Drug Evaluation

Use of lubiprostone in constipating disorders and its potential for -induced bowel dysfunction

Lubiprostone is a novel , approved by the US FDA for the treatment of chronic idiopathic in adults and constipation-predominant in adult women. It is an activator of the CIC-2 chloride channel, indirectly making more water available in the lumen of the gastrointestinal tract. Secondary stretching of the gastrointestinal wall possibly causes increased small- and large-bowel transit, making it beneficial in constipation-based conditions, not only chronic idiopathic constipation and constipation-predominant irritable bowel syndrome, but also possibly opioid-induced bowel dysfunction. Lubiprostone has some preclinical data to support its use in this indication, confirmed by the preliminary efficacy and safety results of the two, very recently completed, randomized, double-blind, placebo-controlled studies.

KEYWORDS: chronic idiopathic constipation n constipation-predominant Egilius LH Spierings irritable-bowel syndrome n lubiprostone n opioid-induced bowel dysfunction Department of Neurology, Brigham and Women’s Hospital, Harvard Medical Lubiprostone is a novel medication that, in in this case, of chloride ions, for which the School, and January 2006, was approved by the US FDA lipid-bilayer cell membrane is not permeable. It Craniofacial Pain Center, for the treatment of chronic idiopathic constipa- facilitates diffusion down a concentration gra- Department of General tion in adults, and in April 2008, was approved dient, which is created by the uptake of chloride Dentistry, Tufts University for the treatment of constipation-predominant ions into the cell across the basolateral mem- School of Dental Medicine irritable bowel syndrome (IBS) in adult women. brane through sodium–potassium–chloride 25 Walnut Street, This review will discuss lubiprostone’s pharma- cotransport activity. Suite 400, Wellesley Hills, cology, as well as its efficacy and safety in the In simplified terms, there are four types MA 02481-2150, USA approved indications; in addition the preclinical of chloride channels: voltage-gated, calcium- Tel.: +1 781 431 1113 and preliminary clinical efficacy and safety data gated, protein-kinase-gated and -gated. Fax: +1 781 431 1086 supporting its potential usefulness in the treat- The CIC-2 channel, the selective target of [email protected] ment of opioid-induced bowel dysfunction will lubiprostone, is one of nine voltage-gated be presented. chloride channels. Activation of this channel results in an efflux of chloride ions from the Lubiprostone epithelial intracellular space into the lumen of „„Structure the gastro­intestinal tract. The efflux of chloride ® Lubiprostone (SPI-211/RU-211, Amitiza ) [101] ions is followed by a flow of sodium ions from is a bicyclic fatty-acid derived from the 15-keto the gastro­intestinal extracellular space through

(Figure 1) metabolite of E1 . It is a paracellular pathways in between the epithelial member of a new class of compounds called pros- cells, to maintain electroneutrality. The accu- tones, a collective name for the 15-keto metabolites mulation of sodium ions in the gastrointestinal of natural and structurally similar lumen, in turn, draws extracellular water into compounds. The only other FDA-approved pros- the lumen to maintain osmotic balance. tone is , indicated for the lowering of intraocular pressure in patients with open-angle „„Metabolism glaucoma or ocular hypertension. As a , lubiprostone is highly lipophilic, but its absorption is negligible due to rapid „„Function metabolism locally in the gastrointestinal tract, Lubiprostone is an activator of the CIC-2 chlo- resulting in a of less than 1%. Its ride channel, which is a transmembrane protein, main metabolite is M3 or 15-hydroxy-lubipros- located in the apical or luminal membrane of tone, which is pharmacologically active and does the epithelial cells lining the gastrointestinal get absorbed. However, its systemic bioavailabil- tract (Figure 2). The protein allows the passage, ity is also low, and accounts for less than 10% of

10.2217/THY.09.52 © 2009 Future Medicine Ltd Therapy (2009) 66(5),(5), 657–665 ISSN 1475-0708 657 Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

also opioid-induced bowel dysfunction. The slow- O ing of gastric emptying, causing gastric disten- O H sion, may account for its most common adverse OH event, . H An important function of the colon is to extract water from the stool; with the increased transit H the colon has less time to perform this function, O resulting in softer stool, which, in turn, is easier to evacuate. A schematic of lubi­prostone’s mode of HO action in relieving constipation-based conditions F is shown in Figure 3. F CH3 From a safety perspective, the studies in healthy volunteers have shown lubiprostone not to affect Figure 1. Lubiprostone. serum electrolytes and not to impact the elec- trocardiogram, which was also confirmed in the the administered lubiprostone dose. It has a time studies of lubiprostone in subjects with chronic to maximum plasma concentration and plasma- constipation and constipation-predominant IBS elimination half-life of approximately 1 h; its reviewed below. protein binding is 94%. Chronic idiopathic constipation „„Mode of action „„Definition In healthy volunteers, lubiprostone has been Rome III refers to chronic idiopathic constipa- shown to decrease gastric emptying and increase tion as that presents as small-bowel and large-bowel transit [1], but not to persistently difficult, infrequent or seemingly increase colonic motor function [2]. The motility incomplete defecation, not meeting IBS crite- effects that occur with lubiprostone are secondary ria [3]. It estimates constipation to occur in up to the secretion of water it causes into the lumen of to 27% of the population, affecting all ages, and the gastrointestinal tract. The increased water, in to be most common in women and nonwhites. turn, distends the gastro­intestinal tract and causes The diagnostic criteria listed for functional mural stretching, delaying gastric emptying to constipation require them to be fulfilled for facilitate digestion and accelerating bowel transit the last 3 months, with symptom onset at least to facilitate stool evacuation. The latter makes the 6 months prior to diagnosis:

medication beneficial in constipation-based con- n Must include two or more of the following: ditions, such as chronic idiopathic constipation, constipation-predominant IBS and, potentially, ––Straining during at least 25% of defecations ––Hard or lumpy stools in at least 25% of Apical Basolateral defecations ––Sensation of incomplete evacuation for at least 25% of defecations CFTR - Cl + Cl- channel K Cl- Na–K–2Cl ––Sensation of anorectal obstruction or Na+ cotransporter blockage for at least 25% of defecations Na+ ClC-2 Cl- ~ Na+ pump ––Manual maneuvers to facilitate in at least Cl- channel K+ 25% of defecations K+ K+ channel ––Fewer than three defecations per week

n Loose (mushy) or watery stools are rarely Na+ Paracellular path present without the use of

n There are insufficient criteria for IBS Figure 2. Chloride-ion (Cl-) transport in intestinal epithelial cells. At the basolateral membrane, chloride ions enter the cell from the blood across the In the above diagnostic criteria, hard or sodium–potassium–chloride (Na–K–2Cl) cotransporter. Sodium ions are expelled lumpy stools is defined as types 1 or 2 of the by the sodium pump and potassium ions leave via a potassium channel. Sodium Bristol Stool Form Scale – that is, separate ions are shown crossing the cell layer via a paracellular pathway, but sodium hard lumps like nuts (difficult to pass) or sau- channels also exist (not shown). Reproduced with permission from [11]. sage shaped but lumpy; loose (mushy) or watery

658 Therapy (2009) 6(5) future science group Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

Lubiprostone

Increased intraluminal chloride

Increased intraluminal sodium

Decreased Increased Softer stool water intraluminal absorption water

Decreased Increased transit time intraluminal Easier volume evacuation

Increased Luminal Easier motility distension evacuation

Mural stretching

Figure 3. Mode of action of lubiprostone in constipation-based conditions.

stools are defined as types 6 or 7 on the Bristol 33 subjects were randomized to placebo, Stool Form Scale – that is, fluffy pieces with 30 subjects to 24-µg lubiprostone, 32 subjects ragged edges, a mushy or watery stool, no solid to 48-µg lubiprostone and 34 subjects to 72-µg pieces or entirely liquid. lubiprostone. A spontaneous bowel movement was defined as a bowel movement not preceded „„Lubiprostone within 24 h by intake of rescue medication, Dose exploration consisting of a 10-mg suppository or A randomized, double-blind, placebo-controlled a sodium-phosphate . The subjects also study evaluated lubiprostone in the treatment had to have abdominal bloating or discomfort of chronic idiopathic constipation in doses and one or more of the following symptoms: of 24, 48 and 72 µg per day, administered as (very) hard stool, subjectively incomplete evacu- 24 µg once-daily, twice-daily and three-times ation and straining at defecation. The eligibil- daily, respectively, for 3 weeks [4]. The study ity requirements were verified after a 14-day randomized 129 adult subjects with a history of washout/baseline period during which the fewer than three spontaneous bowel movements subjects discontinued all nonprescription and per week, on average, for at least 6 months: prescription laxatives and fiber supplements.

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The primary end point was the average num- Safety ana­lysis ber of spontaneous bowel movements per week In the dose-ranging study, 75% of the sub- over the 3-week treatment period. The study jects receiving lubiprostone, 24 µg twice-daily, was powered to detect a minimum difference reported adverse events, versus 40% of those of 2.5 spontaneous bowel movements per week receiving placebo (p = 0.006). The most com- (a = 0.05; b = 0.86). Of the 129 randomized mon adverse event was nausea (43.8 vs 0.0%), subjects, 127 subjects were in the intention-to- followed by (12 vs 12%) and dizzi- treat population, with two randomized subjects ness (9 vs 3%). In the confirmatory study, 70% not having taken study medication. The primary of the subjects receiving lubiprostone, 24 µg end point was met for the 24 µg twice-daily treat- twice-daily, reported adverse events versus 51% ment regimen. This treatment regimen also dem- of those receiving placebo (p = 0.003). The most onstrated significant differences versus placebo common adverse event was nausea (32 vs 3%; over the 3-week treatment period for straining, p < 0.001), followed by headache (12 vs 6%; stool consistency, abdominal bloating, severity p = 0.115), (6 vs 1%; p = 0.035) and of constipation and subject rating of treatment dizziness (6 vs 1%; p = 0.035). effectiveness, but not for abdominal discomfort. Constipation-predominant IBS Effect confirmation „„Definition Two randomized, double-blind, placebo- Rome III defines IBS as a functional bowel controlled studies with lubiprostone 24 µg, disorder in which abdominal discomfort or twice-daily, provided confirmatory evidence of pain is associated with defecation or a change efficacy in the treatment of chronic idiopathic in bowel habit, and with features of disordered constipation, of which one was published in full defecation [3]. It estimates that 10–20% of ado- [5]. This study randomized 244 adult subjects lescents and adults have symptoms consistent with a history of fewer than three spontane- with it; most studies find a female preponder- ous bowel movements per week, on average, ance. IBS symptoms come and go over time, for at least 6 months – 124 subjects to placebo often overlap with other functional disor- and 120 subjects to lubiprostone. The subjects ders, impair quality of life and result in high also had to have one or more of the following healthcare costs. symptoms with at least 25% of the spontaneous The diagnostic criteria listed for IBS require bowel movements: (very) hard stool, subjectively them to be fulfilled for the last 3 months, with incomplete evacuation and straining at defeca- symptom onset at least 6 months prior to diag- tion. The eligibility requirements were verified nosis. Recurrent abdominal discomfort or pain, after a 14-day prospective baseline period, which defined as an uncomfortable sensation not was followed by a 4-week treatment period. described as pain, must be present at least 3 days The primary end point was the number of per month in the last 3 months, associated with spontaneous bowel movements during the first two or more of the following: week of treatment, with spontaneous bowel move- ment defined as above, and the same rescue medi- n Improvement with defecation cations allowed. The study was powered to detect n Onset associated with a change in frequency a minimum difference of two spontaneous bowel of stool movements per week (a = 0.05; b = 0.90). Of the 244 subjects, 242 were in the intention-to- n Onset associated with a change in form treat population, with two randomized subjects (appearance) of stool discontinuing the study before receiving study medication. The primary end point was met, Supportive symptoms that are not part of the with 5.69 spontaneous bowel movements in the diagnostic criteria include: lubiprostone group and 3.46 in the placebo group n Abnormal stool frequency: (p = 0.0001). The differences in number of spon- taneous bowel movements between lubiprostone ––≤3 bowel movements per week or and placebo were also significant for the subse- ––≤3 bowel movements per day quent three 1-week treatment periods. For week 1, the treatment regimen also demonstrated signifi- n Abnormal stool form: cant differences for stool consistency, straining ––Lumpy/hard and constipation severity, but not for abdominal bloating and abdominal discomfort. ––Loose/watery

660 Therapy (2009) 6(5) future science group Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

n Abnormal stool passage: The primary end point was change from ––Defecation straining baseline in mean abdominal discomfort/ pain score, rated on a 4-point scale (1 = mild; ––Urgency or also a feeling of incomplete bowel 2 = moderate; 3 = severe; 4 = very severe), dur- movement, passing mucus and bloating ing the first month of treatment. Of the 194 Assuming no use of antidiarrheals or laxatives, randomized subjects, 193 were in the intention- the following system can be used to subtype IBS to-treat population, with one randomized sub- by predominant stool pattern: ject not providing post-treatment assessments.

n IBS with constipation (IBS-C) – hard or lumpy The primary end point was met for the high- stools at least 25% and loose (mushy) or watery est dose regimen, that is, 24 µg twice-daily stools less than 25% of bowel movements (p = 0.023); significant differences versus pla- cebo for all three dose regimens were observed n IBS with (IBS-D) – loose (mushy) or for month 2. For month 1, the highest dose watery stools at least 25% and hard or lumpy regimen also demonstrated significant differ- stools less than 25% of bowel movements ences versus placebo for abdominal bloating,

n Mixed IBS (IBS-M) – hard or lumpy stools at degree of straining, severity of constipation, least 25% and loose (mushy) or watery stools weekly rate of spontaneous bowel movements at least 25% of bowel movements and stool consistency.

n Unsubtyped IBS – insufficient abnormality of Effect confirmation stool consistency to meet criteria for IBS-C, Two randomized, double-blind, placebo-con- -D or -M trolled studies with lubiprostone, 8 µg twice- In the above diagnostic criteria, hard or lumpy daily, analyzed as one, provided confirmatory stools are defined as types 1 or 2 of the Bristol evidence of efficacy in the treatment of consti- Stool Form Scale; loose (mushy) or watery stools pation-predominant IBS [7]. In total, the two are defined as types 6 or 7 of the Bristol Stool studies randomized 1171 adult subjects meeting Form Scale. the Rome II modular questionnaire criteria for constipation-predominant IBS and with an aver- „„Lubiprostone age assessment of abdominal discomfort/pain of Dose exploration at least mild intensity, as well as any two of the A randomized, double-blind, placebo-controlled following symptoms during a 4-week prospective study evaluated lubiprostone in the treatment of baseline period:

constipation-predominant IBS in dosages of 16, 32 n Fewer than three spontaneous bowel move- and 48 µg per day, administered in a twice-daily ments per week at least 25% of the time dosing regimen for 3 months (3 × 28 days) [6]. The study randomized 194 adult subjects meeting n At least 25% of the spontaneous bowel move- Rome II modular questionnaire criteria for consti- ments recorded a straining assessment of at pation-predominant IBS: 48 subjects to placebo, least moderate

52 subjects to 16-µg lubiprostone, 49 subjects to n At least 25% of the spontaneous bowel move- 32-µg lubiprostone, and 45 subjects to 48-µg lubi- ments recorded a stool consistency assessment prostone, with an average assessment of abdominal of hard or very hard discomfort/pain of at least mild intensity, as well as at least two of the following symptoms during Spontaneous bowel movement was defined as a 4-week prospective baseline period: above with the same rescue allowed.

n Fewer than three spontaneous bowel move- The primary end point was calculated from the ments per week weekly assessments of symptom relief, based on the responses to the following questions: How would n At least 25% of the spontaneous bowel move- you rate your relief of IBS symptoms (abdomi- ments accompanied by at least moderate nal discomfort/pain, bowel habits, and other IBS straining symptoms) over the past week compared with how

n At least 25% of the spontaneous bowel move- you felt before you entered the study? ments associated with a stool consistency rat- n 1. Significantly worse ing of hard or very hard n 2. Moderately worse Spontaneous bowel movement was defined as above with the same rescue medications allowed. n 3. A little bit worse

future science group www.futuremedicine.com 661 Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

n 4. Unchanged µ-opioid receptors in the neuronal plexi, located n 5. A little bit relieved between the longitudinal and circular muscle lay- ers (myenteric plexus) and just underneath the n 6. Moderately relieved mucosa (mucosal plexus). Under the influence n 7. Significantly relieved of on the myenteric plexus, the longitu- dinal smooth-muscle layer relaxes and the circu- A weekly responder was defined as reporting lar smooth-muscle layer increases in tone. These either moderately (6) or significantly relieved effects are thought to be mediated through inhibi- (7) for that week. A monthly responder was tion of acetylcholine release and inhibition of the defined as a moderate responder for all 4 weeks release of vasoactive intestinal polypeptide and of the month, or a significant responder for at nitric oxide, respectively. The result of this differ- least 2 weeks of the month, without ratings of ential effect on the longitudinal and circular intes- moderately (2) or significantly worse (1). An tinal smooth muscles is an increase in segmental overall responder, the primary end point, was contraction and a decrease in peristaltic activity. defined as a monthly responder for at least 2 Normal peristalsis consists of sweeping move- of the 3 months of the study. The study was ments in the small bowel, occurring every 90 powered to detect a minimum relative increase min to move its luminal content from the duo- in overall responders for lubiprostone, compared denum to the ileum, and mass movements in with placebo, of 70.6% (a = 0.05; b = 0.88). the large bowel, occurring one- to three-times Of the 1171 randomized subjects, 1154 were per day on average, moving its content over large in the intention-to-treat population, with four distances. A secondary effect of the decrease in randomized subjects not receiving study medi- peristaltic activity is that food stays longer in cation and 13 subjects not providing post-treat- the and stool stays longer in the small ment assessments. The primary end point was and large bowel. The former effect causes gas- met in both studies, with p-values of 0.009 and tric distension, resulting in nausea, and the latter 0.031, respectively; in the two studies combined, contributes to the constipation by allowing more the overall responder rate was 17.9% for lubi- time for fluid absorption, a predominant func- prostone and 10.1% for placebo (p = 0.001). In tion of the large bowel in particular. A decrease comparison with the nonresponders, the overall in bowel-movement frequency is the primary responders had a significantly greater decrease symptom of constipation, with secondary symp- from baseline in abdominal discomfort/pain, toms being hard stool, the need for straining bloating, constipation severity, stool consistency with bowel movements, and a sense of incom- and straining. plete evacuation afterwards. Tertiary symptoms are abdominal bloating/distension, discomfort, Safety ana­lysis pain from stool or gas, borborygmi, flatulence, In the dose-ranging study, 67% of the sub- and dyspnea from interference of the abdomi- jects receiving lubiprostone, 8 µg twice-daily, nal stool and gas content with diaphragmatic reported adverse events, versus 58% of those contraction aiding inspiration. receiving placebo. The most common adverse event was nausea (19 vs 13%), followed by diar- „„Prevalence rhea (14 vs 4%). In the confirmatory study, A systematic review was performed of 11 ran- 50% of the subjects receiving lubiprostone, 8 µg domized, double-blind, placebo-controlled stud- twice-daily, reported adverse events, versus 51% ies of oral opioids in the treatment of chronic of those receiving placebo. The most common, noncancer pain, given for periods ranging from treatment-related adverse event was nausea (8 vs 4 days to 8 weeks [8]. The opioids were morphine 4%), followed by diarrhea (6 vs 4%). in five studies, morphine or methadone in one study, and oxycodone in four studies; all studies Opioid-induced bowel dysfunction used inactive placebo, except two in which benz- „„Definition tropine was given as active placebo. Of the 1025 Opioids induce gastrointestinal dysfunction subjects randomized, 674 completed the study indirectly through an effect on the CNS and they were in and 698 were evaluable. Adverse directly through an effect on the gastro­intestinal events and lack of efficacy were the most fre- tract. Related to the indirect effect, it has been quent reasons for discontinuation during both shown that intrathecal administration of opioids opioid and placebo treatment. The mean final decreases gastrointestinal motility and intestinal daily dose of the oral opioids varied from 30 to secretion. The direct effect is mediated through 120 mg for morphine, and from 20 to 45 mg for

662 Therapy (2009) 6(5) future science group Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

oxycodone (30–68.5 mg morphine equivalents); of potential extrapyramidal side effects, par- it was 15 mg for methadone (150 mg morphine ticularly tardive dyskinesia. , a equivalents). synthetic analog, US FDA- Constipation was the most common adverse approved for the prevention of nonsteroidal event in the opioid-treated subjects, reported by anti-inflammatory drug-induced gastric ulcers, 41% of the subjects in comparison with 11% of also increases colonic transit and can be used those treated with placebo, followed by nausea off-label. (32 vs 12%). However, the actual occurrence of constipation with oral opioid treatment in the „„Drug development range of 30–150 mg morphine equivalents per Prior to its withdrawal from the market, tega- day is probably higher because of the enriched serod was being studied for opioid-induced nature of the studies, excluding subjects from bowel dysfunction. Another peripherally-acting randomization who did not tolerate the medica- µ-opioid receptor antagonist, , was tion or who did not find it effective in relieving being studied as well, but cardiovascular safety their pain. The subjects who were not random- concerns halted drug development. However, ized because of the latter reason would also the US FDA approved the medication in May have discontinued the medication in practice; 2008 with a Risk Evaluation and Mitigation however, the subjects who were not randomized Strategy for the indication of accelerating the because of tolerability reasons would possibly time to upper and lower gastrointestinal recovery have continued the treatment if the adverse following partial small- or large-bowel resection event was constipation and this was effectively with primary anastomosis. The Risk Evaluation treated. Of the adverse events reported in the and Mitigation Strategy restricts the use of the systematic review – that is, constipation, nausea, medication to short-term (15 doses) treatment in somnolence/sedation, dizziness, , itch- hospitalized patients, and only in hospitals that ing and dry mouth, constipation is the adverse have registered with the program and have met event for which the most treatments are already all the requirements. available, although not necessarily specifically approved by the US FDA for opioid-induced Lubiprostone bowel dysfunction. In relation to opioid-induced bowel dysfunc- tion, lubiprostone was studied in vivo in mice [9] „„Available treatments and in vitro in the human jejunum [10]. In mice, In April 2008, the US FDA approved the the administration of morphine hydrochloride, peripherally-acting µ-opioid receptor antago- 5 mg/kg intraperitoneally, was followed by the nist, methyl­naltrexone, for the treatment of oral administration of a graphite marker as opioid-induced constipation in patients with well as lubiprostone 0.1, 1, 10 and 100 µg/kg advanced illness who are receiving pallia- or vehicle. The animals were sacrificed 150 tive care. Lubiprostone and are US min after administration of the marker, and FDA-approved for the treatment of chronic were scored on the presence of marker in the idiopathic constipation in adults and can, of rectum. Lubiprostone significantly increased course, be used off-label for this condition as the gastrointestinal transit of the marker in well. However, in March 2007, upon US FDA the morphine-treated animals, when com- request, tegaserod was withdrawn from the pared with that of the morphine-treated control market because of cardiovascular safety con- (vehicle) group (p < 0.01 at 1 µg/kg or higher). cerns. Constipation products in general can In addition, the effect of lubiprostone on mor- also be used for opioid-induced bowel dys- phine-induced analgesia was evaluated, but no function, such as bulking agents (cellulose and changes were found. ), stool softeners (), osmotic In isolated human jejunum, morphine agents (, , applied to the serosal side of the preparations and ) and laxatives (senna significantly decreased basal short-circuit cur- or bisacodyl). A prokinetic medication could rent, which is a reflection of chloride secretion. also be used, although not US FDA-approved Lubiprostone, added 5 min later, reversed the for constipation. However, domperidone is inhibitory action of morphine as reflected by not on the market in the USA, cisapride was significant increases in short-circuit current. withdrawn from the market because of long The results of both sets of experiments suggest QT syndrome, and the long-term, daily use of that lubiprostone might also be effective in metoclopramide is not recommended because opioid-induced bowel dysfunction, confirmed

future science group www.futuremedicine.com 663 Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

by the preliminary efficacy and safety results of Opioid-induced bowel dysfunction results the two, very recently completed, randomized, predominantly from the effect of opioids on double-blind, placebo-controlled studies [102]. the µ-opioid receptors in the gastrointestinal The studies were identical Phase III trials tract. Constipation and nausea are its most in which a total of 875 subjects with opioid- common symptoms, probably occurring in at induced bowel dysfunction were randomized least half of the patients treated with oral opi- to 12-week treatment with lubiprostone, 24 µg oids. The constipation in particular is not an twice-daily. The subjects were taking opioid uncommon reason for patients to discontinue medications for chronic noncancer pain, includ- the medication or to take a dose that is much ing fentanyl, methadone, morphine and oxy- lower than required for adequate pain relief. In codone, for at least 30 days prior to screening, addition, it can further decrease the quality of and continued to take these medications for life in patients whose quality of life is generally the duration of the study. During the 2-week already significantly impaired. There is some baseline period before randomization, they preclinical data to support lubiprostone’s use were required to have fewer than three sponta- in this indication, confirmed by the prelimi- neous bowel movements per week. The overall nary efficacy and safety results of the two, very adverse-event rate for the combined studies was recently completed, randomized, double-blind, 54.9% for lubiprostone and 51.6% for placebo, placebo-controlled studies. with nausea being most common (15.0 vs 7.5%), followed by diarrhea (8.5 vs 3.7%). Future perspective The primary end point of the studies was the The development of alvimopan and tegaserod change from baseline in the frequency of sponta- for the treatment of opioid-induced bowel dys- neous bowel movements at week 8 of treatment, function was halted because of cardiovascular which was met in one of the studies (OBD0631) safety concerns. The US FDA recently approved but not in the other (OBD0632). The change for this indication, but in a from baseline in the frequency of spontaneous very special population. Lubiprostone has been bowel movements in the first study was from 1.42 on the US market since 2006, approved for to 4.54 for lubiprostone and from 1.46 to 3.81 for the treatment of chronic idiopathic constipa- placebo; in the second study, these changes were tion in adults and constipation-predominant from 1.60 to 4.10 for lubiprostone and from 1.60 IBS in adult women, with a good safety record. to 3.95 for placebo. An interesting post hoc subana­ Extension of the indication to include opioid- lysis revealed that subjects taking methadone and induced bowel dysfunction would be a welcome randomized to lubiprostone experienced a lower addition to the treatment options available for increase in the frequency of spontaneous bowel this condition. Safe and effective treatment of movements than lubiprostone-treated subjects opioid-induced bowel dysfunction will enhance receiving other opioids. the quality of life of those suffering from the condition, both directly as well as indirectly, by Conclusion allowing less restricted dosing and, hence, better Lubiprostone is a novel medication, approved pain control. by the US FDA for the treatment of chronic idiopathic constipation and constipation-pre- Financial & competing interests disclosure dominant IBS. It is an activator of the CIC-2 The author was an investigator in one of the two random- chloride channel, indirectly making more water ized, double-blind, placebo-controlled studies of lubipro- available in the lumen of the gastrointestinal stone in the treatment of opioid-induced bowel dysfunc- tract. Secondary stretching of the gastrointes- tion, and as such received research funding from Sucampo tinal wall causes delayed gastric emptying and Pharmaceuticals, Bethesda, MD, USA. The author has increased small- and large-bowel transit. The no other relevant affiliations or financial involvement former is likely to cause the medication’s most with any organization or entity with a financial interest common adverse event, nausea, and the latter in or financial conflict with the subject matter or materi- makes it beneficial in constipation-based condi- als discussed in the manuscript apart from those tions, such as chronic idiopathic constipation, disclosed. constipation-predominant IBS, and possibly also No writing assistance was utilized in the production of opioid-induced bowel dysfunction. this manuscript.

664 Therapy (2009) 6(5) future science group Drug Evaluation Spierings Lubiprostone in opioid-induced bowel dysfunction Drug Evaluation

Executive summary ƒƒ Lubiprostone is a novel medication, approved by the US FDA for the treatment of chronic idiopathic constipation in adults and constipation-predominant irritable bowel syndrome in adult women. ƒƒ It is an activator of the CIC-2 chloride channel, indirectly making more water available in the lumen of the gastrointestinal tract. Secondary stretching of the gastrointestinal wall causes increased small- and large-bowel transit. ƒƒ Lubiprostone has some preclinical data to support its potential use in opioid-induced bowel dysfunction, confirmed by the preliminary efficacy and safety results of the two, very recently completed, randomized, double-blind, placebo-controlled studies.

5 Johanson JF, Mortin D, Geenen J, Ueno R: 10 Sun X, Xia Y, Liu S, Wang Y-Z et al.: Bibliography Multicenter, 4-week, double-blind, randomized, Lubiprostone reverses the inhibitory action of placebo-controlled trial of lubiprostone, a morphine on mucosal secretion in the human 1 Camilleri M, Bharucha AE, Ueno R et al.: locally-acting type-2 chloride channel activator, jejunum. Gastroenterology 134(Suppl. 1), Effect of a selective chloride channel activator, in patients with chronic constipation. Am. A122 (2008) (Abstract 844). lubiprostone, on gastrointestinal transit, J. Gastroenterol. 103, 170–177 (2008). gastric sensory, and motor functions in 11 Cuppoletti J, Malinowska DU, Tewari KP healthy volunteers. Am. J. Physiol. 6 Johanson JF, Drossman DA, Panas R, et al.: SPI-0211 activates T84 cell chloride Gastrointest. Liver Physiol. 290, G942–G947 Wahle A, Ueno R: Clinical trial: Phase 2 transport and recombinant human CIC-2 (2006). study of lubiprostone for irritable bowel chloride currents. Am. J. Physiol. Cell Physiol. syndrome with constipation. Aliment 287, C1173–C1183 (2004). 2 Sweetser S, Busciglio IA, Camilleri M et al.: Pharmacol. Ther. 27, 685–696 (2008). Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor 7 Drossman DA, Chey WD, Johanson JF et al.: functions in healthy subjects. Am. J. Physiol. Clinical trial: lubiprostone in patients with „„Websites Gastrointest. Liver Physiol. 296, G295–G301 constipation-associated irritable bowel 101 Lubiprostone (SPI-211/RU-211, Amitiza®) (2009). syndrome – results of two randomized, http://amitiza.com/resource/pi.pdf placebo-controlled studies. Aliment 3 Longstreth GF, Thompson WG, Chey WD, (Accessed 18 July, 2009) Pharmacol. Ther. 29, 329–341 (2009). Houghton LA, Mearin F, Spiller RC: 102 Sucampo Pharmaceuticals, Inc. press release: Functional bowel disorders. Gastroenterology 8 Kalso E, Edwards JE, Moore RA, Takeda and Sucampo Report Top-Line 130, 1480–1491 (2006). McQuay HJ: Opioids in chronic non-cancer Results of Two Phase 3 Trials of Lubiprostone pain: systematic review of efficacy and safety. 4 Johanson JF, Ueno R: Lubiprostone, a locally in Opioid-Induced Bowel Dysfunction Pain 112, 372–380 (2004). acting chloride channel activator, in adult http://investor.sucampo.com/phoenix. patients with chronic constipation: a 9 Ueno R, Osama H, Engelke KJ: Effects of zhtml?c=201197&p=irol- double-blind, placebo-controlled, dose- lubiprostone on morphine-induced constipation newsArticle&ID=1309679&highlight= ranging study to evaluate efficacy and safety. and analgesia. Gastroenterology 130(Suppl. 2), (Accessed 25 July, 2009) Aliment Pharmacol. Ther. 25, 1351–1361 A373–A374 (2006) (Abstract M1810). (2007).

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