Treatment of Opioid-Induced Gut Dysfunction

Review

Central & Peripheral Nervous Systems Treatment of opioid-induced gut dysfunction

Peter Holzer 1. Introduction Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical 2. Opioid peptides and opioid Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria receptors in the gastrointestinal Opioid analgesics are the mainstay in the treatment of moderate-to-severe tract pain, yet their use is frequently associated with adverse effects, the most 3. Opioid actions in the common and debilitating being constipation. Opioid-induced motor stasis gastrointestinal tract results from blockade of gastrointestinal peristalsis and fluid secretion, and 4. Significance of endogenous reflects the action of the endogenous opioid system in the gut. Methyl- opioid peptides in naltrexone and alvimopan are new investigational drugs that selectively tar- gastointestinal physiology get peripheral µ-opioid receptors because they are poorly absorbed in the 5. Homeostatic roles of intestine and do not enter the brain. Clinical studies have proved the concept endogenous opioids in gut that these drugs prevent opioid-induced bowel dysfunction without inter- dysfunction fering with analgesia. As reviewed in this article, opioid receptor antagonists 6. Beneficial effects of opioid with a peripherally restricted site of action also hold therapeutic promise in receptor stimulants under postoperative ileus and chronic constipation due to the fact that they have conditions of gut dysfunction been found to stimulate intestinal transit. 7. Adverse effects of opioid receptor agonists on gut Keywords: alvimopan, constipation, enteric nervous system, intestinal peristalsis, naloxone, N-methylnaltrexone, opioid peptides, opioid-induced bowel dysfunction, peripherally restricted function: opioid-induced bowel opioid receptor antagonists, prokinetic effects dysfunction and prolongation of postoperative ileus Expert Opin. Investig. Drugs (2007) 16(2):181-194 8. Treatment of opioid-induced Printing and distribution strictly prohibited disturbances of bowel function 1. Introduction with laxatives and non-opioid prokinetic drugs Morphine and related substances contained in the unripe seed capsules of 9. Management of opioid-induced Papaver somniferum have been used to treat pain and diarrhoea for thousands of bowel dysfunction by opioid years. At present, opioid analgesics are the mainstay of therapy in many patients receptor antagonists with a with moderate-to-severe pain. Unfortunately, adverse effects can severely com- peripherally restricted site of promise the therapeutic benefit offered by these drugs [1]. The gastrointestinal (GI) action tract is one of the main targets of their unwanted actions and, in this property, opioid analgesics are similar to other neuroactive drugs, notably adrenoceptor ago- 10. Opioid receptor antagonists nists [2-4]. This pharmacological profile reflects the significant role that neurons play with a peripherally Informa restricted UK Ltd. in GI function and the fact that many of the transmitters and transmitter receptors site of action as possible present in the brain have also been localised to the gut. This is particularly true for prokinetic drugs opioid receptors and adrenoceptors whose activation by opiates and catecholamines, 11. Expert opinion respectively, interferes with pathways of the enteric nervous system that regulate motility and secretion [1-9]. To comprehend the adverse actions of opioid analgesics and other neuroactive drugs on the gut, it needs to be considered that the alimentary canal is equipped Copyright of with the largest collection of neurons outside the CNS. Enteric neurons originating from the myenteric and submucosal plexuses supply all of the layers of the alimentary canal and, therefore, are in a position to regulate virtually every aspect of digestion [10-12]. These neurons not only synthesise and release acetylcholine, substance P, NO, ATP, vasoactive intestinal polypeptide and 5-HT but also opioid peptides as their transmitters. The enteric nervous system is arranged in polarised circuits that are typically composed of intrinsic primary afferent neurons, a variable number of interneurons and excitatory or inhibitory output (motor, secretomotor and vasodilator) neurons to the effector tissues [10-12]. With this organisation, the

enteric nervous system is capable of regulating GI peristalsis, animals; however, analysis of the cellular mechanisms of opi- ion and fluid secretion, circulation, endocrine and immune ate action has shown that opioid receptor agonists can inter- activity independently of the brain [10-12]. rupt both excitatory and inhibitory neural inputs to the GI muscle in both human and animal models [21]. 2. Opioid peptides and opioid receptors in the Inhibition of excitatory neural inputs is associated with gastrointestinal tract inhibition of the release of excitatory transmitters such as acetylcholine and blockade of distension-induced peri- The adverse influence of opioid analgesics on GI function staltic contractions, whereas blockade of inhibitory neural remained an enigma to scientists until it was realised that both inputs results in depression of NO release from inhibitory opioid peptides and opioid receptors are expressed in the motor neurons, disinhibition of GI muscle activity, eleva- digestive tract; therefore, it is important to briefly consider the tion of resting muscle tone and non-propulsive motility endogenous opioid system in the gut and its physiological and patterns [6,8,13,21,23,24]. A direct activation of the interstitial pathophysiological implications (Figure 1) to understand the cell–muscle network has also been envisaged [25,26]. In the basis of opioid-induced bowel dysfunction (OBD). canine gut, µ-opioid receptor agonists have a biphasic exci- Met-enkephalin, leu-enkephalin, β-endorphin and dynorphin tatory and inhibitory influence on the migrating myo- are among the endogenous opioids that are present in the GI electrical complex [27], and transit in the human colon is tract where they have been localised to both neurons and retarded by activation of µ-opioid (but not κ-opioid) endocrine cells of the mucosa [1,5,13]. Neuroanatomical tracing receptors [28,29]. Other studies have shown that activation of studies have revealed that opioid peptides are present in dis- µ-opioid receptors in the human gut can increase pyloric tinct classes of enteric neurons in the guinea-pig, notably in tone, induce pyloric (as well as duodenojejunal phasic) myenteric neurons projecting to the circular muscle and in pressure activity and elevate the resting anal sphincter pres- neurons of descending enteric pathways [13-15]. sure [30,31]. The relative contribution of these multiple The presence of endogenous opioids in the alimentary effects to opioid-induced constipation is not clear [7]. canal is matched by the expression of opioid receptors that Apart from affecting GI motor activity, opioids also influ- mediate the effect of both endogenous and exogenous opioid ence GI ion and fluid transport (Figure 1). Blunted peristalsis receptor ligands on bowel function. By using mRNA quantifi- delays GI transit and, thereby, prolongs the contact of the cation and immunocytochemistry, opioid receptors of the µ-, intestinal contents with the mucosa [1]. As a result, absorption κ- and δ-subtype have been localised to the GI tract of rats, of fluid is increased, whereas the secretion of electrolytes and guinea-pigs and humans [13,16-18]. In the rat and guinea-pig, Printingwater is decreased and distributionin the small and large strictlyintestines [6,21,32,33] prohibited. all three subtypes of opioid receptors are found on neurons of The antisecretory effect of opiates is mediated by opioid the myenteric and submucosal plexuses and on nerve fibres receptors on enteric neurons, whose activation results in the supplying muscularis and mucosa; however, their relative dis- interruption of prosecretory enteric reflexes [6,21]. tribution varies with GI layer, GI region and species [13]. In The actions of endogenous opioids on the GI tract are the human gut, µ-opioid receptors are present on myenteric mediated by multiple opioid receptors. Studies with isolated and submucosal neurons and on immune cells of the lamina tissues from the human intestine suggest that δ-, κ- and propria [13]. µ-opioid receptors contribute to opiate-induced inhibition of muscle activity [34,35]. Propulsion in the rat intestine is 3. Opioid actions in the gastrointestinal tract blocked by δ- and µ- (but not κ-) opioid receptor agonists [6], whereas peristalsis in the guinea-pig intestine is suppressed by When released from Informa enteric neurons, UK it is Ltd. likely that opioid activation of κ- and µ- (but not δ-) opioid receptors [20]. Opi- peptides play a mediator role in the regulation of propulsion ate-induced inhibition of cholinergic transmission in the and secretion [2,5,6,8,9,19-21]. This conjecture is reflected by the guinea-pig gut is similarly mediated by µ- and κ-opioid actions of exogenous opioid receptor agonists and antagonists receptors [36]. on GI function (Figure 1). The inhibitory effect of opioid Opioid receptors belong to the family of metabotropic

receptor agonists on peristalsis in the guinea-pig small intes- membrane receptors that couple via the Gi/Go subtypes of Copyrighttine is thought of to arise primarily from the interruption of G proteins to cellular transduction processes. Once activated transmission within enteric nerve pathways governing muscle by an agonist, µ-opioid receptors undergo endocytosis in a activity [13,21,22]. Transmission can be blocked both via pre- concentration-dependent manner [13,16,21]. The cellular effects synaptic and postsynaptic sites of action on enteric neurons, of myenteric µ-opioid receptor activation are instigated by a whereby the release of acetylcholine and other transmitters is multiplicity of signalling pathways including activation of K+ attenuated [6,21]. It has previously been believed that opiates channels, membrane hyperpolarisation, inhibition of Ca2+ inhibit GI propulsion in some species such as the guinea-pig channels and reduced production of cAMP [21,36]. by suppression of peristaltic contractions, whereas GI pro- Taken together, opioid-induced constipation results from pulsion is interrupted through induction of non-propulsive multiple effects, such as suppression of enteric neuron contractions in the intestine of humans and non-rodent excitability, inhibition of excitatory and inhibitory neural

182 Expert Opin. Investig. Drugs (2007) 16(2) Holzer

Gastrointestinal actions

Cellular sources Inhibition of enteric nerve activity Met-enkephalin • Suppression of enteric nerve excitability Leu-enkephalin • Pre- and postsynaptic inhibition of β-Endorphin transmission in excitatory and inhibitory Dynorphin motor as well as secretomotor pathways • Inhibition of the release of acetylcholine, Enteric neurons substance P and NO • Neurons of the myenteric plexus with projections within the plexus to the circular Inhibition of propulsive motor activity muscle and to the mucosal plexus • Inhibition of distension-induced peristalsis • Neurons of the submucosal plexus • Elevation of muscle tone • Induction of non-propulsive motility patterns Endocrine cells • Disturbance of migrating myoelectrical complex • Inhibition of gastric emptying Molecular/cellular targets • Delay of gastrointestinal transit • Constipation µ-Opioid receptors κ-Opioid receptors Inhibition of secretory activity δ-Opioid receptors • Inhibition of ion and fluid secretion • Constipation Enteric neurons (somata and axons) Immune cells Immune activity • Alteration of immune cell function

Figure 1. Schematic summary of the endogenous opioid system in the gastrointestinal tract.

inputs to the GI muscle and mucosa, inhibition of propul- It follows that the endogenous opioid peptides that are sion, induction of non-propulsive motility patterns Printing and released and in thedistribution course of propulsive strictly motility [37] prohibited participate depression of secretory activity (Figure 1) [21]. Although there in the neural control of peristalsis as they dampen peri- are species differences in the GI distribution of opioid recep- staltic performance via activation of µ- and κ-opioid receptors in the gut and the GI effect profile of opiates, emerging tors [20]. This inference is further supported by the ability evidence indicates that the principal opioid actions on the of µ- and κ-opioid receptor antagonists to enhance the enteric nervous system are seen in all mammalian species, release of acetylcholine from the guinea-pig myenteric although to a different degree depending on the experimental plexus [38]; by the ability of methylnaltrexone to enhance conditions. As a systematic comparison of opioid peptide neurogenic contractions in the isolated human small intes- occurrence, opioid receptor distribution and opioid effect tine [39]; and by the ability of naloxone to increase the profile in the gut of various species has not been performed, release of substance P from the peristaltically active the true extent of species differences and the most appropriate guinea-pig ileum [37]. Naloxone has been found to acceler- animal model Informafor OBD remain UK uncovered. Ltd. ate transit in the colon but not the small intestine of healthy human volunteers [28,40]. This prokinetic effect is 4. Significance of endogenous opioid peptides shared by the µ-opioid receptor-preferring antagonists in gastointestinal physiology methylnaltrexone [41] and alvimopan [42].

There is evidence for a role of endogenous opioid peptides 5. Homeostatic roles of endogenous opioids in in the fine-tuning of gut functions. This concept is pri- gut dysfunction Copyrightmarily based of on the ability of opioid receptor antagonists to influence GI physiology and pathophysiology; for exam- Schaumann [43] interpreted the pharmacological effects of ple, distension-evoked peristalsis can be facilitated by the exogenous opiates on pain and bowel function as indicative of pan-opioid receptor antagonist naloxone in various pre- an endogenous protective system a long time before endo- parations of the guinea-pig, rabbit, cat and rat isolated genous opioid peptides were identified [44]. Backed by increas- small intestine [6,8,19,20]. In the guinea-pig small intestine, ing experimental support, it is now thought that endogenous the effect of naloxone is mimicked by selective antagonists opioids in the GI tract represent a system that defends the at µ-(cyprodime) and κ- (norbinaltorphimine) opioid intestine against functional derangements created by receptors, but not by antagonism at δ-opioid receptors [20]. inappropriate or adverse conditions such as prolonged

Expert Opin. Investig. Drugs (2007) 16(2) 183 Treatment of opioid-induced gut dysfunction

intestinal distension, inflammation, stress and trauma [8,9]; for noradrenaline, atropine or hexamethonium [19,46,60,61]. With example, prolonged intraluminal distension of the guinea-pig all of these findings together, it follows that endogenous ileum causes peristaltic activity that is interrupted by periods opioids contribute to GI homeostasis, particularly under of inactivity during which the release of met-enkephalin is conditions of disturbed gut function. significantly enhanced [45]. This observation is consistent with the ability of naloxone to reduce the intermittent periods of 6. Beneficial effects of opioid receptor peristaltic inactivity observed during prolonged periods of stimulants under conditions of gut distension [46-48]. Studies of the effects of naloxone in rats sug- dysfunction gest that endogenous opioids contribute to the ileal brake of the stomach-to-caecum transit caused by ileal infusion of The actions of opioid receptor agonists to inhibit GI secretory lipids [49]. activity and transit are therapeutically used in acute and Disruption of the migrating myoelectrical complex caused chronic diarrhoea as well as in irritable bowel syndrome asso- by the administration of Escherichia coli endotoxin to fasted ciated with diarrhoea [7]. Inhibition of diarrhoea is achieved rats is reduced by naloxone [50]. This opioid receptor antago- by two strategies. The first strategy is to target opioid recep- nist has no effect on the delay in rat GI transit (measured with tors in the gut, a possibility that has long been accomplished a liquid dye marker) that is caused by abdominal skin incision by the development of loperamide. The antidiarrhoeal action or abdominal laparotomy but inhibits the delay in transit of this compound is predominantly mediated by µ-opioid measured after abdominal laparotomy plus manipulation of receptors and is restricted to the gut because loperamide is the small and large intestines [51]. Furthermore, naloxone and poorly absorbed and fails to cross the blood–brain barrier at methylnaloxone minimise the increase in rat colonic epithelial concentrations needed to produce analgesia [6,30,62]. The sec- ion secretion and permeability that was observed after ond strategy is to inhibit enkephalinases that degrade endo- prolonged periods of stress [52]. genous opioids once they have been released from neurons or There is increasing evidence that GI pathophysiology other cells in the GI tract. Inhibition of GI enkephalinases by leading to gut motor inhibition is associated with racecadotril (acetorphan, a compound that does not enter the upregulation and/or overactivity of the opioid system in the brain) prolongs the presence – and increases the concentration alimentary canal; for example, experimental inflammation – of endogenous opioid peptides at opioid receptors in the ali- enhances the potency of µ-opioid receptor agonists to mentary canal [63,64]. In this way, the antisecretory and anti- inhibit GI transit and to increase the transcription and transit effects of endogenous opioid peptides are enforced, a expression of µ-opioid receptors in the intestine ofPrintingresult that and is therapeutically distribution used for strictly the treatment prohibited of mice [53,54]. Abdominal surgery leads to an increase in the diarrhoea [65,66]. circulating levels of endomorphin in humans [55] and causes a profound internalisation of µ-opioid receptors in the 7. Adverse effects of opioid receptor agonists myenteric plexus of the guinea-pig intestine [13], observa- on gut function: opioid-induced bowel tions that may reflect a role of endogenous opioids in the dysfunction and prolongation of pathophysiology of postoperative motor disturbances; there- postoperative ileus fore, it is emerging that endogenous opioids play a more important role in the pathological than in the physiological There are two key GI syndromes associated with the use of inhibition of gut motility [2,8]. Consistent with this concept opioid analgesics: OBD and postoperative ileus in which opi- is a limited number of small studies showing that naloxone ates are one of many factors contributing to prolonged GI can reverse idiopathic Informa chronic constipation UK Ltd. [56] and can have motor stasis [1,7]. beneficial activity in patients with intestinal pseudo-obstruc- A delay in GI transit and constipation are the most com- tion [57] and constipation-predominant irritable bowel syn- mon and often disabling side effects of opioid analgesics, drome [58]; however, these studies need to be confirmed by which result from their spectrum of pharmacological actions larger controlled trials involving opioid receptor antagonists to block propulsive peristalsis, inhibit intestinal ion and that have a more favourable pharmacokinetic profile than fluid secretion, and increase intestinal fluid absorption [6]; Copyrightthe short-lived naloxoneof to prove the concept. however, constipation is just one symptom of OBD, whose The effect of naloxone to normalise pathologically deranged manifestations comprise incomplete evacuation, abdominal GI motor activity is consistent with its ability to rescue peri- distension, bloating, abdominal discomfort and increased stalsis from experimentally induced inhibition. Thus, opioid gastro- oesophageal reflux. In addition, OBD may lead to receptor antagonism does not affect propulsion in the secondary complications such as pseudo-obstruction of the guinea-pig isolated colon under normal conditions but attenu- bowel, anorexia, nausea and vomiting as well as interference ates the inhibition of faecal pellet transport caused by graniset- with oral drug administration and absorption [1,7,67]. The ron, morphine or clonidine [59]. Similarly, naloxone is capable symptoms associated with OBD can profoundly impair the of reversing the inhibition of peristalsis in the guinea-pig small quality of life and (in some patients) can be so severe that intestine caused by purinoceptor ligands, haloperidol, they prefer to discontinue analgesic therapy rather than

184 Expert Opin. Investig. Drugs (2007) 16(2) Holzer

experience the discomfort arising from OBD [1,67]. Unlike postoperative ileus include metoclopramide, domperidone other adverse effects of chronic opioid therapy such as seda- and erythromycin to stimulate primarily foregut motility; tion, nausea and vomiting, which often resolve with contin- the cholecystokinin (CCK) analogue caerulein to stimulate ued use, OBD generally persists throughout treatment [1,68]; small intestinal motility; acetylcholinesterase inhibitors such however, tolerance to the effects of morphine on enteric as neostigmine to enforce small and large intestinal tone;

neurons has been found to occur in animal experiments and the 5-HT4 receptor agonist tegaserod to stimulate in vitro [21]. colonic transit [1,4,76]. Erythromycin-related motilides, ghre-

Although centrally mediated effects of opiates to slow GI lin analogues, the mixed 5-HT4 receptor agonist/5-HT3 transit have been implicated in the pathophysiology of receptor antagonist renzapride and the CCK1 receptor OBD [62], opiate-induced blockade of gut motility correlates antagonist dexloxiglumide represent further prokinetic drug better with opiate concentrations in the gut than with opiate candidates that are in clinical development [4,76]; however, concentrations in the brain [67,69]. In addition, the N-methyl the therapeutic value of prokinetic drugs in the relief of quaternary analogues of naloxone and naltrexone (which do postoperative ileus with or without opiate use remains not cross the blood–brain barrier) have been found to fully unsubstantiated [1]. It seems that epidural local anaesthesia antagonise the effects of morphine on opioid-induced (among all of the available pharmacological treatment effects in the canine and rat intestines [70,71]; therefore, it options) is the most effective method for relieving pain and would seem that the adverse effects of opiates on GI func- shortening the duration of ileus [1]. tion result primarily from interaction with opioid receptors Similarly, prokinetic drugs are used to ameliorate in the gut [1,62]. OBD, although laxatives are most commonly used in this sit- Postoperative ileus occurs most commonly following uation [1,67,75]; however, these regimens often do not provide abdominal or pelvic surgery and is characterised by bowel dis- satisfactory relief from the GI manifestations of tension, lack of bowel sounds, accumulation of GI gas and opioid-induced analgesia [1]. fluid, nausea, vomiting and delayed passage of flatus and stool [1,4,7]. Motor stasis involves all segments of the digestive 9. Management of opioid-induced bowel tract, the colon being most severely affected because the dysfunction by opioid receptor antagonists average paralytic state in this part of the intestine persists for with a peripherally restricted site of action 48–72h [1]. Opioid analgesics have a profound inhibitory effect on postoperative GI motility and their use for post- The primary objective in the management of OBD operative analgesia delays recovery from postoperative Printing ileus. (whether and or distribution not associated with strictlypostoperative prohibited ileus) is to There is a significant relationship between the amount of prevent GI symptoms rather than treat established motor morphine administered and time required for resolution of stasis due to opioid use [1]. For this reason, many ileus following colectomy [72]. The inhibitory effects of opioid opioid-sparing regimens (e.g., NSAIDs and tramadol) have analgesics on postoperative GI motility are observed during been tested to circumvent the adverse GI sequelae of opioid systemic opioid administration with patient-controlled use [1]; however, these regimens may lack efficacy in severe analgesia and conventional intramuscular as well as epidural pain states or may themselves have adverse effects on the opioid administration [1]. As the pathophysiology of pro- gut. Although transdermal administration of opiates such as longed postoperative ileus involves inflammatory, immuno- fentanyl causes less constipation and results in a better logical and neurogenic mechanisms [73,74], it should not be quality-of-life rating than oral administration of neglected that the effects of opioid analgesics on the immune morphine [1,77,78], this approach also represents only a system may beInforma of relevance UK to their Ltd. adverse influence on partial solution of the problem. postoperative ileus [7]. Given that opioid-induced analgesia is primarily mediated by µ-opioid receptors in the CNS, the rational approach to 8. Treatment of opioid-induced disturbances of prevent OBD would be to combine opioid analgesics with bowel function with laxatives and non-opioid opioid receptor antagonists that cannot penetrate the prokinetic drugs blood–brain barrier. As a result, the adverse effects of opioid Copyright of analgesics on the GI system would be avoided, whereas their The pharmacological treatment of OBD and postoperative central analgesic action would remain unaltered. This ileus associated with opiate use involves two approaches: approach has been validated by the use of opioid receptor non-specific treatment with laxatives and prokinetic drugs; antagonists with limited systemic absorption and by the and specific treatment with opioid receptor antagonists. As development of peripherally restricted opioid receptor this review focuses on the second approach, the first antagonists (PRORAs) such as methylnaltrexone and alvi- approach involving non-opioid drugs is only briefly mopan. The latter two compounds are presently in clinical addressed. Laxative drugs (including softening, stimulant trials for the management of OBD and postoperative ileus and osmotic laxatives) have long been used to ameliorate (Table 1) and may also turn out to become prokinetic drugs OBD [1,67,75]. The prokinetic treatment options for to relieve intestinal stasis unrelated to opiate use.

Expert Opin. Investig. Drugs (2007) 16(2) 185 Treatment of opioid-induced gut dysfunction

Table 1. Overview of fully published clinical trials of methylnaltrexone and alvimopan in OBD and postoperative ileus.

Ref. Compound and dose Trial type Major outcome

[41] Methylnaltrexone 0.3 mg/kg i.v. every 6 h Phase I Safety, pharmacokinetics and efficacy of methylnaltrexone to stimulate GI transit [85] Methylnaltrexone 0.64, 0.7, 2.1, 6.4 or Phase I Safety and efficacy of methylnaltrexone to prevent OBD 19.2 mg/kg p.o. [86] Methylnaltrexone 0.45 mg/kg i.v. Phase I Safety and efficacy of methylnaltrexone to prevent OBD [88] Methylnaltrexone 0.04, 0.08, 0.16, 0.32, Phase I Safety and pharmacokinetics of methylnaltrexone 0.64 or 1.25 mg/kg i.v. [89] Methylnaltrexone 0.3 mg/kg i.v. Phase I Efficacy of methylnaltrexone to ameliorate morphine-induced delay of gastric emptying [90] Methylnaltrexone 0.1 or 0.3 mg/kg s.c. Phase I Pharmacokinetics and efficacy of methylnaltrexone to ameliorate OBD [91] Methylnaltrexone 3.2 or 6.4 mg/kg p.o. Phase I Pharmacokinetics and efficacy of methylnaltrexone to ameliorate OBD [92] Methylnaltrexone 0.1 mg/kg/day i.v. Phase II Safety and efficacy of methylnaltrexone to ameliorate OBD due to chronic methadone [93] Methylnaltrexone 0.3 or 1 mg/kg p.o. Phase II Safety and efficacy of methylnaltrexone to ameliorate OBD due to chronic methadone [42] Alvimopan 12 mg b.i.d. p.o. Phase I Safety and efficacy of alvimopan to stimulate GI transit and prevent OBD [99] Alvimopan 4 mg p.o. Phase I Efficacy of alvimopan to prevent OBD [100] Alvimopan 0.5 or 1 mg q.d. p.o. Phase II Safety and efficacy of alvimopan to ameliorate OBD [101] Alvimopan 1 or 6 mg b.i.d. p.o.* Phase II Efficacy of alvimopan to shorten postoperative ileus [102] Alvimopan 6 or 12 mg b.i.d. p.o.* Phase III Safety and efficacy of alvimopan to shorten postoperative ileus [103] Alvimopan 6 or 12 mg b.i.d. p.o.* Phase III Safety and efficacy of alvimopan to shorten postoperative ileus [104] Alvimopan 12 mg b.i.d. p.o.* Phase III Safety and efficacy of alvimopan to shorten postoperative ileus [105] Alvimopan 6 or 12 mg b.i.d. p.o.* Phase III Safety Printing and efficacy and of alvimopan distribution to shorten postoperative strictly ileus prohibited *The initial dose of alvimopan was given 2 h before surgery. GI: Gastrointestinal; OBD: Opioid-induced bowel dysfunction.

9.1 Opioid receptor antagonists with limited systemic 9.2 Methylnaltrexone absorption An important advance in the search for PRORAs was the The first attempt to selectively target opioid receptors in the development of quarternary opioid receptor antagonists periphery was made with naloxone and related tertiary opioid such as methylnaltrexone. Attaching a methyl group to the receptor antagonists such as nalmefene [1]. Naloxone is a amine configuration in naltrexone results in methyl- pan-opioid receptor antagonist [79] whose systemic bio- naltrexone (Figure 2), a drug that has greater polarity and availability following Informa oral administration UK Ltd.is as low as 2% lower lipid solubility than its parent compound [84]. Due to because of extensive first-pass metabolism. For this reason, its quaternary structure, methylnaltrexone exhibits low oral oral naloxone has been found to improve OBD without bioavailability due to limited absorption and does not cross inhibiting opiate-induced analgesia [80-82]. However, it needs the blood–brain barrier [67,84,85]. As a result, this µ-opioid to be realised that naloxone can easily cross the blood–brain receptor-preferring antagonist (MIC = 70 nM) offers the barrier; therefore, naloxone can reverse analgesia if given in therapeutic potential of preventing or reversing the Copyrightsufficient dosage of despit e its low bioavailability [1]. Con- undesired side effects of opioids in the gut without com- sequently, the therapeutic index of naloxone has turned out to promising analgesia or precipitating the opioid withdrawal be very narrow and its use limited because of the need to symptoms that are predominantly mediated by opioid recep- titrate active doses peripherally versus centrally [81]. tors in the brain [84]. Early studies have revealed that the Nalmefene is a µ-opioid receptor antagonist and its adverse effect of the opiate on GI function is prevented metabolite (nalmefene glucuronide) has been observed to without attenuation of analgesia following subcutaneous or selectively antagonise the GI effects of opioid analgesics in intravenous administration of methylnaltrexone together rodents; however, nalmefene glucuronide does not seem to be with a centrally active opiate to dogs and humans [67,86], sufficiently selective for the gut to be clinically useful in whereas analgesia is appreciably compromised in rats [70]. humans [83]. This species dependence of the peripheral selectivity of

186 Expert Opin. Investig. Drugs (2007) 16(2) Holzer

Box 1. Significant adverse effects of

+ methylnaltrexone and alvimopan relative to N N placebo.

HO HO Methylnaltrexone Intravenous administration in healthy volunteers No adverse effects of clinical importance with O O HO O HO O methylnaltrexone ≤ 0.45 mg/kg [41,86] Orthostatic hypotension and lightheadedness following Naltrexone Methylnaltrexone administration of methylnaltrexone 0.64 or 1.25 mg/kg at plasma levels in excess of 1.4 µg/ml [88]

Figure 2. Chemical structures of naltrexone and Intravenous administration in methadone-maintained methylnaltrexone. subjects Mild-to-moderate abdominal cramping following administration of methylnaltrexone 0.1 mg/kg [92] methylnaltrexone arises from its demethylation to naltrexone, which readily penetrates the blood–brain barrier: Subcutaneous administration in healthy volunteers demethylation occurs in mice and rats but is negligible in No adverse effects of clinical importance with dogs and humans [87]. methylnaltrexone ≤ 0.3 mg/kg [90] A substantial series of Phase I and II studies conducted by the group of Yuan [84] has established the pharmacodynamic, Oral administration in healthy volunteers pharmacokinetic, therapeutic and safety profiles of No adverse effects of clinical importance with methylnaltrexone [84]. The drug has been formulated as a methylnaltrexone ≤ 19.2 mg/kg [85] solution for intravenous or subcutaneous administration as Oral administration in methadone-maintained subjects well as capsules/tablets for oral administration [84]. Both the parenteral and oral formulations as well as single- and No adverse effects of clinical importance with methylnaltrexone 0.3 or 1 mg/kg [93] repeated-dose regimens have been found to be effective in preventing the morphine-induced prolongation of gastric empty- Alvimopan ing and oral-to-caecal transit time without significantly Printing andOral administration distribution in healthy volunteers strictly prohibited attenuating morphine-induced analgesia (Table 1) [41,85-90]. No significant adverse effects with alvimopan 4 or Following injection of methylnaltrexone 0.3 – 0.45 mg/kg 12 mg [42,99] i.v., the time to maximum plasma concentration is ∼ 20 min, the elimination half-life in plasma is ∼ 1.5 – 3 h and the ter- Oral administration in patients receiving chronic opioid minal half-life is ∼ 6 – 9 h [84]. Repeated administration of therapy 0.3 mg/kg i.v. at 6-h intervals does not result in an accumula- Bowel-related adverse effects (abdominal cramping, nausea, vomiting and diarrhoea) with alvimopan 1 mg [100] tion of the drug [41] and the available data indicate that the metabolism of methylnaltrexone does not play a major role in Oral administration in patients undergoing surgery that is its predominantly renal route of elimination [84]. likely to result in postoperative ileus Although readily bioavailable following parenteral admin- No significant adverse effects and no significant istration, methylnaltrexone Informa is UKabsorbed Ltd. from the GI tract only exacerbation of treatment-emergent adverse effects to a limited extent [85]. The plasma levels of methylnaltrexone postoperatively with alvimopan 1, 6 or 12 mg [101-105] are even lower when the drug is administered orally as an Nominal enhancement in the proportion of patients enteric-coated formulation, yet enteric-coated methyl- experiencing postoperative nausea and/or vomiting by alvi- naltrexone is more efficient in preventing morphine-induced mopan 12 mg during the inpatient period in 1 study [104] as retardation of oral-to-caecal transit time than the uncoated opposed to a significant reduction in the incidence of Copyrightpreparation of [91] . Thus reduced oral bioavailability is associated post-operative nausea and vomiting by alvimopan 6 and with enhanced efficacy, which suggests that oral methyl- 12 mg, respectively, in 2 other studies [101,103] naltrexone acts locally in the gut to reverse morphine-induced GI motor stasis. Methylnaltrexone is well tolerated at therapeutic doses (0.3 – 0.45 mg/kg i.v. and ≤ 19.2 mg/kg p.o.) Phase II studies have established that methylnaltrexone is with no significant adverse reactions, an outcome that is also capable of relieving constipation in methadone-maintained, true when methylnaltrexone 0.3 mg/kg i.v. is repeatedly opioid-dependent volunteers (Table 1). In a double-blind, administered every 6 h [41]. The only adverse reaction of note randomised and placebo-controlled trial, it has been found seen at supra-therapeutic doses (≤ 1.25 mg/kg i.v.) is transient that intravenous methylnaltrexone shortens the oral-to-caecal orthostatic hypotension (Box 1) [88]. transit time and causes laxation associated with mild

Expert Opin. Investig. Drugs (2007) 16(2) 187 Treatment of opioid-induced gut dysfunction

abdominal cramping but does not elicit any signs of opioid ≥ 8h[98]. Early Phase I studies established the clinical efficacy withdrawal [92]. Compared with placebo, oral methyl- and safety of oral alvimopan [95]. In a double-blind cross-over naltrexone is also capable of provoking laxation in study (Table 1), it was found that alvimopan 4 mg was capable methadone-maintained patients without precipitating opioid of preventing morphine from delaying GI transit in healthy withdrawal in any subject [93]; however, the latency to the first subjects as measured by the lactulose hydrogen breath test, bowel movement is significantly longer following oral intake without antagonising central morphine effects such as of the drug than after intravenous administration. The doses analgesia and pupillary constriction [95,99]. Similar results were of methylnaltrexone required to induce bowel movements in obtained in a double-blind, randomised and placebo-control- subjects on chronic methadone were lower than those led trial involving 74 healthy volunteers in which gastric required in subjects who were not opioid dependent (Table 1). emptying, and small bowel and colonic transit were assessed The usefulness of methylnaltrexone to selectively counter- by scintigraphy [42]. Alvimopan 12 mg b.i.d. reversed the act opiate-induced stasis in the GI tract has also been proven effect of codeine to delay small bowel, proximal and overall in Phase II and III studies of patients with advanced medical colonic transit but failed to antagonise the effect of codeine to illness requiring high doses of opiates for pain control [84]. slow gastric emptying [42]. Similarly, patients with postoperative ileus following open The clinical testing of alvimopan was subsequently segmental colonic resection have been reported to benefit expanded to explore its usefulness in preventing or treating from treatment with methylnaltrexone. Thus upper and lower OBD and postoperative ileus [7,95-97]. In a randomised and bowel function recovers ∼ 1 day earlier in patients receiving placebo-controlled study involving 168 patients with OBD intravenous methylnaltrexone than in placebo-treated due to chronic opioid therapy for non-malignant pain or opi- patients, whereas no difference in opioid use or mean pain oid addiction (Table 1), alvimopan 0.5 or 1 mg q.d. for scores is observed [84]. This report of clinical efficacy is con- 21 days showed significant efficacy in ameliorating con- trasted by an experimental study in rats in which intragastric stipation without compromising opioid analgesia [100]. The methylnaltrexone (100 mg/kg) was found to be inactive in adverse effects that were associated with alvimopan were pri- reversing postoperative inhibition of GI transit in the absence marily bowel related, occurred during the first week of treat- and presence of postoperative morphine treatment [94]. ment and were of mild-to-moderate severity [100]. Compared with healthy subjects or patients with postoperative ileus, it 9.3 Alvimopan seems that patients receiving chronic opioid treatment are Following the proof-of-concept with methylnaltrexone, a particularly sensitive to alvimopan [7]. µ-opioid receptor-preferring antagonist was developed with Printinga Given thatand OBD distribution is thought to contribute strictly to postoperative prohibited peripherally restricted site of action and a potency ileus, several studies have addressed the ability of alvimopan (MIC = 0.77 nM) ∼ 100-fold higher than that of methyl- to shorten postoperative bowel dysfunction (Table 1). An naltrexone. This compound, alvimopan (ADL 8-2698, for- experimental study in rats has shown that intragastric alvi- merly known as LY-246736), exhibits both low systemic mopan 1 or 3 mg/kg is capable of reversing postoperative absorption (oral bioavailability of 0.03% in dogs and 6% in inhibition of GI transit in the absence and presence of post- humans) and a limited ability to enter the brain due to its operative morphine treatment; the effect of alvimopan being polar structure (Figure 3) [95-97]. Following intravenous admin- most pronounced when it is administered before surgery [94]. istration, the half-life of alvimopan in the systemic circulation Similar results have been reported in patients with post- of dogs and rabbits is as short as 10 min. For this reason, alvi- operative ileus, although with somewhat varying results, mopan is intended primarily for oral administration, in which which may partly have been due to the rather wide range of case it potently blocks Informa µ-opioid receptors UK Ltd.in the gut with a doses (1 – 12 mg) tested. In these studies, the initial dose of prolonged duration of action. Due to its pharmacokinetic alvimopan was usually administered ∼ 2 h before surgery and properties, orally administered alvimopan mainly stays in the the drug subsequently dosed twice daily. Postoperatively, GI tract [95] and the main route of its excretion is via the faecal patient-controlled analgesia with intravenous opioids was route, either in unchanged form or in the form of metabolites instituted. In a first Phase II trial carried out with 78 patients generated by microfloral activity [7,97]. There is no evidence of who underwent partial colectomy or total abdominal hyster- Copyrightdrug accumulation of following chronic dosing of alvimopan [7]. ectomy, alvimopan 6 mg (but not 1 mg) shortened the time Studies addressing the acute safety of alvimopan in animals to achieve normal bowel function after the operation and the and humans have shown that the drug is well tolerated; the duration of hospitalisation by a median of 1 day [101]. In addi- only adverse effects of note include nausea, vomiting and tion, the overall incidence of GI side effects including post- abdominal discomfort [7]. operative nausea and vomiting was also reduced by The selectivity of the action of alvimopan for peripheral alvimopan, whereas analgesia was not compromised [101]. opioid receptors was first demonstrated by its ability to elicit Following this promising outcome, several Phase III trials diarrhoea in morphine-dependent mice without reversing were initiated, four of which have been published so far morphine-induced analgesia [98]. In this study, alvimopan was (Table 1). In a placebo-controlled trial involving 469 patients found to have a prompt onset of action, which lasted for undergoing bowel resection or radical hysterectomy, it was

188 Expert Opin. Investig. Drugs (2007) 16(2) Holzer

volunteers, in which methylnaltrexone can stimulate GI tran- 2H O 2 sit as measured by the lactulose hydrogen breath test [41] and alvimopan is capable of accelerating colonic transit as meas- HO O H ured by scintigraphy [42]. In view of this prokinetic activity, it N N OH has been hypothesised that PRORAs may ameliorate pathological states of GI motor stasis unrelated to opiate use, such O as chronic idiopathic constipation and intestinal pseudo-obstruction [7,84]. Opioid receptor antagonists are expected to normalise pathological inhibition of gut function Figure 3. Chemical structure of alvimopan. that arises from an upregulation and/or overactivity of the opioid system in the GI tract [2]. There is indeed preliminary evidence that naloxone has beneficial effects in idiopathic confirmed that alvimopan 6 and 12 mg accelerated the time chronic constipation [57], intestinal pseudo-obstruction [57] to recovery of GI function by a mean of 15 and 22 h, respec- and constipation-predominant irritable bowel syndrome [58]. tively [102]. The time to writing the hospital discharge order In addition, preliminary data indicate that alvimopan is also was shortened on average by 20 h in the group receiving capable of shortening bowel transit time in patients with alvimopan 12 mg [102]. In a similar Phase III study involving chronic constipation [107]. 451 patients subjected to partial colectomy or radical hysterectomy, alvimopan 6 mg was found to significantly accelerate 11. Expert opinion the time to recovery of GI function by a mean of 14 h, whereas alvimopan 12 mg failed to significantly shorten Opiates will remain the mainstay in the treatment of moder- recovery of bowel function [103]. In another double-blind, ate-to-severe pain in the foreseeable future because the intro- randomised and placebo-controlled Phase III trial involving duction of analgesic drugs with equal efficacy but a more 519 women scheduled for simple total abdominal hysterec- favourable safety profile is not yet in sight. Consequently, any tomy, alvimopan 12 mg was observed to hasten the time to measure that improves the tolerability of opioid analgesics the first bowel movement by an average of 22 h and to represents a progress in the treatment of pain. As outlined in increase the frequency of bowel movements [104]. Similar this review, the GI tract is one of the main sites of the unde- results were found in a study in 615 patients undergoing sired effects of opiates because the enteric nervous system laparotomy for bowel resection or hysterectomy, in Printing which expresses and all distribution of the key subtypes strictly of opioid receptors prohibited that both alvimopan 6 and 12 mg significantly accelerated GI (when activated) compromise GI function. This may be recovery in terms of toleration of solid food, first bowel physiologically meaningful under conditions where the movement and writing of hospital discharge order [105]. endogenous opioid system is activated but represents a nui- In all of these trials, the incidence of adverse events was sance when exogenous opiates are administered for thera- similar among the placebo and alvimopan treatment groups peutic purposes. The potential of opiates to cause (Box 1) [106]. Postoperatively, the main treatment-emergent constipation and other bowel-related adverse reactions is (in adverse effects were bowel related and included nausea, vom- fact) a serious drawback to the patients’ satisfaction with opi- iting and abdominal discomfort. The incidence of post- oid analgesics. In addition, the use of opioids for postoperative nausea and vomiting was significantly reduced by operative pain control prolongs hospitalisation because of alvimopan 6 and 12 mg, respectively, in 2 studies [101,103], their potential to enforce and prolong postoperative ileus. As a whereas the proportionInforma of patients UK Ltd.who experienced nausea result, many opioid-sparing approaches have been explored and/or vomiting was nominally enhanced by alvimopan but the outcome has generally been unsatisfactory and has at 12 mg in another study [104]. The failure of alvimopan to best resulted in a partial solution of the problem. antagonise opioid-induced analgesia was confirmed in all of The development of opioid receptor antagonists with the studies [100-105]. restricted access to the CNS has opened up a new approach to selectively control the adverse actions of opioid analgesics Copyright10. Opioid of receptor antagonists with a in the gut. This concept has been validated in an impressive peripherally restricted site of action as manner by the clinical evaluation of methylnaltrexone and possible prokinetic drugs alvimopan, which are capable of preventing the undesired opioid effects on gut function at the same time as preserving As outlined in Section 5, PRORAs may have potential to alle- the desired analgesic action of opiates on central pain con- viate intestinal motor stasis unrelated to opiate use. Thus trol. This conclusion has been validated by a recent naloxone is capable of stimulating peristalsis in the guinea-pig meta-analysis of the effect of alvimopan in the treatment of isolated small intestine [20], which suggests that peripheral postoperative ileus [106]. Therefore, it is evident that analgesia opioid receptor antagonists may have a prokinetic action on and OBD can be dissociated in a pharmacological manner, the GI tract [2]. This prediction has been validated in healthy which will theoretically allow for a more aggressive use of

Expert Opin. Investig. Drugs (2007) 16(2) 189 Treatment of opioid-induced gut dysfunction

opioid analgesics with better pain relief but fewer side • How does the efficacy of alvimopan and methylnaltrexone, effects [67]; however, this claim has not yet been substanti- administered at optimal dosage, in preventing post- ated. Although methylnaltrexone and alvimopan display an operative ileus compare with the efficacy of epidural excellent safety profile, they have bowel-related adverse anaesthesia/analgesia? effects of mild-to-moderate severity. It may by speculated • What are the optimal routes of administration of that part of the undesired actions of PRORAs reflect a with- alvimopan and methylnaltrexone relative to the conditions drawal reaction, especially in patients who have a history of to be treated? As oral alvimopan does not prevent the effect long-term use of opiates. of codeine to delay gastric emptying [42], it could be argued The concept of pharmacological dissociation of analgesia that the benefit of alvimopan in postoperative ileus is and OBD has been proven not only in healthy volunteers but limited by the delay of gastric emptying and consequently also in patients with chronic opioid use for pain relief or sub- by the delay of its delivery to the intestine. Should this drug stitution therapy for addiction. Both methylnaltrexone and be administered by a postpyloric tube to ensure optimal alvimopan have been found to alleviate the symptoms of prokinetic activity? OBD without antagonising analgesia or precipitating signs of • Is the therapeutic benefit gained by alvimopan and opioid withdrawal. Further studies defining optimal dosage methylnaltrexone cost-effective? and dosing regimen as well as long-term efficacy and safety are • Which group of patients undergoing a particular type of needed. To date, only 1 study in which alvimopan was given abdominal surgery benefit most from the ability of to patients with OBD due to chronic opioid therapy or opi- PRORAs to shorten postoperative ileus? oid addiction for 21 days has been published [100]. In this trial, • Does the reported variability in the therapeutic efficacy of alvimopan 1 mg was found to induce a bowel movement in alvimopan reflect different degrees of endogenous opioid ∼ 50% of the patients, the effect being most prominent involvement in postoperative ileus? during the first 2 weeks [100]. • As parenteral methylnaltrexone is mostly eliminated by the Several Phase II and III trials have addressed the efficacy of renal route, does its dose need to be adjusted in patients methylnaltrexone and particularly of alvimopan to hasten the with impaired renal function? resolution of postoperative ileus under patient-controlled Another important discovery emanating from the clinical opioid analgesia. In assessing these trials, it has to be borne in evaluation of methylnaltrexone and alvimopan is their mind that there is currently no consensus for defining potential to stimulate bowel activity in healthy volunteers. postoperative ileus in terms of onset, duration and resolution This attests to the concept that endogenous opioid peptides of symptoms. Alvimopan and methylnaltrexone were reported Printingplay a role and in reducing distribution bowel function strictlyunder physiological prohibited to shorten the time to recovery of GI function (tolerance of conditions. As there is evidence that the endogenous opioid solid food, and passage of flatus or stool) and to writing the system in the gut may be overactive under certain patho- hospital discharge order by variable degrees ≤ 1 day. As no logical conditions, PRORAs may turn out to be prokinetic approved treatment schedule for postoperative ileus exists as drugs in their own right. Preliminary findings of a therapeutic yet, these findings herald a significant advance in the clinical effect in patients with chronic constipation support this con- management of postoperative ileus and are encouraging to tention. It is now important to determine which GI motor address a number of questions that remain unanswered: disorders will benefit most from the prokinetic potential of • Are the effects of alvimopan and methylnaltrexone relevant methylnaltrexone and alvimopan. for the patient and do they represent a clinically relevant improvement in terms of shortening the hospital stay for Acknowledgements the patient and reducing Informa ileus-related UK complications? Ltd. • Which dose of alvimopan and methylnaltrexone has the Work in the author’s laboratory is supported by the Austrian optimal efficacy/safety profile? Research Funds, the Austrian Federal Ministry of Education, • What is the optimal dosage of alvimopan and Science and Culture, the Jubilee Funds of the Austrian methylnaltrexone in the long-term management of OBD? National Bank and the Zukunftsfonds Steiermark. Copyright of Bibliography 2. HOLZER P: Opioids and opioid receptors FRIGO G: Adrenergic mechanisms in the Papers of special note have been highlighted as in the enteric nervous system: from a control of gastrointestinal motility: from either of interest (•) or of considerable interest problem in opioid analgesia to a possible basic science to clinical applications. (••) to readers. new prokinetic therapy in humans. Pharmacol. Ther. (1996) 69:59-78. Neurosci. Lett. (2004) 361:192-195. 1. KURZ A, SESSLER DI: Opioid-induced 4. FRUHWALD S, HOLZER P, • Review of the prokinetic potential of bowel dysfunction: pathophysiology and METZLER H: Intestinal motility opioid receptor antagonists in the gut. potential new therapies. 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