The Journal of International Medical Research 2011; 39: [first published online as 39(1) 9]

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1 The Journal of International Medical Research 2011; 39: [first published online as 39(1) 9] The Bowel Function Index for Evaluating Constipation in Pain Patients: Definition of a Reference Range for a Nonconstipated Population of Pain Patients MA UEBERALL 1, S MÜLLER-LISSNER 2, C BUSCHMANN-KRAMM 3 AND B BOSSE 3 1 Institut für Neurowissenschaften, Algesiologie und Pädiatrie IFNAP, Nuremberg, Germany; 2 Park-Klinik Weissensee, Berlin, Germany; 3 Mundipharma Research GmbH & Co. KG, Limburg, Germany Opioid-induced constipation (OIC) is a severe, persisting side-effect of opioid therapy. The Bowel Function Index (BFI a, numerical analogue scale 0 100), calculated as the mean of three variables (ease of defaecation, feeling of incomplete bowel evacuation, and personal judgement of constipation) was developed to evaluate bowel function in opioidtreated patients with pain. This clinicianadministered tool allows easy measurement of OIC from the patient s perspective. The purpose of this investigation was to define a reference range reflecting BFI values in nonconstipated chronic pain patients who were recruited into a cross-sectional survey and asked for their perceptions of constipation. The BFI scores were assessed and compared with those of patients with confirmed OIC obtained from two previously published trials. Results were analysed and a reference range of BFI values of , into which 95% of nonconstipated chronic pain patients fell, was defined. This permits discrimination between chronic pain patients with, or without, constipation. KEY WORDS: BOWEL FUNCTION INDEX; OPIOID-INDUCED BOWEL DYSFUNCTION; CHRONIC PAIN; CONSTIPATION; OPIOIDS; PATIENT-REPORTED OUTCOMES; ORAL PROLONGED-RELEASE OXYCODONE/NALOXONE COMBINATION Introduction Constipation is a known side-effect of a range of medications that are used to treat a broad spectrum of disorders. Opioids are well known for their constipating properties: a Copyright for the BFI is owned by Mundipharma Research, The BFI is the subject of European Patent Application Publication No. EP and corresponding patents and applications in other countries. while they are a mainstay of the treatment of moderate-to-severe pain, 1 and often offer the most effective option for patients with severe cancer or non-cancer pain, constipation remains a limitation of their use. Other side-effects associated with opioids may improve over time, but opioidinduced constipation (OIC) persists 2,3 and can lead to symptoms including hard dry 41

2 stools, straining, pain, cramping, delayed digestion and nausea. 4 Together, such symptoms are also known as opioid-induced bowel dysfunction, 3 which can also interfere with drug administration and absorption. 3 Symptoms of constipation have a clear impact on a patient s quality of life (QoL) 5 and may become so severe that some patients are forced to reduce or omit their opioid medication, even when such medication offers effective pain management. 6 Many strategies for constipation relief are used to manage this drawback of opioid treatment: e.g. following fibre-rich diets, encouraging mobility and administering laxatives. These strategies are, however, often ineffective. 6 More recently, agents including alvimopan, methylnaltrexone and a combination of fixed oral prolongedrelease (PR) oxycodone and PR naloxone drugs which have the potential to address the causes of OIC have entered the market or are under development. 7 9 Up to 90% of pain patients who take opioids are affected by OIC, 6 which underlines the fact that this condition, and options for its management or prevention, is an area of interest and active research. To analyse the different approaches to OIC, particularly in study settings, standardized assessment tools are needed that evaluate bowel function adequately and reveal and discriminate changes in OIC. In clinics, stool frequency has been used to quantify bowel function as it is simple to measure. Stool frequency varies widely between patients: values between three movements a day and three movements a week can be considered statistically normal. 10 Moreover, assessing stool frequency alone does not account for the discomfort and impact of constipation experienced by patients. To standardize the diagnosis of functional constipation, the ROME III criteria 11 defines a list of symptoms including straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, and necessity of manual manoeuvres to facilitate defaecation. Functional constipation is indicated if these symptoms are fulfilled in at least 25% of defaecations and the patient experiences fewer than three bowel movements per week. Although these criteria allow for the diagnosis of functional constipation, they are not an adequate tool for measuring clinically meaningful changes in constipation severity as response to treatment. In addition, quality aspects and subjective criteria from the patient s perspective, such as severity and impact, are not captured by these objective criteria. To address the need for a patient-reported outcome measure, the Patient Assessment of Constipation (PAC) has been developed. 12 This measure includes complementary symptom (PAC-SYM) 13 and QoL (PAC- QOL) 14 questionnaires. The 12 items of the PAC-SYM and 28 items of the PAC-QOL are rated on a five-point scale. The PAC-SYM is validated for use in OIC, but is complex and contains items that do not specifically address OIC. 13 The Bowel Function Index (BFI) is another scale that has been developed and validated for the quantitative assessment of bowel function. 15 This tool was developed in the context of the clinical development programme for an opioid agonist/antagonist combination (oxycodone PR/naloxone PR) for the treatment of chronic pain and the reduction or prevention of OIC The BFI is a clinician-administered tool that allows easy measurement of OIC from the patient s perspective and includes three variables: 42

3 ease of defaecation ; feeling of incomplete bowel evacuation ; and personal judgement of constipation. Using a numerical analogue scale (NAS) of 0 100, patients rate these variables according to their experience of the preceding 7 days, where 0 represents freedom from the symptom and 100 represents maximum difficulty or the most severe symptom. The BFI score is calculated as the mean of the three component scores. Chronic-pain patients tend to be familiar with the NAS concept and assessments that use NAS are commonly employed for rating pain, both in study settings and routine check-ups. The present study was designed to evaluate BFI in different groups of patients with pain in order to define a reference range of BFI values that reflect the scores of nonconstipated chronic pain patients. Patients and methods REFERENCE POPULATION For recruitment of the reference population for this cross-sectional survey, chronic pain patients were enrolled from 11 pain clinics across Germany, starting in October 2006 and ending in March All these patients were being treated for their pain but, as treatment with World Health Organization (WHO) step III analgesics 1 was specifically defined as an exclusion criterion due to their constipating properties, only patients treated with WHO step I and II analgesics were permitted to take part. All the patients recruited provided written informed consent before being included in the study. Due to the non-interventional design of the study, no specific ethics approval was required. Basic data regarding type of pain, medication use, concomitant diseases and demographics were documented for each patient using a questionnaire administered by the attending physician. Afterwards, data on bowel habits were collected from each patient by telephone interview during which they were also questioned about their perception of constipation during the preceding 7 days ( Are you currently constipated or have been constipated in the past 7 days? ); during the interview the patients completed the BFI. Chronic pain patients who stated that they were not constipated were identified and they comprised the reference population for this study. Patients identified with bowel impairment were not eligible for inclusion in the reference population. OIC POPULATION To set the results into the context of OIC, data from a group of chronic pain patients who were receiving the WHO step III analgesic oxycodone PR were analysed. These data were taken from a meta-analysis of the safety and efficacy of oxycodone PR/naloxone PR tablets versus oxycodone PR tablets. 21 This comprised two very similar controlled, randomized, double-blind studies undertaken in 119 and 99 centres, respectively, involving 587 patients with moderate-to-severe chronic pain. 16,22 The BFI values at randomization were used to determine symptoms of constipation; subjects who reported fewer than three complete spontaneous bowel movements per week, without the need to strain, fulfilled the opioid-related constipation criterion required by the protocol of the present study and were included in the OIC population. STATISTICAL ANALYSES Data were analysed descriptively and statistical tests were performed in an exploratory manner. Mean ± SD and median values were determined for each group. Data sets were tested for Gaussian distribution and 43

4 BFI scores were found to be non-normally distributed. Accordingly, the reference range was indicated non-parametrically as the 95% confidence interval. For one-sided reference ranges it is sufficient to eliminate values of only one side and, by convention, 5% were eliminated. The BFI scores were tested for significant differences between the OIC population and the reference population using the two-sample Mann Whitney U-test with SAS statistical software, version 9.2 (SAS Institute Inc., Cary, NC, USA). Results For recruitment of the reference population, 474 chronic pain patients who were receiving WHO step I and II analgesics only were questioned. The majority (366 patients; 77.2%) had not experienced constipation when questioned, or within the previous 7 days, and they were included in the reference population. The remaining 108 patients (22.8%) complained about constipation and were, therefore, excluded. The mean ± SD age of the reference population was 57.3 ± 15.6 years (range years) and they were predominantly female. For the OIC population, 580 patients from the fullanalysis population of the meta-analysis were eligible to be included; full demographics of the meta-analysis have been published elsewhere. 21 All patients in the OIC population reported moderate-tosevere chronic non-malignant pain that required continuous opioid therapy. The reference and the OIC populations were well matched in terms of gender, age and weight (Table 1). The types and category (causes) of pain reported in the reference population are summarized in Table 2; pain reported by patients in the OIC group has previously been described elsewhere. 21 An overview of the types of pain medications used in the reference population is given in Table 3. Only WHO step I and step II analgesics were used because treatment with WHO step III opioids was an exclusion criterion for the reference population. Patients in the OIC population were generally receiving WHO step II or III (opioid) analgesics prior to entering the published studies. 16,22 The distribution of BFI values is shown in Fig. 1. Values for the reference and OIC populations were significantly different (Fig. 2, Table 4; P < 0.001). The individual BFI items were not tested for significance; however, the respective mean scores for the BFI dimensions ( ease of defaecation, TABLE 1: Comparison of demographic characteristics for the reference population (non-constipated patients with chronic pain receiving World Health Organization [WHO] step I and II analgesics) and the opioid-induced constipated (OIC) population (treated with the WHO step III analgesic oxycodone) Characteristic Reference population (n = 366) OIC population (n = 580) Gender a Male 138 (37.7) 207 (35.7) Female 228 (62.3) 373 (64.3) Age (years) b 57.3 ± ± 11.4 Weight (kg) b 75.0 ± ± 19.4 Data presented as n (%) or mean ± SD. No statistically significant between-group differences (P > 0.05): a χ 2 test, b two-sample t-test. 44

5 TABLE 2: Pain type and category (causes) reported in the reference population (non-constipated patients with chronic pain receiving World Health Organization [WHO] step I and II analgesics) Pain type or category Reference population (n = 366) Pain type Nociceptive 307 (83.9) Neuropathic 31 (8.5) Not classified 28 (7.7) Pain category Post-herpetic neuralgia 18 (4.9) Diabetic peripheral neuropathy 0 Neuropathic pain 11 (3.0) Fibromyalgia 3 (0.8) Cancer/malignant pain 1 (0.3) Back pain 207 (56.6) Osteoarthritis 140 (38.3) Rheumatoid arthritis 4 (1.1) Complex regional pain syndrome 2 (0.5) Other pain (not classified) 53 (14.5) Data presented as n (%) of patients. feeling of incomplete bowel evacuation and personal judgement of constipation ) are given in Table 4 for general information. The BFI reference range (95% confidence interval) was (Fig. 3), with excellent sensitivity (92.1%) and specificity (7.9% false-negatives). Discussion The present study defined a reference range of for BFI values in non-constipated patients with chronic pain that covered 95% of the reference population; hence the majority of subjects. 23 Comparison with the OIC population, which comprised chronic pain patients receiving the WHO III analgesic TABLE 3: Overview of medications received by patients in the reference population (nonconstipated patients with chronic pain receiving World Health Organization [WHO] step I and II analgesics) Medication Reference population (n = 366) WHO step I analgesics only 168 (45.9) WHO step II analgesics only 47 (12.8) Adjuvants only 29 (7.6) WHO step I and II analgesics 34 (9.3) WHO step I analgesics and adjuvants 38 (10.4) WHO step II analgesics and adjuvants 31 (8.5) WHO step I and II analgesics and adjuvants 19 (5.2) Data presented as n (%) of patients. Patients received only WHO step I and step II analgesics because treatment with WHO step III opioids was an exclusion criterion for the reference population. 45

6 Relative frequency of BFI values (%) OIC population (n = 580) Reference population (n = 366) BFI FIGURE 1: Comparison of the distribution of Bowel Function Index (BFI) in the reference population (non-constipated patients with chronic pain who were receiving World Health Organization [WHO] step I and II analgesics) and in the opioid-induced constipated (OIC) population (treated with the WHO step III analgesic oxycodone) 28.8 Reference population (n = 366) OIC population (n = 580) BFI Median Key to box and whisker plot: 5% 25% Mean 75% 95% Statistics: 5% 25% Mean Median 75% 95% Reference population OIC population FIGURE 2: Box-and-whisker plots of Bowel Function Index (BFI) for the reference population (non-constipated patients with chronic pain who were receiving World Health Organization [WHO] step I and II analgesics) and for the opioid-induced constipated (OIC) population (treated with the WHO step III analgesic oxycodone) (P < for the reference population versus the OIC population; two-sample Mann Whitney U-test) 46

7 TABLE 4: Comparison of Bowel Function Index (BFI) scores in the reference group (non-constipated patients with chronic pain receiving World Health Organization [WHO] step I and II analgesics) and the opioid-induced constipated (OIC) population (treated with the WHO step III analgesic oxycodone) Reference population (n = 366) OIC population (n = 580) BFI item Ease of defaecation 11.4 ± ± 21.3 Feeling of incomplete evacuation 7.8 ± ± 25.2 Personal judgement of constipation 6.9 ± ± 23.8 Overall BFI score a 8.7 ± ± 21.7 Data presented as mean ± SD. a P < (two-sample Mann Whitney U-test); individual BFI items were not tested for statistical significance. oxycodone (opioid treatment), showed a low false-negative rate and a high test sensitivity. The OIC population was chosen because the BFI was originally developed to investigate OIC, which is a prominent side-effect of opioid therapy. The BFI has been successfully used in studies investigating the beneficial effect of PR naloxone added to the WHO III opioid PR oxycodone in a fixed-combination regimen Thus, the OIC group is an adequate model that reflects the target patient population. For the OIC population % Relative cumulative frequency (%) % BFI FIGURE 3: Relative cumulative frequencies of Bowel Function Index (BFI) values for the reference population (non-constipated patients with chronic pain who were receiving World Health Organization [WHO] step I and II analgesics; light shaded curve) and for the opioid-induced constipated (OIC) population (treated with the WHO step III analgesic oxycodone; dark shaded curve); 95.0% and 7.9% of the nonconstipated and constipated patients, respectively, had a BFI

8 used in the present study, a reduction in the mean overall BFI score of 34.6 (from 63.4 to 28.8) would represent a clear improvement in symptoms, especially as the validation programme of the BFI suggested that changes in BFI scores of 12 points are likely to be related to clinically meaningful changes in patients perceptions of their bowel habits. 15 Thus, in the context of OIC, the defined BFI of 28.8 as being non-constipated represents an adequate reference range. Patients with chronic pain who are treated with opioids often have severe underlying disease. Thus, it is particularly helpful if health-related questionnaires can be completed with little effort. Nevertheless, such questionnaires have to capture the depth of information required. 13 For OIC, many observations have shown that, in addition to objective measures (e.g. stool frequency), subjective measures such as straining or the feeling of incomplete bowel evacuation, must be considered. 10,24,25 The BFI takes these subjective criteria into account. The PAC-SYM, another patient reported outcome tool, was developed to assess idiopathic constipation. 12 Although the PAC- SYM was later validated for use in OIC, by having 12 items, it constitutes a relatively complex questionnaire. The PAC-SYM assesses three domains: stool, abdominal and rectal symptoms. For the latter, responsiveness to changes in bowel function could not be shown for OIC patients and this may be explained by the fact that this rectal symptom domain in the PAC-SYM includes severe symptoms, such as rectal bleeding, 13 in order to identify the most severe cases of constipation, yet they are rarely seen in and are not specific for OIC. The BFI is easy to use: it is shorter than the PAC-SYM, captures relevant information, focuses specifically on patients with OIC and uses a NAS (commonly applied in pain therapy). All validation studies demonstrated a high internal consistency, with Cronbach s α > 0.7 for all individual BFI items and the overall BFI score. 15,26 In a brief three-item inventory such as the BFI, item redundancy is not, however, a concern. Moreover, the validation process has shown that the BFI can detect meaningful changes in constipation and demonstrates the psychometric properties necessary to interpret data effectively. 15,26 In fact, the BFI has been successfully used as the primary or secondary outcome measure in several studies undertaken during the development programme of an oral PR oxycodone/naloxone combination ,20,22 In summary, the BFI reference range for non-constipated patients with chronic pain can be defined as Results of the BFI validation programme and the definition of specific BFI score changes that can be used for establishing thresholds for clinically meaningful changes in OIC in chronic pain patients being treated with WHO step III opioids have been reported elsewhere. 15 The present study showed that the BFI represents a useful validated tool that is easily administered for the clinical evaluation of OIC in patients with chronic pain. Conflicts of interest MA Ueberall and S Müller-Lissner have provided scientific advice to Mundipharma Research GmbH & Co. KG. C Buschmann- Kramm and B Bosse are employed by Mundipharma Research GmbH & Co. KG. Mundipharma Research GmbH & Co. KG developed a fixed PR oxycodone/pr naloxone combination. Studies of the clinical development programme for this opioid agonist/antagonist combination are referred to in this paper. 48

9 Received for publication 24 September 2010 Accepted subject to revision 8 October 2010 Revised accepted 17 December 2010 Copyright 2011 Field House Publishing LLP References 1 World Health Organization (WHO): Cancer Pain Relief. Geneva: WHO, 1996 (available at: pdf). 2 Ballantyne JC: Opioid analgesia: perspectives on right use and utility. Pain Physician 2007; 10: Pappagallo M: Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001; 182(5A suppl): 11S 18S. 4 Panchal SJ, Müller-Schwefe P, Wurzelmann JI: Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 2007; 61: Leslie J, Annunziata K, Freedman D: Opioidinduced constipation compromises pain management and impacts patients quality of life. Anaesthesiology 2006; 105: A1490 (abstract). 6 Kurz A, Sessler DI: Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003; 63: Becker G, Galandi D, Blum HE: Peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review. J Pain Symptom Manage 2007; 34: Reimer K, Hopp M, Zenz M, et al: Meeting the challenges of opioid-induced constipation in chronic pain management a novel approach. Pharmacology 2009; 83: Yuan CS, Israel RJ: Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects. Expert Opin Investig Drugs 2006; 15: Connell AM, Hilton C, Irvine G, et al: Variation of bowel habit in two population samples. Br Med J 1965; 2: Longstreth G, Thompson W, Chey WD, et al: Functional bowel disorders. Gastroenterology 2006; 130: Frank L, Kleinman L, Farup C, et al: Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol 1999; 34: Slappendel R, Simpson K, Dubois D, et al: Validation of the PAC-SYM questionnaire for opioid-induced constipation in patients with chronic low back pain. Eur J Pain 2006; 10: Marquis P, De La Loge C, Dubois D, et al: Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol 2005; 40: Rentz AM, Yu R, Müller-Lissner S, et al: Validation of the Bowel Function Index to detect clinically meaningful changes in opioidinduced constipation. J Med Econ 2009; 12: Löwenstein O, Leyendecker P, Hopp M, et al: Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe nonmalignant chronic pain: a randomised controlled trial. Expert Opin Pharmacother 2009; 10: Meissner W, Leyendecker P, Mueller-Lissner S, et al: A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioidinduced constipation. Eur J Pain 2009; 13: Nadstawek J, Leyendecker P, Hopp M, et al: Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. Int J Clin Pract 2008; 62: Smith K, Hopp M, Mundin G, et al: Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/antagonist prolonged-release combination in healthy adult volunteers. Clin Ther 2008; 30: Vondrackova D, Leyendecker P, Meissner W, et al: Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008; 9: Löwenstein O, Leyendecker P, Lux EA, et al: Efficacy and safety of combined prolongedrelease oxycodone and naloxone in the management of moderate/severe chronic nonmalignant pain: results of a prospectively designed pooled analysis of two randomized, double-blind clinical trials. BMC Clin Pharmacol 2010; 10: Simpson K, Leyendecker P, Hopp M, et al: Fixedratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-tosevere noncancer pain. Curr Med Res Opin 2008; 24: Wright EM, Royston P: Calculating reference intervals for laboratory measurements. Stat Methods Med Res 1999; 8: Bell TJ, Panchal SJ, Miaskowski C, et al: The prevalence, severity, and impact of opioidinduced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 2009; 10: McMillan SC: Assessing and managing opiateinduced constipation in adults with cancer. Cancer Control 2004; 11(3 suppl):

10 26 Rentz AM, van Hanswijck de Jonge P, Leyendecker P, et al: Observational, nonintervention, multicenter study for validation of the bowel function index for constipation in European countries. Curr Med Res Opin 2011; 27: Author s address for correspondence Björn Bosse Mundipharma Research GmbH & Co. KG, Höhenstrasse 10, Limburg, Germany. Bjoern.Bosse@mundipharma-rd.eu 50