suggests that PEG is a better alternative in the treatment of chronic constipation in adult populations, only one study in this review compared hypotonic PEG with isotonic PEG in LTC patients, which appeared to be equally efficacious. 28 Therefore, there is a need for more studies to compare PEG with other laxatives in LTC patients. Moreover, there are groups of laxatives not studied in LTC patients, such as bulk- forming laxatives including methylcellulose, calcium polycarbophil and wheat dextrin. Suppositories and enemas, such as glycerine, bisacodyl and sodium phosphate enema, are commonly used for constipation, but they were not studied in LTC patients. Furthermore, the role of newer laxatives, such as intestinal chloride secretagogues, opioid antagonists and 5HT4 receptor antagonists, in the treatment of chronic constipation in LTC patients needs to be determined. The second part of the review s clinical question concerned the safety of the use of laxatives in adults and elderly individuals in LTC settings. Although four of the included trials did not discuss or assess the safety profiles of the laxatives of interest, three RCTs provided data on the safety of majorly two laxatives: senna alone or with fibres (ie, Plantago ovata) and lactulose. 23,25,28 The safety of PEG and SPS was also assessed. As expected from commonly used laxatives such as senna and lactulose, ADRs were basically confined to the gastrointestinal system, where flatulence and abdominal pain were the most frequent. However, more serious ADRs of senna and lactulose can result from their chronic use None of these serious ADRs were reported in the studies, as they did not assess the longterm safety of the laxatives due to the relatively short duration of study treatments. Electrolyte imbalance, however, was assessed in one study by Seinelä et al 28 comparing hypotonic and isotonic PEG. Neglect of the long- term safety of these laxatives could be due to the familiarity of the medical practice in the use of senna and lactulose for a number of decades as safe medical treatments for constipation in adults. Nevertheless, considering the relatively short study durations of the trials presented in this review, laxatives were shown to be safe for the short- term use of LTC patients, whereas the longterm safety of laxatives in nursing home residents is not conclusive. The quality of studies was assessed by the Jadad scale, which covers three main aspects of the internal validity of RCT protocols: randomization, blinding and dropouts. 22,38 The studies reviewed in this article were published over four decades; thus, it is noteworthy to mention that some of the earlier studies were conducted with less methodological rigour. The studies by Bhatt and Moher et al 39,40 discussed this topic and showed that studies methodological quality improved significantly over time. According to previous evidence, allocation bias can result in a 13% increased estimate of benefit in the intervention arms when compared to other trials that used appropriate allocation concealment. 41 Three studies lacked blinding of interventions, and therefore, their findings should be interpreted with caution. 23,24,26 The inclusion of three trials with low Jadad scores ( 3) might lead to one to question their impact on the overall conclusion of this systematic review. 23,24,26 However, the low number of published studies that have answered the clinical question of the review and were deemed fit to be included made it necessary for the

10 604 authors to use all the available literature and to not exclude trials that had low- quality scores. On the other hand, four studies scored from four to five. These studies highlighted the efficacy of senna (with or without fibres), PEG and CCH1 in managing constipation when compared to senna, lactulose or other laxatives. 25,27,28 Nevertheless, due to the high risk of bias in some of the included studies in this review, the lack of placebo- controlled trials and the short duration of the trials, the authors agreed that there is insufficient evidence to provide a recommendation on the safest and most effective laxative for constipation in LTC patients. This review was limited to published RCT studies. Conference abstracts and proceedings, as well as the results of ongoing clinical trials, were excluded from this review, as the authors intended to use peerreviewed evidence for the synthesis of the review s conclusion. The literature search was confined to publications in English, which could have deprived the review of some valuable data pertaining to herbal laxatives from studies written in Chinese or German. The low quality of some of the included trials might compromise the integrity of the review findings. However, we believe that it is in the readers best interest to be aware of all available published evidence concerning the topic. 5 WHAT IS NEW AND CONCLUSION This review included seven RCTs published over four decades that studied a group of laxatives including senna (with or without fibre), lactulose, SPS, docusate calcium, docusate sodium, CCH1 and hypotonic and isotonic PEG. Senna and lactulose were the most studied laxatives in LTC patients; senna was found superior to or as effective as other laxatives. However, considering the short duration of these trials and the low quality of some of the existing RCTs, the long- term efficacy and safety of these laxatives are not conclusive. 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