Table of Contents  
Year : 2015  |  Volume : 6  |  Issue : 3  |  Page : 188-192  

Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation

Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission25-Sep-2014
Date of Decision09-Feb-2015
Date of Acceptance29-May-2015
Date of Web Publication4-Aug-2015

Correspondence Address:
Tejus Anantharamu
Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra
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Source of Support: Nil, Conflict of Interest: None declared.

DOI: 10.4103/0976-500X.162015

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Opioid-induced constipation (OIC) is one of the most troublesome and the most common effects of opioid use leading to deterioration in quality of life of the patients and also has potentially deleterious repercussions on adherence and compliance to opioid therapy. With the current guidelines advocating liberal use of opioids by physicians even for non-cancer chronic pain, the situation is further complicated as these individuals are not undergoing palliative care and hence there cannot be any justification to subject these patients to the severe constipation brought on by opioid therapy which is no less debilitating than the chronic pain. The aim in these patients is to prevent the opioid-induced constipation but at the same time allow the analgesic activity of opioids. Many drugs have been used with limited success but the most specific among them were the peripherally acting mu opioid receptor antagonists (PAMORA). Methylnaltrexone and alvimopan were the early drugs in this group but were not approved for oral use in OIC. However naloxegol, the latest PAMORA has been very recently approved as the first oral drug for OIC. This article gives an overview of OIC, its current management and more specifically the development and approval of naloxegol, including pharmacokinetics, details of various clinical trials, adverse effects and its current status for the management of OIC.

Keywords: Naloxegol, opioid-induced constipation, peripherally acting mu opioid receptor antagonists

How to cite this article:
Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK. Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother 2015;6:188-92

How to cite this URL:
Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK. Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother [serial online] 2015 [cited 2022 Jan 21];6:188-92. Available from:

   Introduction Top

Opioids are the potent analgesics which remain the mainstay of treating moderate to severe cancer pain as suggested by World Health Organisation (WHO) in its step ladder approach for choosing analgesics in cancer pain.[1] There is an emerging trend of using opioids even for non-cancer pain and incidence has almost doubled over the past 15–20 years. It has been estimated that more than 3% of adult population receive long-term opioids for chronic non-cancer pain.[2] The prevalence of chronic pain in adult population is expected to be around 2–40%. The condition causing chronic pain may be diverse but the ultimate treatment goal remains pain relief and improvement in functioning of the individual, guiding many physicians to use not only mild opioids but also potent agents like morphine to provide pain relief.[3]

Opioid Induced Constipation (OIC) is one of the most troublesome and the common side-effects of using opioids for a prolonged duration. It was observed that on using opioids for 8 weeks an average 4% of patients developed OIC.[3] Various studies report constipation as a side effect in up to 40–95% of patients using opioids, which is potentially iatrogenic. It has been defined as “a condition in which a person has fewer than three spontaneous bowel movements in a week or has bowel movements with hard, dry, and small stools that are painful/difficult to pass.” The major reason for OIC becoming a clinical deadlock in the use of opioids is the pattern of tolerance developed for opioid-induced adverse effects, wherein with the chronic use of opioids an individual develops tolerance to most of the adverse effects except constipation. OIC is known to have a significant impact on quality of life and interferes with day to day activities of the patients. It is also known to affect the adherence and compliance to opioid therapy and many patients may even prefer their chronic pain over the pain induced by severe constipation.[4],[5]

Patho-physiology of OIC

Opioid receptors mu, kappa and delta, belonging to the class of G-protein coupled receptors are expressed widely on GIT with mu receptors seen over intestinal submucosa and ileal mucosa where as kappa and delta receptors predominate in stomach and proximal colon. The predominant actions of opioids on gastrointestinal tract are mediated by mu receptors located prejunctional modulating the release of acetylcholine and on postjunctional receptors decrease the release of neurotransmitters and inhibit calcium channels. The above-mentioned mechanisms delay intestinal transit leading to a decrease in peristalsis, inhibit gastric emptying and also reduce mucosal secretions. The ultimate effects are complicated wherein opioids also stimulate non-propulsive motility and increase the tone of anal sphincters and segmentation in intestines, facilitating fluid absorption from intestines. The final outcome of all these mechanism is constipation, to which there is no development of tolerance even on chronic use.[5],[6]

   Current Management of Opioid Induced Constipation Top

Various non-pharmacological measures like increased consumption of fluids, dietary fibers and increase in physical exercises are initial measures, recommended along with the use of opioids. Pharmacotherapy may be nonspecific like use of laxatives, although effective it does not provide complete symptomatic relief as it is not targeting underlying pathophysiology.[3],[7]

The specific treatment of OIC began with the use of opioid antagonist naloxone, but it could easily cross the blood–brain barrier and was found to reverse the analgesia induced by opioids; this problem was addressed by combining prolonged release oxycodone/naloxone (OXN) approved in Germany and currently reviewed by FDA. Another drug that was developed is Lubiprostone, which is a derivative of PGE1, and a selective activator of chloride channels. Lubiprostone acts locally in the intestine by increasing secretions and gut motility and although FDA approved currently there are no guidelines recommending its use in OIC.[7]

Peripheral Acting Mu Opioid Receptor Antagonists (PAMORAs)

The management of OIC got a shot in the arm with the development of quarternary opioid antagonists acting only in periphery (PAMORAs). They have been found to selectively antagonize the μ-opioid receptors within the gastrointestinal (GI) tract and have very limited ability to block the opioid receptors in the central nervous system and thus these drugs reverse the OIC without any effect on the analgesic actions of the opioids.[7],[8]

Methylnaltrexone a derivative of opioid antagonist naltrexone was approved by US-FDA in April 2008 as alternative day subcutaneous injection for OIC and is regarded as a first-line drug in patients of advanced illness undergoing palliative care suffering from OIC. Being a methyl derivative which is charged, it has limited access across the blood–brain barrier and effectively countered OIC without affecting analgesic actions of opioids. Injected at a dose of 8 mg for patients weighing 38–62 kg and 12 mg for patients weighing 62–114 kg and all others receive dose at 0.15 mg/kg. After injections it produced bowel evacuation within 4 hours in half of the patients. There were many inherent drawbacks with its use, as it has to be given parenterally and is expensive. The application of methylnaltrexone for OIC in non-cancer pain has not been approved.[8]

Alvimopan, another PAMORA approved in May 2008, had relatively higher affinity (approximately 200 times) for peripheral mu opioid receptors compared to methylnaltrexone, but was approved only for postoperative ileus. It was noted in GSK14 studies that alvimopan after long-term use (1-4 months) produced an increase in cardiovascular mortality especially myocardial infarction and further advanced studies were demanded by FDA. Hence, it received approval only for acute short-term treatment of postoperative ileus (POI) as 6 and 12 mg twice a day dose preoperatively and postoperatively for a maximum duration of 7 days. Although alvimopan has shown some efficacy in recent trials, it is not approved at present for OIC in non-cancer pain. The latest PAMORAs at various stages of development for OIC are ADL5945, ALKS37, S-297995 and TD-1211. The other drugs used for constipation, which can also be considered for treating OIC, are lubiprostone (FDA approved for all types of constipation except OIC), prucalopride, linaclotide and plecanatide (guanylate-cyclase C receptor agonists).[4],[7]

   Development and approval of naloxegol Top

The latest drug in this group to be developed is naloxegol (NKTR-118) which is a novel PEGylated form of naloxol, a naloxone analog. Naloxegol has shown strong selectivity (more than 6000 folds) toward peripheral mu receptors and has been approved as first oral PAMORA for OIC due to use of opioids for non-cancer pain. PEGylation greatly restricts the activity of naloxegol to periphery. Naloxegol has been developed by Nektar Therapeutics and is marketed by AstraZeneca under the brand name MOVANTIK and received US-FDA approval on 16 Aug 2014.[7],[9]

   Pharmacokinetics Top

Naloxegol undergoes rapid absorption after oral administration, with peak plasma concentration (Cmax) achieved in less than 2 hours.[10] Being a PEGylated analog, naloxegol stays for longer time in circulation, metabolized predominantly in liver by CYP3A4 enzymes and is also a substrate of p-glycoprotein transporter. It has shown significant interaction with drugs altering CYP3A4/P-glycoprotein transporter, hence avoided with drugs which are strong CYP3A4 inhibitors. The effect of mild–moderate renal/hepatic failure is found to be nonsignificant and there is no need for dose reduction, but those patients with creatinine clearance less than 60 ml/min are started off with a low dose and if well tolerated they can be switched over to normal dose. The metabolites (six in number) are predominantly excreted in feces (67%) and rest in urine. These pharmacokinetic parameters have been confirmed in 14C studies in humans. It has been assigned Category C status for use in pregnancy.[11] Pharmacokinetics of existing PAMORAs has been compared [Table 1].
Table 1: Approved PAMORAs: Comparison of pharmacokinetic parameters[10][11][12][13][14]

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Preclinical and clinical trials

Pre-clinical studies

The in vitro assays using Chinese Hamster Ovary (CHO) cells with cloned human opioid receptors and membrane preparations of cells expressing opioid receptors clearly demonstrated the antagonism of naloxegol at μ and δ opioid receptors, partial agonism at κ opioid receptors. In vivo Rat model of reversal of morphine-induced opioid effects demonstrated the peripheral action of naloxegol, compared to naloxone effectively inhibiting the effects of morphine both in central nervous system and in periphery. The conventional safety pharmacological studies, repeated dose toxicity, genotoxicity and fertility studies have revealed no special hazard for humans. Carcinogenicity studies performed demonstrate an increase in leydig cell adenomas and interstitial cell hyperplasia but at a dose in excess of human dose. The studies in suckling rats demonstrated the secretion of naloxegol in milk.[12]

Clinical trials

A phase I open label multicenter study (NCT02099591) to assess the pharmacokinetics and safety of naloxegol in paediatric ages ≥6 months to ≤18 months receiving opioid treatment is currently under trial.

A phase 2, double-blind, randomized, placebo-controlled, dose escalation study conducted in patients on stable regimen of 30–1000 mg/day of morphine for non-cancer pain with less than three spontaneous bowel movements (SBMs) per week. After a week of placebo, individuals were randomized into either placebo or naloxegol (5, 25 or 50 mg) groups. The primary endpoint was a change in baseline SBMs after 1 week of drug administration. The results demonstrated a statistically significant change in SBMs in 25 and 50 mg naloxegol group compared to placebo.[10]

The predominant studies on which naloxegol got its FDA approval are KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790): Two identical Phase III, multicenter, randomized, double-blind, placebo-controlled trials conducted in 652 and 700 patients, respectively. Selected patients were on stable regimen of 30–1000 mg/day of morphine for non-cancer pain with less than three SBMs and patients were randomly assigned to naloxegol 12.5, 25 mg or placebo once a day for 12 weeks. The primary endpoint considered was ≥3 SBMs per week or an increase of ≥1 SBMs from baseline for ≥9 of 12 weeks and an increase of ≥3 for final 4 weeks. KODIAC-04 showed significant improvement with naloxegol compared to placebo at both the doses, but in KODIAC-05 trial only 25 mg of naloxegol produced statistically significant results.[13]

An additional study for efficacy KODIAC-8 (NCT01336205): A 52 week, multicenter, open-label study included 804 patients out of these 84 patients were taken as roll over from previous KODIAC-4 trial. All were on 30–1000 mg/day morphine for more than 4 weeks for non-cancer pain with less than three SBMs. The subjects were randomly assigned into 25 mg/day of naloxegol or usual palliative care. The results demonstrated that 25 mg/day of naloxegol for up to 52 weeks is safe and usually well tolerated.[14] There was no reversal of analgesic effect of opioids used in these studies as measured by the pain rating scale and need of opioid.[13],[14]

To rule out any adverse cardiac events noted with its precursor alvimopan, an additional trial was conducted (NCT01325415). A randomized, placebo-controlled crossover thorough the QT/QTC study with therapeutic (25 mg) and supratherapeutic (150 mg) of naloxegol or moxifloxacin 400 mg or placebo in health volunteers demonstrated no significant cardiovascular changes.[15]

   Adverse effects Top

The most common adverse effect that forced the patients to leave the trial was abdominal pain. The other adverse effects noted were diarrhea, nausea, headache, and flatulence. The very rare adverse effects were abdominal distension, hyperhydrosis, fatigue, sinusitis, nasopharyngitis and dizziness. KODIAC-04 and 05 studies reported death of seven patients, two were on naloxegol 25 mg and three patients were on 12.5 mg dose and were due to cardiovascular cause as assessed by cardiovascular event adjudication committee. To ensure safety the QT/QTc study was undertaken which showed no ECG/other significant changes from baseline.[13],[14]

   Current status of naloxegol Top

Naloxegol is the first oral PAMORA for OIC in adults with chronic non-cancer pain, with approval from US-FDA and European Union. It is administered at a dose of 25 mg twice daily in empty stomach or 2 hours after the meal. The starting dose is 12.5 mg twice daily for individuals with creatinine clearance less than 60 ml/min and increased up to 25 mg twice daily if well tolerated. The exact cost of the product is not yet known. The STEP criterion for selection of PAMORAs in OIC has been tabulated [Table 2].
Table 2: Therapeutic selection of PAMORAs using step criteria[10],[11],[13]

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   Conclusion Top

Opioid-induced constipation is a particularly burdensome problem causing considerable misery and morbidity in patients on opioid therapy. Drugs like methylnaltrexone and alvimopan although were intended to be used for OIC had many drawbacks and currently methylnaltrexone given parenterally is restricted for use in only patients on palliative care and alvimopan restricted for short-term use in post operative ileus. Against this backdrop, the approval of naloxegol as first oral PAMORA has opened up new horizons for treating opioid-induced constipation. Naloxegol’s approval comes as a great relief to many patients in need of opioids and will provide more freedom to physicians to use opioids in patients who need them without subjecting them to the agony of constipation. However, it must be used with caution and judiciously as it could be potentially misused.

   References Top

Gehdoo RP. Cancer pain management. Indian J Anaesth 2006;50:375-90.  Back to cited text no. 1
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Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Mernil JO, Sullivan MD, et al. Opioid prescription for chronic pain and overdose: A cohort study. Ann Intern Med 2010;152:85-92.  Back to cited text no. 2
Camilleri M. Opioid-induced constipation: Challenges and therapeutic opportunities. Am J Gastroenterol 2011;106:835-42; quiz 843.  Back to cited text no. 3
Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: Pathophysiology, clinical consequences, and management. Gastroenterol Res Pract 2014;2014:141737.  Back to cited text no. 4
Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155:11-7.  Back to cited text no. 5
Chung HH. The novel role of opioid -receptors in gastroenterology. J Gastroenterol Hepatol Res 2013;2:614-7.  Back to cited text no. 6
Aurilio C, Pace MC, Pota V, Sansone P. Opioid induced constipation. In: Smith AC, editor. Constipation-Causes, Diagnosis and Treatment. Croatia: InTech; 2012. p. 81-8.  Back to cited text no. 7
Clemens KE, Klaschik E. Managing opioid-induced constipation in advanced illness: Focus on methylnaltrexone bromide. Ther Clin Risk Manag 2010;6:77-82.  Back to cited text no. 8
FDA Okays Naloxegol (Movantik) in Opioid-Induced Constipation. Available from: [Last accessed on 2014 Sep 24].  Back to cited text no. 9
Webster L, Dhar S, Eldon M, Masuoka L, Lappalainen J, Sostek M. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of Naloxegol in patients with opioid-induced constipation. Pain 2013;154:1542-50.  Back to cited text no. 10
Bui K, She F, Sostek M. The effects of renal impairment on the pharmacokinetics, safety, and tolerability of Naloxegol. J Clin Pharmacol 2014;54:1375-82.  Back to cited text no. 11
Poulsen JL, Brock C, Olesen AE, Nilsson M, Drewes AM. Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction. Clin Exp Gastroenterol 2014;7:345-58.  Back to cited text no. 12
Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with non-cancer pain. N Engl J Med 2014;370:2387-96.  Back to cited text no. 13
Webster L, Chey WD, Tack J, Lappalainen J, Diva U, Sostek M. Randomised clinical trial: The long-term safety and tolerability of Naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther 2014;40:771-9.  Back to cited text no. 14
Gottfridsson C, Carlson G, Lappalainen J, Sostek M. Evaluation of the effect of naloxegol on cardiac repolarization: A randomized, placebo- and positive-controlled crossover thorough QT/QTc study in healthy volunteers. Clin Ther 2013;35:1876-83.  Back to cited text no. 15


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