Methylnaltrexone for the Management of Unwanted Peripheral Opioid Effects

DRUG EVALUATION

Methylnaltrexone for the management of unwanted peripheral opioid effects

Peter Holzer For many a patient suffering from moderate to severe pain, opioid analgesics offer the Medical University of Graz, Research Unit of anxiously sought-after relief, but at a high price. While the pain is wearing off, distressful Translational constipation, abdominal discomfort, nausea and urinary retention ensue. These unwanted Neurogastroenterology, effects have been difficult to deal with, and the laxatives that are usually prescribed Institute of Experimental and Clinical Pharmacology, ameliorate constipation in no more than 50% of the patients receiving opiates. A new Universitätsplatz 4, treatment concept emerged from the development of opioid receptor antagonists with a A-8010 Graz, Austria peripherally restricted site of action. One of these treatments is methylnaltrexone, which Tel.: +43 316 380 4500 Fax: +43 316 380 9645 clinical trials have shown to be of benefit in opioid-induced constipation, postoperative [email protected] ileus and urinary retention, while analgesia remains unabated. The drug is well tolerated and holds great promise in freeing opioid therapy of some of its most-feared adverse aspects. In 2008, methylnaltrexone (RelistorTM) was approved in the USA, Canada and Europe for the treatment of opioid-induced constipation in patients with advanced illness.

Opioids denominate exogenous and endogenous the bowel, anorexia, nausea and vomiting, as well compounds that activate the principal µ-, κ- and as interference with oral drug administration and δ-opioid receptors. The term opioid has been absorption [1,2]. The symptoms associated with derived from opium, which refers to the dried OBD can profoundly impair the quality of life, latex collected from the unripe seed capsules of and in some patients can be so severe that they Papaver somniferum. Due to its efficacy, opium prefer to discontinue analgesic therapy rather has been used since ancient times to treat pain than experience the discomfort of OBD [1,3]. and diarrhea – the major opioid alkaloids being Unlike other adverse effects of chronic opioid morphine and codeine. Despite many attempts therapy, such as sedation, nausea and vomiting, to develop other strong pain medications, opioid which often resolve with continued use, OBD analgesics have remained the mainstay of therapy generally persists throughout treatment [1]. in many patients with moderate to severe pain. The distressing nature of OBD is underscored Unfortunately, adverse effects can severely com- by the frequency of its occurrence. Since GI promise the therapeutic benefit offered by these function is impaired by subanalgesic opioid drugs [1]. In the periphery, these unwanted doses, OBD affects 40–90% of patients taking effects of opioids comprise gastrointestinal (GI) opioids for chronic pain [1,4]. There are data in stasis, urinary retention and pruritus, and can be the literature that indicate that the distress of disabling to a degree that opioid treatment needs OBD can rival that of pain associated with the to be reduced or even abandoned. underlying disease [1]. Although less well studied, urinary retention Opioid-induced bowel dysfunction, owing to impaired micturition is another side prolongation of postoperative ileus & effect of opioid therapy, and a significant source urinary retention of morbidity. Studies in postoperative patients In the GI tract, the adverse effects of opioids indicate that total urinary retention requiring Keywords: constipation, manifest themselves primarily in constipation, catheterization may develop in 3.8–18.1% of methylnaltrexone, opioid characterized by a reduction of defecation fre- the patients, the use of patient-controlled anal- analgesics, opioid-induced quency, hard, dry stools, fecal impaction, incom- gesia with morphine being a significant risk fac- bowel dysfunction, opioid-induced urinary plete evacuation, defecation-associated straining, tor [4,5]. Partial urinary retention is thought to retention, peripherally abdominal bloating and distention, abdominal be an even more frequent adverse reaction to restricted opioid receptor discomfort and pain, and increased gastro- opioid therapy. antagonists, postoperative ileus esophageal reflux. Collectively, these symptoms Another unwanted condition related to opioid are embodied in the term opioid-induced bowel medication is postoperative ileus (POI), which part of dysfunction (OBD), which may lead to second- occurs most commonly following abdominal or ary complications such as pseudo-obstruction of pelvic surgery. POI is characterized by bowel

distention, lack of bowel sounds, accumulation via the Gi/Go subtypes of G-proteins to various of gas and fluid in the GI lumen, intolerance of cellular transduction processes [10,11]. Studies in solid food, nausea, vomiting and delayed passage isolated tissues from the human intestine show of flatus and stool [1,6,7]. Motor stasis occurs in that µ-, κ- and δ-opioid receptors contribute to all segments of the digestive tract, the colon usu- opiate-induced inhibition of muscle activity [1,2]. ally being most severely affected, and lasts on Propulsive motility in the rat intestine is blocked average 3–7 days [4]. Opioid analgesics have an by µ- and δ-opioid receptor agonists [12], whereas adverse influence on postoperative GI motility, peristalsis in the guinea-pig intestine is sup- as their use for postoperative analgesia delays pressed by activation of µ- and κ-opioid recep- recovery of normal bowel function [1,4]. tors [16]. Although these data indicate that OBD is mediated by opioid receptors in the gut [1,2], Mechanisms of action of opioid-induced there are experimental data to show that intra- inhibition of GI function & micturition cerebral injection of opioid analgesics also delays The effect of opioid analgesics on the GI tract is intestinal transit [17]. However, opiate-induced thought to reflect the action of endogenous opi- blockade of gut motility correlates better with oid peptides on GI physiology. Both endogenous opiate concentrations in the gut than with opiate and exogenous opioids modify GI function by concentrations in the brain [18]. In addition, the interaction with µ-, κ- and δ-opioid receptors, all N-methyl quaternary analogs of naloxone and of which are present in the enteric nervous sys- naltrexone, which do not cross the blood–brain tem [8–11]. Opioid receptor agonists can interrupt barrier, are able to fully antagonize the effects of both excitatory and inhibitory enteric pathways morphine in the canine and rat intestine [1,18]. It governing muscle activity [2,11]. For this reason, follows that the adverse influence of opiates on the net effect on motility can be quite diverse. GI function results primarily from interaction Suppression of excitatory neural pathways results with opioid receptors in the gut. in suppression of acetylcholine release and peri- The pathophysiology of prolonged POI staltic contractions, whereas blockade of inhibi- involves inflammatory, immunological, muscu- tory neural pathways results in depression of lar and neurogenic mechanisms [7,19,20]. Post- nitric oxide release from inhibitory motor neu- operative pain control with opioids is thought to rons, disinhibition of GI muscle activity, eleva- exacerbate POI, as the time required for resolution of resting muscle tone and nonpropulsive tion of POI following colectomy is related to the motility patterns [2,9,11–13]. dose of morphine administered [21]. In addition, Depending on whether interruption of excita- it is assumed that the GI opioid system contrib- tory or inhibitory neural pathways is prevailing, utes to the condition [2,8]. muscle relaxation or spasm will ensue in response The pathophysiology of opioid-induced uri- to opiate administration. As a result, opioid nary retention is not completely understood. receptor agonists inhibit gastric emptying, Opioids decrease the force of detrusor contrac- increase pyloric muscle tone, induce pyloric and tion, decrease the sensation of bladder filling, duodenojejunal phasic pressure activity, disturb but probably do not increase sphincter tone [22]. the migrating myoelectrical complex, delay tran- These adverse effects involve opioid actions in sit through the small and large intestine and ele- the CNS and, possibly, in the periphery [23–25]. vate the resting anal sphincter pressure [1,2,11]. The halt in propulsive motility combines with Unmet needs in the current inhibition of GI ion and fluid transport. management of unwanted opioid Through prolonged contact of the intestinal effects in the periphery contents with the mucosa and interruption of The frequency and distress of OBD profoundly prosecretory enteric reflexes, opioids attenuate impairs the quality of life, and often necessitates the secretion of electrolytes and water, and facili- rescue treatment, which is difficult to achieve. tate the net absorption of fluid [12,14,15]. The There are two main approaches to the patient experiences constipation, hard, dry stools pharmacological management of OBD: nonspe- and abdominal discomfort. cific treatment with laxatives, and specific treat- In considering pharmacological opportunities ment with opioid receptor antagonists (Box 1). to manage OBD, it is important to know the Softening, stimulant and osmotic laxatives are opioid receptor subtypes responsible for this most commonly used to ameliorate OBD, and condition. Opioid receptors belong to the family treatment attempts with prokinetic drugs have of metabotropic membrane receptors that couple also been made [1,3,6,26]. Unfortunately, only

532 Therapy (2008) 5(4) futurefuture sciencescience groupgroup Methylnaltrexone in management of unwanted peripheral opioid effects – DRUG EVALUATION

Box 1. Nonspecific and specific treatment of unwanted effects treat established motor stasis [1,2]. Since opioid- of opioids in the periphery. induced analgesia is primarily mediated by µ-opioid receptors in the CNS, the rational Nonspecific treatment of opioid-induced bowel dysfunction approach to prevent OBD would be to combine Drugs without affinity for opioid receptors opioid analgesics with opioid receptor antago- • Drug classes nists that cannot penetrate the blood–brain bar- – Laxatives rier. As a result, the adverse effects of opioid – Prokinetic drugs – Opioid-sparing regimen analgesics in the periphery would be avoided, • Unsatisfactory control of opioid-induced constipation whereas their central analgesic action would be preserved. This approach has been validated by Specific treatment of opioid-induced bowel dysfunction the use of opioid receptor antagonists with lim- Opioid receptor antagonists with limited intestinal absorption ited systemic absorption, and by the develop- • Drugs ment of peripherally restricted opioid receptor – Oral naloxone antagonists [1,2,4,32]. • Prevention of opioid-induced constipation Peripherally restricted opioid receptor antagonists Opioid receptor antagonists with limited • Drugs systemic absorption – Parenteral and oral methylnaltrexone Naloxone is a pan-opioid receptor antagonist [33] – Oral alvimopan with an oral bioavailability as low as 2% due to • Prevention of opioid-induced constipation extensive first-pass metabolism. Consequently, • Shortening of postoperative ileus • Attenuation of opioid-induced urinary retention oral naloxone has been found to reduce constipa- • Attenuation of opioid-induced pruritus tion, but not pain caused by morphine in rats [34]. These observations have been confirmed in clinical studies in which oral naloxone turned approximately 50% of the patients treated with out to improve OBD without necessarily com- laxatives experience relief from OBD [3,27]. Due to promising opiate-induced analgesia [35–37]. Once the limited efficacy, rescue treatment requires fre- it has passed the liver, however, naloxone can eas- quent dose adjustments, combination therapy and ily enter the brain and reverse opioid-induced laxative switching [3,6,27]. For this reason, many analgesia [1]. Thus, the therapeutic range of opioid-sparing regimens have been tested, includ- naloxone is rather narrow because of the need to ing transdermal administration of opiates [1,28], titrate peripherally versus centrally active doses but none of these attempts have solved the prob- [35]. Despite this limitation, a combination of lem of OBD in a satisfactory manner. Apart from oral oxycodone and naloxone at the weight ratio catheterization, the treatment options for opioid- of 2:1 has been licensed in Germany and, being induced urinary retention are likewise limited [25]. formulated as a prolonged-release preparation, Proactive management of POI includes the has been shown to have analgesic efficacy at a use of epidural anesthesia and analgesia, laparo- low rate of OBD [38]. scopic instead of open-abdominal surgery, early nasogastric tube removal, early oral nutrition Peripherally restricted opioid and early ambulation following surgery [1,6,7,29]. receptor antagonists This polymodal fast-track postoperative manage- Quaternary analogs of opioid receptor antago- ment can be combined with the use of laxatives nists such as naloxone and naltrexone display a and prokinetic drugs to accelerate recovery of GI pharmacokinetic profile of limited absorption function [1,7,30,31]. However, the therapeutic from the gut and inability to enter the brain [1,6]. value of these medications in the relief of POI As a consequence, these compounds antagonize with or without opiate use remains largely the effects of morphine in the periphery at doses unsubstantiated [1]. Among all available treat- that are devoid of effects on the CNS [39]. Like ment options, epidural local anesthesia appears methylnaltrexone, alvimopan is a µ-opioid to be the most efficacious method for relieving receptor-preferring antagonist, which, owing to pain and shortening POI [1]. its polar structure, exhibits low systemic absorption and a limited ability to enter the brain Specific treatment of unwanted opioid [2,4,40,41]. Since it is rapidly degraded after intra- effects in the periphery venous injection, alvimopan is formulated for The primary objective in the management of oral intake, in which case it potently blocks OBD is to prevent GI symptoms, rather than µ-opioid receptors in the gut with a prolonged

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duration of action. Preclinical and Phase I stud- Methylnaltrexone ies have established the pharmacokinetics, safety, Methylnaltrexone (Relistor™) was among the efficacy and selectivity of alvimopan in its antag- first quaternary derivatives of opioid receptor onism of peripheral opioid receptors [1,2,4,40,41]. antagonists that were shown to antagonize In these studies, alvimopan was found to prevent peripheral, but not central, effects of morphine opioid receptor agonists from delaying GI transit [39]. This property was subsequently confirmed in healthy subjects without antagonizing central in humans, and the compound was scheduled opioid effects, such as analgesia and pupillary for clinical development. The available study constriction [40–42]. results attribute methylnaltrexone efficacy and Several Phase II and III trials attest to the util- safety in managing the peripheral side effects of ity of alvimopan in treating OBD and POI opioid analgesics, at least in the short term. [2,5,40,41,43–46]. In patients on chronic opioid therapy for non-malignant pain, alvimopan (0.5 Chemistry or 1 mg twice daily for 6 weeks) is able to Methylnaltrexone is obtained by attaching a increase spontaneous bowel movements during methyl group to the amine configuration in nal- the initial 3 weeks of treatment and improve trexone (Figure 1). The positively charged quater- other symptoms of OBD over the whole treat- nary configuration increases the polarity and ment period, while analgesia is not compro- reduces the lipid solubility of the compound, rel- mised [41,44]. Four Phase III trials conducted in ative to naltrexone [49]. Used as a bromide salt, North America have shown that alvimopan (6 methylnaltrexone is a white, odorless powder or 12 mg twice daily) accelerates GI recovery that is freely soluble in water. For clinical trials, and shortens the duration of hospitalization the compound has been formulated both as a after abdominal or pelvic surgery, whereas an solution for infusion or injection, and as capsules international Phase III trial failed to reveal a sig- or tablets for oral intake [49]. nificant effect of alvimopan on POI unless subjects were maintained on intravenous patient- Pharmacodynamics controlled opioid analgesia [41,45–47]. The varia- Methylnaltrexone is a µ-opioid receptor-prefer- bility in the efficacy of alvimopan may, in part, ring antagonist, exhibiting a half-maximal inhib- be due to differences in pharmacokinetics and itory concentration (IC50) of 70 nM at human dosing, as the rate of alvimopan absorption is µ-opioid receptors [49]. It has a reduced affinity slowed in surgical patients [48]. for κ-opioid receptors and considerably less Studies addressing the acute (up to 6 weeks) affinity for δ-opioid receptors, although the data safety of alvimopan in patients with OBD have in this respect are somewhat conflicting [49–51]. shown that the drug is well tolerated, the adverse Basically categorized as a pure antagonist [49], effects being primarily gut-related and including methylnaltrexone has some agonist activity at nausea, vomiting and abdominal discomfort heterologously expressed µ-opioid receptors [50]. [40,41,43,44,47]. However, the long-term safety of Preclinical studies have confirmed that methyl- alvimopan remains to be established, given that a naltrexone antagonizes the action of µ-opioid 1-year Phase III trial of patients receiving opiate receptor agonists to inhibit GI transit and evoke therapy for chronic noncancer pain revealed a emesis [49–51]. numerical imbalance in the number of ischemic cardiovascular events, neoplasms and fractures in Pharmacokinetics & metabolism patients receiving alvimopan (0.5 mg perorally Owing to its quaternary structure, methyl- twice daily), relative to placebo [41,101]. A 2-year naltrexone exhibits low oral bioavailability and carcinogenicity study in mice and rats showed does not cross the blood–brain barrier [3,49,50]. Its that oral alvimopan significantly increased the ability to prevent the undesired effects of opioids incidence of cutaneous/subcutaneous fibroma, in the periphery without interfering with opioid fibrosarcoma and sarcoma, and osteoma/osteo- actions in the brain has been substantiated in sarcoma in female mice [101]. In May, 2008, alvi- preclinical and clinical studies [49,51]. Whereas in mopan (Entereg™) was approved by the US dogs and humans methylnaltrexone prevents the FDA for the treatment of POI following bowel adverse effect of opioid analgesics on GI func- resection in hospitalized patients aged 18 years or tion without attenuation of analgesia, analgesia older. The recommended dosing is 12 mg just in rats is appreciably compromised [3]. This spe- before surgery, and 12 mg twice daily post-surgery cies dependence of the peripheral selectivity of for up to 7 days [102]. methylnaltrexone arises from its demethylation

534 Therapy (2008) 5(4) futurefuture sciencescience groupgroup Methylnaltrexone in management of unwanted peripheral opioid effects – DRUG EVALUATION

Figure 1. Naltrexone and methylnaltrexone bromide.

- Br

Naltrexone Methylnaltrexone bromide

to naltrexone, which readily penetrates the gastric emptying and orocecal transit time blood–brain barrier: demethylation occurs in without significantly attenuating morphine- mice and rats, but is negligible in dogs and induced analgesia [53,54,56–60]. humans [3,52]. Double-blind, randomized and placebo-con- While readily bioavailable after parenteral trolled Phase II studies proved that methyl- administration, methylnaltrexone is absorbed naltrexone is capable of relieving constipation in from the GI tract only to a limited extent [53]. methadone-maintained, opioid-dependent vol- The plasma levels of methylnaltrexone are even unteers (Table 1). Intravenous methylnaltrexone lower when the drug is administered orally as an shortens the orocecal transit time and causes lax- enteric-coated formulation, although enteric- ation associated with mild abdominal cramping, coated methylnaltrexone is more efficient in pre- but does not elicit any sign of opioid withdrawal venting morphine-induced retardation of oroce- [61]. Compared with placebo, oral methylnal- cal transit time than the uncoated preparation trexone is likewise able to provoke laxation in [54]. Thus, reduced oral bioavailability is associ- methadone-maintained patients without precipi- ated with enhanced efficacy, which suggests that tating opioid withdrawal in any subject [62]. oral methylnaltrexone acts locally in the gut to However, the latency to the first bowel move- reverse morphine-induced motor stasis. ment is significantly longer following oral intake Following parenteral injection of methyl- of the drug than after intravenous administra- naltrexone 0.3–0.45 mg/kg, the time to maxi- tion. The doses of methylnaltrexone required to mum plasma concentration is approximately induce bowel movements in subjects on chronic 20 min, the elimination half-life in blood plasma methadone were lower than those required in is approximately 1.5–3 h, and the terminal half- subjects who were not opioid dependent. life is approximately 6–9 h [49,51,55]. Repeated The utility of subcutaneous methylnaltrexone intravenous administration of 0.3 mg/kg doses at to selectively counteract opiate-induced stasis in 6-h intervals does not result in accumulation of the GI tract has been proven in Phase II and III the drug [56], and metabolism of methylnaltrexone studies of patients with advanced illness requiring does not play a major role in its predominantly high doses of opiates for pain control (Table 1). renal route of elimination [49,51]. The efficacy and dose–response relationship of methylnaltrexone in relieving opioid-induced Clinical efficacy constipation was first evaluated in a multicenter, The therapeutic and safety profile of methyl- randomized and parallel-group Phase II trial naltrexone has been evaluated in several Phase involving 33 adult patients with advanced illness I, II and III trials (Table 1). In healthy volun- (terminal or end-stage diseases such as metastatic teers, both the parenteral and oral formula- cancer and AIDS) who were receiving chronic tions, as well as single and repeated dosage opioid therapy for pain on a daily basis [63]. regimens, were found to be efficacious in pre- Patients were eligible for the study if they had no venting the morphine-induced prolongation of bowel movements for 2 days, even if they received

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Table 1. Overview of fully or partially published clinical trials of methylnaltrexone in opioid-induced bowel dysfunction, opioid-induced urinary retention and postoperative ileus associated with opiate medication. Dose and route of administration Type of trial Major outcome from the use Ref. of methylnaltrexone

0.64, 0.7, 2.1, 6.4 or 19.2 mg/kg p.o. Phase I Efficacy and safety in preventing OBD [53] 3.2 or 6.4 mg/kg p.o Phase I Pharmacokinetics and efficacy in ameliorating OBD [54] 0.3 mg/kg every 6 h iv. Phase I Safety, pharmacokinetics and efficacy in stimulating [56] GI transit 0.45 mg/kg iv. Phase I Efficacy and safety in preventing OBD [57] 0.04, 0.08, 0.16, 0.32, 0.64 or 1.25 mg/kg iv. Phase I Safety and pharmacokinetics [58] 0.3 mg/kg iv. Phase I Efficacy of methylnaltrexone in ameliorating [59] morphine-induced delay of gastric emptying 0.3 mg/kg iv. Phase I Efficacy in ameliorating urinary retention due to [25] intravenous remifentanil 0.1 or 0.3 mg/kg sc. Phase I Pharmacokinetics and efficacy in ameliorating OBD [60] 19.2 mg/kg p.o Phase I Efficacy of methylnaltrexone in ameliorating pruritus [66] and flushing due to morphine 0.1 mg/kg daily iv. Phase II Efficacy and safety in ameliorating OBD due to [61] chronic methadone 0.3 or 1.0 mg/kg p.o. Phase II Efficacy and safety in ameliorating OBD due to [62] chronic methadone 1, 5, 12.5 or 20 mg every other day for 3 weeks sc. Phase II Efficacy and safety in causing laxation in [63] patients with advanced illness on high-dose opiate medication

0.3 mg/kg every 6 h for up to 1 week iv. Phase II Efficacy and safety in accelerating resolution of POI [49]* after open segmental colonic resection

0.15 or 0.3 mg/kg sc. as a single dose, followed Phase III Efficacy and safety in causing laxation in [64]* by pro re nata dosing for 4 weeks patients with advanced illness on high-dose opiate medication 0.15 mg/kg sc. every other day for 2 weeks, Phase III Efficacy and safety in causing laxation in [65] followed by 3-month open-label trial patients with advanced illness on high-dose opiate medication *Clinical trials that have not yet been fully published. GI: Gastrointestinal; iv.: Intravenously; OBD: Opioid-induced bowel dysfunction; p.o.: Per os; POI: Postoperative ileus; sc.: Subcutaneously.

conventional laxative therapy. The schedule of Eligible patients were on stable opioid and laxative repeated methylnaltrexone treatment included a therapy, but had no laxation for 48 h [64,65]. No double-blind phase for 1 week, followed by an rescue laxatives were allowed within 4 h before and open-label phase for a maximum of 3 weeks. The after dosing. In the first Phase III study [64], opioid receptor antagonist was administered every methylnaltrexone (0.15 or 0.30 mg/kg) was other day at doses comprising 1, 5, 12.5 and administered as a single subcutaneous double- 20 mg. The median time to laxation was 1.3 h for blind dose, 24 h after which the patients were eli- all patients receiving a 5 mg or higher dose of gible to receive open-label methylnaltrexone pro methylnaltrexone, and there was no apparent re nata over the next 4 weeks. The primary effi- increase in efficacy at doses above 5 mg [63]. cacy end point was laxation within 4 h after a sin- Based on this study, two Phase III trials of sub- gle dose of study drug, a time span within which cutaneous methylnaltrexone in patients with end- subcutaneous methylnaltrexone at either dose, stage diseases suffering from opioid-induced unlike placebo, was found to cause laxation in the constipation were conducted [64,65]. These multi- majority of patients [64]. center, double-blind, randomized, placebo-con- The other Phase III study was designed to trolled studies involved a total of 287 patients in assess the efficacy of subcutaneous methyl- hospice, nursing home or palliative care programs, naltrexone (0.15 mg/kg) versus placebo admin- who had a life expectancy of less than 6 months. istered every other day for 2 weeks in patients

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with advanced illness suffering from opioid- from cutaneous mast cells [49]. In human volun- induced constipation [65]. Patients were permit- teers, it was found that oral methylnaltrexone ted to double the initial volume of the blinded (19.2 mg/kg) decreased the subjective ratings of study drug in week 2 if they had fewer than three ‘skin itching’ and ‘flushing’ caused by intrave- rescue-free bowel movements in the first week. nous morphine [66]. It thus appears as if opioid The 2-week double-blind phase was followed by receptor antagonists with a peripherally an open-label extension trial, during which the restricted site of action could be of benefit in patients received subcutaneous methylnaltrex- controlling unwanted cutaneous manifestations one (0.075–0.30 mg/kg) as needed up to every of opioid therapy. A further effect of opioid 24 h for up to 3 months [65]. The results showed analgesics is to suppress the cough reflex, which that within 4 h after receiving the first dose, is an important mechanism to clear and protect 48% of the patients treated with methylnaltrex- the airways. Although this antitussive action is one achieved laxation, relative to 15% of the thought to take place in the CNS, preclinical patients receiving placebo. Similarly, 52% of the data show that intraperitoneal methylnaltrex- patients had a bowel movement within 4h after one can prevent morphine from inhibiting the two or more of the first four doses of methylnal- cough reflex in guinea pigs, while analgesia trexone, compared with 8% of the placebo-treated remains unabated [67]. Whether methylnaltrex- patients. This response rate remained consistent one has a similar effect in humans awaits to be throughout the double-blind and open-label investigated. extension phase. The median time to laxation was approximately 30 min after administration of Safety & tolerability methylnaltrexone [65]. At therapeutic doses (0.3–0.45 mg/kg intra- POI is another indication in which intravenous venously, and up to 19.2 mg/kg per os) methyl- methylnaltrexone is being evaluated in Phase II naltrexone is well tolerated, an outcome that is and III trials [49,51]. Patients undergoing open seg- also true when methylnaltrexone is repeatedly mental colonic resection were reported to benefit administered at 0.3 mg/kg intravenously every from treatment with methylnaltrexone, as upper 6h [56]. Taking all Phase I studies together, only and lower bowel function recovered approximately two types of adverse reactions to methyl- 1 day earlier in patients receiving intravenous naltrexone have been reported (Table 2). One of methylnaltrexone than in placebo-treated patients, them relates to the vascular system, given that whereas no difference in opioid use or mean pain transient orthostatic hypotension can occur at scores was observed [49]. Subsequently, two Phase supratherapeutic doses (0.64 mg/kg or higher) III studies were initiated to establish the efficacy and plasma levels of more than 1.4 µg/ml and safety of methylnaltrexone in POI [51], one of [2,6,49,51]. This reaction may be related to facial which ([103]; identifier: NCT00387309) has been flushing and mild light-headedness, symptoms completed and its outcome announced in a press that have occasionally been reported [35]. The release on 13 March 2008 [104]. As the data of this other type of adverse effect comprises gut-related trial show, intravenous methylnaltrexone failed to reactions such as abdominal cramps, soft stools significantly accelerate postoperative recovery of and diarrhea [2,6,49,51,56,63]. GI function in patients who underwent segmental This safety profile was confirmed in Phase II colectomy [104]. The results of the other Phase III and III trials of patients with advanced illness. In trial addressing the efficacy of intravenous these studies, most adverse effects of intravenous methylnaltrexone in POI are expected to become methylnaltrexone affected the GI system, were available later in 2008. mild in intensity, did not reduce analgesia or The beneficial effect of methylnaltrexone is cause opioid withdrawal symptoms, and did not not limited to the GI tract, since urinary reten- lead to discontinuation of the drug [63–65]. The tion owing to opioid therapy is also ameliorated most common adverse events were transient by the drug. In a study involving healthy male abdominal pain (in up to 45% of patients), volunteers receiving intravenous remifentanil, diarrhea, flatulence and nausea. intravenous methylnaltrexone (0.3 mg/kg) was found to partially restore micturition, while opi- Economic implications oid-induced miosis remained unaltered [25]. The opportunity to specifically suppress Other adverse actions that opioids exert in unwanted effects of opioid analgesics in the some patients include pruritus and flush, which periphery has important healthcare implications may, in part, be owing to release of histamine in the treatment of conditions ranging from

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Table 2. Overview of significant adverse effects of methylnaltrexone and its competitor alvimopan, relative to placebo, encountered in clinical trials. Drug, dose and route of administration Adverse effects Ref.

Methylnaltrexone up to 0.3 mg/kg sc., up to No adverse effects of clinical importance in [25,53,56,57,60] 0.45 mg/kg iv., up to 19.2 mg/kg p.o. healthy volunteers Methylnaltrexone 0.64 or 1.25 mg/kg iv. at plasma Orthostatic hypotension, facial flushing and [58] levels in excess of 1.4 µg/ml light-headedness in healthy volunteers Methylnaltrexone 0.3 or 1.0 mg/kg p.o. No adverse effects of clinical importance in [62] methadone-maintained subjects Methylnaltrexone 0.1 mg/kg iv. Mild-to-moderate abdominal cramping in [61] methadone-maintained subjects Methylnaltrexone 0.3 mg/kg iv. No adverse effects of clinical importance in healthy [25] volunteers; reduction of nausea and vomiting caused by remifentanil Methylnaltrexone 0.3 mg/kg every 6 h for up to No adverse effects of clinical importance in [49]* 1 week iv. postoperative patients; reduction of nausea, vomiting and abdominal pain Methylnaltrexone 1, 5, 12.5 or 20 mg every other day Gut-related adverse effects of mild intensity: abdominal [63] for 3 weeks sc. pain, flatulence, diarrhea and nausea

Methylnaltrexone 0.15 or 0.3 mg/kg sc. as a single Gut-related adverse effects of mild intensity: abdominal [64]* dose, followed by pro re nata dosing for 4 weeks pain, flatulence and diarrhea Methylnaltrexone 0.15 mg/kg sc. every other day for Gut-related adverse effects of mild intensity: abdominal [65] 2 weeks, followed by 3-month open-label trial pain and flatulence Alvimopan 4 or 12 mg p.o. No significant adverse effects in healthy volunteers [2,40–42] Alvimopan 1 mg p.o. Bowel-related adverse effects (abdominal cramping, [43] nausea, vomiting and diarrhea) in patients receiving chronic opioid therapy Alvimopan 1, 6 or 12 mg p.o. No significant adverse effects in postoperative patients [2,31,41,45–47] Alvimopan 6 or 12 mg p.o. No change (one study) or reduction (two studies) of [2,46] nausea and vomiting in postoperative patients

Alvimopan 0.5 mg twice daily for 12 months p.o. Numerical imbalance in ischemic cardiovascular events, [41,101]* neoplasms and fractures in patients receiving alvimopan, relative to placebo *Clinical trials that have not yet been fully published. iv.: Intravenously; p.o.: Per os; sc.: Subcutaneously.

malignant and nonmalignant chronic pain to Regulatory affairs POI. The immediate benefit for the patient lies Methylnaltrexone has been developed jointly by in a significant improvement in the quality of Progenics Pharmaceuticals (NY, USA) and Wyeth life due to the prevention of some of the most Pharmaceuticals (NJ, USA) for the management disabling adverse effects of opioids. In addition, of the unwanted effects of opioid analgesics in the there are important economic implications that periphery. In 2008, subcutaneous methylnaltrex- may emerge from the use of methylnaltrexone. one was approved by Health Canada and the FDA The use of this specific adjunct to opioid ther- for the management of opioid-induced constipa- apy in patients with chronic malignancy-associ- tion in patients with advanced illness who receive ated pain may reduce the burden of hospice, opioids for palliative care, but do not appropri- nursing home and palliative care programs to ately respond to laxative therapy [68,105]. The deci- provide patient care. If the duration of postoper- sion from the FDA came on the same day on ative hospitalization can be shortened by up to 1 which the European Medicines Agency’s Commit- day owing to accelerated recovery of postopera- tee for Medicinal Products for Human Use issued tive bowel function, a significant reduction of a positive opinion on the drug for the same indica- direct and indirect healthcare costs can be tion [106]. In addition, Progenics and Wyeth devel- achieved [31,41]. oped an oral formulation of methylnaltrexone for

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the management of opioid-induced constipation Unlike its direct competitor, oral alvimopan, in patients with chronic non-malignant pain, and methylnaltrexone can be administered by the have initiated Phase II trials to test its efficacy and oral, subcutaneous and intravenous route to safety in this indication ([103]; identifiers: manage the peripheral adverse effects of opiates. NCT00547586 and NCT00605644). Since oral drug intake may be impossible in seri- Based on promising Phase II results, intravenous ously ill or postoperative patients, the parenteral methylnaltrexone was granted fast-track status for route of administration represents an important evaluation of its efficacy and safety in POI by the advantage of methylnaltrexone [51]. This FDA in 2006 [51]. However, a press release on 13 pharmacokinetic versatility of methylnaltrexone March 2008 revealed that a Phase III trial of intra- combines favorably with its safety profile, venous methylnaltrexone ([103]; identifier: whereas the future of alvimopan is overshadowed NCT00387309) failed to significantly accelerate by its potential long-term toxicity. Although recovery from POI caused by segmental colec- methylnaltrexone’s potency at opioid receptors is tomy [104]. The outcome of another Phase III inferior to that of alvimopan, it is difficult to tell trial of methylnaltrexone in POI is due to be whether this translates to an appreciable differ- released later in 2008, and will be of prime rele- ence in clinical efficacy because no comparative vance to the further development of the drug as a studies have thus far been carried out. POI therapy. Further clinical studies are needed to define the optimal dosage, optimal dosing regimen and Conclusion optimal efficacy/safety profile of methyl- Like oral naloxone and alvimopan, subcutaneous naltrexone in the long term [2]. The available and intravenous methylnaltrexone offers the data indicate that, at therapeutic doses, methyln- potential to pharmacologically dissociate the altrexone has a favorable short-term safety pro- peripheral unwanted effects of opioid analgesics file, the only adverse reactions of note affecting from their central action to control pain. By pre- the GI tract. It has been speculated that part of venting or attenuating opioid-induced constipa- the undesired action of methylnaltrexone on the tion, POI, urinary retention and pruritus, this bowel reflects a withdrawal reaction, especially in drug can significantly improve opioid therapy. patients who have a history of long-term use of The full advantage of this new treatment concept opiates [2]. The therapeutic value of methyl- will be seen if methylnaltrexone proves effica- naltrexone can not be fully appreciated before its cious and well tolerated not only in the short long-term efficacy and safety have been dis- term, but also in the long term. closed. Since methylnaltrexone is likely to be Opiates will remain the mainstay in the treat- used in multimorbid patients, its interaction ment of moderate to severe pain in the foreseeable with other drugs and the necessity of dose future, given that the introduction of analgesic adjustment in patients with renal insufficiency drugs with equal efficacy but a more favorable or failure also need to be determined [2,51]. safety profile is not yet in sight. Thus, any meas- ure that improves the tolerability of opioid anal- Future perspective gesics represents a progress in the treatment of The available data show that methylnaltrexone pain [2]. The GI tract is one of the major targets of is able to prevent the peripheral adverse effects the undesired effects of opiates in the periphery, of opioid analgesics, while their central analge- because the enteric nervous system expresses all sic action remains unaltered. Currently major subtypes of opioid receptors. OBD is a seri- approved for the relief of opioid-induced con- ous drawback to the patients’ satisfaction with stipation in patients with advanced illness, opioid analgesics, and the use of opioids for post- methylnaltrexone will turn into an important operative pain control prolongs hospitalization adjunct to opioid therapy of pain if it will prove because of their potential to prolong POI. While efficacious and safe in patients with chronic the search for opioid-sparing approaches has, in non-malignant pain. Peripherally restricted opi- general, been unsatisfactory, the development of oid receptor antagonists may also become use- opioid receptor antagonists with restricted access ful in other indications. Thus, both to the CNS has opened up a new avenue to signif- methylnaltrexone and alvimopan have been icantly improve opioid therapy. The pharmaco- found to stimulate GI transit in healthy volun- logical dissociation of OBD and analgesia allows teers [42,56]. Since the GI opioid system may be for a more aggressive use of opioid analgesics with overactive under certain pathological condi- better pain relief but fewer side effects [3]. tions, peripherally restricted opioid receptor

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Executive summary Clinical problem • Opioid analgesics are the mainstay of therapy in many patients with moderate to severe pain, but their therapeutic benefit is severely compromised by adverse effects. • In the periphery, the unwanted effects of opioids comprise constipation, urinary retention and pruritus. • The peripheral side effects of opioids can not be managed by nonspecific treatment options (laxatives and prokinetics) in a satisfactory manner. • Specific management of opioid-induced bowel dysfunction entails selective inhibition of peripheral opioid receptors by opioid receptor antagonists with limited systemic bioavailability and/or a peripherally restricted site of action, such as alvimopan and methylnaltrexone. Mechanisms of action • Methylnaltrexone is a µ-opioid receptor-preferring antagonist. Pharmacokinetic properties • The quaternary compound methylnaltrexone has limited oral bioavailability and does not enter the brain. • The major route of elimination is via the kidney. Clinical efficacy • Intravenous, subcutaneous and oral methylnaltrexone antagonizes opioid-induced bowel dysfunction, urinary retention and pruritus in healthy volunteers, but leaves the analgesic action of opiates unabated. • Intravenous and oral methylnaltrexone relieves constipation in methadone-maintained, opioid-dependent volunteers, but does not elicit signs of opioid withdrawal. • Subcutaneous methylnaltrexone counteracts opiate-induced constipation, but does not impair analgesia, in patients with advanced illness requiring high doses of opiates for pain control. • Intravenous methylnaltrexone may shorten postoperative ileus and hasten recovery of normal bowel function in patients on opiates following open colectomy. Safety & tolerability • Methylnaltrexone is well tolerated, the only effects at therapeutic doses being bowel related (abdominal cramping, flatulence and diarrhea). • Reports on the long-term safety of methylnaltrexone are not yet available. Drug interactions • Information on drug interactions has not yet been released. Dosage & administration • Methylnaltrexone has been formulated for intravenous, subcutaneous and oral administration. • The doses tested in Phase II and III trials are in the range of 0.1–0.3 mg/kg intravenously and subcutaneously, and up to 1 mg/kg perorally. Regulatory affairs • In 2008, subcutaneous methylnaltrexone has been approved in Canada, the USA and Europe for the treatment of opioid-induced constipation in patients with advanced illness. • Phase II studies are underway to evaluate the efficacy and safety of oral methylnaltrexone in the management of opioid-induced bowel dysfunction in patients receiving opioid therapy for chronic non-malignant pain. • The efficacy of methylnaltrexone in shortening postoperative ileus awaits to be confirmed in additional Phase III studies.

antagonists may become prokinetic drugs in Financial & competing interests disclosure their own right [2,8,69]. In addition, methylnal- Work in the author’s laboratory is supported by FWF – The trexone can suppress opioid-facilitated HIV Austrian Scientific Research Funds, the Austrian Federal Minis- infection in human macrophages and inhibit try of Science and Research, and the Zukunftsfonds Steiermark. angiogenesis in vitro, the latter effect being The authors have no other relevant affiliations or financial independent of opioid receptors [51]. involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or mate- Acknowledgements rials discussed in the manuscript apart from those disclosed. The author thanks Ulrike Holzer-Petsche for drawing No writing assistance was utilized in the production of Figure 1 and critically reading the manuscript. this manuscript.

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