Abstract
Background and aims
Opioid-induced bowel dysfunction (OIBD) is an increasing problem due to the common use of opioids for pain worldwide. It manifests with different symptoms, such as dry mouth, gastro-oesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation and incomplete evacuation. Opioid-induced constipation (OIC) is one of its many symptoms and probably the most prevalent. The current review describes the pathophysiology, clinical implications and treatment of OIBD.
Methods
The Nordic Working Group was formed to provide input for Scandinavian specialists in multiple, relevant areas. Seven main topics with associated statements were defined. The working plan provided a structured format for systematic reviews and included instructions on how to evaluate the level of evidence according to the GRADE guidelines. The quality of evidence supporting the different statements was rated as high, moderate or low. At a second meeting, the group discussed and voted on each section with recommendations (weak and strong) for the statements.
Results
The literature review supported the fact that opioid receptors are expressed throughout the gastrointestinal tract. When blocked by exogenous opioids, there are changes in motility, secretion and absorption of fluids, and sphincter function that are reflected in clinical symptoms. The group supported a recent consensus statement for OIC, which takes into account the change in bowel habits for at least one week rather than focusing on the frequency of bowel movements. Many patients with pain receive opioid therapy and concomitant constipation is associated with increased morbidity and utilization of healthcare resources. Opioid treatment for acute postoperative pain will prolong the postoperative ileus and should also be considered in this context. There are no available tools to assess OIBD, but many rating scales have been developed to assess constipation, and a few specifically address OIC. A clinical treatment strategy for OIBD/OIC was proposed and presented in a flowchart. First-line treatment of OIC is conventional laxatives, lifestyle changes, tapering the opioid dosage and alternative analgesics. Whilst opioid rotation may also improve symptoms, these remain unalleviated in a substantial proportion of patients. Should conventional treatment fail, mechanism-based treatment with opioid antagonists should be considered, and they show advantages over laxatives. It should not be overlooked that many reasons for constipation other than OIBD exist, which should be taken into consideration in the individual patient.
Conclusion and implications
It is the belief of this Nordic Working Group that increased awareness of adverse effects and OIBD, particularly OIC, will lead to better pain treatment in patients on opioid therapy. Subsequently, optimised therapy will improve quality of life and, from a socio-economic perspective, may also reduce costs associated with hospitalisation, sick leave and early retirement in these patients.
1 Introduction and methods
This review summarizes the consensus recommendations of the multidisciplinary Nordic Working Group on the clinical care of patients with opioid-induced bowel dysfunction (OIBD) and particularly opioid-induced constipation (OIC). Opioid-induced bowel dysfunction is a pharmacologically induced condition, which manifests with different symptoms, such as dry mouth, gastrooesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation and incomplete evacuation [1,2]. Opioid-induced constipation is one of the many symptoms of OIBD and probably the most prevalent and bothersome symptom. Since opioids affect the enteric nervous system throughout the gut, OIBD is the most appropriate term, although for practical and traditional reasons most studies have focused on OIC.
The aim of the current work was to evaluate the available literature on the definition, diagnosis and management of OIBD/OIC using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method (http://www.gradeworkinggroup.org/publications/JCE_series.htm) to aid Nordic healthcare personnel to expand their understanding of OIBD/OIC. The group was formed to provide multidisciplinary expert input for the report and included Scandinavian specialists in different relevant areas. Six members of the Nordic Working Group (AMD, PM, MS, HB, UK, JGH) formed the Steering Committee and, after an opening meeting, wrote the initial manuscript over a six-month period and proposed seven main topics with associated statements. The working plan provided a structured format for systematic reviews, and included instructions on how to evaluate the level of evidence and clinical implications according to the GRADE guidelines, as adapted for “UpToDate” (http://www.uptodate.com/home/grading-tutorial). Evidence, where available, was ranked according to the GRADE method; in the absence or limited availability of literature, the Nordic Working Group decided if a recommendation would be included in the consensus report. The quality of evidence supporting the different statements was graded as (i) “high” if there was very low probability of further research completely changing the presented conclusions, (ii) “moderate” if further research may completely change the conclusions, (iii) “low” if further research is likely to change the presented conclusions completely. The term “very low” (iv) could be used if new research will most probably change the presented conclusions completely; however, the term was not used in the present work.
During a second meeting, after receiving instructions on how to grade both the level of evidence and strength of the recommendations, five members of the Steering Committee (MS excused) discussed and voted on each section; recommendations could be “weak”, “strong” or “not applicable”. The final manuscript was then reviewed critically and commented upon by specialists in pharmacology (LLC), nursing (MF) and general practice (LA) to ensure a multidisciplinary approach and general relevance and applicability of the conclusions.
Based on these evaluations, the Nordic Working Group created a clinical treatment strategy for OIBD/OIC in the advent of new medications specifically designed to treat the debilitating adverse effects of opioid treatment.
2 Mechanisms of opioid-induced bowel dysfunction
Delta- (δ-), kappa- (κ-) and mu- (μ-) opioid receptors have been identified in the gastrointestinal tract [3]. Whilst they are predominantly present in the enteric nervous system, their relative distribution varies with region and histological layers of the gut and, most importantly, between species [4,5]. In humans, μ- receptors are considered to be of greatest importance and have been identified in neuronal cells of submucosal and myenteric neurones and on mononuclear cells in lamina propria [5]. Whilst endogenous ligands influence normal regulation of gastrointestinal function, opioid receptors are also activated by exogenous opioids [5, 6, 7]. All opioid receptors belong to the G-protein-coupled receptor family. Opioid-induced intracellular signalling is complex and involves direct activation of K+-channels (membrane hyperpolarization) and inhibition of Ca2+-channels (decreased neurotransmitter release); it may also involve Na+-channels [8]. The main effect, however, is probably decreased formation of cyclic adenosine monophosphate [9], which subsequently activates several target molecules and leads to decreased neuronal excitability with an overall inhibitory effect on the cells.
Opioid receptor activation in the gut has three main effects: (i) a change in gut motility, (ii) decreased gut secretion, and (iii) increased sphincter tone. Gut motility is controlled from the myenteric plexus via neurotransmitters released onto the smooth muscle cells [1,10]. Since opioid administration inhibits release of these neurotransmitters, it directly causes abnormal coordination of gut motility as reflected by increased tone and decreased propulsive activity. Results from in vivo human studies have confirmed that opioid administration causes oesophageal and gallbladder dysmotility, increased stomach tone [10,11,12,13], and delays in gastric emptying, oral-coecal transit and colonic transit [14,15,16].
Intestinal fluid secretion is essential for an ideal intestinal environment. In the gut, the submucosal plexus (influenced by opioid receptors) controls local secretory and absorptive activity of the epithelial cells [17,18]. Opioids inactivate chloride channels and decrease chloride transport from the enterocyte into the gut lumen and less water follows due to lower osmotic gradient [7,19]. This results in decreased gut secretion and absorption of water together with less gastric and pancreatico-biliary secretion [4,20,21]. Slowing of gut motility also allows more time for water absorption. The resultant decrease in faecal volume negatively affects motility since intrinsic reflexes that cause propulsive contractions depend on mechanoreceptor activation [4].
The knowledge on the opioid effect on human sphincters is limited, since only few studies have been carried out. Moreover, the influence on, for example, the lower oesophageal sphincter is still controversial. Nonetheless, results from most studies have shown opioid treatment to cause increased resting pressure but abnormal coordination that leads to symptoms, such as reflux and sphincter of Oddi spasms [22,23,24]. Opioid-induced dysfunction of anorectal function is especially relevant because contraction leads to excessive straining and incomplete evacuation. The importance of anal sphincter dysfunction has only been evaluated sparsely [16], but results from preclinical studies indicate that opioids inhibit the detection of stools and internal anal sphincter relaxation [25,26].
2.1 Statements according to GRADE
Opioid receptors are expressed throughout the gastrointestinal tract and are involved in an array of cellular functions (high quality, strong recommendation)
Opioids cause motility changes that instigate slowing of normal motility, segmentation, increased tone and dis-coordinated motility (moderate quality, strong recommendation)
Opioids decrease gut fluid secretion, causing dry faeces and less propulsive motility (low quality, strong recommendation)
Opioids increase sphincter tone, which may lead to symptoms, such as sphincter of Oddi spasms and defecation difficulties (moderate quality, strong recommendation).
3 Definition and diagnosis of opioid-induced constipation
No generally accepted definition of OIC exists; methods used to define OIC differ across disciplines and studies [27]. Nevertheless, the majority of definitions consider the history of current or recent opioid treatment combined with some of the symptoms used to define functional constipation according to the Rome III criteria [28], particularly infrequent, hard or lumpy stools, straining and incomplete evacuation [29]. Yet such definitions may overlook many patients suffering from constipation; their definitions of constipation after initiating opioid treatment are often subjective and based on bowel habits before treatment initiation [30]. Moreover, other conditions that cause or exacerbate constipation, such as metabolic and neurological conditions, mechanical colonic obstruction, non-opioid drugs and any underlying rectal evacuation disorder (more common than previously thought), should be excluded with reasonable certainty before diagnosing OIC [31].
A recently published consensus statement and proposed OIC definition by a multidisciplinary working group has taken into account the change in bowel habits from baseline recorded for at least one week as opposed to a specific number of bowel movements per week [32]. The group proposed that OIC is defined as a change from baseline bowel habits upon opioid treatment initiation characterized by any of the following symptoms:
Reduced bowel movement frequency
Development or worsening of straining to pass bowel movements
A sense of incomplete rectal evacuation
Harder stool consistency.
The need for future psychometric validation of this definition and the possibility of restricting it by requiring that two or more of the aforementioned symptoms are present before OIC is diagnosed were acknowledged. This definition was supported by a systematic review in 2015 by Gaertner et al. [33] who analysed 47 publications relating to the definition of OIC. They concluded that a definition of OIC should include (a) objective measures such as stool frequency, (b) patient reported outcome measures, and (c) a change in these parameters since initiation of opioid therapy. The Rome Committee is also working on a definition of OIC for the forthcoming Rome IV criteria for functional gastrointestinal disorders.
Notably, some patients suffer from abdominal pain that worsen despite escalating doses of opioids [34]. This condition is labelled “narcotic bowel syndrome” and has many similarities with the opioid-induced hyperalgesia described in somatic tissues; it is characterized by allodynia and/or hyperalgesia that, paradoxically, is caused by opioid use and fails to improve despite increased dosing. The mechanism is centrally mediated and should be distinguished from OIBD where the pathophysiology is peripheral. For a review, please see Kurlander and Drossman [35].
3.1 Statement according to GRADE
Opioid-induced constipation can be defined as a change from baseline bowel habits upon opioid treatment initiation, characterized by any of the following symptoms: reduced bowel movement frequency; development or worsening of straining to pass stool; a sense of incomplete rectal evacuation; and/or harder stool consistency (low quality, strong recommendation).
4 Epidemiology and cost of opioid-induced constipation
Opioid-induced constipation is an underdiagnosed, yet common and debilitating adverse effect of opioid treatment. Many patients with acute and chronic, moderate-to-severe pain receive opioid treatment [32]. In the US, more than 240 million opioid prescriptions are dispensed per year, the majority for non-cancer pain, such as back pain and other musculoskeletal causes [36]. In placebo trials, constipation occurs in 11% of patients, whereas the chronic constipation frequency ranges from 33 to 94% in non-cancer and cancer opioid-treated patients [37,38,39,40,41,42] (Table 1).
Prevalence of opioid-induced constipation (OIC) in chronic opioid users.
| OIC | |
|---|---|
| Single opioid [37] | 67% |
| Patients ± cancer [36,42] | 33-70% |
| Non-cancer patients [39,40,41] | 41-57% |
| Patients with cancer [40] | 94% |
The frequency of OIC varies depending on the number and types of opioids used [38,39] and acute OIC also occurs when opioids are used to treat acute pain [11]. In the Patient Reports of Opioid-related Bothersome Effects (PROBE) survey of 322 patients with chronic pain in the US and EU, 33% stated that they had missed doses, decreased the dose of or stopped using opioid medication in order to relieve bowel-related side effects; 92% of patients subsequently experienced increased pain, 86% of whom reported that it reduced their Quality of Life (QoL) and daily activities [37,39].
In the non-interventional, Swedish UPPSIKT study that included patients treated with all types and administration forms of strong opioids during six months, 60-70% of the 197 OIC patients reported some degree of bothersome constipation each month. Moreover, approximately 12% of patient-months were categorized as months with severe problems due to OIC, 25% as moderate, 26% as mild and 37% as months with no constipation [43]. Clearly, OIC is uncomfortable, affects patient QoL and mortality and can prevent effective clinical management of pain.
Constipation may lead to colonic distension, ileus and perforation [44] and is associated with increased morbidity and increased utilization of healthcare resources [45,46]. Indeed, the economic burden of constipation is substantial in terms of both direct and indirect costs [47,48,49]. The direct costs include physician visits, hospitalisation, procedures and medications. Indirect costs include self-medication, lost earnings, restricted activity and costs of caregivers [48]. Hence, opioid use is expensive to society and costs vary with OIC severity [43]. Patients with severe constipation incur the highest total costs, i.e., 1525 EUR per patient-month, whereas patients with mild, moderate and no problems cost 1196 EUR, 1088 EUR, and 1034 EUR, respectively [43]. The indirect cost associated with sick leave is the largest cost item across all disease severity groups [43].
4.1 Statements according to GRADE
Many patients with acute and chronic, moderate-to-severe pain receive opioid treatment (moderate quality, strong recommendation)
The majority of opioids are prescribed for non-cancer pain (high quality, strong recommendation)
Constipation may lead to colonic distension, ileus and perforation (moderate quality, strong recommendation)
Constipation is associated with increased morbidity and utilization of healthcare resources (moderate quality, strong recommendation)
The economic burden (direct and indirect costs) of constipation is high (moderate quality, strong recommendation).
5 Assessment tools for opioid-induced bowel dysfunction
The first step in diagnosing constipation is to clarify the patient complaints. Opioid-induced bowel dysfunction has a plethora of symptoms, many of which resemble other conditions. A set of definitive diagnostic criteria, therefore, would clearly aid clinicians in understanding the different mechanisms involved and initiating a treatment strategy to solve this problem.
Many rating scales for assessing constipation, each of which addresses a specific need, have been developed over the past 20 years. The high number of constipation scales highlights increasing awareness of this disorder, yet also suggests that individual scales are not sensitive enough to assess constipation in all patient types. A systematic search for assessment scales identified 16 studies focused on a selection of diverse symptoms of constipation. The scales were evaluated in different patient groups [50]. Table 2 shows the most common rating scales, all of which potentially can be used for OIC.
An overview of the most common constipation assessment tools.
| Acronym | Name | Studies | No. of items | Patientgroups |
|---|---|---|---|---|
| CSS | Constipation Scoring System (Cleveland Clinic Score) | Agachan 1996 [51] | 8 | Chronic constipation and OIBD |
| CAS | Constipation Assessment Scale | McMillan 1989 [52] | 8 | OIBD |
| KESS | The Knowles-Eccersley-Scott symptom questionnaire | Knowles 2000[53] | 11 | Chronic constipation |
| SBFQ | Subjective Bowel function Questionnaire | Griffenberg 1997 [54] | 20 | Chronic constipation |
| PAC-SYM | Patient Assessment of Constipation Symptoms | Frank 2001 [55] | 36 | OIBD |
| VSAQ | Visual Scale Analogue Questionnaire | Pamuk 2003 [56] | 4 | Chronic constipation |
| GQ | Garrigues Questionnaire | Garrigues 2004 [57] | 21 | Chronic constipation |
| BFI | Bowel Function Index | Rentz 2009 [58] | 3 | OIBD |
| CM | Rome III Constipation Questionnaire Module | Drossman 2006 [59], Drossman 2006 [60] | Irritable bowel syndrome, functional constipation | |
| FICA | Faecal Incontinence and Constipation Assessment scale | Bharucha 2004[61] | 98 | Bowel disorders |
Whilst some of these scales are easy to use in daily clinical practice, particularly when the cause of constipation is known, others are time consuming and adapted primarily for research. Four different assessment scales have been used for OIC [51,52,55,58] (Table 2); probably the most straightforward is the Bowel Function Index (BFI). The three numerical scales of the BFI provide a single, easy, scoring method (ease of defecation + feeling of incomplete bowel evacuation + patient’s personal judgment of constipation). Inclusion of these items in the BFI is supported by psychometric tests that demonstrate validity, reliability and responsiveness [50,58,62,63]. Recently, Argoff et al. [64] reviewed 5 validated assessments for constipation and concluded that BPI is the most practical and easy-to-use tool in clinical assessment of OIC. Permission from Mundipharma may be needed, however, to use the scale in clinical trials. Outcome measures were also evaluated in the systematic review from Gaertner et al. [33] as mentioned previously. They concluded that single surrogate measures such as stool consistency should be avoided and replaced with a combined measure including (a) objective assessments such as the Bristol Stool Form Scale, (b) integrate patient reported outcome measures such as BFI and (c) assess the patients’ burden of OIC.
Notably, there is no consensus as to which assessment tools should be used for the whole spectrum of OIBD, either in clinical practice or in research studies. Whilst standardized assessment scales are used in some studies [63,64,65,66], other intervention studies report primarily on spontaneous bowel movements and laxative use [67,68]. Questionnaires, such as the Gastrointestinal Symptom Rating Scale, are well validated, available in many languages and assess most relevant gastrointestinal symptoms [70]. Sensitivity to opioid-induced adverse effects, however, requires further investigation; such a questionnaire would require supplementary questions to increase its specificity for OIBD.
Physical examination is always important, for example, checking for palpable masses and anal sphincter tone in order to exclude faecal impaction. Other diagnostic investigations, such as colonoscopy, abdominal radiographs [71], colonic transit time studies [53] and anorectal physiology measurement may also be necessary to unravel the reasons behind constipation yet these tools are more expensive and not always easily accessible. An optimal diagnosis of OIBD essentially requires patient diaries, including information on bowel movements, stool consistency, pain, use of rescue laxatives and opioid medication.
5.1 Statements according to GRADE
No consensus in the choice of assessment tools for OIBD or OIC exists (moderate quality, strong recommendation)
The Bowel Function Index (BFI) is a valid, reliable and responsive tool to assess OIC (moderate quality, strong recommendation).
6 Opioid-induced constipation in postoperative settings
Postoperative pain will, like all acute pain conditions, inhibit gastrointestinal motility partly due to increased sympathetic excitation of the intestines. This “normal” postoperative gastrointestinal ileus resolves spontaneously once the pain and stress after the surgical trauma dissipate. Epidural analgesia with weak concentrations of a local anaesthetic drug infused into the thoracic and thoraco-lumbar epidural space dramatically reduces the time to first bowel movement after abdominal surgery [72,73,74]. This effect is partially antagonised by co-administration of morphine, but maintained if either a low concentration (2 μg/ml) or dose (20 μg/h) of fentanyl is co-administered with the local anaesthetic and adrenaline [75,76]. It is also well documented that opioid treatment for postoperative pain will prolong postoperative ileus [77] especially after abdominal surgery with intestinal resection/anastomosis [78].
Opioid-induced, postoperative constipation can be reduced by co-administering a peripherally-acting mu-opioid receptor antagonist (PAMORA) [1]. For example, the PAMORA alvimopan is reported to significantly reduce the time to first bowel movement after bowel surgery and is approved only for the prevention or shortening of the duration of postoperative ileus after bowel resection [78]. However, results from long-term safety studies have indicated that alvimopan may increase the risk of adverse cardiovascular events and so far alvimopan is available solely in the US and restricted for hospital use only. Interestingly, a six- to twelve-fold higher dose of alvimopan (12 mg/day) is required for the prevention/reversal of OIC after bowel surgery in opioid-naïve patients compared to that needed to reverse OIC in chronic pain patients on long-term opioid treatment (1-2 mg/day) [11,79].
6.1 Statements according to GRADE
Opioid analgesic treatment for acute postoperative pain will prolong the postoperative ileus (moderate quality, strong recommendation)
Opioid-induced constipation and bowel dysfunction, including post-operative ileus, can be reduced significantly by PAMORAs (moderate quality, weak recommendation).
7 Differential diagnosis of opioid induced bowel dysfunction
Other gastrointestinal disorders may present with the same symptoms as OIBD. Patients frequently experiencing chronic constipation or irritable bowel syndrome (IBS) with constipation for long periods of time are particularly susceptible to increased complaints upon initiation of opioid treatment. Gastroduodenal ulcerations induced by, for example, non-steroidal anti-inflammatory drugs (NSAIDs) with or without complications may underlie the nausea, pain or even vomiting in the case of pyloric stenosis [80]. Gastro-oesophageal reflux disease is also aggravated by NSAIDs, and predisposed patients may experience worsening of symptoms with increasing time spent in a recumbent position; it may also contribute to upper abdominal symptoms. In such cases, upper gastrointestinal endoscopy or even 4-8 weeks’ treatment with a proton pump inhibitor is often indicated [81]. Intestinal obstruction due to tumours (primary or secondary) can mimic symptoms of severe constipation and should also be ruled out as a cause of new abdominal complaints, particularly in cases with a history of malignant disorders. Moreover, nausea may be caused by intracranial pathology, including central nervous system (CNS) tumours. Finally, clinicians should also be aware of the “narcotic bowel syndrome” which is an equivalent of opioid induced hyperalgesia in somatic diseases [34]. The syndrome is characterized by chronic or intermittent abdominal pain, which often increases in severity despite continued or escalating dosages of opioids, and treatment is opioid withdrawal.
7.1 Statements according to GRADE
Polypharmacy with medications, such as NSAIDs, may cause abdominal complaints that can be mistaken for OIBD (medium quality, strong recommendation)
Abdominal disorders, including gastroduodenal ulcerations and the narcotic bowel syndrome, may mimic OIBD and patients should be investigated when in doubt (high quality, strong recommendation)
Abdominal malignant disease may cause intestinal obstruction, which must be ruled out (medium quality, strong recommendation).
8 Non-pharmacological and pharmacological treatment of opioid-induced bowel dysfunction
8.1 Fibres, diet and exercise
The basic advice of clinicians to patients complaining of constipation, such as having a high fibre dietary content and ample daily intake of fluid volumes, has been difficult to prove efficacious [82] and has not been specifically evaluated in OIBD. The type of dietary fibre is likely to be important; ispaghula (psyllium) is commonly recommended because it is associated with fewer complaints of intestinal gas, as are probiotics [83]. Although physical exercise increases gastrointestinal motility in healthy subjects [84,85] and its usefulness in chronic constipation associated with IBS has not been well documented [86], and specific information on its efficacy in OIBD is lacking. Nevertheless, mild exercise should at least be recommended due to its positive influence on appetite and social activities, although many patients are treated with opioids because of back pain or other musculoskeletal disorders, which limit the possibility of recommending increased physical exercise.
8.1.1 Statements according to GRADE
Soluble fibre, such as ispaghula, is effective in relieving constipation, including OIC (low quality, weak recommendation)
Physical exercise is likely to be beneficial in reducing complaints of OIC (medium quality, weak recommendation).
8.2 Conventional laxatives
Treatment with conventional laxatives is commonly recommended in all opioid-treated patients [87]. Laxatives can be divided into different subgroups, including osmotic agents (magnesium, lactulose, polyethylene glycol), stimulant laxatives (bisacodyl, senna), and bulking agents (methylcellulose, psyllium). Combined treatment with osmotic laxatives and stimulant agents are often recommended despite anecdotal evidence for laxatives in this setting and no evidence when preferring one laxative agent over the other. Usually, oral laxative treatment is initiated, and enemas are used in many patients especially when constipation affects the most anal segments of colon.
The efficacy of laxatives in the treatment of functional constipation is still debatable [88,89]. As pointed out by Brenner and Chey in a recent review, most conventional laxatives are insufficient for treatment of OIBD [90], possibly because the key symptoms related to opioid receptor blockade in the gastrointestinal tract are not targeted by laxatives, which primarily affect the colon [1,91]. As a consequence of the current lack of randomized, controlled, doubleblinded trials investigating the efficacy of conventional laxatives in OIC patients, no evidence exists to suggest which laxatives are beneficial. Results from a study in OIC patients, however, showed that when the choice of rescue laxative was left to the patients, approximately 80-90% preferred stimulant laxatives [92]. Furthermore, it has been shown that prophylactic administration of laxatives in opioid-naïve patients generally was effective in preventing OIC. In this Japanese study magnesium oxide and senna were mostly used; however, no apparent difference in efficacy between the laxatives was demonstrated [93].
Moreover, laxative treatment per se may cause side effects, such as bloating, abdominal distension, rumbling, flatulence and gastro-oesophageal reflux. Together with the possible lack of efficacy, this may explain why approximately one third of patients omit, reduce or even discontinue their opioid treatment to relieve adverse effects instead of taking laxatives [36]. Sugar and sugar alcohol metabolism by intestinal microbiota produces short chain carbonic acids and gas, which may lead to or worsen the abdominal distension in OIBD [94]. Many of the bothersome symptoms associated with OIC, therefore, may not be improved by treatment with laxatives. Indeed, large-scale studies report that most (81%) patients treated chronically with opioids suffer from OIC despite using laxatives [2]. However, since many patients do experience a sufficient effect with conventional laxatives, most of which are relatively cheap, conventional laxatives are still recommended as first-line treatment in OIC patients (see Fig. 1, Section 9).
Proposed algorithm for the treatment of opioid induced bowel dysfunction, especially constipation. The arrows indicate a failure of the first recommendation and thus continuation to next step. Treatment goals are to establish regular bowel function and eliminate upper gastrointestinal symptoms, improve quality of life and avoid complications, such as haemorrhoids, rectal prolapse and faecal impaction. As support for clinical evaluation questionnaires such as the Bowel Function Index may be used, where a score >30 should lead to more intensive treatment.
8.2.1 Statements according to GRADE
Laxatives are recommended as first-line treatment in OIC patients (low quality, strong recommendation)
Recommendations often suggest combined treatment with stool softeners and stimulant agents (low quality, weak recommendation)
Laxative treatment in OIBD may cause side effects per se (high quality, strong recommendation).
8.3 Opioid rotation and alternative opioids
An individual’s responsiveness and sensitivity to opioids involves interplay between genetic, physiological, and pharmacokinetic and -dynamic factors; together these determine both the analgesic response and tolerance to a particular drug [95]. Opioids may have a direct local effect on opioid receptors in the gastrointestinal tract, and changing from oral to parenteral or transdermal administration may partially alleviate symptoms of OIC/OIBD. Results from two studies have indicated that transdermal administration of fentanyl administered is associated with a significantly lower rate of constipation than morphine administered orally [96,97], although a Cochrane review of its effects and side effects stated that constipation was reported inconsistently [98]. Hence, gut receptors invariably will be affected when opioids reach the systemic circulation and, from a mechanistic perspective, transdermal treatment may not be better than systemic administration.
Gastrointestinal function in OIBD patients may be improved by rotating one opioid with another, whilst maintaining analgesia [99,100,101]. The balance between cross-tolerance to analgesic response and adverse effects contribute to the relative success of any rotation. Opioid rotation is frequently used in clinical practice; however, few prospective, randomized trials that support opioid rotation for either efficacy or adverse effects exist.
The “new” opioid tapentadol, used for pain relief, is both a μ-opioid agonist and norepinephrine reuptake inhibitor; it exhibits weaker μ-receptor activity than pure opioid agonists [102] and may be associated with a lower incidence of constipation than other opioids [103,104]. When patients with lower back or osteoarthritis pain were treated with tapentadol, oxycodone or placebo, tapentadol was shown to cause less bowel function impairment than oxycodone, i.e., significantly fewer days without a bowel movement, softer stools, less straining, and improved constipation assessment scores [105]. The proportions of treatment days with no bowel movements or with incomplete bowel movements were similar among tapentadol- and placebo-treated patients. A recent systematic review in which prolonged-release oxycodone/naloxone were compared with extended-release tapentadol, however, favoured the oxycodone/naloxone combination regarding patient-reported constipation [106].
Daeninck and colleagues [107] reported on four cancer pain patients with OIBD who experienced an improvement in constipation and a reduction in laxative dose after opioid rotation to methadone. Results from another study demonstrated significant improvement in several morphine-related adverse effects, including constipation, in 52 cancer patients after rotation to methadone [108]. Moreover, a study of 189 consecutive patients who underwent methadone initiation/rotation showed improved constipation and nausea after the initiation/rotation [104]. These findings, however, must be confirmed in prospective studies with clearly defined endpoints and longer follow-up periods.
8.3.1 Statements according to GRADE
Tapentadol causes less bowel function impairment than oxycodone (moderate quality, strong recommendation)
Transdermal fentanyl is associated with a significantly lower rate of constipation than oral morphine (low quality, weak recommendation)
Rotation from different opioids to methadone leads to reduced laxative doses and an improvement in constipation (low quality, weak recommendation).
8.4 Other treatments relevant for opioid-induced constipation
In patients suffering from OIBD, tapering the opioid to lowest possible dose or replacing it with other analgesics may be optional. Non-opioid analgesics are often insufficient in treating chronic pain, although guidelines recommend a basic regimen of paracetamol (acetaminophen) to reduce the required opioid dose [109,110]. Adjuvant analgesics, such as anti-epileptics (e.g., carbamazepine, gabapentin and pregabalin), are also recommended therapies for chronic pain, although mainly proven efficacious in specific conditions like neuropathic pain associated with diabetes mellitus or post-herpetic nerve injury [111]. In humans, a recent meta-analysis confirmed that at doses of 1200 mg daily or more, gabapentin was associated with pain reduction in significantly more patients than placebo, but the “number needed to treat” was as high as 6-8 for neuropathic pain and little documentation exists for other pain conditions [112]. Recently, morphine requirement in the 72-hour postoperative phase was investigated in patients randomized either to gabapentin or placebo, yet no difference in morphine consumption or in adequacy of pain relief was seen [113].
Various classes of antidepressants, often at low doses, are also used to treat neuropathic and other chronic conditions of pain and may reduce the opioid dose. A Cochrane review of the different antidepressant classes was optimistic in its support for using antidepressants to avoid opioid treatment [114]; in contrast, recent reviews of single antidepressants have shown little evidence for this [115,116]. Notably, the balance between adverse effects and analgesia often lead to other treatment alternatives.
Apart from changes in analgesic therapy, new treatment options are available for chronic idiopathic constipation and IBS with constipation and can potentially be used in special cases in patients with OIC. For example, lubiprostone specifically activates the ClC-2 chloride channels on the apical aspect of gastrointestinal epithelial cells to produce a net secretion into the gut lumen [117]. This softens the stools, stimulates motility and increases the number of spontaneous bowel movements. Lubiprostone was tested successfully in patients with chronic idiopathic constipation [118] and IBS with constipation [119] and recent randomized, placebo-controlled trials showed that it effectively relieves OIC and associated signs and symptoms, whilst being well tolerated in chronic, non-cancer pain patients [120,121]. Conversely, another smaller study showed no advantage of lubiprostone compared to the less expensive senna in postoperative orthopaedic surgery patients [122]. The drug has been approved for OIC in adults with chronic, non-cancer pain in the US since 2013, but not in Europe.
Linaclotide is a potent and selective guanylate cyclase C agonist, which induces secretion into the gut lumen, accelerates transit and reduces pain perception [123,124]. In large clinical trials, linaclotide improved abdominal and bowel symptoms in patients with chronic idiopathic constipation [125] and IBS with constipation [126]. Based on its mechanism of action, it is likely to be effective in OIC; currently a clinical trial programme is underway to assess this. Linaclotide is approved for chronic idiopathic constipation in the US and for IBS with constipation in the US and in Europe.
Prucalopride is a highly selective 5-HT4 agonist with strong gastro-prokinetic effects [127,128]. Clinical data support its value in treating chronic idiopathic constipation, where it is safe and increases the number of bowel movements [129]. One Phase II trial has compared prucalopride with placebo in non-cancer pain patients with OIC; although several outcome variables were improved in the prucalopride group, some failed to reach statistical significance [130]. Prucalopride is currently approved in Europe for women with chronic constipation in whom laxative treatment has failed.
8.4.1 Statements according to GRADE
Pregabalin and gabapentin may be effective alternative therapies for relieving neuropathic and other chronic pain conditions (moderate quality, strong recommendation)
Antidepressants may be useful in treating neuropathic pain (moderate quality, weak recommendation)
Lubiprostone can be tried for OIC (moderate quality, strong recommendation)
Prucalopride can be tried for OIC (low quality, weak recommendation)
Linaclotide can be tried for OIC (low quality, no recommendation).
8.5 Combination therapies: slow-release tablets with an opioid agonist and peripherally-restricted opioid antagonist (slow-release oxycodone and naloxone)
Naloxone is the classical opioid antagonist, which, when administered by parenteral injection, reverses all effects of opioid agonists and precipitates severe pain and withdrawal symptoms in chronic pain patients on long-term opioid treatment. Orally administered naloxone is well absorbed from the gastrointestinal tract and is subject to an extensive first pass metabolism. In a randomized clinical trial (RCT), however, the effect of either 2 mg or 4 mg of naloxone administered three times to nine patients with constipation on stable doses of opioids was evaluated [131]. All patients who received oral naloxone showed some improvement in bowel frequency, although the analgesic effect was reversed in three patients. Thus, when given orally in conventional tablets, naloxone might reach the systemic circulation and cause anti-analgesic and withdrawal effects. On the other hand, when naloxone is administered orally in a prolonged-release formulation, >97% is metabolised due to the hepatic first-pass mechanism, leaving only tiny amounts to reach the systemic circulation and CNS [132,133]. The effect of a combination of prolonged-release (or slow- or controlled-release) oxycodone/naloxone compared to prolonged-release oxycodone/placebo has been investigated in four RCTs in a total of 974 patients, and in which the primary outcome was the BFI scores [134,135,136]. A 2:1 ratio of oxycodone:naloxone was identified by the manufacturer to be the most suitable to ensure alleviation of constipation without risk for systemic effects [137]. Doses ranged between 40-120 mg for oxycodone and 10-60 mg for naloxone and trials lasted 4-12 weeks. Oxycodone/naloxone-treated patients experienced improved bowel function compared to those on oxycodone/placebo and no serious adverse effects were reported.
Ultra-low doses of naloxone may suppress some of the adverse effects of morphine, such as nausea, sedation, and itching [138,139]. Hence, improved pain control with intravenous morphine has been observed even with ultra-low doses of intravenous naloxone, which reduces opioid-induced hyperalgesia, allodynia and tolerance [140,141,142]. These surprising effects of ultra-low doses of naloxone may be explained by the hypothesis that μ-opioid receptor excitatory G-protein complexes are inhibited whilst the inhibitory G-protein receptors are left undisturbed [142].
For further information on these aspects of controlled- or slow-release oxycodone/naloxone, see Breivik and Werner [143] and Hesselbarth and colleagues [144].
8.5.1 Statements according to GRADE
Naloxone, taken orally in doses sufficient to treat OIC, may cause withdrawal symptoms and reverse analgesia (moderate quality, strong recommendation)
Slow-release naloxone-oxycodone is more efficacious than oxycodone in avoiding OIC (high quality, strong recommendation).
8.6 Peripherally-acting μ-opioid receptor antagonists
Opioid agonists cause OIBD, including OIC, primarily by binding to submucosal μ-opioid receptors in the gastrointestinal tract (see Section 2). Opioid antagonists that block only these peripheral opioid receptors should, therefore, reduce OIBD and OIC with no reduction in central opioid analgesia. In addition to naloxone administered in slow-release tablets, the effects of three PAMORAs (methylnaltrexone, naloxegol and alvimopan) have been evaluated in RCTs and are available in some countries. Alvimopan is described in the postoperative section and will be not be dealt with here.
Methylnaltrexone is a quaternary ammonium compound and thus an extremely polar compound, which does not readily cross biological membranes, such as the epithelial cells in the gut and endothelial cells in the blood-brain barrier. Thus, the compound does not gain access to the CNS and must be administered parenterally. The effects of methylnaltrexone have been investigated in five RCTs with different numbers and types of patients suffering from OIC. Treatment duration, and outcome measurements varied in the single studies (time to defecation, number of patients with drugrelated bowel movements) [92,145,146]. Dosing schedules and administration routes of methylnaltrexone also differed. Doses of 0.15 mg/kg, 0.30 mg/kg or a fixed dose of 12 mg were administered daily or every second day, and by intravenous or subcutaneous injections. Results from all studies showed significantly better outcomes with methylnaltrexone compared with placebo. Secondary outcomes, such as decreased laxative use, were also reported. Generally, methylnaltrexone was well tolerated by all patients, but its high price and parenteral route of administration limits its use.
Naloxegol is a PEGylated derivative of the naloxone molecule; the PEGylation process prevents it from crossing the blood-brain barrier due to the increased size of the molecule, as well as reduced passive and active permeability. Results from two RCTs have shown that at a daily dose of 25 mg, naloxegol significantly increased the number of days per week with spontaneous and normal bowel movements (defecations) compared to that seen after administration of placebo. Pain intensity and opioid requirements were unchanged, and no withdrawal symptoms or serious cardiovascular events were observed [67,69]. Moreover, opioid-induced upper gastrointestinal dysfunctions improved (i.e., there was less regurgitation of stomach content, heartburn and nausea). It is an advantage that naloxegol can be used as an add-on to existing pain therapy, as many pain patients are on a stable and satisfactory analgesic regime, but suffer from OIBD symptoms [147]. Tack et al. [148] reported the outcome of two Phase 3 trials confirming the high efficacy of naloxegol in relieving OIC in patients with laxative-inadequate response. Naloxegol has been approved by the FDA in the US and the European Medicines Agency for the treatment of laxative-resistant OIC, which includes cancer and non-cancer patients in Europe.
Three other PAMORAs are in development for the treatment of OIBD: bevenopran, TD-1211 and naldemedine [143].
8.6.1 Statements according to GRADE
Methylnaltrexone blocks peripheral opioid receptors and can be used to reduce OIC (moderate quality, weak recommendation)
Naloxegol blocks peripheral opioid receptors and can be used to reduce OIC (moderate quality, strong recommendation).
9 Conclusions and treatment practice advisory recommendations
Opioid-induced bowel dysfunction is an increasing problem due to the common use of opioids worldwide. In most countries, concurrent use of laxatives with opioids is recommended. Despite the use of conventional laxatives, however, a substantial portion of patients still suffers from OIBD, which causes a significant decrease in QoL [149]. Opioid antagonists with mechanism-based local effects on the gut are, therefore, a well-validated treatment option. Awareness of the problem is mandatory for the treating physician, and it is important to stress that constipation is only part of the plethora of OIBD symptoms, which can also be dominated by other symptoms, such as reflux and gas.
Fig. 1 summarizes a recommendation for OIBD and OIC treatment based on the current evidence outlined in this article. With regards to conventional laxatives, local traditions often guide treatment choice. Magnesium sulphate, bisacodyl, sodium picosulfate and macrogol are the most frequently used laxatives in Scandinavia and recommended as first-line medication. Lifestyle changes and alternative analgesics should always be considered. Tapering the opioid dosage, opioid rotation and dual action opioids like tapentadol may also improve OIBD. Should conventional treatment fail to alleviate symptoms, mechanism-based treatment with opioid antagonists should be considered, which shows advantages over conventional laxative use. As support for the clinical evaluation Argoff et al. [64] recently recommended that after evaluation of first-line interventions, a BFI score of >30 points should lead to prescription of PAMORAs. These treat OIC effectively and are also likely to treat other symptoms associated with opioid use, although this must still be demonstrated in experimental and clinical studies. In difficult cases, particularly in hospitalised patients, methylnaltrexone may be used as an initial “OIC test therapy” due to its parenteral administration and strong effect that may unmask the nature of the symptoms. Newer drugs, such as prucalopride, lina-clotide or lubiprostone may also be tried in specific cases. It should not be overlooked that there are many other reasons for constipation than OIBD, which should also be taken into consideration in the diagnosis of an individual patient.
It is the belief of this Nordic Working Group that increased awareness of adverse effects associated with opioid therapy, particularly OIC and OIBD, will lead to better pain treatment in patients. Subsequently, optimised treatment will improve QoL and, from a socio-economic perspective, may also reduce costs associated with hospitalisation, sick leave and early retirement in patients suffering from pain.
Highights
Opioid-induced bowel dysfunction and constipation (OIC) are underdiagnosed and undertreated.
Pain management and quality of life in chronic pain patients is reduced by OIC.
Conventional laxatives have limited effects on OIC and may cause adverse effects.
Peripherally-acting opioid antagonists that do not enter the brain are effective against OIC without major adverse effects.
An evidence-based practice guideline for OIC based on the GRADE-method is proposed.
DOIs of original articles: http://dx.doi.org/10.1016/j.sjpain.2015.12.007, http://dx.doi.org/10.1016/j.sjpain.2016.02.003
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Conflict of interest: AMD has received financial support from Mundipharma, AstraZeneca, Shire, Almirall, Grunenthal and Pfizer. HB has received honoraria from Weifa, Mundipharma, AstraZeneca, Grunenthal and Pfizer. LA has no conflicts of interest. MS has served as an advisory board member and has been a speaker for AstraZeneca, Shire and Almirall. UEK has served as an advisory member and been on the speaker’s bureau for AstraZeneca, Mundipharma and Takeda Nycomed. JH has no relevant disclosures. MS has served as an advisory board member and has been on the speaker’s bureau for AstraZeneca, Shire and Almirall. HB has received honoraria from Weifa, Mundipharma, AstraZeneca, Grunenthal and Pfizer. LLC has received financial support from norpharma and has been participating in advisory boards for Grunenthal and teaching for Norpharma and AstraZeneca. MF and LA had no relevant disclosures.
Acknowledgements
This manuscript was developed by expert advisors who attended an advisory round-table meeting in Copenhagen, Denmark in December, 2014 and 15th June, 2015, sponsored by AstraZeneca. All authors participated in the preparation and review of this manuscript, critical revisions and final approval for submission. Manuscript editing was sponsored by AstraZeneca.
References
[1] Brock C, Olesen SS, Olesen AE, Frakjsr JF, Andresen T, Drewes AM. Opioid-induced bowel dysfunction: pathophysiology and management. Drugs 2012;72:1847-65, http://dx.doi.org/10.2165/11634970-000000000-00000Search in Google Scholar
[2] Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182:11S-8S, pii:S0002961001007826.Search in Google Scholar
[3] Holzer P. Pharmacology of opioids and their effects on gastrointestinal function. Am J Gastroenterol Suppl 2014;2:9-16.Search in Google Scholar
[4] Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003;63:649-71.Search in Google Scholar
[5] Sternini C, Patierno S, Selmer IS, Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterol Motil 2004;16:3-16.Search in Google Scholar
[6] Camilleri M, Malagelada JR, Stangilellini V, Zinsmeister AR, Kao PC, Li CH. Dose-related effects of synthetic human and naloxone on fed gastrointestinal motility. AmJ Physiol 1986;251:G147-54.Search in Google Scholar
[7] Galligan JJ, Akbarali HI. Molecular physiology of enteric opioid receptors. Am J Gastroenterol 2014;2:17-21, http://dx.doi.org/10.1038/ajgsup.2014.5Search in Google Scholar
[8] Smith K, Hopp M, Mundin G, Bond S, Bailey P, Woodward J, Bell D. Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther 2012;50:360-7.Search in Google Scholar
[9] SharmaSK, NirenbergM, Klee WA. Morphine receptors as regulators of adenylate cyclase activity. Proc Natl Acad Sci USA 1975;72:590-4.Search in Google Scholar
[10] Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil 2004;16:17-28.Search in Google Scholar
[11] Gonenne J, Camilleri M, Ferber I, Burton D, Baxter K, Keyashian K, Foss J, Wallin B, Du W, Zinsmeister AR. Effect of alvimopan and codeine ongastroeintestinal transit: a randomized controlled study. Clin Gastroenterol Hepatol 2005;3:784-91.Search in Google Scholar
[12] Kraichely RE, Arora AS, Murray JA. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther 2010;31:601-6, http://dx.doi.org/10.1111/j.1365-2036.2009.04212.xSearch in Google Scholar
[13] Penagini R, Allocca M, Cantu P, Mangano M, Savojardo D, Carmagnola S, Bianchi PA. Relationship between motor function of the proximal stomach and transient lower oesophageal sphincter relaxation after morphine. Gut 2004;53:1227-31.Search in Google Scholar
[14] Hawkes ND, Rhodes J, Evans BK, Rhodes P, Hawthorne AB, Thomas GA. Naloxone treatment for irritable bowel syndrome—a randomized controlled trial with an oral formulation. Aliment Pharmacol Ther 2002;16:1649-54.Search in Google Scholar
[15] Smith K, Hopp M, Mundin G, Bond S, Bailey P, Woodward J, Palaniappan K, Church A, Limb M, Connor A. Naloxone as part of a prolonged release oxycodone/naloxone combination reduces oxycodone-induced slowing of gastrointestinal transit in healthy volunteers. Expert Opin Investig Drugs 2011;20:427-39, http://dx.doi.org/10.1517/13543784.2011.563236Search in Google Scholar
[16] Sun WM, Read NW, Verlinden M. Effects of loperamide oxide on gastrointestinal transit time and anorectal function in patients with chronic diarrhoea and faecal incontinence. Scand J Gastroenterol 1997;32:34-8.Search in Google Scholar
[17] Holzer P. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs 2007;16:181-94.Search in Google Scholar
[18] Thomas J. Opioid-induced bowel dysfunction. J Pain Symptom Manage 2008;35:103-13.Search in Google Scholar
[19] Barrett KE, KeelySJ. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu Rev Physiol 2000;62:535-72.Search in Google Scholar
[20] Glad H, Ainsworth MA, Svendsen P, Fahrenkrug J, Schaffalitzky de Muckadell OB. Effect of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide on pancreatic, hepatic and duodenal mucosal bicarbonate secretion in the pig. Digestion 2003;67:56-66.Search in Google Scholar
[21] KromerW. Endogenous and exogenous opioids inthe control of gastrointestinal motility and secretion. Pharmacol Rev 1988;40:121-62.Search in Google Scholar
[22] Dowlatshahi K, EvanderA, Walther B, Skinner DB. Influence of morphine on the distal oesophagus and the lower oesophageal sphincter—a manometric study. Gut 1985;26:802-6.Search in Google Scholar
[23] Blackshaw LA, Bordin DS, Brock C, Brokjaer A, Drewes AM, Farmer AD, Krarup AL, Lottrup C, Masharova AA, Moawad FJ, Olesen AE. Pharmacologic treatments for esophageal disorders. Ann N Y Acad Sci 2014;1325:23-39, http://dx.doi.org/10.1111/nyas.12520Search in Google Scholar
[24] Sharma SS. Sphincter of Oddi dysfunction in patients addicted to opium: an unrecognized entity. Gastrointest Endosc 2002;55:427-30.Search in Google Scholar
[25] Bouvier M, KirschnerG, GonellaJ. Actions of morphine and enkephalins on the internal anal sphincter of the cat: relevance for the physiological role of opiates.J Auton Nerv Syst 1986;16:219-32.Search in Google Scholar
[26] Burleigh DE, D’Mello A. Neural and pharmacologic factors affecting motility of the internal anal sphincter. Gastroenterology 1983;84:409-17.Search in Google Scholar
[27] Gaertner J, Siemens W, Camilleri M, Davies A, Drossman DA, Webster LR, Becker G. Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review. J Clin Gastroenterol 2015;49:9-16, http://dx.doi.org/10.1097/MCG.0000000000000246Search in Google Scholar
[28] Longstreth GF, Thompson WG, CheyWD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006;130:1480-91.Search in Google Scholar
[29] Choung RS, Locke 3rd GR, Schleck CD, Zinsmeister AR, Talley NJ. Cumulative incidence of chronic constipation: a population-based study 1988-2003. Aliment Pharmacol Ther 2007;26:1521-8.Search in Google Scholar
[30] Clark K, Currow DC. Constipation in palliative care: what do we use as definitions and outcome measures? J Pain Symptom Manage 2013;45:753-62, http://dx.doi.org/10.1016/jjpainsymman.2012.03.016Search in Google Scholar
[31] Bharucha AE, Pemberton JH, Locke 3rd GR. American Gastroenterological Association technical review on constipation. Gastroenterology 2013;144:218-38, http://dx.doi.org/10.1053Zj.gastro.2012.10.028Search in Google Scholar
[32] Camilleri M, Drossman DA, Becker G, Webster LR, Davies AN, Mawe GM. Emerging treatments in neurogastroenterology: a multidisciplinary working group consensus statement on opioid-induced constipation. Neurogastroenterol Motil 2014;26:1386-95, http://dx.doi.org/10.1111/nmo.12417Search in Google Scholar
[33] Gaertner J, Siemens W, Camilleri M, Davies A, Drossman DA, Webster LR, Becker G. Definitions and outcome measures of clinical trials regarding opioid-induced constipation: a systematic review. J Clin Gastroentero 2015;49:9-16, http://dx.doi.org/10.1097/MCGSearch in Google Scholar
[34] Drossman D, Szigethy E. The narcotic bowel syndrome: a recent update. Am J Gastroenterol 2014;2:22-30, http://dx.doi.org/10.1038/ajgsup.20146Search in Google Scholar
[35] Kurlander JE, Drossman DA. Diagnosis and treatment of narcotic bowel syndrome. Nat RevGastroenterol Hepatol 2014;11:410-8, http://dx.doi.org/10.1038/nrgastro.201453Search in Google Scholar
[36] Institute for Healthcare Informatics IMS. The use of medicines in the United States: review of2010. Parsippany, NJ;2011.Search in Google Scholar
[37] Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid-induced boweldysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med 2009;10:35-42, http://dx.doi.org/10.1111/j.1526-4637.2008.00495.xSearch in Google Scholar
[38] Cook SF, Lanza L, Zhou X, Sweeney CT, Goss D, Hollis K, Mangel AW, Fehnel SE. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment Pharmacol Ther2008;27:1224-32, http://dx.doi.org/10.1111/j.1365-2036.2008.03689.xSearch in Google Scholar
[39] Holzer P. New approaches to the treatment of opioid-induced constipation. EurRev Med Pharmacol Sci 2008;12:119-27.Search in Google Scholar
[40] Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004;112:372-80.Search in Google Scholar
[41] Sykes NP.The relationship between opioid use and laxative use interminally ill cancerpatients. Palliat Med 1998;12:375-82.Search in Google Scholar
[42] Tuteja AK, Biskupiak J, Stoddard GJ, Lipman AG. Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic noncancer pain. Neurogastroenterol Motil 2010;22:424-30, http://dx.doi.org/10.1111/j.1365-2982.2009.01458.xSearch in Google Scholar
[43] Hjalte F, Berggren A-C, Bergendahl H, Hjortsberg C. The direct and indirect costs of opioid-induced constipation. J Pain Symptom Manage 2010;40:696-703, http://dx.doi.org/10.1016/j.jpainsymman.2010.02.019Search in Google Scholar
[44] Gekas P, Schuster MM. Sterocoral perforation of the colon: case report and review of the literature. Gastroenterology 1981;80:1054-8.Search in Google Scholar
[45] Locke 3rd GR, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: guidelines on constipation. Gastroenterology2000;119:1761-6.Search in Google Scholar
[46] Thorpe DM. Management of opioid-induced constipation. Curr Pain Headache Rep 2001;5:237-40.Search in Google Scholar
[47] Candrilli SD, Davis KL, Iyer S. Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy. J Pain Palliat Care Pharmacother 2009;23:231-41, http://dx.doi.org/10.1080/15360280903098440Search in Google Scholar
[48] Dennison C, Prasad M, Lloyd A, Bhattacharyya SK, Dhawan R, Coyne K. The health-related quality of life and economic burden of constipation. Pharmacoeconomics 2005;23:461-76.Search in Google Scholar
[49] Morlion B, Clemens KE, Dunlop W. Quality of life and healthcare resource in patients receiving opioids for chronic pain: a review of the place of oxycodone/naloxone. Clin Drug Investig 2015;35:1-11, http://dx.doi.org/10.1007/s40261-014-0254-6Search in Google Scholar
[50] Coffin B, Causse C. Constipation assessment scales in adults: a literature review including the new Bowel Function Index. Expert Rev Gastroenterol Hepatol 2011;5:601-13, http://dx.doi.org/10.1586/egh.11.53Search in Google Scholar
[51] Agachan F, Chen T, Pfeifer J, Reissman P, Wexner SD. A constipation scoring system to simplify evaluation and management of constipated patients. Dis Colon Rectum 1996;39:681-5.Search in Google Scholar
[52] McMillan SC, Williams FA. Validity and reliability of the Constipation Assessment Scale. Cancer Nurs 1989;12:183-8.Search in Google Scholar
[53] Knowles CH, Eccersley AJ, Scott SM, Walker SM, Reeves B, Lunniss PJ. Linear discriminant analysis of symptoms in patients with chronic constipation: validation of a new scoring system (KESS). Dis Colon Rectum 2000;43:1419-26.Search in Google Scholar
[54] Griffenberg L, Morris M, Atkinson N, Levenback C. The effect of dietary fibre on bowel function following radical hysterectomy: a randomized trial. Gynecol Oncol 1997;66:417-24.Search in Google Scholar
[55] Frank L, FlynnJ, Rothman M. Use of a self-report constipation questionnaire with olderadults in long-term care. Gerontologist 2001;41:778-86.Search in Google Scholar
[56] PamukON, PamukGE, CelikAF. Revalidation of description of constipation in terms of recall bias and visual scale analogue questionnaire. J Gastroenterol Hepatol 2003;18:1417-22.Search in Google Scholar
[57] Garrigues V, Galvez C, Ortiz V, Ponce M, Nos P, Ponce J. Prevalence of constipation: agreement among several criteria and evaluation of the diagnostic accuracy of qualifying symptoms and self-reported definition in a populationbased survey in Spain. AmJ Epidemiol 2004;159:520-6.Search in Google Scholar
[58] Rentz AM, Yu R, Muller-Lissner S, Leyendecker P. Validation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipation. J Med Econ 2009;12:371-83, http://dx.doi.org/10.3111/13696990903430481Search in Google Scholar
[59] Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377-90.Search in Google Scholar
[60] Drossman DA, Dumitrascu DL. Rome III: newstandard for functional gastro intestinal disorders. J Gastrointestin Liver Dis 2006;15:237-41.Search in Google Scholar
[61] Bharucha AE, Locke 3rd GR, Seide BM, Zinsmeister AR. A new questionnaire for constipation and faecal incontinence. Aliment Pharmacol Ther 2004;20:355-64.Search in Google Scholar
[62] Rentz AM, van Hanswijck de Jonge P, Leyendecker P, Hopp M. Observational, non-intervention, multicentre study for validation of the Bowel Function Index for constipation in European countries. Curr Med Res Opin 2011;27:35-44, http://dx.doi.org/10.1185/03007995.2010.535270Search in Google Scholar
[63] Ueberall MA, Muller-Lissner S, Buschmann-Kramm C, Bosse B. The Bowel Function Index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients. J Int Med Res 2011;39:41-50.Search in Google Scholar
[64] Argoff CE, Brennan MJ, Camilleri M, Davies A, Fudin J, Galluzzi KE, Gudin J, Lembo A, Stanos SP, Webster LR. Consensus recommendations in initiating therapies for opioid-induced constipation. Pain Med 2015, http://dx.doi.org/10.1111/pme.12937Search in Google Scholar
[65] Clemens KE, Quednau I, Klaschik E. Bowel function during pain therapy with oxycodone/naloxone prolonged-release tablets in patients with advanced cancer. Int J Clin Pract 2011;65:472-8, http://dx.doi.org/10.1111/j.1742-1241.2011.02634.xSearch in Google Scholar
[66] Mehta V, Alaward S, Kuravinakop S, Nikolic S. Effect of a fixed-dose opioid agonist/antagonist on constipation in patients on long-term opioids for nonmalignant pain unabletotolerate laxatives. Pain Physician 2014;17:415-24.Search in Google Scholar
[67] Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014;370:2387-96, http://dx.doi.org/10.1056/NEJMoa1310246Search in Google Scholar
[68] Webster L, Jansen JP, Peppin J, Lasko B, Irving G, Morlion B, Snidow J, Pierce A, Mortensen E, Kleoudis C, Carter E. Alvimopan, a peripherallyacting mu-opioid receptor (PAM-OR) antagonist for the treatment of opioid-induced bowel dysfunction: results from a randomized, double-blind, placebo-controlled, dose-finding study in subjects taking opioids for chronic non-cancer pain. Pain 2008;137:428-40, http://dx.doi.org/10.1016/j.pain.200711.008Search in Google Scholar
[69] Webster L, Dhar S, Eldon M, Masuoka L, Lappalainen J, Sostek M. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Pain 2013;154:1542-50, http://dx.doi.org/10.1016/j.pain.201304.024Search in Google Scholar
[70] Kulich KR, Madisch A, Pacini F, Pique JM, Regula J, VanRensburg CJ, Ujszaszy L, Carlsson J, Halling K, Wiklund IK. Reliabilityand validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: a six-country study. Health Qual Life Outcomes 2008;6:12, http://dx.doi.org/10.1186/1477-7525-6-12Search in Google Scholar
[71] StarreveldJS, Pols MA, Van Wijk HJ, Bogaard JW, Poen H, Smout AJ. The plain abdominal radiograph in the assessment of constipation. Z Gastroenterol 1990;28:335-8.Search in Google Scholar
[72] Breivik H. Local anesthetic blocks and epidurals. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack’s textbook of pain. 6th ed. Philadelphia PA: Elsevier; 2013. p. 523-37.Search in Google Scholar
[73] Lubawski J, Saclarides T. Postoperative ileus: strategies for reduction. Ther Clin Risk Manag 2008;4:913-7.Search in Google Scholar
[74] Popping DM, Elia N, Van Aken HK, Marret E, Schug SA, Kranke P, Wenk M, Tramer MR. Impact of epidural analgesia on mortality and morbidity after surgery: systematic review and meta-analysis of randomized controlled trials. Ann Surg 2014;259:1056-67, http://dx.doi.org/10.1097/SLA.0000000000000237Search in Google Scholar
[75] Niemi G [PhD thesis] Optimizing postoperative epidural analgesia. Faculty of Medicine, University of Oslo. Series of dissertations submitted to the Faculty of Medicine, University of Oslo, no. 219;2004, ISBN 82-8072-176-2.Search in Google Scholar
[76] Stenseth R, Sellevold O, Breivik H. Epidural morphine for postoperative pain: experiencewith 1085 patients. ActaAnaesth Scand 1985;29:146-56.Search in Google Scholar
[77] Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil 2004;16:54-60.Search in Google Scholar
[78] Vaughan-Shaw PG, FecherIC, Harris S, Knight JS. Ameta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in patients enrolled in a standardized accelerated recoveryprogram after abdominal surgery. Dis Colon Rectum 2012;55:611-20, http://dx.doi.org/10.1097/DCR.0b013e318249fc78Search in Google Scholar
[79] Camilleri M. Opioid-induced constipation: challenges and the rapeuticopportunities. Am J Gastroenterol 2011;106:835-42, http://dx.doi.org/10.1038/ajg.201130Search in Google Scholar
[80] Malmi H, Kautiainen H, Virta LJ, Farkkila N, Koskenpato J, Farkkila MA. Incidence and complications of peptic ulcer disease requiring hospitalisation have markedly decreased in Finland. Aliment Pharmacol Ther 2014;39:496-506, http://dx.doi.org/10.1111/apt.12620Search in Google Scholar
[81] Hatlebakk JG, Emken BE, Glazkov V, Hoff DA, Hausken T. Correct use of proton pump inhibitors for gastro-oesophageal reflux disease. Tidsskr Nor Laegeforen 2013;133:43-6, http://dx.doi.org/10.4045/tidsskr.12.0019Search in Google Scholar
[82] Markland AD, Palsson O, Goode PS, Burgio KL, Busby-WhiteheadJ, Whitehead WE. Association of low dietary intake of fibre and liquids with constipation: evidence from the National Health and Nutrition Examination Survey. Am J Gastroenterol 2013;108:796-803, http://dx.doi.org/10.1038/ajg.201373Search in Google Scholar
[83] Quigley EM. Probiotics in the management of functional bowel disorders: promise fulfilled? Gastroenterol Clin North Am 2012;41:805-19, http://dx.doi.org/10.1016Zj.gtc.2012.08.005Search in Google Scholar
[84] Strid H, Simren M, Storsrud S, Stotzer PO, Sadik R. Effect of heavy exercise on gastrointestinal transit in endurance athletes. Scand J Gastroenterol 2011;46:673-7, http://dx.doi.org/10.3109/00365521.2011.558110Search in Google Scholar
[85] Wang Y, Kondo T, Suzukamo Y, Oouchida Y, Izumi S. Vagal nerve regulation is essential for the increase in gastric motility in response to mild exercise. Tohoku J Exp Med 2010;222:155-63.Search in Google Scholar
[86] El-Salhy M, Svensen R, Hatlebakk JG, Gilja OH, Hausken T. Chronic constipation and treatment options. Mol Med Rep 2014;9:3-8, http://dx.doi.org/10.3892/mmr.2013.1770Search in Google Scholar
[87] Twycross R, Sykes N, Mihalyo M, Wilcock A. Stimulant laxatives and opioid-induced constipation. J Pain Symptom Manage 2012;43:306-13, http://dx.doi.org/10.1016/jjpainsymman.2011.12.002Search in Google Scholar
[88] Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut 2011;60:209-18, http://dx.doi.org/10.1136/gut.2010.227132Search in Google Scholar
[89] Jones MP, Talley NJ, Nuyts G, Dubois D. Lack of objective evidence of efficacy of laxatives in chronic constipation. Dig Dis Sci 2002;47:2222-30.Search in Google Scholar
[90] Brenner DM, Chey WD. Anevidence-base dreview of novel and emerging therapies for constipation in patients taking opioid analgesics. Am J Gastroenterol Suppl 2014;2:38-46.Search in Google Scholar
[91] Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Evolving paradigms in the treatment of opioid-induced bowel dysfunction. Therap Adv Gastroenterol 2015, http://dx.doi.org/10.1177/1756283X15589526 [published online before print June 15]Search in Google Scholar
[92] Chamberlain BH, Cross K, Winston JL, Thomas J, Wang W, Su C, Israel RJ. Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage 2009;38:683-90, http://dx.doi.org/10.1016/jjpainsymman.2009.02.234Search in Google Scholar
[93] Ishihara M, Ikesue H, Matsunaga H, Suemaru K, Kitaichi K, Suetsugu K, Oishi R, Sendo T, Araki H, Itoh Y, Japanese Study Group for the Relief of Opioid-induced Gastrointestinal Dysfunction. A multi-institutional study analyzing effect of prophylactic medication for prevention of opioid-induced gastrointestinal dysfunction. Clin J Pain 2012;28:373-81, http://dx.doi.org/10.1097/AJP.0b013e318237d626Search in Google Scholar
[94] Basilisco G, Marino B, Passerini L, Ogliari C. Abdominal distension after colonic lactulose fermentation recorded by a new extensometer. Neurogastroenterol Motil 2003;15:427-33.Search in Google Scholar
[95] Nalamachu SR. Opioid rotation inclinical practice.AdvTher2012;29:849-63, http://dx.doi.org/10.1007/s12325-012-0051-7Search in Google Scholar
[96] Allan L, Richarz U, Simpson K, Slappendel R.Transdermal fentanyl versus sustained release oral morphine in strong-opioid naive patients with chronic low back pain. Spine (Phila Pa 1976) 2005;15:2484-90.Search in Google Scholar
[97] van Seventer R, SmitJM, Schipper RM, Wicks MA, Zuurmond WW. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Curr Med Res Opin 2003;19:457-69.Search in Google Scholar
[98] Hadley G, Derry S, Moore RA, Wiffen PJ. Transdermal fentanyl for cancer pain. Cochrane Database Syst Rev 2013;10, http://dx.doi.org/10.1002/14651858.CD010270.pub2.CD010270Search in Google Scholar
[99] Fine PG. Clinical approaches to special issues related to opioid therapy. Semin Oncol Nurs 2009;25:20-8, http://dx.doi.org/10.1016/j.soncn.2009.03.011Search in Google Scholar
[100] Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev 2004;3:CD004847.Search in Google Scholar
[101] Webster LR, Fine PG. Review and critique of opioid rotation practices and associated risks of toxicity. Pain Med 2012;13:562-70, http://dx.doi.org/10.1111/j.1526-4637.2012.01357.xSearch in Google Scholar
[102] Kress HG. Tapentadol and itstwo mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon? Eur J Pain 2010;14:781-3, http://dx.doi.org/10.1016/j.ejpain.2010.06.017Search in Google Scholar
[103] Dorn S, Lembo A, Cremonini F. Opioid-induced bowel dysfunction: epidemiology, pathophysiology, diagnosis, and initial therapeutic approach. Am J Gastroenterol 2014;2:31-7, http://dx.doi.org/10.1038/ajgsup.20147Search in Google Scholar
[104] Parsons HA, de la Cruz M, El Osta B, Li Z, Calderon B, Palmer JL, Bruera E. Methadone initiation and rotation in the outpatient setting for patients with cancerpain. Cancer2010;116:520-8, http://dx.doi.org/10.1002/cncr.24754Search in Google Scholar
[105] Kwong WJ, Hammond G, Upmalis D, Okamoto A, Yang M, Kavanagh S. Bowel function after tapentadol and oxycodone immediate release (IR) treatment in patients with low back or osteoarthritis pain. Clin J Pain 2013;29:664-72, http://dx.doi.org/10.1097/AJP.0b013e318274b695Search in Google Scholar
[106] Thakur D, Dickerson S, Kumar Bhutani M, Junor R. Impact of prolonged-release oxycodone/naloxone on outcomes affecting patients’ daily functioning in compar is on with extended-releaset a pentadol:asystematic review. ClinTher 2015;37:212-24, http://dx.doi.org/10.1016/jxlinthera.201412.001Search in Google Scholar
[107] Daeninck PJ, Bruera E. Reduction in constipation and laxative requirements following opioid rotation to methad one: are port off ourcases. J Pain Symptom Manage 1999;18:303-9.Search in Google Scholar
[108] Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001;19:2898-904.Search in Google Scholar
[109] Abdulla A, Adams N, Bone M, Elliott AM, Gaffin J, Jones D, Knaggs R, Martin D, Sampson L, Schofield P. British Geriatric Society Guidance on the management of pain in older people. Age Ageing 2013;42, http://dx.doi.org/10.1093/ageing/afs200,11-57Search in Google Scholar
[110] Devin CJ, McGirt MJ. Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and functional outcomes. J Clin Neurosci 2015;22:930-8, http://dx.doi.org/10.1016/jjocn.201501.003Search in Google Scholar
[111] Centre forClinical Practiceat NICE (UK). Neuropathicpain.The pharmacological management of neuropathic pain in adults in non-specialist settings. NICE Clinical Guidelines, No. 173; November2013; last modified December 2014. http://www.nice.org.uk/guidance/cg173/resources/guidance-neuropathic-pain-pharmacological-management-pdf[accessed 25.05.15].Search in Google Scholar
[112] Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014;4, http://dx.doi.org/10.1002/14651858.CD007938.pub3.CD007938Search in Google Scholar
[113] Zhang S, Paul J, Nantha-Aree M, Buckley N, Shahzad U, Cheng J, DeBeer J, Winemaker M, Wismer D, Punthakee D, Avram V, Thabane L. Reanalysis of morphine consumption from two randomized controlled trials of gabapentin using longitudinal statistical methods. J Pain Res 2015;8:79-85, http://dx.doi.org/10.2147/JPR.S56558Search in Google Scholar
[114] Tornblom H, Drossman DA. Centrally targeted pharmacotherapy for chronic abdominal pain. Neurogastroenterol Motil 2015;27:455-67, http://dx.doi.org/10.1111/nmo.12509[Epub 03.02.15]Search in Google Scholar
[115] Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev 2015;1, http://dx.doi.org/10.1002/14651858.CD011209.pub2.CD011209Search in Google Scholar
[116] Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev 2014;9, http://dx.doi.org/10.1002/14651858.CD011003.pub2.CD011003Search in Google Scholar
[117] Lacy BE, Levy LC. Lubiprostone: a chloride channel activator.J Clin Gastroenterol 2007;41:345-51.Search in Google Scholar
[118] Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci 2010;55:1090-7, http://dx.doi.org/10.1007/s10620-009-1068-xSearch in Google Scholar
[119] Drossman DA, Chey WD, Johanson JF, Fass R, Scott C, Panas R, Ueno R. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome—results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009;29:329-41, http://dx.doi.org/10.1111/j.1365-2036.2008.03881.xSearch in Google Scholar
[120] Cryer B, Katz S, Vallejo R, Popescu A, Ueno R. A randomized study of lubiprostone for opioid-induced constipation in patients with chronic noncancer pain. Pain Med 2014;15:1825-34, http://dx.doi.org/10.1111/pme.12437Search in Google Scholar
[121] Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic non-cancer pain. Am J Gastroenterol 2015;110:725-32, http://dx.doi.org/10.1038/ajg.2015106Search in Google Scholar
[122] Marciniak CM, Toledo S, Lee J, Jesselson M, Bateman J, Grover B, Tierny J. Lubiprostone vs Senna in postoperative orthopedic surgery patients with opioid-induced constipation: a double-blind, active-comparator trial. World J Gastroenterol 2014;20:16323-33, http://dx.doi.org/10.3748/wjg.v20.i43.16323Search in Google Scholar
[123] Bryant AP, Busby RW, Bartolini WP, Cordero EA, Hannig G, Kessler MM, Pierce CM, Solinga RM, Tobin JV, Mahajan-Miklos S, Cohen MB, Kurtz CB, Currie MG. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 2010;86:760-5, http://dx.doi.org/10.1016Zj.lfs.2010.03.015Search in Google Scholar
[124] Eutamene H, Bradesi S, Larauche M, Theodorou V, Beaufrand C, Ohning G, Fioramonti J, Cohen M, Bryant AP, Kurtz C, Currie MG, Mayer EA, Bueno L. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil 2010;22:312-84, http://dx.doi.org/10.1111/j.1365-2982.2009.01385.xSearch in Google Scholar
[125] Lembo AJ, Schneier HA, Shiff SJ, Kurtz CB, MacDougall JE, Jia XD, Shao JZ, Lavins BJ, Currie MG, Fitch DA, Jeglinski BI, Eng P, Fox SM, Johnston JM. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011;365:527-36, http://dx.doi.org/10.1056/NEJMoa1010863Search in Google Scholar
[126] Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, Shi K, MacDougall JE, Shao JZ, Eng P, Fox SM, Schneier HA, Kurtz CB, Johnston JM. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107:1714-24.Search in Google Scholar
[127] BriejerMR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, Prins NH, Schuurkes JA. The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound. Eur J Pharmacol 2001;29:71-83.Search in Google Scholar
[128] Briejer MR, Prins NH, Schuurkes JA. Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs. Neurogastroenterol Motil 2001;13:465-72.Search in Google Scholar
[129] TackJ, Quigley E, Camilleri M, Vandeplassche L, Kerstens R. Efficacy and safety of oral prucalopride in women with chronic constipation in whom laxatives have failed: an integrated analysis. United European. Gastroenterol J 2013;1:48-59, http://dx.doi.org/10.1177/2050640612474651Search in Google Scholar
[130] Sloots CE, Rykx A, Cools M, Kerstens R, De Pauw M. Efficacy and safety of prucalopride in patients with chronic non-cancer pain suffering from opioid-induced constipation. Dig Dis Sci 2010;55:2912-21, http://dx.doi.org/10.1007/s10620-010-1229-ySearch in Google Scholar
[131] Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced constipation and analgesia. J Pain Symptom Manage 2002;23:48-53.Search in Google Scholar
[132] De Schepper HU, Cremonini F, Park MI, Camilleri M. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil 2004;16:383-94.Search in Google Scholar
[133] Smith TH, Grider JR, Dewey WL, Akbarali HI. Morphine decreases enteric neuron excitability via inhibition of sodium channels. PLoS ONE 2012;7:e45251, http://dx.doi.org/10.1371/journal.pone.0045251Search in Google Scholar
[134] Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med 2012;26:50-60, http://dx.doi.org/10.1177/0269216311418869Search in Google Scholar
[135] Lowenstein O, Leyendecker P, Hopp M, Schutter U, Rogers PD, Uhl R, Bond S, Kremers W, Nichols T, Krain B, Reimer K. Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial. Expert Opin Pharmacother 2009;10:531-43, http://dx.doi.org/10.1517/14656560902796798Search in Google Scholar
[136] MeissnerW, Leyendecker P, Mueller-LissnerS, NadstawekJ, Hopp M, Ruckes C, Wirz S, Fleischer W, Reimer K. A randomized controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. EurJ Pain 2009;13:56-64, http://dx.doi.org/10.1016/j.ejpain.2008.06.012Search in Google Scholar
[137] Simpson K, Leyendecker P, Hopp M, Muller-Lissner S, Lowenstein O, De Andres J, Troy Ferrarons J, Bosse B, Krain B, Nichols T, Kremers W, Reimer K. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe non-cancer pain. Curr Med Res Opin 2008;24:3503-12, http://dx.doi.org/10.1185/03007990802584454Search in Google Scholar
[138] Movafegh A, Shoeibi G, Ansari M, Sadeghi M, Azimaraghi O, Aghajani Y. Naloxone infusion and post-hysterectomy morphine consumption: a doubleblind, placebo-controlled study. Acta Anaesthesiol Scand 2012;56:1241-9, http://dx.doi.org/10.1111/j.1399-6576.2012.02764.xSearch in Google Scholar
[139] Murphy JD, Gelfand HJ, Bicket MC, Ouanes JP, Kumar KK, Isaac GR, Wu CL. Analgesic efficacy of intravenous naloxone for the treatment of postoperative pruritus: a meta-analysis. J Opioid Manag 2011;7:321-7.Search in Google Scholar
[140] Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence. Pain 2000;84:121-31.Search in Google Scholar
[141] Monitto CL, Kost-Byerly S, White E, Lee CK, Rudek MA, Thompson C, Yaster M. The optimal dose of prophylactic intravenous naloxone in ameliorating opioid-induced side effects in children receiving intravenous patient-controlled analgesia morphine for moderate to severe pain: a dose finding study. Anesth Analg 2011;113:834-42, http://dx.doi.org/10.1213/ANE.0b013e318229a44Search in Google Scholar
[142] Wang HY, Friedman E, Olmstead MC, Burns LH. Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signalling. Neuroscience 2005;135:247-61.Search in Google Scholar
[143] Breivik H, Werner MU. Combining an oral opioid-receptor agonist and the antagonist naloxone: a smart drug design that removes some but not all adverse effects of the opioid analgesic. Scand J Pain 2014;5:72-4.Search in Google Scholar
[144] Hesselbarth S, Hermanns K, Oepen P. Prolonged-release oxycodone/naloxone in opioid-naive patients - subgroup analysis of a prospective observational study. Expert Opin Pharmacother 2015;16:457-64, http://dx.doi.org/10.1517/14656566.2015.1001737Search in Google Scholar
[145] Anissian L, Schwartz HW, Vincent K, Vincent HK, Carpenito J, Stambler N, Ramakrishna T. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation: phase 2 study in rehabilitation after orthopaedic surgery. J Hosp Med 2012;7:67-72, http://dx.doi.org/10.1002/jhm.943Search in Google Scholar
[146] Michna E, Weil AJ, Duerden M, Schulman S, Wang W, Tzanis E, Zhang H, Yu D, Manley A, Randazzo B. Efficacy of subcutaneous methylnaltrexone in the treatment of opioid-induced constipation: a responder post hoc analysis. Pain Med 2011;12:1223-30.Search in Google Scholar
[147] Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction. Clin Exp Gastroenterol 2014;7:345-58, http://dx.doi.org/10.2147/CEG.S52097Search in Google Scholar
[148] Tack J, Lappalainen J, Diva U, Tummala R, Sostek M. Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response. United Eur Gastroenterol 2015, http://dx.doi.org/10.1177/2050640615604543(epub before print)Search in Google Scholar
[149] Nordahl Christensen H, Olsson U, From J, Breivik H. Opioid-induced constipation, use of laxatives, and health-related quality of life. Scand J Pain 2016;11:104-10.Search in Google Scholar
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