Literature DB >> 28339544

Laxatives Do Not Improve Symptoms of Opioid-Induced Constipation: Results of a Patient Survey.

Anton Emmanuel1, Martin Johnson2, Paula McSkimming3, Sara Dickerson4.   

Abstract

INTRODUCTION: Laxatives are commonly used to treat opioid-induced constipation, the commonest and most bothersome complication of opioids. However, laxatives have a nonspecific action and do not target underlying mechanisms of opioid-induced constipation; their use is associated with abdominal symptoms that negatively impact quality of life.
OBJECTIVE: To assess the effects of laxatives in patients taking opioids for chronic pain.
METHODS: One hundred ninety-eight UK patients who had taken opioid analgesics for at least one month completed a cross-sectional online or telephone survey. Questions addressed their pain condition, medication, and laxative use (including efficacy and side effects). The survey also assessed bowel function using the Bowel Function Index.
RESULTS: Since starting their current opioid, 134 of 184 patients (73%) had used laxatives at some point and 122 (91%) of these were currently taking them. The most common laxatives were osmotics and stimulants. Laxative side effects were reported in 75%, most commonly gas, bloating/fullness, and a sudden urge to defecate. Side effects were more common in patients less than 40 years of age. Approximately half of patients said laxatives interfered with work and social activities, and one-fifth needed an overnight hospital stay because of their pain condition and/or constipation. Laxatives did not improve the symptoms of constipation, as assessed by the Bowel Function Index. Constipation was not related to opioid strength, dose of opioid, or number of laxatives taken.
CONCLUSIONS: Use of laxatives to treat opioid-induced constipation is often ineffective and associated with side effects. Instead of relieving the burden of opioid-induced constipation, laxative use is associated with a negative impact.
© 2016 American Academy of Pain Medicine.

Entities:  

Keywords:  Bowel Function Index; Chronic Pain; Laxatives; Opioid-Induced Constipation; Survey;  Opioid

Mesh:

Substances:

Year:  2017        PMID: 28339544      PMCID: PMC5914325          DOI: 10.1093/pm/pnw240

Source DB:  PubMed          Journal:  Pain Med        ISSN: 1526-2375            Impact factor:   3.750


Introduction

Opioids have been important in pain management for a number of years. According to the World Health Organization’s three-step analgesic ladder, weak opioids (e.g., codeine, dihydrocodeine, tramadol) should be used for moderate pain (at Step 2) and strong opioids (e.g., oxycodone, morphine) for severe pain (at Step 3) [1]. Despite being originally developed for cancer pain, this stepwise approach has been extended for use in chronic noncancer pain. Opioids are known to cause a number of gastrointestinal (GI) side effects that are collectively termed opioid-induced bowel dysfunction (OIBD). OIBD is characterized by hard, dry stools, straining, incomplete evacuation, bloating, abdominal distension, and increased gastric reflux [2]. The most common symptom of OIBD is opioid-induced constipation (OIC) [3,4]. Opioids cause constipation by binding to µ-opioid receptors in the GI tract, which reduces GI secretions and peristaltic activity and increases fluid reabsorption [5]. The result is hard, dry stools that pass slowly through the gut. OIC is dose-dependent, and, unlike other GI symptoms, patients rarely develop tolerance to the constipating effects of opioids, so OIC does not resolve over time [6]. As well as being the most common symptom of OIBD, constipation is the most bothersome and debilitating [3,7,8]. Some patients will reduce or miss their dose of opioid medication to avoid OIC [7,8,9], preferring to tolerate the pain than experience constipation symptoms [10]. OIC negatively impacts patients’ quality of life, no matter how advanced their disease or condition [11]. It also carries a significant economic burden in terms of both direct costs (patients may use additional health care resources) [12,13] and indirect costs (patients’ ability to work may be affected, leading to both absenteeism and presenteeism) [13]. Studies carried out in Sweden and the United States showed that total health costs are significantly higher for patients with OIC than for those without [14-17]. Laxatives are commonly used to treat OIC. However, they do not target the underlying mechanism of OIC, as they do not impact binding to µ-opioid receptors in the GI tract, and many patients will not have their constipation resolved with this therapeutic approach. In one survey of patients with chronic noncancer pain, 54% of those treated for OIC with laxatives did not achieve the desired effect even half of the time [2]. In another survey, 96% of patients taking one laxative and 38% taking two laxatives had an inadequate response to treatment [9]. The multinational Prevalence, Severity, and Impact of Opioid-Induced Bowel Dysfunction (PROBE1) survey assessed OIBD in 322 patients who were receiving opioids for chronic pain and taking laxatives [7]. Eighty-one percent of patients reported that they experienced constipation despite taking laxatives, and more than half said that constipation had a “moderate-to-great” or “great” impact on their quality of life. Patients also reported a number of other symptoms, such as bloating and gas, which negatively impacted their quality of life. As all patients were taking laxatives, it may have been possible that this reflected the side effects of laxatives as well as the symptoms of OIBD. We therefore carried out a survey to specifically look at laxative use in patients receiving opioids, focusing on: 1) the types of laxatives used to treat OIC, 2) the effect of laxatives on symptoms of constipation, 3) the side effects associated with laxatives, and 4) the impact of laxatives on quality of life.

Methods

This was a cross-sectional survey carried out in the United Kingdom between May 2013 and October 2014. Patients were recruited via social media, pharmacies, and advertisements in newspapers and on patient websites. Patients with any pain condition (including back pain, arthritis, cancer, headache and nerve pain) who had been taking Step 2 or 3 oral opioid medication (e.g., codeine, dihydrocodeine, oxycodone, morphine, or tramadol) for at least one month were eligible to take part. Back pain could include failed back surgery, osteoporosis, and nonspecific pain. At screening, any patients who had not been taking opioids for at least one month were excluded from completing the full survey and no further details were collected. Patients completed the survey online or over the telephone. The survey included questions on patients’ pain condition, opioid medication, laxative use, bowel movements, and contact with health care professionals. Patients who said they were using laxatives were asked to select side effects they had experienced from a list of common symptoms. Those who reported at least one side effect were then asked how much laxatives interfered with their work and social activities on a five-point scale, where 1 = all of the time and 5 = none of the time. Patients were also asked about any other measures they had taken to try and ease their constipation. Bowel movements were assessed using the Bowel Function Index (BFI) [18]. Patients rated ease of defecation, feeling of incomplete bowel evacuation, and personal judgement of constipation on a scale of 0–100, where a lower score indicated better bowel function [18]. Their total BFI score was calculated as the mean of these three scores. Normal bowel function was defined as a BFI score of 28.8 or lower [19]. The BFI is a validated tool [20,21] that has been endorsed by the American Academy of Pain Medicine Foundation and the American Gastroenterological Association for assessment of OIC [22,23]. The study was submitted to the National Research Ethics Centre, who confirmed that it would not require formal approval. Data were analyzed descriptively. For categorical variables, the number and percentage falling into each category were reported. For continuous variables, the mean, standard deviation, median, interquartile range (IQR), and range were reported. Statistical analyses were performed using SAS v9.2.

Results

Patient Characteristics

In total, 362 patients were screened and 198 were eligible to participate. Their median age was 50.2 years; 81% were over age 40 years. Most (85%) were female, and just over half (52%) reported they were unable to work owing to illness or disability (Table 1). Most (65%) were recruited via advertisements on the internet (Table 1).
Table 1

Patient demographics

Analysis population (N = 198) N (%)
Age, y
 N (missing)194(4)
 Mean (±SD)49.36(11.60)
 Median (IQR)50.22(43.46–56.53)
 Min, max18.48, 79.74
Age category
 N (missing)194(4)
 <40 y, N (%)37(19.1)
 >40 y, N (%)157(80.9)
Sex
 N (missing)198(0)
 Male, N (%)29(14.6)
 Female, N (%)169(85.4)
Current employment status, N (%)
 N (missing)181(17)
 Employed/in education, N (%)62(34.3)
 Retired, N (%)19(10.5)
 Unable to work owing to illness/disability, N (%)94(51.9)
 Other, N (%)6(3.3)
Method of recruitment to study, N (%)
 N (missing)196(2)
 Internet advert128(65.3)
 Newspaper article5(2.6)
 Pain clinic6(3.1)
 Patient organization website10(5.1)
 Pharmacist leaflet4(2.0)
 Other43(21.9)

IQR = interquartile range.

Patient demographics IQR = interquartile range. Back pain, nerve pain, and arthritis were the most common indications for opioid use (Table 2). The most common types of back pain were sciatica, arthritis of the spine, and slipped disc. Codeine and codeine combinations were the most common currently prescribed opioids (Table 3). The mean (±SD) number of opioids prescribed was 1.5 (±0.6), and 84 patients (42%) reported that they were currently prescribed two or more opioids; of these, 40 patients were taking a combination of weak and strong opioids. One hundred fifty-four patients (154/183, 84%) had been on their current opioid for at least six months; 82 of 188 patients (44%) reported that codeine and codeine combinations were their longest-prescribed opioid.
Table 2

Pain conditions

Pain typeNumber of patients (%) (N=198)
Back pain130(65.7)
 Osteoporosis12(6.1)
 Slipped disc34(17.2)
 Arthritis of the spine44(22.2)
 Failed back surgery20(10.1)
 Sciatica62(31.3)
 Nonspecific back pain27(13.6)
 Other45(22.7)
 Not sure7(3.5)
Arthritis81(40.9)
 Osteoarthritis48(24.2)
 Rheumatoid arthritis17(8.6)
 Other6(3.0)
 Not sure16(8.1)
Cancer3(1.5)
Headache45(22.7)
Nerve pain95(48.0)
Ongoing pain after accident33(16.7)
Ongoing pain after surgery43(21.7)
Other44(22.2)
Not sure2(1.0)

Patients could record more than one type of back pain or arthritis.

Table 3

Currently prescribed opioid medications

Number of patients (%) (N=198)
Prescribed opioid medication
 Codeine and codeine combinations102(51.5)
 Dihydrocodeine28(14.1)
 Hydromorphone2(1.0)
 Methadone3(1.5)
 Morphine65(32.8)
 Oxycodone18(9.1)
 Tapentadol1(0.5)
 Tramadol and tramadol combinations78(39.4)
Strength of prescribed opioid
 Strong only42(21.2)
 Weak only116(58.6)
 Combination of weak and strong40(20.2)

Patients could record more than one opioid.

Pain conditions Patients could record more than one type of back pain or arthritis. Currently prescribed opioid medications Patients could record more than one opioid.

Constipation and Laxative Use

More than three-quarters of patients reported that they had no history of constipation before taking opioids (142/185, 77%). Eighty-eight patients (88/198, 44%) said that their general practitioner had discussed constipation with them, and most patients said they had made lifestyle changes to try and help with their symptoms: 142 (72%) reported altering their diet (e.g., eating more fiber and increasing water intake), and 40 (20%) reported starting exercise (e.g., walking or swimming) or physical therapy. However, it was not clear whether patients made these lifestyle changes as a result of GP advice. More than half of patients (110/198, 56%) said that their GP had offered no advice on dealing with their constipation. Since starting their current opioid, 134 of 184 patients (73%) had taken a laxative at some point; of these, 122 (91%) were currently taking them. The mean (±SD) number of laxatives currently used was 1.36 (±0.81). Twenty-eight (23%) of the 122 patients currently taking laxatives were taking two or more, and 74 (61%) had been taking them for more than six months. The most common laxatives used were osmotics and stimulants (Table 4). In general, laxatives had been prescribed by a health care professional; over-the-counter (OTC) use was low, with the exception of stimulants: 50 (37%) of the 134 patients who had used laxatives since being prescribed their current opioid said that they had used OTC stimulants (most often senna).
Table 4

Types of laxatives used

Laxative typeNumber of patients (%) (N=134)
Osmotic
 Ever prescribed62(46.3)
 Ever OTC7(5.2)
 Currently taking53(39.6)
Stimulant
 Ever prescribed46(34.3)
 Ever OTC50(37.3)
 Currently taking56(41.8)
Bulk forming
 Ever prescribed12(9.0)
 Ever OTC8(6.0)
 Currently taking16(11.9)
Softener
 Ever prescribed8(6.0)
 Ever OTC1(0.7)
 Currently taking9(6.7)
Enema
 Ever prescribed7(5.2)
 Ever OTC3(2.2)
 Currently taking5(3.7)
Suppository
 Ever prescribed3(2.2)
 Ever OTC5(3.7)
 Currently taking5(3.7)
Other
 Ever prescribed5(3.7)
 Ever OTC13(9.7)
 Currently taking9(6.7)

Patients could record more than one type of laxative.

OTC = over the counter.

Types of laxatives used Patients could record more than one type of laxative. OTC = over the counter.

Side Effects and Impact on Quality of Life

Three-quarters of patients currently taking opioids reported side effects with their use (91/122, 75%). The most common side effects were gas, bloating or fullness, and sudden urge to defecate (Table 5). Side effects were more common in younger patients: 83% of patients (19/23) younger than age 40 years reported at least one side effect, compared with 73% (69/95) older than age 40 years. The most common side effects in younger patients were gas, sudden urge to defecate, and false alarm (Table 5). There appeared to be no association between side effects and opioid strength or occupational status (data not shown).
Table 5

Side effects experienced by laxative users

N (%)
All patientsAge < 40 yAge 40+ y
(N = 122)(N = 23)(N = 95)
None31(25.4)4(17.4)26(27.4)
Unpleasant taste/texture21(17.2)7(30.4)13(13.7)
Nausea22(18.0)6(26.1)15(15.8)
Bloating or fullness37(30.3)5(21.7)31(32.6)
Gas52(42.6)13(56.5)39(41.1)
Dehydration20(16.4)5(21.7)15(15.8)
Urge/fecal incontinence18(14.8)5(21.7)11(11.6)
Sudden urge to defecate31(25.4)9(39.1)21(22.1)
False alarm25(20.5)8(34.8)15(15.8)
Other6(4.9)1(4.3)5(5.3)

Patients could record more than one side effect. Age was not recorded for four patients.

Side effects experienced by laxative users Patients could record more than one side effect. Age was not recorded for four patients. Laxatives were considered to interfere “at least a little of the time” with work for 58 of the 122 patients currently taking them (48%) and with social activities for 62 (51%). Sixteen patients (13%) reported that laxatives substantially interfered with social activities; this was most commonly attributed to gas, bloating, urge/fecal incontinence, and false alarm. Almost half of the patients (95/198, 48%) reported that they had used other interventions to help with their constipation since starting their current laxative. These included herbal remedies, massage, and use of enemas. Forty-two patients (21%) said that they removed hard or dry stools by hand. Almost half of patients who had experienced frequent constipation before starting opioids, 20 of 43 (47%), used manual evacuation methods (colon irrigation therapy, enemas, massage, and removal by hand), compared with 42 of 142 (30%) who were not previously constipated.

Health Care Contacts

Most patients (169/198, 85%) reported that they had seen either a GP or a practice nurse about their pain condition and/or constipation since starting current treatment. One hundred and eight patients (55%) reported that they had visited their GP more than five times about their pain condition. For constipation alone, the corresponding figure was 15 patients (8%). Some patients had also had health care contacts in a secondary care setting, including 39 (20%) who had required an overnight stay in the hospital (Table 6).
Table 6

Health care contacts owing to pain and/or constipation

Number of patients (%) (N=198)
Primary care
 Pain and/or constipation169(85.4)
 Neither29(14.6)
Emergency care
 Pain and/or constipation47(23.7)
 Neither151(76.3)
Outpatients department
 Pain and/or constipation97(49.0)
 Neither101(51.0)
Overnight hospital stay
 Pain and/or constipation39(19.7)
 Neither159(80.3)
Other
 Pain and/or constipation28(14.1)
 Neither170(85.9)

Patients could record more than one health care contact.

Health care contacts owing to pain and/or constipation Patients could record more than one health care contact.

Bowel Function Index

In total, 185 patients completed the BFI questionnaire. Their mean (±SD) total score was 52.1 (±31.5), and 75% had a total score higher than 28.8 (i.e., were constipated). Patients’ BFI scores according to laxative use, opioid strength, and number of laxatives taken are shown in Table 7. Laxative use did not appear to improve the symptoms of constipation: patients who had used laxatives (N = 134) since starting their current opioid had a mean (±SD) BFI score of 58.2 (±30.2), compared with 36.5 (±29.0) for patients who had not used laxatives (N = 50). BFI scores were not related to opioid strength, with a mean difference of less than two points in the total score between patients taking weak and strong opioids. Taking more laxatives did not improve BFI scores; in fact, the mean total score and the proportion of patients with a total score higher than 28.8 increased with increasing number of laxatives used.
Table 7

Results from the Bowel Function Index questionnaire

Total population
Ever used laxatives?*
Opioid strength
Number of laxatives
Yes
No
Weak only
Strong only
1
2
≥3
(N = 198)(N = 134)(N = 50)(N = 116)(N = 42)(N = 92)(N = 19)(N = 9)
N (missing)185(13)134(0)50(0)106(10)39(3)92(0)19(0)9(0)
BFI total score, mean (SD)52.06(31.51)58.24(30.24)36.52(29.00)49.83(31.01)51.35(33.05)55.80(29.50)65.30(32.57)85.59(13.42)
BFI total score >28.8, N (%)139(75.1)109(81.3)30(60.0)80(75.5)27(69.2)74(80.4)16(84.2)9(100.0)

BFI = Bowel Function Index.

Excludes 14 patients whose laxative use was unknown.

Excludes 40 patients taking combined strong and weak opioid therapy.

Excludes 50 patients taking no laxatives.

Results from the Bowel Function Index questionnaire BFI = Bowel Function Index. Excludes 14 patients whose laxative use was unknown. Excludes 40 patients taking combined strong and weak opioid therapy. Excludes 50 patients taking no laxatives. Forty-three patients (43/185, 23%) reported that they had experienced frequent constipation before starting their current opioid, suggesting that they may have been particularly prone to the condition. A post hoc analysis revealed that the BFI scores in these individuals did not differ from those of the total study cohort: their mean (±SD) total score was 51.8 (±31.4), and 32 (74%) had a BFI score higher than 28.8.

Opioid Exposure

A post hoc analysis showed that patients were taking a median daily morphine equivalent dose of 40 mg (range = 4.8–580 mg) (Table 8). The descriptive data suggested there was no relationship between increasing daily morphine equivalent dose and higher BFI scores (although this was not formally tested). Patients’ median daily morphine equivalent doses were similar, regardless of whether they had experienced frequent constipation before starting on opioids or not (Table 8). The descriptive data also suggested there was also no clear relationship between daily morphine equivalent dose and laxative use (again, this was not formally tested). Patients who had never taken a laxative tended to be taking lower morphine equivalent doses than those who had used a laxative at some point since starting their current opioid (Table 8).
Table 8

Morphine equivalent doses

 Total population
BFI category*
Previously constipated?
Ever used laxatives?
Currently using laxatives?§
  ≤28.8
>28.8
Yes
No
Yes
No
Yes
No
(N = 198)(N = 46)(N = 139)(N = 43)(N = 142)(N = 134)(N = 50)(N = 122)(N = 12)
Total daily morphine equivalent, mg         
 N (missing)126 (72)30 (16)92 (47)30 (13)92 (50)90 (44)31 (19)82 (40)8 (4)
 Mean (SD)68.3 (88.8)83.8 (95.9)64.0 (88.1)80.6 (106.0)65.0 (84.5)73.2 (84.1)57.8 (107.1)66.0 (73.9)147.2 (141.1)
 Median (IQR)40403039.54044244292
(24.0–69.0)(20.0–100.0)(24.0–64.0)(24.0–80.0)(21.2–66.5)(24.0–80.0)(12.0–60.0)(24.0–80.0)(27.0–257.5)
 Min, max4.8, 580.04.8, 360.06.0, 580.06.4, 402.04.8, 580.06.0, 402.04.8, 580.06.0, 360.022.4, 402.0
Categories, N (%)        
 20 mg or less22 (17.5)5 (16.7)17 (18.5)4 (13.3)18 (19.6)12 (13.3)10 (32.3)12 (14.6)0 (0.0)
 21 to 50 mg54 (42.9)11 (36.7)41 (44.6)15 (50.0)37 (40.2)38 (42.2)13 (41.9)35 (42.7)3 (37.5)
 51 to 80 mg25 (19.8)5 (16.7)18 (19.6)4 (13.3)19 (20.7)19 (21.1)4 (12.9)19 (23.2)0 (0.0)
 81 to 120 mg11 (8.7)4 (13.3)7 (7.6)3 (10.0)8 (8.7)10 (11.1)1 (3.2)8 (9.8)2 (25.0)
 Over 120 mg14 (11.1)5 (16.7)9 (9.8)4 (13.3)10 (10.9)11 (12.2)3 (9.7)8 (9.8)3 (37.5)
 Less than 20 mg30 (23.8)9 (30.0)21 (22.8)7 (23.3)23 (25.0)17 (18.9)12 (38.7)17 (20.7)0 (0.0)
 20 to 90 mg72 (57.1)13 (43.3)55 (59.8)16 (53.3)52 (56.5)53 (58.9)15 (48.4)49 (59.8)4 (50.0)

Total daily morphine equivalent doses were calculated only for those patients who had data available for type of opioid, dose, and frequency. The following conversion ratios were used: buprenorphine:morphine, 0.5:1; codeine:morphine, 10:1; dihydrocodeine:morphine, 10:1; fentanyl:morphine, 0.2:1; methadone:morphine, 0.5:1; tapentadol:morphine, 2.5:1; tramadol:morphine, 10:1.

BFI = Bowel Function Index; IQR = interquartile range.

Excludes 13 patients who did not complete the BFI questionnaire.

Defined as patients who experienced frequent constipation before starting on opioids, excludes 13 patients whose previous constipation status was unknown.

Excludes 14 patients whose laxative use was unknown.

Excludes 64 patients whose laxative use was unknown.

Morphine equivalent doses Total daily morphine equivalent doses were calculated only for those patients who had data available for type of opioid, dose, and frequency. The following conversion ratios were used: buprenorphine:morphine, 0.5:1; codeine:morphine, 10:1; dihydrocodeine:morphine, 10:1; fentanyl:morphine, 0.2:1; methadone:morphine, 0.5:1; tapentadol:morphine, 2.5:1; tramadol:morphine, 10:1. BFI = Bowel Function Index; IQR = interquartile range. Excludes 13 patients who did not complete the BFI questionnaire. Defined as patients who experienced frequent constipation before starting on opioids, excludes 13 patients whose previous constipation status was unknown. Excludes 14 patients whose laxative use was unknown. Excludes 64 patients whose laxative use was unknown.

Discussion

The results of our survey confirm that constipation is very common among patients receiving oral opioids to treat pain and does not appear to be related to opioid strength or dose. Laxatives do not appear to resolve the problem; instead they frequently added to the patients’ burden by causing unpleasant side effects and negatively impacting quality of life. An important message for practice is that, despite constipation being a common side effect of opioid treatment, less than half of the patients in our survey received any advice on how to manage it. More than one in five patients said they had to resort to removing stools by hand, giving an indication of the severity of the constipation still endured by them, despite treatment with laxatives. The use of manual evacuation techniques was not restricted just to patients who had frequently experienced constipation before starting opioids and may have been predisposed to rectal evacuation disorders: approximately a third of those who had not experienced constipation previously found they also had to use one or more such interventions. A number of patients decided to try nonpharmacological methods (e.g., 72% altered their diet and 20% took up exercise), but these appear not to have worked, as almost three-quarters of patients reported that they had used laxatives since being prescribed their current opioid. This indicates an important role for the health care professional, not just the patient, in managing OIC. The range of patients who took part in the survey shows that OIC cannot be predicted by demographics or employment status, so each patient needs to be assessed individually. In the absence of any formal guidance, a wide range of laxatives was prescribed, the most common being osmotics and stimulants. This is consistent with prescribing patterns seen among UK respondents in a pan-European survey of female patients with chronic idiopathic constipation [24]. OTC use was lower than we had anticipated based on our own clinical experience and results from previous surveys [9,24]. The exception was use of OTC stimulants, which was assumed to be driven by the use of senna. Three-quarters of patients reported side effects with their laxatives. The most common (e.g., gas and bloating) were typical of laxatives. These unwanted effects reflect the lack of specificity in the mode of action of laxatives, which leads to overstimulation of the GI tract. Interestingly, younger patients reported more side effects than older patients. This is rather surprising given that older patients are generally considered to be more susceptible to side effects than younger patients [25]. One explanation could be that the relative minority of younger respondents represented a group who were more distressed by their symptoms. Approximately half of patients reported that laxatives interfered with their work or social life; this could tie in with the higher incidence of side effects in younger patients and points to a socioeconomic impact of laxative use in patients with OIC. Gas and bloating were two of the most common factors cited by patients reporting a substantial interference with work or social life. This supports the findings of a pan-European survey in which female patients with chronic constipation reported that relief from bloating was the aspect of their laxative that they were least satisfied with [24]. Most patients had seen a primary care health care provider about their pain condition and/or constipation since starting their current treatment, suggesting that a proportion of the patients in our survey had inadequate pain control as well as constipation. There were also a number of secondary care visits: Approximately one-fifth of patients had required an overnight stay in the hospital, which would have had negative health care cost implications in addition to the burden on patients. Patients’ BFI scores provide the most compelling evidence that OIC does not respond to laxatives. In fact, patients who were using laxatives recorded a higher BFI score (i.e., they were more constipated) than those who did not use laxatives. BFI scores were not related to opioid strength, even though weak opioids are often prescribed over strong opioids as they are perceived to be “less constipating.” Coyne etal. have previously shown that as the number of laxatives taken is increased, the proportion of patients with an inadequate response decreases [9]. We found that constipation appeared to worsen with increasing number of laxatives taken: 60% of patients who had never taken laxatives had a BFI score higher than 28.8, compared with all of those who were taking three or more laxatives. The proportion of patients who had a BFI score higher than 28.8 was similar to the proportion who reported that they had needed a laxative since starting their current opioid. Approximately one-quarter of patients said that they had a history of constipation before they started taking opioids, raising the possibility of a vulnerability to the condition. However, a post hoc analysis showed that their BFI scores were very similar to those of the total study cohort; therefore, these patients do not appear to have influenced the results. It might be expected that patients with a total BFI score higher than 28.8 would be taking higher morphine equivalent doses than those with scores lower than 28.8. It was clear, however, that constipation was not linked to opioid strength and dose, but it was anticipated that patients may lower their dose of opioid in an attempt to control their constipation, an observation that correlates with previous studies [3,7,9]. Patients with a history of constipation might be expected to be taking lower opioid doses than those without, but we found that the morphine equivalent doses were generally similar between these groups. Laxative use may be seen as an indicator that patients are taking higher doses of opioid, but our analysis gave conflicting results depending on whether the patients had ever taken a laxative since starting their current opioid or were currently using laxatives. Although not formally tested, the descriptive data suggested no clear relationship between increasing total daily morphine equivalent dose and constipation or laxative use; this emphasizes the need for patients to be assessed individually. As this was a survey, patients self-reported their symptoms and laxative use, so there is the potential for inaccuracies and recall bias; this must be considered as a limitation of these data. However, by answering anonymously via the internet, patients may have felt able to give more truthful responses to sensitive questions about bowel function than if the survey was conducted face-to-face. It should be noted that the BFI is validated as a tool to be used by health care professionals during consultations with patients; it has not yet been validated in the context of patient self-reporting. Although patients were asked how much opioid and laxative medication they were taking relative to the recommended daily dose, the survey did not collect information on compliance. It would have been interesting to see whether the negative effects of laxatives that patients described affected their dosing pattern, or whether patients had ever reduced or missed doses of their opioid medication to have a bowel movement (as has been documented by several other studies [7,8,9]). By conducting a survey, we have obtained a “real world” perspective on prescribing, rather than a guideline-based one. The data reflect current practice and show that opioids are being used in a wide range of conditions (including headache) and in combination. These prescribing patterns emphasize the importance of recognizing and managing OIC.

Conclusions

Use of laxatives to treat OIC is often ineffective and associated with side effects that reflect their lack of specificity. Instead of relieving the burden of OIC, laxatives themselves have a negative impact: approximately half of the patients surveyed reported that laxatives interfere with their work or social lives. A number of treatments that target the underlying cause of OIC are now available or in development [22]. There is a need to develop evidence-based treatment guidelines, which, combined with better education for health care professionals and patients, would be likely to shift prescribing away from multiple courses of laxatives and toward these newer treatments.
  24 in total

Review 1.  Incidence, prevalence, and management of opioid bowel dysfunction.

Authors:  M Pappagallo
Journal:  Am J Surg       Date:  2001-11       Impact factor: 2.565

2.  Prevention of opioid side effects.

Authors:  T D Walsh
Journal:  J Pain Symptom Manage       Date:  1990-12       Impact factor: 3.612

3.  The Bowel Function Index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients.

Authors:  M A Ueberall; S Müller-Lissner; C Buschmann-Kramm; B Bosse
Journal:  J Int Med Res       Date:  2011       Impact factor: 1.671

Review 4.  Opioid-Induced Constipation.

Authors:  Lynn R Webster
Journal:  Pain Med       Date:  2015-10       Impact factor: 3.750

5.  Gastrointestinal side effects in chronic opioid users: results from a population-based survey.

Authors:  S F Cook; L Lanza; X Zhou; C T Sweeney; D Goss; K Hollis; A W Mangel; S E Fehnel
Journal:  Aliment Pharmacol Ther       Date:  2008-03-21       Impact factor: 8.171

6.  Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy.

Authors:  Sean D Candrilli; Keith L Davis; Shrividya Iyer
Journal:  J Pain Palliat Care Pharmacother       Date:  2009

7.  Factors affecting satisfaction with treatment in European women with chronic constipation: An internet survey.

Authors:  Anton Emmanuel; Eamonn Mm Quigley; Magnus Simrén; Yue Feng; Stefan Müller-Lissner; Daniel Urbain; Jan Tack; Albert J Bredenoord; Jean-Marc Sabaté; Yan Yiannakou; Viola Andresen; Rosario Cuomo; Enrique Rey; Renate Specht Gryp; Lieve Vandeplassche; Dory Solomon
Journal:  United European Gastroenterol J       Date:  2013-10       Impact factor: 4.623

8.  The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1).

Authors:  Timothy J Bell; Sunil J Panchal; Christine Miaskowski; Susan C Bolge; Tsveta Milanova; Russell Williamson
Journal:  Pain Med       Date:  2008-08-18       Impact factor: 3.750

Review 9.  Opioid-induced bowel dysfunction: pathophysiology and potential new therapies.

Authors:  Andrea Kurz; Daniel I Sessler
Journal:  Drugs       Date:  2003       Impact factor: 9.546

Review 10.  Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden.

Authors:  S J Panchal; P Müller-Schwefe; J I Wurzelmann
Journal:  Int J Clin Pract       Date:  2007-05-04       Impact factor: 2.503

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  19 in total

Review 1.  Pathophysiology and management of opioid-induced constipation: European expert consensus statement.

Authors:  Adam D Farmer; Asbjørn M Drewes; Giuseppe Chiarioni; Roberto De Giorgio; Tony O'Brien; Bart Morlion; Jan Tack
Journal:  United European Gastroenterol J       Date:  2018-12-14       Impact factor: 4.623

2.  Randomized phase 3 and extension studies: Efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

Authors:  N Katakami; T Harada; T Murata; K Shinozaki; M Tsutsumi; T Yokota; M Arai; Y Tada; M Narabayashi; N Boku
Journal:  Ann Oncol       Date:  2018-04-18       Impact factor: 32.976

Review 3.  Insights into the Use of Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

Authors:  Ana Fernández-Montes; Guillermo de Velasco; Santiago Aguín; Cristina Farriols; María Guirado-Risueño; Vanessa G Jerviz-Guía; María Victoria Baeza-Nadal; Rodolfo Chicas-Sett; José Luis Fírvida; Francisco García-Navalón; Patricia Martín; Carmen Perezagua-Marín; Dulce Rodríguez; Joan Santamaría; Tamara Saurí; Manuel Cobo
Journal:  Curr Treat Options Oncol       Date:  2021-02-26

4.  Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies.

Authors:  Iwao Osaka; Hiroto Ishiki; Takaaki Yokota; Yukio Tada; Hiroki Sato; Masaharu Okamoto; Eriko Satomi
Journal:  ESMO Open       Date:  2019-07-31

5.  Naldemedine in Japanese patients with opioid-induced constipation and chronic noncancer pain: open-label Phase III studies.

Authors:  Yoji Saito; Takaaki Yokota; Masatsugu Arai; Yukio Tada; Masahiko Sumitani
Journal:  J Pain Res       Date:  2018-12-24       Impact factor: 3.133

6.  Incidence of opioid-induced constipation in Japanese patients with cancer pain: A prospective observational cohort study.

Authors:  Akihiro Tokoro; Hisao Imai; Soichi Fumita; Toshiyuki Harada; Toshio Noriyuki; Makio Gamoh; Yusaku Akashi; Hiroki Sato; Yoshiyuki Kizawa
Journal:  Cancer Med       Date:  2019-06-24       Impact factor: 4.452

7.  Prolonged-release oxycodone/naloxone reduces opioid-induced constipation and improves quality of life in laxative-refractory patients: results of an observational study.

Authors:  Carsten Bantel; Shiva S Tripathi; David Molony; Tony Heffernan; Susmita Oomman; Vivek Mehta; Sara Dickerson
Journal:  Clin Exp Gastroenterol       Date:  2018-01-24

8.  Long-term use of naldemedine in the treatment of opioid-induced constipation in patients with chronic noncancer pain: a randomized, double-blind, placebo-controlled phase 3 study.

Authors:  Lynn R Webster; Srinivas Nalamachu; Bart Morlion; Jyotsna Reddy; Yuko Baba; Tadaaki Yamada; Juan C Arjona Ferreira
Journal:  Pain       Date:  2018-05       Impact factor: 7.926

9.  Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

Authors:  N Katakami; T Harada; T Murata; K Shinozaki; M Tsutsumi; T Yokota; M Arai; Y Tada; M Narabayashi; N Boku
Journal:  Ann Oncol       Date:  2019-12-04       Impact factor: 32.976

Review 10.  Naldemedine for the Use of Management of Opioid Induced Constipation.

Authors:  Ivan Urits; Anjana Patel; Hayley Cornwall Kiernan; Conner Joseph Clay; Nikolas Monteferrante; Jai Won Jung; Amnon A Berger; Hisham Kassem; Jamal Hasoon; Alan D Kaye; Adam M Kaye; Omar Viswanath
Journal:  Psychopharmacol Bull       Date:  2020-07-23
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