How Long After Taking Opioids Will U Start to Poop Again
Curr Gastroenterol Rep. Author manuscript; available in PMC 2017 Feb 8.
Published in final edited course as:
PMCID: PMC5297124
NIHMSID: NIHMS511349
Opioid-Induced Bowel Dysfunction
Gyanprakash A. Ketwaroo
Beth State of israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215, Us. 617-667-2136. 617-667-1234 (fax)
Vivian Cheng
Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215, USA. 617-667-0682
Anthony Lembo
Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215, USA. 617-667-2138. 617-667-1171 (fax)
Abstract
Opioid-induced bowel dysfunction (OIBD) is a potentially debilitating side result of chronic opioid utilize. Information technology refers to a collection of primarily gastrointestinal motility disorders induced by opioids, of which opioid-induced constipation (OIC) is the most common. Management of OIBD is hard, and affected patients will oft limit their opioid intake at the expense of experiencing more than pain, to reduce the negative affect of OIBD on their quality of life. Effective pharmacologic therapy for OIC is considered an unmet need and several agents have recently been given priority review and approving for OIC. Furthermore, multiple agents currently in evolution show promise in treating OIC without meaning impact on analgesia or precipitation of withdrawal symptoms. The blessing and availability of such medications would correspond a pregnant improvement in the management of OIC and OIBD in patients with chronic pain.
Keywords: Constipation, opioid, bowel dysfunction
INTRODUCTION
Chronic use of opioids to manage hurting is common in clinical practice [1–3]. In the United States, opioid employ has increased sharply over the past decade and it is estimated that approximately 3 % of the population receives long-term opioid therapy for chronic non-cancer pain [iv]. Amongst patients who require chronic opioids, the residue betwixt the incidence and severity of side furnishings and analgesia plays an important role in the success or failure of adequate pain management programs. The gastrointestinal (GI) tract is a particularly of import source of opioid-related side furnishings, collectively termed opioid-induced bowel dysfunction (OIBD). Although opioid-induced constipation (OIC) is the most common side effect of opioids, other symptoms related to OIBD include nausea, vomiting, and dyspepsia [5]. Patients taking opioids may also endure from decreased gastric emptying (often leading to gastroesophageal reflux and heartburn), abdominal cramping, spasm, and bloating [6–nine]. Consequently, OIBD can take a dramatic negative impact on quality of life, both as a result of the direct, unwanted effects of opioids as well as a consequence of side effect-induced limitations of adequate dosing of narcotic analgesics.
FREQUENCY AND IMPACT OF OPIOID-INDUCED CONSTIPATION
In a survey of patients with non-cancer pain taking a median daily dose of 127.five mg morphine-equivalent (range vii.v–600 mg) the most normally reported GI side result was constipation (46.9 %; 95 % CI 36.8–57.3), followed by gastro-esophageal reflux disease (33 %; 95 % CI 23.5–42.9), nausea (27 %; 95 % CI 17.2–35.three), and vomiting (9 %; 95 % CI 17.two–35.3) [10]. Chronic abdominal hurting was also common (58.2 %; 95 % CI 53.2–73.ix) and was associated with reduction in quality of life. A Cochrane systematic review of adults on opioids for non-cancer pain for at least half-dozen months institute 22.0 % (95 % CI, fifteen.2–32.8) of patients discontinuing therapy due to adverse furnishings [xi].
A multi-national study involving 322 patients taking oral opioids and laxatives found that OIC was most often characterized every bit astringent, with 45 % reporting <iii bowel movements per week [12]. Importantly, nearly a third of patients contradistinct their doses of opioid therapy in an attempt to mitigate the constipating side furnishings of these medications.
PATHOPHYSIOLOGY OF OPIOID-INDUCED GASTROINTESTINAL EFFECTS
The activity of opioids in the gut is mediated by μ-, δ-, and κ-opioid receptors, the distribution of which varies within the layers of the GI tract. In particular, μ-opioid receptors—through which most opioid analgesics role [thirteen]—are present on the myenteric and submucosal neurons and on immune cells in the lamina propria. These receptors are present in the highest concentrations in the tummy and proximal colon [6, 14]. Endogenous opioids, such equally met-enkephalin, leu-enkephalin, β-endorphin, and dynorphin [fifteen], inhibit both propulsive motor and secretory activities [6].
Exogenous opioids cause constipation through multiple mechanisms. Through their effects on enteric neurons, opioids delay intestinal transit by stimulating nonpropulsive motility, increasing intestinal tone, and stimulating the pyloric and ileocecal sphincters [sixteen]. Opioid agonists too stimulate fluid absorption in the gut by increasing contact time for assimilation and stimulating mucosal sensory receptors. These agents also appear to inhibit chloride secretion past suppressing the excitation of cholinergic secretomotor neurons in the enteric nervous organization [sixteen]. Genetic polymorphisms and variety may play a role in variation of people'south responses to opioids [17]. Such genetic diversity may impact the potential for developing OIBD, though the evidence for this remains limited.
Management OPTIONS FOR OPIOID-INDUCED CONSTIPATION
Since the dose that produces constipation is mostly only 25 % of that required to provide acceptable analgesia, simple opioid dose reduction is more often than not non an effective pick for the management of OIC. Thus, alternative options for managing this condition must be explored.
Opioid rotation
Opioids have slightly different propensities to cause constipation in private patients. Switching opioids, or "opioid rotation", may be used equally a strategy to relieve OIC or other adverse furnishings. A prospective trial enrolled 118 cancer patients at a single institution [18], who underwent opioid switching due to an unacceptable remainder betwixt analgesia and opioid-induced adverse effects. 80-1 pct of substitutions were successful in finding a more acceptable remainder between analgesia and adverse effects after the showtime switch in opioids and an additional vi % responded later on a 2d switch in therapy. The hateful time required to identify an appropriate dose later switching was 3.two days and the fourth dimension to hospital belch was straight related to the time needed to attain dose stabilization. While this small trial suggests that algorithm-guided opioid rotation can exist constructive, prospective randomized trials regarding the efficacy and cost of this strategy are lacking and caution is necessary as equianalgesic doses tin vary from person to person.
Novel opioids with less constipation
Few studies accept directly compared the prevalence of GI side effects among opioids. Four controlled studies, however, found that transdermal fentanyl was associated with less frequent laxative utilize compared with morphine [19–22]. Tapentadol is a novel μ-opioid agonist that as well inhibits norepinephrine, which is believed to augment its analgesic activity [23]. In a trial conducted in patients with lower dorsum pain, tapentadol extended release 100–250 mg twice daily and oxycodone HCl controlled release twenty–fifty mg twice daily were both effective in decision-making pain; however, the GI side outcome profile of tapentadol was substantially meliorate than that of oxycodone [24]. Similar results were seen in trials conducted in patients with moderate-to-severe chronic joint and back pain [25–28].
Adjunctive pharmacologic treatment
Laxatives
Conventionally, OIC is first approached through the utilize of laxatives such as osmotic (due east.g., polyethylene glycol, magnesium) and stimulant laxatives (e.g., senna, bisacodyl). However, only about l % of patients experience satisfactory relief using this strategy [29, 30]. For this reason, handling with laxatives often requires frequent dose adjustments, combination therapy, and laxative switching before achieving satisfactory results.
Lubiprostone
Lubiprostone, a chloride channel blazon ii activator, is the only oral medication approved past the Nutrient and Drug Assistants (FDA) for use in chronic constipation and irritable bowel syndrome (IBS) with constipation. It was recently canonical for treating OIC at a dose of 24 mcg twice daily, based on three Phase 3 randomized double-bullheaded controlled trials involving patients with chronic not-cancer hurting [31].
One Phase 3 trial, Study 1, was conducted in 431 patients with non-cancer-related pain treated with any opioid agonist except methadone. Subjects were randomized to lubiprostone 24 mcg twice daily or placebo for 12 weeks. This written report'south master endpoint was the spontaneous bowel motility (SBM) response rate, divers every bit 3 or more than SBMs per week for at least ix weeks and at least 1 additional SBM per week over the hateful at baseline. At the end of the 12-week treatment menstruum, significantly more patients taking lubiprostone were "overall responders" compared with those receiving placebo (27.ane vs. 18.9 %, p = 0.03) [31].
In the other two identically designed Phase 3 trials, patients with chronic non-cancer pain on chronic opioid therapy including methadone received lubiprostone 24mcg twice daily or placebo for 12 weeks [31]. The main endpoint was the mean change from baseline in the frequency of SBMs at week 8. In one study (n = 418), there was a statistically significant handling difference of 0.nine SBM (three.3 vs. 2.4 for the lubiprostone and placebo treated groups, respectively; p = 0.004). Furthermore, there was a college proportion of "overall responders" (3 or more SBMs per week for at least ix weeks and at least 1 additional SBM per week over the hateful at baseline),in the lubiprostone-treated grouping compared to the placebo group (24.3 vs. 15.3 %, respectively). In the 3rd study (n = 451), there was no statistically significant change in SBM at week viii for the lubiprostone treated group compared with placebo [31].
Among all iii studies (n = 1,492), the well-nigh common adverse events in the lubiprostone group compared with the placebo group were nausea (11 vs. 5 %), diarrhea (viii vs. 2 %), and abdominal pain (4 vs. ane %). There were no serious adverse events [31].
Naloxone
Naloxone, a competitive adversary at opioid receptors with much higher affinity for μ-receptors than both κ- and δ-receptors, has been used to reverse OIC. Naloxone has a low oral systemic bioavailability due to extensive first pass-metabolism. Nevertheless, information technology is still widely distributed throughout the torso and central nervous organisation, and when used at even a low dosage (two–4 mg three times daily) analgesia reversal and induction of opioid withdrawal symptoms tin occur [32]. Combining oxycodone with naloxone has been shown to improve symptoms of constipation without significant reduction in analgesia for upward to 52 weeks [33]. In a contempo randomized command trial of 185 patients with chronic cancer hurting, oxycodone/naloxone prolonged-release tablets were as effective every bit prolonged-release oxycodone in maintaining analgesia with significantly less constipation symptoms [34].
Methylnaltrexone
Methylnaltrexone, a fourth ammonium derivative of naltrexone, is largely restricted to the periphery due to poor lipid solubility and is thus less likely than naloxone to opposite analgesia and induce opioid withdrawal symptoms [35]. It tin be administered intravenously, subcutaneously, and orally, and all forms have been associated with a reduction in OIC. Only the subcutaneous administration grade of methylnaltrexone is FDA canonical for the treatment of OIC in advanced disease.
When administered intravenously, infusion of methylnaltrexone has been shown to opposite the constipation induced by methadone, increasing stool frequency and decreasing orocecal transit time [36, 37]. Subcutaneous methylnaltrexone was examined in 133 patients with advanced disease and opioid-induced constipation that had not responded to ≥3 days of laxatives [38]. In the methylnaltrexone grouping, 48 % of patients had a bowel motion inside 4 h after the first study dose compared to 15 % in the placebo grouping, and 52 % had a bowel move within 4 h after ≥2 of the first iv doses, compared with 8 % in the placebo grouping (p ≤ 0.001 for both comparisons; Fig. i). The response rate remained consistent throughout a 3-month extension trial. Evidence of withdrawal mediated past fundamental nervous organization opioid receptors or changes in pain scores was not observed. Intestinal pain and flatulence were the virtually mutual adverse events. Subsequent studies have confirmed a similar efficacy of subcutaneous methylnaltrexone at a dose of 12 mg either in one case daily or every other day in treating OIC [39–41]. Subcutaneous methylnaltrexone was approved past the FDA in 2008 for opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient [42]. It is usually dosed once every other day, merely no more oftentimes than one dose in a 24-h period. The recommended dose of methylnaltrexone is 8 mg for patients weighing between 38 and 62 kg, 12 mg for patients weighing 62 to 114 kg, and 0.15 mg/kg for patients outside these ranges.
Primary outcomes of a clinical trial comparing methylnaltrexone and placebo in patients with opioid-induced constipation [38]
Results from a 12-week phase iii trial in 803 patients with chronic non-cancer pain and OIC with oral methylnaltrexone (150, 300, or 450 mg; 4 weeks daily dosing, followed by 8 weeks PRN dosing) were recently presented [43]. Patients receiving the 300 and 450 mg doses accomplished a statistically significant higher incidence of bowel movements without the demand for laxatives compared with placebo. Throughout the study, there were minimal changes from baseline in pain intensity scores, regardless of the treatment group.
Alvimopan
Alvimopan is an oral μ-opioid receptor antagonist that does not cross the blood–brain barrier [44]. Alvimopan was approved by the FDA in 2008 for post-operative ileus with a Risk Evaluation and Mitigation Strategy due to an increased number of myocardial infarctions in one 12-calendar month study. This imbalance has not been observed in other studies. While alvimopan is non approved for the management of OIC, it has been extensively studied for this indication. In ane pivotal trial, 522 patients taking ≥30 mg of oral morphine and with associated constipation (i.e., <3 SBMs per week), were randomized to 6 weeks of alvimopan 0.v mg twice daily, 1 mg once daily, 1 mg twice daily, or placebo. Alvimopan at all doses evaluated was associated with a meaning increment in the hateful number of SBMs per week over the first 3 weeks of treatment. Alvimopan was also associated with improvements in straining, stool consistency, incomplete evaluation, decreased appetite, and abdominal bloating/discomfort. In this study, the side effect profile of the 0.5 mg twice daily dose was similar to placebo [45].
Later on, two large Phase 3 clinical trials have been published comparing alvimopan 0.5 mg once daily, twice daily, or placebo for 12 weeks in non-cancer OIC [46, 47]. Only one of the two studies met the primary endpoint (i.eastward., the proportion of patients experiencing ≥iii SBM per calendar week over the treatment period and an boilerplate increase from baseline of ≥1 SBM). Both studies showed comeback in straining, stool consistency, incomplete evacuation, and abdominal bloating/discomfort. Alvimopan did non significantly contrary opioid analgesia.
Agents under investigation
Naloxegol (formerly known as NKTR-118) is a combination of oral naloxol, a derivative of the opioid antagonist naloxone, and a polyethylene glycol moiety, which reduces offset-pass metabolism, thereby increasing bioavailability and reducing penetration into the central nervous system. The results of ii Phase 3 trials (KODIAC-04 and -05) and a safe extension trial for naloxegol were recently announced, although they take not yet appeared in a peer-reviewed literature [48]. Both studies evaluated the efficacy of 12 weeks of treatment with naloxegol 12.5 and 25 mg compared with placebo. The primary endpoint was response at 12 weeks defined every bit ≥iii SBMs per calendar week with a ≥1 SBM increment over baseline for ≥9 of 12 weeks. In KODIAC-04, both the 12.5 and 25 mg doses of naloxegol demonstrated statistically meaning results for the primary endpoint (p = .015 and 0.001, respectively). In KODIAC-05, but the 25-mg dose was statistically significant (p = 0.021). Arthralgia was the only adverse event that occurred at a greater frequency in the naloxegol 25-mg arm compared to placebo.
TD-1211 is an oral multivalent inhibitor of the μ-opioid receptor currently nether investigation for the direction of OIC. In a recent Stage 2 trial, 217 patients with non-cancer OIC were randomized to one of three doses of TD-1211 (5, 10, or 15 mg after a lead in period of 5 mg in all groups) or placebo for 5 weeks. All doses of TD-1211 met the primary endpoint of an increment in weekly average complete spontaneous bowel movements (CSBMs) over treatment weeks 2–5 compared to baseline. The placebo-treated grouping reported an increase from baseline of 0.8 CSBMs per week versus 2.5 (p = 0.0003), two.6 (p = 0.001), and one.five (p = 0.04) CSBMs per week for the TD-1211-treated groups (15, x, and 5 mg, respectively). The most common agin events were abdominal pain, nausea, diarrhea, and headache and at that place was no adverse result on analgesia with TD-1211 [49].
Benvenopran (CB-5945, formerly ADL5945) is another peripherally-acting μ-opioid receptor antagonist under investigation for OIC. Two Stage 2 trials recently compared benvenopran with placebo in patients with non-cancer chronic pain and OIC. The principal endpoint was change in SBMs over the iv-week treatment period. Benvenopran-treated patients receiving 0.25 mg daily and 0.25 mg twice daily showed statistically significant increases from baseline compared to those receiving placebo daily and twice daily (2.58, 3.42, 1.40, and one.44 SBM, respectively). The most commonly reported adverse events were intestinal pain and upper respiratory tract infection. At that place were no changes in analgesic effect or evidence of CNS effects [50].
Prucalopride is a v-HT4 agonist that accelerates colonic transit in healthy humans and in patients with functional constipation. It is canonical in the European Union and Canada for chronic idiopathic constipation. A Stage ii trial randomized 196 chronic non-cancer hurting patients with OIC and no history of chronic constipation prior to kickoff opioid therapy to either prucalopide 2 or 4 mg or placebo for four weeks. The primary endpoint was the proportion of patients with an increment of at to the lowest degree ≥1 CSBM per calendar week from baseline. During the starting time week of treatment, both prucalopride-treated groups had a statistically significant increase in the proportion of patients reporting an increase of ≥1 CSBM over the first calendar week compared to placebo (43.eight % of prucalopride 2 mg, 50.0 % of prucalopride iv mg, and 23.4 % of placebo-treated patients). When averaged over the 4 weeks, a greater proportion of prucalopride-treated patients reported an increase of ≥1 CSBM per week from baseline (35.nine % with prucalopride two mg, 40.3 % with prucalopride iv mg) compared to placebo (23.four %); however, these differences did not achieve statistical significance. The most common adverse events observed in these trials were intestinal pain and nausea [51].
Due south-297995 (Naldemedine) is an oral, peripherally interim μ-opioid receptor antagonist that recently completed a placebo-controlled unmarried-ascending dose report in patients with OIC. Patients were randomized if they had chronic pain requiring 90 mg or more morphine equivalents daily for at least 3 months. A full of 75 subjects were randomized to ane of half dozen S-297995 cohorts: 0.01, 0.03, 0.ane, 0.3, ane.0, or 3.0 mg. Preliminary results suggest that the medication was well tolerated with balmy or moderate adverse events and no testify of opioid central withdrawal and a dose-dependent increase from baseline in the number of SBMs [52].
Management Guidelines
The National Comprehensive Cancer Network (NCCN) and the American Academy of Pain Medicine (AAPM) have issued guidelines for the management of OIC [53, 54]. Both advocate prophylaxis including adequate fluid and cobweb intake, laxatives, and stool softeners. While the AAPM advise that there is insufficient testify to recommend oral opioid antagonists to treat OIBD, the NCCN back up the apply of stool softeners, magnesium hydroxide, bisacodyl, lactulose, sorbitol, magnesium citrate, or polyethylene glycol, and/or the use of Fleets, saline, or tap water enemas. The NCCN as well suggest opioid rotation to potentially less constipating agents, such as fentanyl or methadone, and the use of the opioid adversary, methylnaltrexone, in astringent cases.
CONCLUSION
Opioids are the foundation of the management of moderate to severe hurting. Given the aging population and an increasing focus on improved management of hurting, it is likely that chronic apply of opioids, and OIBD, will continue to increase. For these reasons, information technology is disquisitional for physicians to recognize the GI side effects of these agents and manage them appropriately. There is a broad range of management strategies for OIC with stimulant laxatives, with or without stool softeners, as the get-go-line pharmacologic treatment used in most patients. Unfortunately, these inexpensive and readily available agents rarely provide consummate relief from OIC. In resistant patients, opioid rotation, lubiprostone, and methylnaltrexone should be considered. There have also been promising data on the benefits of investigational drugs such as benvenopran and naloxogel, amongst others. With electric current therapies and ongoing research into new pharmacological options, there is hope that eventually the impact of OIC and other GI side effects associated with chronic opioid use will be minimized while permitting acceptable pain relief.
Footnotes
Conflict of Interest
Gyanprakash A. Ketwaroo, Vivian Cheng, and Anthony Lembo declare that they have no disharmonize of interest
Human being and Animal Rights and Informed Consent
This article does not incorporate any studies with man or animal subjects performed by any of the authors.
Contributor Information
Gyanprakash A. Ketwaroo, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215, United states of america. 617-667-2136. 617-667-1234 (fax)
Vivian Cheng, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215, The states. 617-667-0682.
Anthony Lembo, Beth Israel Deaconess Medical Centre, 330 Brookline Ave, Boston MA 02215, USA. 617-667-2138. 617-667-1171 (fax)
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297124/
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