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

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 [[2] and one of the main reasons for dose reduction, treatment failure and premature treatment discontinuation [[5]. 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 [[9].

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 [[14],[25].

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 [26], 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 [[25], with a special focus on the gastrointestinal effects in patients without vs. with a pre-existent non-opioid-related constipation.

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 [[28]. 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, [29],[35],[32]. In parallel OIC-related changes in bowel function parameters (such as the percentages of individuals presenting with a BFI deterioration of at least 12 mm VAS, three or even less CSBMs per week or a decrease in CSBMs of one or more – each at week 12 vs. baseline) were significantly less with OXN vs. OXY and/or MOR. These discrepancies were neither related to differences in dosing (as daily morphine equivalents were comparable among treatment groups), nor to a different use of laxatives or related countermeasures between the treatment groups (as the proportion of patients receiving these agents by prescription or over the counter were significantly lower for OXN compared with OXY and MOR), supporting not only the rationale that OXN counteracts OIC via naloxone through mechanisms specifically addressing the underlying processes, but also highlighting the limited efficacy of conventional laxative regimens in OIC.

OIC is obviously not an inevitable consequence of classical WHO-step III opioids, as not all patients treated with the pure µ-receptor agonists OXY or MOR experienced a significant increase in related parameters such as the BFI or reported relevant CSBM changes. Overall, 43.1% (185/429) of NCP patients treated either with MOR or OXY presented with 'normal' BFI scores at study end, 29.8% (128/429) experienced only minor and neither statistically significant nor clinically relevant BFI changes in response to these opioids, and 18.4% (76/429) of patients did so without any prescribed laxatives or other documented countermeasures. Although corresponding percentages for OXN were with 76.2 / 59.3 / 59.3% (163/127/127 of 214; OR: 4.22 / 3.43 / 6.78; p<0.001 for each comparison) significantly greater than those rates found for MOR and OXY, the percentages reported for latter ones underline that the level of our understanding of the pathophysiological mechanisms of OIC in pain patients treated with WHO-step III opioids is still insufficient.

The importance of OIC, respective its prevention by adequate countermeasures for patients suffering from chronic pain with/without an opioid-independent bowel dysfunction is highlighted by the reported differences for MOR, OXY and OXN with respect to pain relief as well as related effects on disability in daily life and overall quality-of-life. As reported, treatment with OXN was – independent of the BFI-status at baseline – not only associated with significantly less bowel dysfunction and a superior tolerability in comparison to OXY and MOR, but also with a biometrical and clinically relevant superior analgesic efficacy, which was associated with significantly superior improvements of pain-related disabilities in daily life as well as quality-of-life. Consequently, the proportion of NCP/COP patients whose overall condition improved with the opioid treatment was significantly superior for OXN vs. OXY/MOR and corresponding odds ratios of 7.2/5.8 for NCP and 6.5/6.4 for COP underline the clinical relevance of the combined opioid agonist/antagonist combination and its importance for chronic pain patients.

Overall and irrespective of the pre-existent BFI-status, treatment with any of the three WHO-step III opioids was safe. None of the study patients died nor showed any serious or unexpected TEAEs or persistent adverse effects after treatment discontinuation. Drug treatments differed significantly with respect to the number of patients affected by TEAEs, the overall number of TEAEs observed and the percentage of patients forced to discontinue opioid treatment in favour of OXN vs. OXY and MOR. Spectrum of TEAEs reported was comparable to those mentioned in the current SPCs. The number of OXN patients with TEAEs was close to those reported in previous studies, however, discontinuation rates were somewhat higher, which may reflect minor differences with respect to study design and/or conduct of study.

Study limitations

This study has certain limitations. PROBE-designed studies such as those underlying the present post-hoc analysis suffer several limitations in comparison to randomized controlled trials50. Most of these limitations are inherent to the open-label design, which comes along with a significant risk of bias. That is, patients or investigators may add concomitant treatments to address lack of efficacy, to improve tolerability or to manage symptoms or risk based on their knowledge and beliefs of treatment allocation. However, although opioid medications were open label, determination of endpoints in the original study was blinded. The results of the differential evaluation of patients who presented at baseline with vs without a clinical relevant bowel dysfunction allows further insight on differential opioid-effects with respect to OIC and related health problems and expands our current knowledge how to use these agents in chronic pain patients.

OIC is the most frequently reported adverse event experienced by patients receiving long-term opioid therapy, and interferes significantly with opioid treatment effects such as pain relief, improvement in functionality and/or quality-of-life. This post-hoc analysis of data from a prospective randomized open-label blinded endpoint study provides valuable GI safety, tolerability and efficacy data for MOR, OXY and OXN, three WHO-step III opioids frequently used to treat patients with elsewhere refractory LBP in patients with vs. without a pre-existent bowel dysfunction. Patient-reported data revealed significant differences between these opioid analgesics with respect to the development of OIC and the occurrence of opioid-related adverse events, with superior effects of OXN both vs. OXY and MOR – irrespective of the BFI status at baseline. Overall, this data provides evidence that the fixed agonist/antagonist combination of OXN is a safe, superior tolerated and effective alternative to conventional opioid agonists such as OXY and MOR and worth to be used first line for pain patients with and/or without opioid-independent bowel problems.

Declaration of financial/other relationships

The concept for the original PROBE study as well as this post-hoc analysis was developed by the Institute for Neurological Sciences (IFNAP) on behalf of the German Pain Association (Deutsche Gesellschaft für Schmerzmedizin, DGS) and the German Pain League (Deutsche Schmerzliga, DSL). The original study was realized by an independent CRO and partly (<49%) sponsored by an unrestricted scientific grant from Mundipharma, Germany. Neither the study sponsor, nor any of its employees exerted any influence on the conduct of the study, or on analyses, interpretation and publication of the results. The current post-hoc analysis was done independently from any financial and/or intellectual influences by the authors. M.A.U and G.H.H.M-S. Are physicians and independent of any significant/relevant financial or other relationship to the sponsor, except for minor reimbursements for occasional lecture or consulting fees.

Data of the PROBE study have been presented at the World Pain Congress of the International Association for the Study of Pain (IASP), October 6-11, 2014, Buenos Aires, Argentina. Data of this post-hoc analysis will be presented at the 9th Congress of the European Pain Federation (EFIC), September 2-5, 2015, Vienna, Austria.

Authors' contribution

All authors were equally involved in developing the conceptual framework, in the organization of the paper, in the analysis and interpretation of data presented, and in the critical revision and review of the paper. All authors have seen and approved the final paper.