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Managing and treating opioid-induced constipation in patients with cancer
Abstract
Constipation is a common symptom in cancer and palliative care patients. It can affect this patient group at any stage of their disease and for a variety of reasons. This article aims to highlight the contribution opiods make in inducing the symptom of constipation and highlights the need for a detailed assessment and interventions tailored to the needs of the patient.
History Physical Examination Diagnostics Clinical Question Discussion Back to Our Case Take Away Points References
ABSTRACT Perceived experiences of patients are important hallmarks of symptom control not only for physical symptoms, but also for the psychological, social, and spiritual dimensions. Listening to patients' narratives opens window to diagnosing the patients' symptoms. This reflection outlines the importance of this practice in managing symptoms of a terminally ill cancer patient.
Constipation can cause unnecessary discomfort and suffering for patients, and there appears to be a lack of awareness among nurses and doctors about its cause, impact and management. A large proportion of the evidence for the assessment and management of constipation in the context of palliative care is derived from the perspective of advanced cancer and from guidelines developed at a European level. Although constipation remains a problem for palliative care patients, early intervention combined with continuous and impeccable assessment can assist in its management and improve patient comfort at the end of life.
About one-third of cancer patients who receive opioid drugs to control pain experience constipation. While clinical healthcare personnel often deal with constipation problems by adopting professional suggestions, effective evidence-based solutions remain lacking. Thus, cancer patient constipation problems are often not effectively solved. In this article, 2009 American National Comprehensive Cancer Network guidelines for palliative care in cancer were modified as the basis of evidence-based nursing research. Constipation assessments should first be conducted before the initiation of opioid drug treatment to relieve pain in cancer patients. Before the patient develops opioid-induced constipation, preventive action should be conducted, such as using drug combinations (e.g., sennoside and docusate). Non-pharmaceutical interventions include exercising, maintaining a high-fiber diet, conducting abdominal massage and having correct bowel habits. If the patient is already experiencing constipation, bisacodyl (ducolax) may be used. However, if no improvement is observed, pharmaceutical treatments (e.g., a lactulose-sennoside combination) may be administered. If stool impaction occurs during the testing process, digital and glycerine should be implemented to remove stool impaction. Eliminating stool impaction enhances medication effectiveness. Nurses should advise doctors regarding preventive measures related to commencing treatment with opioid drugs. Further, nurses must evaluate degree of constipation and educate patients on following non-pharmaceutical strategies to alleviate constipation to improve quality of life.
Because the range of bowel habits and stool types in the community is unknown we questioned 838 men and 1059 women, comprising 72.2% of a random stratified sample of the East Bristol population. Most of them kept records of three consecutive defecations, including stool form on a validated six point scale ranging from hard, round lumps to mushy. Questionnaire responses agreed moderately well with recorded data. Although the most common bowel habit was once daily this was a minority practice in both sexes; a regular 24 hour cycle was apparent in only 40% of men and 33% of women. Another 7% of men and 4% of women seemed to have a regular twice or thrice daily bowel habit. Thus most people had irregular bowels. A third of women defecated less often than daily and 1% once a week or less. Stools at the constipated end of the scale were passed more often by women than men. In women of child bearing age bowel habit and the spectrum of stool types were shifted towards constipation and irregularity compared with older women and three cases of severe slow transit constipation were discovered in young women. Otherwise age had little effect on bowel habit or stool type. Normal stool types, defined as those least likely to evoke symptoms, accounted for only 56% of all stools in women and 61% in men. Most defecations occurred in the early morning and earlier in men than in women. We conclude that conventionally normal bowel function is enjoyed by less than half the population and that, in this aspect of human physiology, younger women are especially disadvantaged.
The carcinogenicity of chrysazin (1,8-dihydroxy-9,10-anthracenedione) was examined by dietary administration to C3H/HeN mice. All of the effective mice (17) which were given 0.2% chrysazin diet and which survived more than 500 days developed adenomatous hyperplasia with cystic glands of the cecum. Similar lesions were also seen in the colon of mice in this group. These intestinal lesions were not obtained in any effective mouse (19) of the control group. The incidence of hepatocellular carcinoma of mice given chrysazin (4/17) was significantly higher than that of the controls (0/19). These results indicate that chrysazin is carcinogenic in mice as well as in rats. Some mechanistic aspects of the causation of these intestinal lesions and liver neoplasms are also discussed.
Medical definitions of constipation vary. Some are specific, based on the interval between defecations, with three days or twice weekly as the upper limit of normality. Others are vague.
This study investigates patients definitions, attitudes and management of 'constipation' and compares their definitions with physicians' criteria.
Survey of 1) 531 randomized patients of family clinics of the sick Fund of the General Federation of Labor of Israel, and 2) 100 randomized specialists and residents in family medicine.
The present survey showed that constipation is more common in women and in the older (> 40 years) age group. The most important finding of this investigation was the wide discrepancy in the criteria used by doctors and patients to diagnose constipation. Fifty per cent of the patients defined constipation differently from accepted medical definitions--27% of the patients defined it as defecation every 2 days or less and 25% as hard stool alone. All 57 doctors who were asked the same question defined constipation as defecation every 3 or 4 days or less, sometimes in combination with hard stool.
This study suggests that patients and doctors refer to different entities when they talk of 'constipation'. It is the doctor's responsibility to ensure that this misunderstanding is avoided so that unnecessary tests and treatment are not undertaken and, patient-doctor acrimony is avoided.
The Rome diagnostic criteria for the functional bowel disorders and functional abdominal pain are used widely in research and practice. A committee consensus approach, including criticism from multinational expert reviewers, was used to revise the diagnostic criteria and update diagnosis and treatment recommendations, based on research results. The terminology was clarified and the diagnostic criteria and management recommendations were revised. A functional bowel disorder (FBD) is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation. The irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea are distinguished by symptom-based diagnostic criteria. Unspecified FBD lacks criteria for the other FBDs. Diagnostic testing is individualized, depending on patient age, primary symptom characteristics, and other clinical and laboratory features. Functional abdominal pain (FAP) is defined as either the FAP syndrome, which requires at least six months of pain with poor relation to gut function and loss of daily activities, or unspecified FAP, which lacks criteria for the FAP syndrome. An organic cause for the pain must be excluded, but aspects of the patient's pain behavior are of primary importance. Treatment of the FBDs relies upon confident diagnosis, explanation, and reassurance. Diet alteration, drug treatment, and psychotherapy may be beneficial, depending on the symptoms and psychological features.
Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.
To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.
Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.
Clinical research center of a university hospital.
Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.
Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.
The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.
Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.
Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a mu-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness.
A total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial.
In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events.
Subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (Clinical Trials.gov number, NCT00402038 [ClinicalTrials.gov].).
Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux.
The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes — μ, δ and κ — that mediate the myriad of peripheral and central actions of opioids. Activation of μ-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction.
Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.
In this study 50 hospice and hospital patients with far advanced cancer were asked to select, from a series of cards describing symptoms, those symptoms which they had, and to rank in order the five most distressing to them. Using a scoring system it was possible to assess the frequency of all symptoms nominated and to assess which symptoms were most distressing to the patient. Weakness was the most frequent and distressing symptom overall, according to the patients. Gastrointestinal symptoms such as dry mouth, anorexia, constipation and nausea were also common and were considered to be distressing, dry mouth and anorexia more so than pain. Differences were evident between patients in various subgroups: recent versus long admissions; hospice versus hospital patients; and male versus female patients. However it is important to note that weakness was the most frequent and the most distressing symptom for all patient groups.
Background: Irritable bowel syndrome (IBS) is a common disorder and is the largest diagnostic cohort seen by gastroenterologists. There is a bidirectional comorbidity of IBS and psychiatric illness. Ours is the first study to examine the effect of any selective serotonin reuptake inhibitor in subjects with IBS.
Method: Twenty subjects with Rome I criteria-diagnosed IBS were treated with 20 to 40 mg of paroxetine for 12 weeks. We utilized a computer-administered patient daily questionnaire taken by patients over the telephone using an interactive voice response system.
Results: Sixty-five percent of patients (13/20) reported a reduction in abdominal pain, and 55% (11/20) reported a reduction in pain frequency (total or mean number of days per week in which the patient had the symptom decreased by 50%). Constipation and diarrhea were reduced in 69% and 57% of patients (9/13 and 8/14), respectively. Similarly, a clinically significant reduction in the symptoms of feeling of incomplete emptying (53% [9/17]) and bloating/abdominal distension (55% [11/20]) was apparent at study conclusion compared with baseline. On the Clinical Global Impressions scale at week 12, 47% (8/17) of the patients were much or very much improved.
Conclusion: In our pilot open-label study, paroxetine was very effective in alleviating the abdominal pain and associated symptoms of IBS. These results warrant further examination in a placebo-controlled study.
Constipation is a significant problem in patients receiving neurotoxic chemotherapeutic agents, narcotic analgesics, antidepressants, tranquilizers, and muscle relaxants. Increasingly, as acute care moves into the community, nurses will need valid and reliable methods of assessing constipation in individuals with cancer. The purpose of this project was to study the validity and reliability of the Constipation Assessment Scale, a new tool designed to assess the presence and severity of constipation. The sample consisted of two groups: a control group of 32 working adults and a patient group of 32 adults at risk for constipation because of treatment with Vinca alkaloids or morphine. Consenting subjects were asked to complete the eight-item Constipation Assessment Scale (CAS). A significant difference in intensity of symptoms between the two groups (t = 6.32, p less than 0.0001) demonstrates the ability of the CAS to differentiate between subjects with and without constipation and thus provides evidence of construct validity of the scale. Further analysis of scores of the two subgroups in the patient group (subjects receiving morphine vs. Vinca alkaloids) revealed a significant difference (t = 2.54, p less than 0.01) in symptom intensity. This latter finding supports the ability of the CAS to differentiate between moderate and severe symptom intensity. Subjects completed the CAS in approximately 2 min. To study the test-retest reliability of the scale, a group of 16 apparently healthy working adults were asked to fill out the CAS twice with a 1-h delay. The two sets of scores were correlated (r = 0.98).(ABSTRACT TRUNCATED AT 250 WORDS)
Constipation is a frequent and distressing complication in patients with advanced cancer. However, very few studies have reviewed the assessment and management of these patients. The purpose of this study was to review the documentation and assessment and diagnosis of constipation in patients admitted to a Palliative Care Unit, and the correlation between those findings and radiological evidence of stool in the colon. The records of 122 consecutive patients admitted to the Palliative Care Unit, Edmonton General Hospital were reviewed in order to assess the physician's and the nurse's record of symptoms, physical findings, and diagnosis and treatment of constipation. All patients also underwent a flat abdominal radiograph that scored for the presence of stool in the colon (0 = no stool; and 12 = stool occupying all the lumen of the four quadrants of the colon). The radiograph was scored blindly by two different physicians. Of 103 evaluable patients, a rectal exam was reported only in 42. Correlation between the assessment by the two physicians' radiograph score was high (0.78, P nd nurses' diagnosis of constipation, the presence of laxative treatment, the number of days since the last bowel movement, and the source of the admission (hospital vs home) were not associated with higher radiological scores for constipation. Assessment is insufficient in this population at high risk for severe constipation. Radiological examination may be necessary for adequate diagnosis in some patients. More research is needed in this area.
We investigated the effects of methylnaltrexone on morphine-induced inhibition of smooth muscle-strip contraction in isolated guinea-pig ileum and human small intestine. The longitudinal muscle-strip was immersed in a temperature-controlled (37 degrees C) bath containing a physiological solution of 95% O2 and 5% CO2 with pH 7.4. Muscle contraction was elicited by transmural electrical stimulation with a pulse duration of 0.5 ms at frequencies of 1-50 Hz for 5-10 s at 1-3-min intervals. Muscle contraction was blocked by tetrodotoxin or atropine in both preparations. When methylnaltrexone was applied to the bath, the force produced by muscle contraction was enhanced up to approximately 30%. Stimulation-elicited muscle contraction was inhibited by morphine, which decreased the force of contraction 42 +/- 9.5% (S.D.) in the human intestine preparation and 35 +/- 8.6% in guinea-pig ileum at the inhibitory concentration 70% (IC70). Methylnaltrexone effectively antagonized the effects of morphine-induced inhibition of muscle-strip contraction. In the guinea-pig ileum preparation, methylnaltrexone at 30, 100 and 300 nM blocked 25 +/- 10.5%, 74 +/- 7.2% and 89 +/- 9.9% of morphine-induced (300 nM) inhibition, respectively. In the human intestine preparation, methylnaltrexone at the same concentrations blocked 57 +/- 10.9%, 74 +/- 12.9% and 92 +/- 7.2% of morphine-induced (100 nM) inhibition, respectively. The relative ratio of methylnaltrexone to morphine was higher in human intestine (1:1) than in the guinea-pig ileum preparation (1:3). These data provide preliminary information for clinical studies to evaluate the efficacy of methylnaltrexone in preventing or reducing morphine-induced antimotility and antitransit actions.
Opioids have been used for centuries as antidiarrhoeal drugs. In recent years, their mechanism and sites of action in exerting their antidiarrhoeal effect have been studied intensely. Attempts have been made to propose their general mode of action. Whilst there are numerous similarities in their general effects on motility, fluid secretion, and neuroeffector transmission, the differences between species, in some cases, can be remarkable. We highlight and contrast the similarities and differences in the commonly examined species and compare them to humans. Insights into mechanisms of opioid antidiarrhoeal action now also provide some new perspectives of opioid action in the intestine.
This study was designed to evaluate whether detailed symptom analysis would help to identify pathophysiologic subgroups in chronic constipation.
In 190 patients with chronic constipation (age, 53 (range, 18-88) years; 85 percent of whom were women), symptom evaluation, transit time measurement (radiopaque markers), and functional rectoanal evaluation (proctoscopy, anorectal manometry, defecography) were performed. Patients were classified on the basis of objective data from all tests in four different groups ("disordered defecation," "slow gastrointestinal transit," "disordered defecation combined with slow-transit stool," and "no pathologic finding").
In 59 percent of patients, disordered defecation was found, and 27 percent had slow-transit stool. In 6 percent of patients, a combination of both was found; in only 8 percent of patients, there were no pathologic findings. Straining was reported by the vast majority in all groups (82-94 percent). Infrequent bowel movements and abdominal bloating were more common in slow-transit stool (87 and 82 percent vs. 69 and 55 percent, respectively; both P < 0.01). Feeling of incomplete evacuation was more common in disordered defecation (84 vs. 46 percent; P < 0.0001). However, specificity of these symptoms was discouraging (for slow-transit stool: infrequent bowel movements had a sensitivity of 87 percent and a specificity of 32 percent and abdominal bloating had a sensitivity of 82 percent and specificity of 45 percent; for disordered defecation: feeling of incomplete evacuation had a sensitivity of 84 percent and a specificity of 54 percent). Only the sense of obstruction and digital maneuvers were acceptably specific (79 and 85 percent, respectively) for disordered defecation, but sensitivity was low.
Definition of chronic constipation by infrequent bowel movements alone is of little value; the symptom "necessity to strain" is much better suited (94 percent sensitivity). Specificity of infrequent bowel movements for slow-transit stool was discouraging. Sense of obstruction and digital manipulation for evacuation are relatively specific for disordered defecation but insensitive. Therefore, symptoms of chronically constipated patients are not well suited to differentiate between the pathophysiologic subgroups suffering chronic constipation.
Stool form scales are a simple method of assessing intestinal transit rate but are not widely used in clinical practice or research, possibly because of the lack of evidence that they are responsive to changes in transit time. We set out to assess the responsiveness of the Bristol stool form scale to change in transit time.
Sixty-six volunteers had their whole-gut transit time (WGTT) measured with radiopaque marker pellets and their stools weighed, and they kept a diary of their stool form on a 7-point scale and of their defecatory frequency. WGTT was then altered with senna and loperamide, and the measurements were repeated.
The base-line WGTT measurements correlated with defecatory frequency (r = 0.35, P = 0.005) and with stool output (r = -0.41, P = 0.001) but best with stool form (r = -0.54, P < 0.001). When the volunteers took senna (n = 44), the WGTT decreased, whereas defecatory frequency, stool form score, and stool output increased (all, P < 0.001). With loperamide (n = 43) all measurements changed in the opposite direction. Change in WGTT from base line correlated with change in defecatory frequency (r = 0.41, P < 0.001) and with change in stool output (n = -0.54, P < 0.001) but best with change in stool form (r = -0.65, P < 0.001).
This study has shown that a stool form scale can be used to monitor change in intestinal function. Such scales have utility in both clinical practice and research.
Palliative care is the management of patients with progressive, far-advanced disease for whom the prognosis is limited and the focus of care is quality of life. During the last days of life, it is important to redefine the goals, as previously present symptoms may increase and new symptoms may appear. To assess these symptoms, 176 patients were evaluated. A questionnaire evaluated symptoms during the last week of life and compared these prevalences with those at the first evaluation. The patients comprised 121 men and 55 women. The mean age was 67.7 years. Metastases were present in 66.5% and were multiple in 52%. The most frequent symptoms at the end of life (> 50%) were anorexia, asthenia, dry mouth, confusion, and constipation. The majority of patients died at home (64.2%). We observed good control of "reversible" symptoms, but many symptoms were difficult to control at the end of life. Symptom assessment is important in this population.
Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time.
This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time.
In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation.
Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.
Refractory constipation is a common GI complaint seen by physicians in all practice settings. We have previously shown that p.d. colchicine (0.6 mg t.i.d.) increases the number of spontaneous bowel movements, hastens GI transit, and improves GI symptoms in patients with chronic constipation during an 8-wk, open-label therapeutic trial. The aim of this study was to determine if p.d. colchicine will increase spontaneous bowel movements and accelerate colonic transit in patients with idiopathic chronic constipation in a randomized, placebo-controlled, crossover trial.
A total of 16 patients (15 women, one man) with a mean age of 47 yr (age range 25-89) with chronic idiopathic constipation who were refractory to standard medical therapy participated in the study. Patients randomly received either colchicine 0.6 mg p.o. t.i.d. or an identical placebo p.o. t.i.d. for a total of 4 wk in a double-blind, crossover fashion. Patients recorded their daily number of bowel movements and daily symptoms of daily nausea, abdominal pain, and bloating. Mean colonic transit was calculated at baseline, weeks 6 and 12.
Colchicine increased the number of bowel movements and accelerated colonic transit compared with baseline and placebo conditions. There were no significant differences between conditions on ratings of nausea and bloating. During colchicine administration, mean abdominal pain was greater than the baseline or placebo conditions, however, the pain decreased significantly by the last week the patient was on colchicine.
Colchicine increases the frequency of bowel movements and hastens colonic transit in patients with chronic constipation. Colchicine may be an effective agent available to practitioners to treat a subset of patients with chronic constipation who are refractory to standard medical therapy.
The demographics and prevalence of symptoms in patients at first referral to the different components of palliative care services were identified by a retrospective case note study of 400 patients referred to three palliative care centres in London, UK: Michael Sobell House, Mount Vernon Hospital; The North London Hospice; St Bartholomew's and the Royal London Hospitals. One hundred consecutive referrals to each of the following service components were analysed: a hospice inpatient service; a community team; an NHS hospital support team and an outpatient service. A standardized proforma was used to collect the data. Ninety five per cent (380/400) of patients referred had a cancer diagnosis. The five most prevalent symptoms overall were pain (64%), anorexia (34%), constipation (32%), weakness (32%) and dyspnoea (31%), which is similar to other published reports. However, the commonest symptoms and their prevalence varied depending on the service component to which the patient was referred. Patients referred to hospice and community services had the highest symptom burden (mean number of symptoms per patient 7.21 and 7.13, respectively). This study suggests that different patient subgroups may have different needs in terms of symptoms, which will be relevant for the planning and rationalization of palliative care services.
It is estimated that one third of the population in Western industrial countries suffers from constipation at least from time to time. Constipation may have somatopathic or functional causes. Furthermore, a great number of substances are known to cause medication-induced constipation, i.e. opioid-induced constipation is caused by linkage of the opioid to opioid receptors in the bowel and the central nerve system. Whenever possible, causal therapy should be undertaken. Patients in palliative care mostly suffer from chronic functional constipation. The treatment consists of basic measures and the application of laxatives. According to their mode of action, they are divided into bulk-forming laxatives, osmotic laxatives, stimulant laxatives, lubricating agents and others. Bulk-forming laxatives are not recommended for use in palliative care patients, for such patients are normally not able to take in the required amount of fluids. Osmotic laxatives are divided into (magnesium) salts, saccharine, alcohols and macrogols. Lactulose is the most popular saccharine laxative. Because of its side effects (flatulence, bloating and abdominal cramping), lactulose is not a laxative of our choice; instead, we prefer to give macrogol. Orally administered, macrogol is not metabolised and pH value and bowel flora remain unchanged. Macrogol hydrates hardened stools, increases stool volume, decreases the duration of colon passage and dilates the bowel wall that then triggers the defecation reflex. Even when given for some time, the effectiveness of macrogol will not decrease. Because of its high effectiveness and commonly good tolerance, macrogol has become the laxative of first choice in palliative care patients with all kinds of chronic constipation, if these patients are able to take in the necessary amount of fluids. From the general medical point of view, lubricating agents have become obsolete. In palliative care patients, however, they are still important laxatives for prophylactic treatment or therapy of constipation. Due to clinical experience, in palliative care a laxative ladder has proven successful.
Gastrointestinal motility can be assessed in vitro by investigating the effects of drugs or gene knockouts on intestinal propulsion, and on neurone-mediated responses evoked by electrical field stimulation (EFS). The latter predominantly measure enteric motor activity and can detect prokinetic activity of exogenous agents. Some evidence suggests that naloxone has prokinetic activity when evaluated for an ability to modulate responses to EFS, but the effects are inconsistent across different species or intestinal regions. Models of intestinal peristalsis measure an integrated sensory-motor nerve function and possess more intact neuro-neuronal connections. In such preparations, the effects of naloxone also suggest a prokinetic property but again, this is inconsistent. By contrast, consistent prokinetic activity of naloxone is apparent in models where peristalsis is compromised by drug-induced suppression of motor nerve activity or by modulation of endogenous processes using receptor antagonists or inappropriate intraluminal distension. These data suggest that endogenous opioids play little or no role in normal intestinal physiology, but suppress intestinal motility when motor function is compromised. Consequently, drugs that antagonize opioid receptors may exert prokinetic activity in conditions where intestinal motility is reduced, such as constipation. Further work is required to elucidate the opiate receptor(s) involved.
Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.
Fifty percent of patients admitted to hospices cite constipation as a concern. This study evaluates how constipation was managed in 11 hospices. Patients and nurses completed questionnaires at two time points: baseline and 7-10 days later. Outcomes were evaluated using a Constipation Visual Analogue Scale and a satisfaction with management of constipation questionnaire. A total of 475 patients participated; 413 completed both assessments. Forty-six percent of patients reported no constipation and 15% of patients reported severe constipation. For 75% of patients, no change in the perception of constipation was observed over the study period. Patients expressed satisfaction with their constipation management. The severity of constipation was overestimated by nurses in many patients. The findings indicate that constipation was being prevented or reasonably well managed. However, severe constipation continues to be a problem. Assessment of patients' bowel function needs to be more rigorous and those identified as severely constipated need daily monitoring.
Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.
The pathogenesis of the constipation that is commonly experienced by cancer patients, especially those with advanced disease, is the result of multiple influences on the control of intestinal motility and fluid handling. These factors include the direct effects of malignancy on gut structure, paraneoplastic neural impairment, biochemical disturbance, and adverse effects of cancer treatments. In addition, the debility and reduced oral intake associated with cancer also contribute, as, perhaps, might the older age of many cancer patients. A detailed understanding of the mechanisms of constipation, especially in association with illness, is lacking, and most treatments remain nonspecific.
We have analyzed the prevalence and patterns of constipation in women with urinary symptoms and/or genital prolapse.
Seven hundred and eighty-six consecutive urogynecologic patients underwent a questionnaire and structured clinical assessment. Comparison between constipated and nonconstipated women was made. Fisher exact test, Wilcoxon rank sum test, and logistic regression were used for statistical analysis (P < .05 for significance).
Thirty-two percent of women were constipated (172 difficult stool passage, 13 reduced stool frequency, 64 both). A genital prolapse > or = 2 degree Half Way System (HWS) was present in 44% of women. A posterior colpocele was more frequent in constipated women (35% vs 19%; P < .0001), resulting in a risk factor for constipation (OR 2.31; 95% CI 1.63-3.27). By contrast, higher degrees of anterior colpocele appeared to protect against constipation (OR 0.80; 95% CI 0.66-0.96). No differences in prevalence of constipation were observed for urinary symptoms or urodynamic diagnosis.
Bowel dysfunction correlates exclusively with posterior aspects of the pelvic floor support.
Alvimopan is a selective, competitive mu-opioid receptor antagonist with limited oral bioavailability which may be used to reduce length of post-operative ileus.
The study compared alvimopan with placebo following bowel resection or total abdominal hysterectomy.
A meta-analysis of randomized-controlled trials published between 2001 and 2006 of alvimopan vs. placebo was performed. The primary efficacy end-points were composite measures of passage of flatus, stool, and tolerance of solid food (GI-3) and passage of stool and tolerance of solid food (GI-2). The incidence of treatment emergent adverse events was assessed.
Five trials matched the selection criteria, reporting on 2195 patients. A total of 1521 (69.3%) had alvimopan and 674 (30.7%) placebo. GI-3 significantly improved (hazard ratio 1.30; 95% confidence intervals 1.16, 1.45, P < 0.001), as did GI-2 (hazard ratio 1.61; 95% confidence intervals 1.26, 2.05, P < 0.001) on alvimopan 12 mg. Time to discharge (hazard ratio 1.26; 95% confidence intervals 1.13, 1.40, P < 0.001), time to bowel motion (hazard ratio 1.74; 95% confidence intervals 1.29, 2.35, P < 0.001), and time to solid food (hazard ratio 1.14; 95% confidence intervals 1.01, 1.30, P < 0.04) also improved significantly. No difference was noted in the incidence of treatment emergent adverse events.
Alvimopan showed significant advantages over placebo in restoring gastro-intestinal function, and reduced time to discharge following major abdominal surgery, with acceptable side effects.
There remains insufficient randomised controlled trial data to determine the 'best' management of constipation in palliative care. Constipation is commonly experienced by palliative care patients as a result of the use of medications, such as opioids for pain control; dietary and mobility factors, as well as disease related factors. This review aimed to determine the effectiveness of laxatives for the management of constipation. Four trials involving 280 people were included. Two review authors independently assessed trial quality and extracted patient-reported data measuring changes in stool frequency and ease in passing stools. All of the laxatives used in the trials were ineffective for a significant number of patients and some patients required multiple rescue laxatives, indicating the severity of the problem and relative lack of treatments to relieve constipation. There is a lack of evidence to support the use of one laxative, or combinations of laxative over another.
Constipation is a significant problem in patients taking morphine for cancer pain. The aims of this study were (1) to assess the magnitude of constipation in this study cohort, (2) to analyse the constipation treatment strategies and (3) to look for evidence of inter-individual variation in both susceptibility to constipation and response to treatment with laxatives in this patient group.
This was an observational study carried out in a tertiary referral cancer hospital. Two hundred seventy four patients were recruited to the study. All had a diagnosis of cancer and were on oral morphine for cancer pain. The main outcomes measured were subjective patient assessment of constipation severity in the preceding week and laxative use. Patients were asked to grade constipation in the preceding week on a four-point categorical scale: "not at all" (grade 0), "a little" (grade 1), "quite a bit" (grade 2) and "very much" (grade 3). Laxative dose groups (LDGs) were developed to assess laxative dosing.
Constipation affects 72% of this cohort of patients. Constipation in this population is poorly managed. Eighty nine percent of constipated patients were on inadequate laxative therapy. Inter-individual variation in constipation on morphine exists: some patients do not experience constipation and do not need to take any laxatives, some patients do not experience constipation because they are taking laxatives and some patients experience constipation despite being on high dose laxatives. These three groups were compared in terms of cancer diagnosis, time on morphine, dose of morphine and other concomitant factors. No factor was identified to account for this inter-individual variation. Improvement in the clinical management of constipation is needed, with titration of laxatives according to individual patient need.
Constipation affects a large proportion of cancer patients taking oral morphine. Constipation in these patients is generally inadequately treated.
Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life.
To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD.
We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers.
Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD.
Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events.
Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate.
Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.
Methylnaltrexone, a peripherally-acting quaternary opioid antagonist, is an investigational treatment for opioid-induced constipation in patients with advanced illness. This randomized, parallel-group, repeated dose, dose-ranging trial included a double-blind phase for one week followed by an open-label phase for a maximum of three weeks. Opioid-treated patients with advanced illness who met criteria for opioid-induced constipation despite laxative therapy were potentially eligible. Double-blind treatment occurred on Days 1, 3, and 5; open-label therapy could be administered as often as every other day. The initial dose range of 1mg, 5mg, or 12.5mg was extended by adding a 20mg group during the study while still maintaining the double blind; the initial open-label dose of 5mg could be titrated. The primary outcome was a laxation response within four hours after the first dose. Thirty-three patients received at least one dose of methylnaltrexone. Only one of 10 patients (10%) who received the 1mg dose experienced laxation within four hours of dosing. The median time to laxation was >48 hours for the 1mg dose group, compared to 1.26 hours for all patients receiving >or=5mg (P=0.0003). There was no apparent dose-response above 5mg. Most adverse events were related to the gastrointestinal system, were mild, and did not lead to discontinuation. In conclusion, methylnaltrexone relieved opioid-induced constipation at doses >or=5mg in patients with advanced illness, and did not reduce analgesia or cause opioid withdrawal symptoms.
BACKGROUND: Irritable bowel syndrome (IBS) is a common disorder and is the largest diagnostic cohort seen by gastroenterologists. There is a bidirectional comorbidity of IBS and psychiatric illness. Ours is the first study to examine the effect of any selective serotonin reuptake inhibitor in subjects with IBS. METHOD: Twenty subjects with Rome I criteria-diagnosed IBS were treated with 20 to 40 mg of paroxetine for 12 weeks. We utilized a computer-administered patient daily questionnaire taken by patients over the telephone using an interactive voice response system. RESULTS: Sixty-five percent of patients (13/20) reported a reduction in abdominal pain, and 55% (11/20) reported a reduction in pain frequency (total or mean number of days per week in which the patient had the symptom decreased by >/= 50%). Constipation and diarrhea were reduced in 69% and 57% of patients (9/13 and 8/14), respectively. Similarly, a clinically significant reduction in the symptoms of feeling of incomplete emptying (53% [9/17]) and bloating/abdominal distension (55% [11/20]) was apparent at study conclusion compared with baseline. On the Clinical Global Impressions scale at week 12, 47% (8/17) of the patients were much or very much improved. CONCLUSION: In our pilot open-label study, paroxetine was very effective in alleviating the abdominal pain and associated symptoms of IBS. These results warrant further examination in a placebo-controlled study.