Michael A Ueberall1* and Gerhard HH Mueller-Schwefe2
1Institute for Neurological Sciences, Nordost Park 51, 90411 Nuernberg, Germany
2Interdisciplinary Center for Pain and Palliative Care Medicine, Schillerplatz 8/1, 73033 Goeppingen, Germany
Received: 16 July, 2015; Accepted: September, 2015; Published: 10 September, 2015
Michael A Ueberall, MD, Institute for Neurological Sciences, Nordostpark 51, 90411 Nuernberg, Germany, Tel: +49 (0)911-21773760; Fax: +49 (0)911-21773761; E-mail:
Ueberall MA, Mueller-Schwefe GHH (2015) Differential Gastrointestinal Effects of Who-Step III Opioids in Low Back Pain Patients with vs. Without Constipation: Post-Hoc Analysis of Data from a 12-Week Prospective, Open-Label Blinded Endpoint Streamlined Study. Glob J Anesthesiol 2(2): 037-051. DOI: 10.17352/2455-3476.000015
© 2015 Ueberall MA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Chronic pain; Constipation; Bowel function; Quality-of-life; Oxycodone; Naloxone
Objective: Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality-of-life, and patient compliance. To compare effects of prolonged release (PR) oxycodone and PR naloxone (OXN), vs. PR oxycodone (OXY) vs. PR morphine (MOR) on bowel function under real-life conditions in chronic low back pain (LBP) patients with vs. those without pre-existent constipation.
Research design and methods: Post-hoc analysis of data from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study, carried out in 88 centres in Germany, where a total of 901 patients, requiring WHO-step III opioids to treat low back pain, were enrolled, and prospectively observed for 3 months. Bowel function was graded with respect to the bowel function index and characterized as normal (NCP; n=643) or constipated (COP; n=258). Treatment doses could be adjusted as per the German prescribing information and physicians were free to address all side-effects and tolerability issues as usual.
Main outcome measures: Primary endpoint was the proportion of patients experiencing a decrease of ≥1 complete spontaneous bowel movements (CSBMs) per week at end of observation vs. baseline. Secondary analyses addressed absolute/relative BFI changes, proportion of patients with ≤3 CSBMs per week, use of laxatives, treatment emergent adverse events (TEAEs), analgesic effects, and differences between initially non-constipated vs. constipated patient groups.
Results: CSBMs decreased with all three WHO-step III treatments, however, significantly less with OXN vs. OXY and MOR despite a significantly higher use of laxatives with the latter ones (p<0.001). Overall, percentage of patients who met the primary endpoint was 10.3% (31/301) with OXN and significantly inferior to those seen with OXY (42.3%, 127/300; OR: 6.39, 95%-CI: 14.13-9.89; p<0.001) or MOR (42.0%, 126/300; OR: 6.31, 95%-CI: 4.08-9.77; p<0.001). CSBM changes varied with baseline BFI scores and were higher for COP vs. NCP. Primary endpoint for NCP/COP was met with MOR in 40.1/47.0%, with OXY in 39.6/48.9%, and with OXN in 6.5/19.5%. An absolute (relative) BFI deterioration of ≥12 mm VAS (≥50%) vs. baseline was seen for NCP with OXN/OXY/MOR in 40.7/67.5/72.8% (25.7/36.3/43.8%; p<0.001 for OXN vs. OXY and MOR), and for COP in 43.7/71.6/71.1% (21.8/53.4/54.2%; p<0.001 for OXN vs OXY and MOR). Pain intensity, pain-related functionality in daily life as well as quality-of-life improved significantly with all three opioids, however significantly superior with OXN vs. OXY vs. MOR independent of the constipation status at baseline. Overall 359 TEAEs (OXN: 78, OXY: 134, MOR: 147) in 204 patients (OXN: 41, OXY: 80, MOR: 83) occurred, most affecting the gastrointestinal (49.3%) and the nervous system (39.3%). With exception of constipation, related treatment TEAE contrasts between NCP vs. COP were insignificant.
Conclusion: In this post-hoc analysis of data from a real-life 12-week study, OXN treatment was associated with a significantly lower risk of OIC, superior tolerability and significantly better analgesic efficacy compared with OXY and MOR both in patients with and without a pre-existent constipation.
With a median frequency of 30% among non-cancer patients (range 12%–52%), opioid-induced constipation (OIC) is among the spectrum of opioid-related side effects the most frequently reported adverse event associated with chronic opioid therapy [11. Kalso E, Edwards JE, Moore RA, McQuay HJ (2004) Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain 112: 372-380.,22. Papaleontiou M, Henderson CR, Turner BJ, Moore AA, Olkhovskaya Y, et al. (2010) Outcomes associated with opioid use in the treatment of chronic noncancer pain in older adults: a systematic review and meta-analysis. J Am Geriatr Soc 58: 1353-1369.] and one of the main reasons for dose reduction, treatment failure and premature treatment discontinuation [33. McMillan SC (2004) Assessing and managing opiate-induced constipation in adults with cancer. Cancer Control 11: 3-9.].
Interaction of opioids with μ-opioid receptors of enteric neurons located in the myenteric and submucous plexus of the gut wall increase the absorption of fluids and electrolytes, impair the release of digestive enzymes and reduce the intestinal transit by stimulating nonpropulsive duodenojejunal phasic pressure contractions, and stimulating the pyloric and ileocolonic sphincters [44. Holzer P (2009) Opioid receptors in the gastrointestinal tract. Regul Pept 155: 11-17.,55. Dorn S, Lembo A, Cremonini F (2014) Opioid-Induced Bowel Dysfunction: Epidemiology, Pathophysiology, Diagnosis, and Initial Therapeutic Approach. Am J Gastroenterol Suppl 2: 31-37.]. In total, these effects are associated with serious negative effects on patients' individual health-related quality of life (QoL) and on society in terms of health care resource use and work productivity loss [66. Bell T, Annunziata K, Leslie JB (2009) Opioid-induced constipation negatively impacts pain management, productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J Opioid Manage 5: 137-144.]. Patients with opioid-related bowel dysfunction have more hospital admissions, emergency room visits, home health services, nursing home care, physician visits, and laboratory tests, as well as higher mean all-cause costs for emergency, physician visits, nursing facilities, home health care, and prescription drug services compared to patients without OIC [77. Iyer S, Davis KL, Candrilli S (2010) Opioid use patterns and health care resource utilization in patients prescribed opioid therapy with and without constipation. Managed Care 19: 44-51.-99. Pappagallo M (2001) Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 182: 11S-18S.].
Laxative regimens are recommended for clinical use, both to prevent and treat OIC. However, they are non-specific, associated with several drawbacks (e.g. muscular bowel function damage, nutritional deficits, kidney stones, renal failure and/or interference with other drugs, etc.), and insufficiently effective in the majority of patients, as they do not specifically address the underlying opioid-receptor-mediated mechanisms of OIC [1010. Odegard PS, Burke C (1996) Managements of opioid induced constipation in elderly patients. Consultant Pharmacist 11: 17-22.,1111. Panchal SJ, Mueller-Schwefe P, Wurzelmann JI (2007) Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 61: 1181-1187.].
More recently, few specific alternatives to prevent/treat OIC have been developed, which antagonize opioid-receptor activities in the gut wall without compromising pain control or drug safety of the opioid analgesics [12#12. Kurz A, Sessler DI (2003) Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 63: 649-671.,13#13. Becker G, Galandi D, Blum HE (2007) peripherally acting opioid antagonists in the treatment of opiate-related constipation: a systematic review. J Pain Symptom Manage 34: 547-565.]. Of these options, only naloxone – an opioid receptor antagonist – became available as a fixed prolonged-release (PR) preparation with PR oxycodone (OXY) in a 1:2 ratio within one tablet (OXN), addressing by such compliance and adherence problems of chronic pain patients with increasing tablet prescriptions. When administered orally, naloxone antagonizes the opioid-receptor activity of its counterpart oxycodone in the gut wall, while its prolonged-release in combination with an extensive hepatic first-pass metabolism and the subsequent low systemic bioavailability (~2%) ensures the lack of antagonistic effects on its central analgesic action [1414. Leppert W (2010) The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review. Adv Ther 27: 714-730.,1515. Mercadante S, Giarratano A (2013) Combined oral prolonged-release oxycodone and naloxone in chronic pain management. Expert Opin Investig Drugs 22: 161-166.]. In randomized controlled trials with patients suffering from OIC due to the use of strong-acting WHO-step III opioids, naloxone was able to reduce constipation as well as related comorbidities and few open-label trials present evidence that it is also able to prevent OIC if given first line [1616. Meissner W, Leyendecker P, Mueller-Lissner S, Nadstawek J, Hopp M, et al. (2009) A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 13: 56-64.-2525. Ueberall MA, Mueller-Schwefe GH (2015) Development of opioid-induced constipation: post hoc analysis of data from a 12-week prospective, open-label, blinded-endpoint streamlined study in low-back pain patients treated with prolonged-release WHO step III opioids. J Pain Res 8: 459-475.].
However, with prevalence rates ranging from 2-28% of the whole population in the US and Europe constipation is a common gastrointestinal motility disorder among elsewhere healthy people [2626. Lembo A, Camilleri M (2003) Chronic constipation. N Engl J Med 349: 1360-1368. ], and a common, nevertheless rather complex and multifactorial side effect of chronic pain even in the absence of opioids. Reasons for that are pain-related mobility restrictions and a number of non-opioids, adjuvant agents (e.g. anticonvulsants, antidepressants) as well as concomitant drugs used for the pharmacological treatment of pain and pain-related health disturbances in these patients. In clinical practice pain patients with constipation usually suffer from multiple precipitants ranging from secondary causes (including medications, neuropathic or myopathic disorders, and endocrinopathies) to primary aetiologies such as irritable bowel syndrome, slow-transit, or evacuation disorders.
This heterogeneity in the pathogenesis of constipation in pain patients raises a number of questions with respect to OIC and chronic pain. From a clinical perspective, three questions are important. First: how develops OIC in chronic pain patients already suffering from a non-opioid-related constipation. Second: are there any differences with respect to OIC in these patients in comparison to initially non-constipated pain patients. And third: how effective are specific and/or unspecific countermeasures if given to chronic pain patients without vs. with a pre-existent non-opioid-related bowel dysfunction.
To gain further insight into this problem, the German Pain Association and the German Pain League commissioned a post-hoc analysis of data from a prospective randomized open-label blinded endpoint streamlined real-life study on the safety, tolerability and efficacy of morphine (MOR), oxycodone (OXY) and oxycodone/naloxone (OXN) in patients with chronic moderate-to-severe low-back-pain refractory to other analgesics [2424. Ueberall MA, Mueller-Schwefe GH (2015) Safety and efficacy of oxycodone/naloxone vs. oxycodone vs. morphine for the treatment of chronic low back pain: results of a 12-week prospective, randomized, open-label blinded endpoint streamlined study with prolonged-release preparations. Curr Med Res Opin 31: 1413-1429.,2525. Ueberall MA, Mueller-Schwefe GH (2015) Development of opioid-induced constipation: post hoc analysis of data from a 12-week prospective, open-label, blinded-endpoint streamlined study in low-back pain patients treated with prolonged-release WHO step III opioids. J Pain Res 8: 459-475.], with a special focus on the gastrointestinal effects in patients without vs. with a pre-existent non-opioid-related constipation.
Patients and Methods
Overall study design
The underlying 12-week study followed a prospective, randomized, open-label, blinded endpoint (PROBE) design, developed to address some of the potential limitations of randomized controlled trials (RCTs) and observational studies. Main advantage of such a PROBE trial design is the assessment of clinical outcomes in studies that allow both, the enrolment of a broad patient population (in our case patients who require WHO-step III opioid analgesics owing to elsewhere refractory moderate-to-severe chronic low back pain) as well as open-label non-interventional dose adjustments and the discretionary use of concomitant laxatives etc. on an as needed basis, which better reflect clinical practice but with the advantage of randomization and a rigorous evaluation of study endpoints by blinded data analyses [2727. Higgins PD, Johanson JF (2004) Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 99: 750-759.,2828. Hansson L, Hedner T, Dahlöf B (1992) Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Blood Press 1: 113-119.]. Opioid treatment followed medical requirements according to the decision of the participating physicians.
The study was performed by using electronic case report forms for all data obtained by the participating physicians as well as conventional paper-pencil pain questionnaires/diaries to obtain patient-reported data throughout the whole 12-week observation period. Patient questionnaires/diaries used were those recommended by the German Pain Association and the German Pain League, which cover a broad spectrum of validated instruments addressing amongst other parameters pain intensity, pain-related disabilities in daily life, quality-of-life, quality-of-life impairments by pain, bowel function, use of analgesics and adjuvant therapies, etc, [2929. Cryer B, Li C, Simon LS, Singh G, Stillman MJ, et al. (2013) GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial. Am J Gastroenterol 108: 392-400.,3030. Deutsche Schmerzgesellschaft. Deutscher Schmerzfragebogen [German pain questionnaire]. Available from: http://www.dgss.org/deutscher-schmerzfragebogen. Accessed April 10, 2015.].
Regular study visits were scheduled at baseline (prior start of treatment), as well as after 4 (interim visit) and 12 weeks (end of observation visit). Optional, additional interim visits were possible at all times according to individual patient needs and established procedures (e.g. if patients had to be closely monitored due to commencement of treatment, inadequate pain control, tolerability issues and/or adverse events).
Patients / Study eligibility criteria
Patients eligible for the study were males and non-pregnant, non-lactating females who were at least 18 years with a documented history of moderate to severe non-malignant chronic low back pain, previously treated with WHO-step I or II analgesics with or without adjuvant treatments who experienced either insufficient pain relief and/or unacceptable side effects and who required an around-the clock therapy with any of the three mentioned WHO-step III opioids. Exclusion criteria were those contraindications listed in the German prescribing information of the three opioid analgesics that address situations that would place the patient at risk upon exposure to the medication as well as conditions that would confound the analysis and/or interpretation of the study results. Therefore, patients were excluded if they had previously shown hypersensitivity to any of the product constituents, or if they had severe respiratory depression, chronic obstructive airway disease, pulmonary hypertension, severe bronchial asthma, and paralytic ileus, moderate to severe hepatic impairment and/or renal impairment, or any other condition in which an opioid therapy is contraindicated. In addition, patients with irritable bowel syndrome, gastrointestinal disease, significant structural abnormalities of the gastrointestinal tract, patients with known or suspected alcohol or drug dependence, patients who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days prior study entry, or in whom a surgery was planned during the scheduled observational period that would influence pain or bowel function were excluded as well.
Based on the recommendations of the German National Association of Statutory Health Insurance Physicians and the Drug Commission of the German Medical Association, MOR, OXY and OXN were seen as comparably effective and therefore – at least from a medical point of view – interchangeable for the 1st line treatment of opioid naïve patients suffering from elsewhere refractory low back pain [3131. Deutsche Schmerzgesellschaft. Handbuch zum Deutschen Schmerzfragebogen [Manual for the German pain questionnaire]. Available from: http://www.dgss.org/fileadmin/pdf/12_DSF_Manual_2012.2.pdf. Accessed April 10, 2015.]. Therefore, an electronic treatment allocation system recommended one of these three alternative opioid treatments on a randomized 1:1:1 ratio (block size 9), after completion of the baseline evaluation by the physician and confirmation of a general treatment indication for a WHO-step III opioid. To account for the basically non-interventional character of the original study, physicians were generally allowed to follow this recommendation or to choose alternatively one of the two other opioid treatments, which vice versa implicate the exclusion of this patient from the per-protocol analysis of randomized treatment allocations. Initial starting dose, dose titration and further dose adjustments followed the recommendations given in the marketing authorization in existence at the time of the study and documented in the German prescribing information for those WHO-step III opioids considered to be evaluated in this study. For opioid-naïve patients, the recommended starting dose was 20 mg morphine equivalent (MEQ) of a prolonged release preparation twice daily. Any dose adjustments, prescriptions of analgesic co-medication, rescue medication, or laxatives were done at the discretion of the physician and due to the individual needs of the participating patients.
Bowel function / opioid induced constipation: OIC was assessed using the validated bowel function index (BFI) [3232. Kassenärztliche Bundesvereinigung, Arzneimittelkommission der Deutschen Ärzteschaft. Oxycodon/Naloxon. Wirkstoff Aktuell 2012; 6.,3333. Rentz AM, Yu R, Mueller-Lissner S, Leyendecker P (2009) Validation of the bowel function index to detect clinically meaningful changes in opioid-induced constipation. J Med Econ 12: 371-383.], which calculates as the mean of three items recorded retrospectively by patients for the last seven days on the basis of an 100 mm horizontal visual analogue scale (VAS100) at the end of each treatment week. Single BFI items were: ease of defecation (0 = 'easy/no difficulty' and 100 = 'severe difficulty'), feeling of incomplete bowel evacuation (0 = 'not at all' and 100 = 'very strong'), and personal judgment of constipation (0 = 'not at all' and 100 = 'very strong'). BFI reference (i.e. 'normal') range is 0-28.8 mm VAS and BFI changes ≥12 mm VAS were confirmed to be significant. In addition, the number of complete spontaneous bowel movements (CSBMs; defined as stools not induced by rescue medication or other external measures and associated with a sensation of complete evacuation) in the last seven days and the use of laxatives as well as other pharmacological and non-pharmacological OIC counter measures were documented to assess constipation.
Efficacy assessments were performed on the basis of patient-reported information documented in the German Pain Questionnaire (at baseline) and the German Pain Diary (throughout the whole observation period) for pain intensity, pain-related disabilities in daily life activities/functionality and quality-of-life. Pain intensity measures based on the low back pain intensity index (LBPIX), which was calculated as arithmetic mean of the lowest, average and highest 24 hour LBP intensities on an 100mm visual analogue scale (VAS100; 0 = 'no pain' and 100 = 'worst pain conceivable"). LBP-related disabilities were assessed with a modified version of the pain disability index (mPDI), which recorded the degree of LBP-related functional restrictions on the basis of an 11-point numerical rating scale (NRS11; 0 = 'none' and 10 = 'worst conceivable") with respect to seven distinct domains of daily life. Quality-of-life was measured using the quality-of-life impairment by pain (QLIP) inventory, a seven question tool assessing different pain-related QoL restrictions resulting in an overall QoL-score (ranging from 40 = 'no impairment' to 0 = 'maximum impairment'). All parameters were recorded by patients retrospectively for the last seven days, starting at baseline (to assess the situation prior onset of the WHO-step III opioids) and covering the whole observation period with regular assessments at the end of each treatment week.
Safety and tolerability measures
Safety assessments consisted of monitoring all treatment-emergent adverse events (TEAEs), collected via spontaneous reports and patient visits. TEAEs were collected both through direct questioning by the physicians, as well as spontaneous patient reports and were recorded at each visit.
Aim of this post-hoc analysis was to evaluate the dynamics of bowel dysfunction as consequence of a treatment with three different WHO-step III opioids in patients without vs. with an already established non-opioid-related constipation under real-life conditions. Patients were categorized on the basis of their baseline BFI score as "non-constipated" (NCP; BFI ≤28.8 mm VAS) or as "constipated" (COP; BFI >28.8 mm VAS) and treatment effects were compared between both groups with respect to the end-of-study outcomes after 12 weeks. Primary criterion for this analysis was the treatment contrast for the frequency of patients with a ≥1 decline in the number of CSBMs per week (Table 1). Secondary bowel tolerability aspects were the percentages of patients (a) experiencing a clinically relevant BFI worsening (i.e. an increase ≥12 mm VAS) or (b) with a ≥50% BFI worsening vs. baseline, (c) with ≤3 CSBMs per week, and (d) with prescribed laxatives, each at the end of the 12-week observation period. Secondary efficacy analyses were performed with respect to (a) opioid-related changes in pain intensity, disability and quality-of-life. Safety analyses addressed the percentages of patients with (a) TEAEs, (b) TEAE-related study discontinuations, as well as (c) spectrum and (d) characteristics of TEAEs reported.
Data analyses were performed for all enrolled patients who took at least one dose of OXN, OXY or MOR and who had at least one post-baseline/post-dose measure. Due to the explorative post-hoc character of this analysis no formal sample size estimation has been performed. Linear interpolation was used to impute intermittent missing scores and the last observation carried forward (LOCF) method to impute missing scores after early discontinuation. For continuous variables, descriptive statistics were summarized by the number of patients (n), the mean, standard deviation (SD), 95% confidence intervals (95%-CI) of the mean, median, and range (minimum –maximum) values. For categorical and ordinal variables data were summarized by frequency number (n) and percentage (%) of participants in each category; where appropriate, 95% confidence intervals were added. For between groups comparisons of continuous/categorical variables, Student t / Pearson's chi-squared test were used. For within group (e.g. pre-post) comparisons paired samples t-tests were performed. All statistical tests were carried out using a 2-sided significance level of 0.05. Test procedures were only used to evaluate the biometrical significance of differences found, not to confirm any a-priori defined hypotheses.
The original study has been conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practices, conformed to relevant national and local ethical as well as regulatory requirements and registered in the German pain study registry (DGS: 2012-0012-05a). All patients provided written informed consent prior to study enrollment. The concept for this post-hoc analysis has been approved by the steering committees of the German Pain Association and the German Pain League and is registered in the ENCEPP database of the European Medicines Agency for non-interventional studies (ENCEPP/SDPP/11048).
Between April and August 2013, a total of 901 patients were enrolled, received treatment as assigned and reported at least one post-baseline measure (see patient disposition in Figure 1). With 71.4% (n=643), seven of ten study patients presented with normal BFI scores and were classified as "non-constipated" (NCP), whereas 28.6% (n=258) presented with BFI scores above the normal reference range of 28.8 mm VAS and were therefore classified as "constipated" (COP). Overall, a higher percentage of NCP (67.3%; 433/643) vs. COP (57.4%; 148/258) patients completed the study (OR: 1.53, 95%-CI: 1.14-2.06; p=0.005), however, in both groups, discontinuation rates were significantly less for OXN (22.4/32.2%) in comparison to MOR (41.0/48.2%; OR: 2.41/1.96; p<0.001/0.033) and OXY (34.4/47.7%; OR: 1.82/1.92; p=0.006/0.036). Main reason for premature discontinuation was insufficient tolerability reported by 251 patients (27.9%), followed by TEAEs (171/901, 19.0%) and insufficient analgesic efficacy (69/901, 7.7%). Between group analyses showed comparable TEAE-related discontinuation rates with MOR and OXY for NCP (25.8/25.0%) and COP (22.9/23.9%), which were – for all reasons evaluated – significantly worse than those observed with OXN in both BFI groups (7.0/8.0%; p<0.01 for each comparison).