U.S. Department of Justice

Drug Enforcement Administration

Schedule of Controlled Substances: Removal of Naloxegol (alpha-6mPEG7-Onaloxol) and its Salts from Schedule II

Background, Data, and Analysis:

Eight Factors Determinative of Control

and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by 

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537

October 2014
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I. Background

Naloxegol, or PEG-naloxol, is a new molecular entity and is a polyethylene glycolyated 

(PEGylated) derivative of naloxone. Its chemical names are (5,6)-17-allyl-6-((20-hydroxy3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol or alpha-6mPEG7-Onaloxol. Naloxegol is an antagonist predominantly of peripheral mu opioid receptors. The Food

and Drug Administration (FDA) approved naloxegol for marketing on September 16, 2014 under 

the brand name MovantikTM. It is indicated for the treatment of opioid-induced constipation

(OIC) in adults with chronic non-cancer pain. 

In June 2010, a drug manufacturer requested a determination of the control status of 

naloxegol from the Drug Enforcement Administration (DEA). The DEA conducted a scientific 

review of the chemical structure of mPEG-naloxol in accordance with the definitions within the 

Controlled Substances Act (CSA) and its implementing regulations, and in July 2010, the DEA

determined that the chemical structure of naloxegol can be derived from opium alkaloids and is 

therefore subject to automatic inclusion in schedule II of the CSA pursuant to schedule II(a)(1) 

of 21 U.S.C. § 812(c) and in accordance with 21 CFR § 1308.12(b)(1), which control any salt, 

compound, derivative, or preparation of opium or opiate, including derivatives of 

noroxymorphone. Naloxegol is related in chemical structure to naloxone, which is excluded 

from control, including its salts under the CSA. 21 CFR §1308.12(b)(1). Naloxegol is not a salt 

of naloxone, therefore it is not included under this exclusion. The DEA determined that it can be 

derived from opium alkaloids and meets the requirements for control in schedule II of the CSA 

pursuant to 21 U.S.C. § 812(c), Schedule II (a)(1). 

In accordance with 21 CFR § 1308.43,the DEA received a petition from the drug sponsor

dated March 22, 2012, requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude 

naloxegol as a schedule II controlled substance. The petitioner stated that naloxegol is a mu 

opioid receptor antagonist without mu opioid agonist or partial agonist properties. In accordance 

with 21 CFR § 1308.43(c), the DEA accepted the petition for filing on October 1, 2012.

Pursuant to 21 U.S.C. § 811(b), the DEA gathered the necessary data on naloxegol and 

forwarded the same, the sponsor’s petition, and a request for scheduling recommendation on

naloxegol to the Department of Health and Human Services (HHS) on February 7, 2013. 

According to the HHS, the sponsor submitted a New Drug Application (NDA) for naloxegol on 

September 16, 2013. Based on the NDA, the HHS summarized that naloxegol is an antagonist of 

peripheral mu opioid receptors for the treatment of OIC. Because of its conjugation to 

polyethylene glycol (PEG), naloxegol does not cross the blood-brain barrier (BBB), therefore it 

acts primarily as a peripheral antagonist. 

On August 8, 2014, the HHS provided to the DEA a scientific and medical evaluation 

entitled “Basis for the Recommendation to Decontrol Naloxegol and its Salts from Schedule II of 

the Controlled Substances Act” and a scheduling recommendation. Following consideration of 

the eight factors and findings related to the substance’s abuse potential, legitimate medical use, 

and dependence liability, the HHS recommended that naloxegol and its salts be decontrolled 
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from schedule II of the CSA. The National Institute on Drug Abuse (NIDA) concurred with the 

recommendation.

The CSA requires the DEA to determine whether the HHS’s scientific and medical 

evaluation, scheduling recommendation, and all other relevant data constitute substantial evidence 

that a substance should be scheduled. 21 U.S.C. § 811(b). 

Pursuant to 21 U.S.C. § 811(c), the Attorney General reviews the facts and all other 

relevant data. The Attorney General has delegated this scheduling authority to the Administrator 

of the DEA. 28 CFR 0.100(b). This document is a summarized review of the relevant data, law 

enforcement information, and determination to remove naloxegol from control under the CSA.

Based on the review of the DEA eight-factor analysis and upon the scientific and medical 

evaluation and recommendation of the HHS, the Deputy Administrator finds that the evidence 

establishes that naloxegol does not possess sufficient potential for abuse to justify its continued 

control in any schedule of the CSA.

The information contained in this document is organized according to the eight factors as 

specified in 21 U.S.C. § 811(c).

II. Eight Factors Determinative of Control

Factor 1. The Substance’s Actual or Relative Potential for Abuse

Naloxegol is a conjugation of polyethylene glycol (PEG) to naloxone. PEGylation of 

naloxone decreases the capacity of the substance to cross the blood-brain barrier, limiting the 

availability of naloxegol to peripheral opioid receptors (Diego et al., 2011; HHS review). Due to 

naloxegol being an antagonist at the three opioid receptors, mu, delta, and kappa, the HHS asserts 

that naloxegol does not have opioid agonist properties. 

In vitro studies

Receptor Binding Studies

Naloxegol competitively inhibited binding of [3H]-naloxone, an opioid receptor 

antagonist, to mu and kappa opioid receptors and [

3H]-DPDPE, a delta opioid receptor ligand, to 

delta opioid receptors. According to the HHS, naloxegol binds with a high affinity to the mu 

opioid receptors, moderate-to-high affinity to the kappa opioid receptors, and moderate affinity 

to the delta opioid receptors.

Receptor Activation Studies

According to the HHS, naloxegol did not exhibit full agonistic activity in a [35S]GTPS 

functional assay at the mu, delta, and kappa opioid receptors. Naloxegol acted as an antagonist 

at the three opioid receptors. Naloxegol also acted as a slight partial agonist at the kappa opioid 

receptor. 
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In vivo studies

Drug Discrimination Studies

There is a strong correspondence between the discriminative stimulus effects of a given drug

in animals and its subjective effects in humans. Thus, drug discrimination is widely used to 

determine whether or not a drug or substance is pharmacologically similar to a known drug of abuse.

The HHS summarized the drug discrimination studies done in morphine-trained rats. 

These studies evaluated whether naloxegol produced morphine-like discriminative effects in 

morphine-trained animals. Naloxegol did not produce morphine-like responding at the tested 

doses, producing less than 20% of the morphine responses. The lack of morphine-like 

discriminative effects is indicative of the lack of mu opioid receptor activation. 

Naloxegol (3-300 mg/kg) was also administered orally to morphine-trained rats prior to 

administration of several doses of morphine (0.96-9.6 mg/kg). The purpose of these studies was 

to determine if naloxegol could reverse the discriminative effects of morphine. Naloxegol did 

dose-dependently antagonize morphine responding, but the antagonism was limited by 

increasing doses of morphine. The HHS states that naloxegol can antagonize centrally-mediated 

effects of morphine, but only at high doses. 

Self-administration studies

It has been demonstrated that drugs that are self-administered by animals also have abuse 

potential in humans (Weerts et al., 1999; Ator and Griffith, 2003). The HHS summarized two 

self-administration studies done in rats trained to self-administer morphine. The rats were 

allowed to self-administer different doses of naloxegol (1-30 mg/kg/infusion) and morphine 

(0.03-1 mg/kg/infusion). None of the doses of naloxegol infusions induced self-administration 

infusions different from the vehicle-alone, thereby indicating that naloxegol lacks rewarding 

properties. Morphine self-administration studies showed a dose-response pattern that is typical 

of mu opioid agonists.

Human Clinical Studies

Abuse-related Adverse Effects

According to the HHS, the abuse-related pharmacology of naloxegol in humans was assessed 

from adverse effects (AEs) reported in the Phase I and Phase 2/3 clinical trials. Twelve Phase I 

studies are conducted in healthy volunteers (n=474). The HHS states that the doses of naloxegol 

tested in the Phase I trials represent doses which are one-third up to 80-fold the proposed therapeutic 

doses of naloxegol (12.5 and 25 mg/day) in patients taking opioids for analgesia. In these 12 

naloxegol clinical trials, naloxegol did not produce any euphoria or abuse-related adverse events 

(AEs).

In the Phase 2/3 clinical studies, the patients were taking opioids for pain management. They 

were administered naloxegol to determine the effect of naloxegol in preventing OIC. As with the 

Phase I studies, there were no reports of any euphoria or abuse-related adverse events (AEs).
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 According to the HHS, naloxegol has not been marketed in the United States or in any 

other country, so there is no available information on the actual abuse of naloxegol. 

Summary

Naloxegol has been demonstrated to be a mu opioid receptor antagonist. In animal abuse 

liability studies (drug discrimination and self-administration), naloxegol did not produce 

responses seen with morphine administration. In clinical studies, there have been no reports that 

naloxegol dose-dependently produced AEs associated with abuse potential. Therefore, 

naloxegol does not demonstrate a potential for abuse.

Factor 2. Scientific Evidence of Its Pharmacological Effects

Gastrointestinal AEs effects are commonly experienced by chronic users of opioid 

analgesics. Opioids delay gastric emptying and intestinal transport, which over time leads to 

debilitating constipation. OIC is caused by activation of the mu opioid receptor in the GI tract 

(Asai and Power, 1999; Camilleri, 2011; Diego et al., 2011). 

In vitro studies

The HHS adds that the binding studies show that naloxegol does not bind significantly (> 

50% inhibition) to other molecular central nervous system (CNS) receptors, including dopamine, 

serotonin, glutamate, -aminobutyric acid (GABA), sigma, acetylcholine, norepinephrine, 

cannabinoid, histamine, and monoamine transporters. 

In vivo behavioral studies

Toxicological Studies

General Behavioral Observations

The HHS summarized toxicological studies on oral naloxegol (25-500 mg/kg) that were 

done in rats (28 days) and beagles (14 and 28 days). These studies did not produce behavioral 

signs of abuse potential, e.g. increased or decreased motor behavior, decreased body weight, or 

food intake. At supratherapeutic doses (doses above those comparable to proposed human 

therapeutic doses), naloxegol occasionally produced signs of endogenous opioid system 

antagonism such as diarrhea, soft stool, excessive salivation, retching and emesis. 

Irwin Screen 

The Irwin screen is used to assess acute toxicity of a new substance in rodents. It also 

shows the dose range for chemical-induced CNS responses and the primary effects of the test 

substance on behavior and physiological functions. The animals are observed over a period 

ranging from several hours to the following day after administration. The behaviors being 

assessed are related to neurotoxicity, such as convulsions and tremor and behaviors related to 

either CNS stimulation or depression. Autonomic function responses are also assessed (Roux et 

al., 2004; Moser, 2011). 
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According to the HHS, in a standard Irwin screen test, rats were administered naloxegol 

(100-1000 mg/kg) orally. Naloxegol did not induce any of the behaviors in the battery of tests 

for the Irwin screen. The HHS asserts that an opioid antagonist without abuse potential would 

not induce the behaviors assessed in the Irwin screen, especially those related to predictors of 

abuse potential such as changes in motor activity, body weight, or food intake. 

Analgesia Studies

According to the HHS, there were two analgesia models in which naloxegol was tested in 

rodents, hotplate test and grid stimulation. Naloxegol was administered orally (10–1000 mg/kg). 

In both models naloxegol did not produce any analgesic effects, demonstrating the lack of mu 

opioid receptor activation. Naloxegol was also tested in both analgesia models for its potency in 

reversing morphine-induced (s.c. or i.v. 1-32 mg/kg) analgesia. Naloxegol did not fully reverse 

the analgesia produced by morphine.

Human clinical trials

Withdrawal effects of Naloxegol

According to the HHS, oral naloxegol (12.5 and 25 mg/day) did precipitate opioid 

withdrawal in patients receiving opioids for pain management in the Phase 2/3 clinical trials. 

The incidence of withdrawal was low, the symptoms of opioid withdrawal occurred in patients

taking naloxegol (2%) compared to placebo (< 1%). It occurred with a higher incidence in 

patients receiving naloxegol (3%) at the higher dose (25 mg/day) than those receiving the 12.5 

mg/day dose (1%). The HHS asserts that the withdrawal symptoms reported did not always meet 

the criteria of a clinically meaningful opioid withdrawal syndrome. Though the incidence of 

opioid withdrawal was low, these data show that there may be some involvement of central 

mediated antagonism of mu opioid receptors by naloxegol. 

Factor 3. The State of Current Scientific Knowledge Regarding the Drug or Other 

Substances

According to the HHS, naloxegol is a conjugate of the opioid antagonist alpha-naloxol to 

the polymer polyethylene glycol (PEG). PEGylating naloxone substantially decreases the ability 

the substance from crossing the BBB, thereby containing the drug in peripheral circulation. 

Chemistry

According to the HHS, naloxegol is known as (5,6)-17-allyl-6-((20-hydroxy3,6,9,12,15,18-hexaoxaicos-1-yl)oxy)-4,5-epoxymorphinon-3,14-diol alpha-6mPEG7-O-naloxol. 

The CAS number is 854601-70-0. The molecular formula of naloxegol is C34H53NO11 and the 

molecular weight is 651.8 g/mol. It is a white to off-white powder and is soluble in aqueous 

solvents over a pH range of 1 to 7.5. Naloxegol is synthesized in a five-step process from 

naloxone hydrochloride, an opioid antagonist derived from thebaine. 

The HHS states that though the patients in the Phase 3 trials were given a tablet of 

naloxegol as a free base, the sponsor will market naloxegol as an oxalate salt. 
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Pharmacokinetics

According to the HHS, naloxegol (25 mg/day) is rapidly absorbed following oral 

administration in healthy volunteers. Maximum plasma concentrations were reached in 1.5–2 h. 

The plasma half-life (t 1⁄2) is 7–9 h, with a maximal plasma concentration (Cmax) of 45 ng/ml. 

In a human distribution study with radiolabeled naloxegol, the highest levels of radioactivity 

were in the liver and kidneys. The elimination t 1⁄2 of naloxegol is rapid, with the majority being 

eliminated within 24-hours post-dose. 

Factor 4. Its history and current pattern of abuse

According to the HHS, there has been no evidence of abuse-related signals from the 

human clinical trials. Naloxegol is a mu opioid antagonist, which as a class does not have abuse 

potential.

Factor 5. The scope, duration, and significance of abuse

There have been no reports of abuse of naloxegol. According to the National Forensic 

Laboratory Information System (NFLIS) and the System to Retrieve Information from Drug 

Evidence (STRIDE), there have been no reports of naloxegol seizures from 2010–present. Once 

naloxegol is marketed, the HHS asserts that it is unlikely that it will be abused. 

Factor 6. What, if any, risk there is to the public health

According to the HHS, naloxegol is well-tolerated and safe at the therapeutic doses of 

12.5 mg and 25 mg. Preclinical and clinical studies showed no evidence of potential for abuse of 

naloxegol and thus there is little public health risk from naloxegol.

Factor 7. Its psychic or physiological dependence liability

The HHS summarized a physical dependence liability study of naloxegol in rats. The rats 

were orally administered naloxegol (0 (vehicle), 50, 150 or 500 mg/kg) for 15 days. The rats 

were observed for behavior on the Irwin screen, both during the drug administration period and 

10 days following drug discontinuation. No symptoms of physical dependence were observed 

for naloxegol during either period. The HHS also mentioned that the lack of naloxegol selfadministration by animals is consistent with a lack of psychic dependence liability.

Factor 8. Whether the substance is an immediate precursor of a substance already 

controlled

Naloxegol is not considered an immediate precursor of any substance controlled under 

the CSA.
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References

1. Asai T and Power I. (1999). Anesthesia and Analgesia, 88, 204-208.

2. Ator NA and Griffiths PR. (2003). Drug and Alcohol Dependence, 70: S55-72

3. Department of Health and Human Services, FDA Review (2013). Basis for the 

Recommendation to Decontrol Naloxegol and its Salts from Schedule II of the Controlled 

Substances Act.

4. Camilleri M. (2011). American Journal of Gastroenterology, 106, 835-842.

5. Diego, L, Atayee, R, Helmons, P, Hsiao G and von Gunten, CF. (2011). Expert Opinions 

on Investigational Drugs, 20, 1047-1056.

6. Moser VC (2011). Functional assays for neurotoxicity testing. Toxicologic Pathology, 39: 

36-45.

7. Roux S, Sablé E, and Porsolt RD (2004). Current Protocols in Pharmacology, Chapter 

10: Unit 10.10.

8. Weerts EM, Ator NA, and Griffiths RR. (1999). Drug and Alcohol Dependence, 57: 51-

60.