Opioid antagonists: clinical utility, pharmacology, safety, and tolerability

Abstract

Opioid antagonists block opioid receptors, a mechanism associated with utility in several therapeutic indications. Here, we review the sites of action, clinical uses, pharmacology, and general safety profiles of US Food and Drug Administration (FDA)-approved opioid antagonists. A review of the literature and product labels of opioid antagonists was conducted. The unique clinical uses of approved opioid antagonists are related to their ability to block opioid receptors centrally and/or peripherally. Centrally acting opioid antagonists treat opioid and alcohol use disorders (AUDs) and reverse opioid overdose. Because the opioid system influences weight and metabolism, one opioid antagonist combination product is approved for chronic weight management; another, approved for adults with schizophrenia or bipolar I disorder, mitigates olanzapine-associated weight gain. Peripherally acting opioid antagonists are approved for opioid-induced constipation; another accelerates gastrointestinal recovery after bowel surgery. Opioid antagonists are generally well tolerated; they are not associated with physiologic dependence or abuse. However, opioid antagonists can precipitate acute opioid withdrawal in patients using or undergoing withdrawal from opioid agonists. Likewise, their use can confer a risk for opioid overdose if attempts are made to overcome opioid antagonist blockade of opioid receptors via the intake of additional opioids. Opioid receptor antagonists have diverse therapeutic benefits based on their respective pharmacology and sites of action; understanding their respective nuances facilitates the safe and effective use of these agents.

Introduction

Opioid antagonists are drugs that have been used safely in clinical practice for decades. The opioid system plays a role in several bodily functions, with impacts on pain awareness, mood, gastrointestinal function, metabolism, and body weight. ^{1 , 2} As a result, opioid receptor blockade offers the opportunity for a range of therapeutic effects and uses.

This brief review was undertaken to provide education on available opioid antagonists and their diverse therapeutic roles. Toward that end, we provide details on US Food and Drug Administration (FDA)-approved opioid antagonists (Figure 1), discussing their sites of action, clinical uses, pharmacology, and general safety profiles.

Figure 1. Historical overview of FDA-approved opioid antagonists. AUD, alcohol use disorder; FDA, US Food and Drug Administration; OUD, opioid use disorder.

The opioid system

The opioid system is composed of opioid receptors that are located throughout the body ¹ (Figure 2). There are 3 main types of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DORs), and kappa opioid receptors (KORs). ¹ Endogenous and exogenous ligands can bind to these receptors, thus bringing about physiologic effects.

Figure 2. Distribution of opioid receptors in the central and peripheral nervous systems. Adapted with permission from the authors ¹ under the terms of the Creative Commons Attribution-NonCommercial licence (http://creativecommons.org/licenses/by-nc/4.0). DOR, delta opioid receptor; KOR, kappa opioid receptor; MOR, mu opioid receptor.

For the purposes of this article, we refer to opioid agonists as exogenous ligands (drugs) that bind to and activate opioid receptors (Table 1). If a drug maximally activates 1 or more opioid receptor types, it is considered a full agonist ³ (Figure 3). Partial agonists also exist; drugs of this type activate target receptors to a lesser extent than full agonists, evoking an attenuated physiologic response in comparison ³ (Figure 3). Once bound, opioid agonists elicit several physiological effects, the most well-known being analgesia, and they are used clinically for pain relief. ^{3 , 4} Because opioid receptors are widely distributed in the body, adverse effects from opioid agonists can take several forms. For example, opioid agonists activate opioid receptors that are located in the brain’s respiratory center, causing respiratory depression that can be fatal. ⁵ During opioid agonist treatment, opioid receptors in the gut are stimulated, which results in decreased gastrointestinal motility that may lead to bowel dysfunction (eg, constipation), especially in patients who require ongoing opioid treatment for analgesia. ⁶

Table 1. Definitions of Drug Receptor Interactions ³

Figure 3. Hypothetical drug-receptor interactions. Adapted from https://commons.wikimedia.org/wiki/File:Inverse_agonist_3.svg, Creative Commons Attribution-Share Alike 4.0 International license.

For the purposes of this article, we refer to opioid antagonists as exogenous ligands (drugs) that work in a manner opposite that of opioid agonists; they bind to and prevent the activation of opioid receptors (Figure 3). Available opioid antagonists can be categorized by their primary site of action, in either the central or peripheral nervous system.

Centrally acting opioid antagonists

Samidorphan, nalmefene, naltrexone, and naloxone are centrally acting opioid antagonists (Supplemental Table 1). ^{7 , 8} They bind preferentially to opioid receptors in the brain and spinal cord. Each has affinity for MORs but different antagonism profiles for DORs and KORs. Centrally acting opioid antagonists do not carry the safety concerns that opioid agonists do. As a class, they are not associated with physiologic dependence or abuse. ³ Adverse effects associated with their use are generally mild and may include nausea and vomiting. It is important to understand that opioid antagonists may precipitate withdrawal in patients who are currently taking opioid agonists. The symptoms of withdrawal include nausea, anxiety, and muscle cramps. ^{9 , 10} In addition, a safety consideration shared by centrally acting opioid antagonists is that they confer a risk of opioid agonist overdose if attempts are made to overcome opioid receptor blockade via the intake of opioid agonists.

2021—Samidorphan + Olanzapine (Lybalvi®)

Evidence suggests that the stimulation of central and peripheral opioid receptors can influence both body weight and metabolism via their roles in the regulation of food intake, insulin secretion, and glucose production. ^{11 - 13}

Samidorphan is an opioid antagonist that is combined with olanzapine (OLZ/SAM) in a single tablet and is indicated for the treatment of adults with schizophrenia or bipolar I disorder. ¹⁴ Although olanzapine has established efficacy as a treatment for these conditions, ^{15 , 16} associated weight gain and metabolic dysfunction limit its clinical use. ^{15 , 17} In multiple clinical studies, treatment with OLZ/SAM mitigated the weight gain associated with olanzapine monotherapy without compromising clinical efficacy. ^{18 - 20}

Samidorphan is a MOR antagonist and a partial KOR and DOR agonist. ¹⁴ Central opioid receptors likely contribute to weight regulation by affecting motivational behavior, whereas those in the periphery are known to alter fat accumulation and glucose homeostasis. ^{21 - 23} Thus, the weight-mitigating effects of OLZ/SAM may be attributable to antagonism of both central and peripheral opioid receptors. ⁸

Samidorphan has high bioavailability (69%) and a long half-life (7–11 hours). ¹⁴ Because the samidorphan component of OLZ/SAM has effects centrally, OLZ/SAM may precipitate acute opioid withdrawal in patients who are dependent on opioid agonists. ¹⁴ Samidorphan itself has no abuse potential. ²⁴

OLZ/SAM has a safety profile similar to that of olanzapine. ^{19 , 20} Most adverse events associated with OLZ/SAM in clinical trials were mild to moderate in severity. In patients with schizophrenia, common adverse reactions included weight gain, somnolence, dry mouth, and headache. The safety profile for OLZ/SAM in patients with bipolar I disorder is derived from studies of olanzapine, and the most common adverse reactions included somnolence, dry mouth, dizziness, asthenia, constipation, dyspepsia, increased appetite, and tremor. ¹⁴

1995—Nalmefene (Revex, Opvee)

Brain cells in the central nervous system’s respiratory centers express opioid receptors. Stimulation of these receptors by opioid agonists results in decreased tidal volume and respiratory frequency ^{5 , 25}; this mechanism is responsible for the life-threatening respiratory depression associated with excessive opioid agonist use or overdose.

Nalmefene is a centrally acting opioid antagonist that competes with opioid agonists for binding at MORs and DORs while acting as a partial agonist at KORs. ^{26 - 29} It is indicated for reversing the life-threatening respiratory depression caused by opioid overdose. ^{25 , 27 , 30}

Some full opioid agonists have a duration of action that exceeds that of other reversal agents, such as naloxone. ^{5 , 26} Nalmefene has been added to the clinical armamentarium because its long half-life (~7 hours) provides clinicians with a long-acting overdose-reversing medication. ²⁶

Nalmefene is available as an intravenous, intramuscular, or subcutaneous injection, ²⁷ and an intranasal formulation was also approved by the FDA. ^{30 , 31} Similar to other centrally acting opioid antagonists, nalmefene precipitates acute opioid withdrawal after administration; the sudden physiologic reversal of opioid effects may require medical attention. ²⁷ Otherwise, nalmefene is not associated with toxicity, even at doses that are many times higher than those used clinically. In clinical trials, the adverse effects of nalmefene were generally mild and included nausea, vomiting, tachycardia, and hypotension. ²⁷

1984—Naltrexone (Revia, Vivitrol)

Opioid agonists are well known for their ability to elicit feelings of euphoria, which underlies their abuse potential. ³ The intake of alcohol is also associated with activation of the endogenous opioid system. ³²

Naltrexone is a centrally acting opioid antagonist that has been available for almost 40 years for the treatment of opioid use disorder (OUD). ³³ It was developed to block the euphoric effects of morphine, and it acts as a MOR and KOR antagonist. ^{1 , 34} In patients with OUD, naltrexone is thought to reduce opioid-associated reward by preventing endogenous opioid ligands from binding to opioid receptors. ³³ In 1994, oral naltrexone was approved for the treatment of alcohol use disorder (AUD). ³⁵ In patients with AUD, naltrexone is thought to work by reducing the rewarding effects of alcohol. ³⁵

Naltrexone is available in 2 formulations: an oral tablet and an extended-release intramuscular injection. ^{36 , 37} The oral formulation of naltrexone may have limited utility in treating OUD because of issues with suboptimal adherence. ^{33 , 38} The extended-release formulation, however, is more effective than placebo at reducing the risk of opioid relapse. ³³ Both the oral and extended-release formulations of naltrexone are effective at reducing alcohol intake in patients with AUD. ³⁵

As with other centrally acting opioid antagonists, naltrexone can precipitate opioid agonist withdrawal in patients who are dependent on them. ^{36 , 37} In patients with AUD, nausea, headache, dizziness, nervousness, and fatigue are among the common adverse reactions associated with oral naltrexone, whereas nausea, vomiting, injection site reactions, muscle cramps, and dizziness are associated with the injectable formulation. ^{36 , 37} In patients with OUD, difficulty sleeping, anxiety, nervousness, abdominal pain, nausea, and vomiting are among the common adverse reactions associated with oral naltrexone ³⁶; adverse reactions associated with the injectable formulation were similar to those observed in patients with AUD and included injection site reactions, nausea, and diarrhea. ³⁷

Naltrexone + Bupropion (Contrave)

In 2014, the FDA approved a combination of naltrexone and bupropion, an antidepressant, for chronic weight management in adults who are overweight and have a weight-related comorbidity or in those who are obese. ³⁹ It is an adjunctive therapy to a reduced-calorie diet and increased physical activity. Available as an oral extended-release tablet, naltrexone acts on the opioid system as a MOR and KOR antagonist. ^{1 , 34} Naltrexone alone is associated with minimal weight loss, but it may reduce the palatability of foods. ⁴⁰ When combined with bupropion, it may increase the activity of brain cells that regulate appetite, although the exact mechanisms are unknown. The most common adverse reactions include nausea, constipation, headache, and vomiting.

1971—Naloxone (Narcan, Zimhi)

Naloxone was the first opioid antagonist to be approved by the FDA. When used clinically, naloxone reverses the effects of opioid agonist overdose. ^{41 , 42} It does so by binding to MORs in the central nervous system and also to KORs and DORs. ⁵

As a centrally acting opioid antagonist, naloxone provides rapid reversal of the physiologic effects of opioid agonists when administered intranasally, intramuscularly, or subcutaneously. ⁴³ The oral bioavailability of naloxone is poor, and therefore, it is not available for clinical use in an oral formulation. ² However, when combined with buprenorphine in an oral formulation, data suggest that it might act as a deterrent to attempts by patients with opioid dependence to administer it via injection. ⁴⁴ Naloxone has a short duration of action. The range of its half-life when administered by an injectable route is 0.5 to 2 hours, which may not be long enough to counteract the physiologic effects of synthetic opioid agonists such as fentanyl. ^{5 , 41} Because the duration of action of naloxone may be short relative to that of the specific opioid agonist used, repeat administrations of naloxone may be needed to maintain the reversal of respiratory depression achieved with this agent. ^{26 , 41}

Similar to nalmefene, medical attention may be required after administering naloxone because of the sudden reversal of the physiologic effects of opioid agonists. ⁴¹ In patients who are dependent on opioid agonists, naloxone use precipitates withdrawal symptoms, including body aches, diarrhea, irritability, abdominal cramps, and increased blood pressure. ^{41 , 42} In studies of healthy volunteers, the most common adverse reactions associated with intranasal naloxone were increased blood pressure, musculoskeletal pain, and headache, whereas nausea, dizziness, lightheadedness, and elevated bilirubin level were observed for the injectable formulation. ^{41 , 42}

Naloxone + Buprenorphine (Zubsolv, Suboxone)

Naloxone combined with buprenorphine is available as a sublingual tablet and as a sublingual film for the treatment of opioid dependence. ^{44 , 45} Buprenorphine is a partial MOR and KOR agonist and DOR antagonist. ^{3 , 46} As a partial opioid receptor agonist, buprenorphine activates opioid receptors to a lesser extent than does a full agonist, and it is this property that makes it therapeutically useful in relieving withdrawal symptoms in patients who are dependent on opioid agonists. ³³ However, buprenorphine does activate opioid receptors, meaning that it has abuse potential. Naloxone is combined with buprenorphine to reduce the risk of buprenorphine misuse. Naloxone has no clinically significant effect in the combination when administered sublingually. However, if the combination tablet is crushed and administered parenterally, naloxone blocks the physiologic properties of buprenorphine and precipitates withdrawal symptoms in patients who are dependent on opioid agonists, an attribute that may deter illicit diversion of the medication. ⁴⁴

Common adverse reactions associated with the sublingual tablet formulation of the naloxone and buprenorphine combination are headache, nausea, and vomiting. Oral hypoesthesia (loss of sensation in the mouth) has been reported as an adverse effect of the sublingual film formulation. Other common adverse events with this formulation include glossodynia, oral mucosal erythema, headache, nausea, and vomiting. ^{45 , 47} Also, buprenorphine may cause life-threatening respiratory depression if used with another drug(s) that decreases respiratory drive.

Peripherally acting opioid antagonists

Naldemedine, naloxegol, alvimopan, and methylnaltrexone are peripherally acting opioid antagonists (Supplemental Table 2). ⁶ They bind preferentially to opioid receptors in the gastrointestinal tract and have limited ability to reach the brain. ⁶ Each has affinity for MORs but different antagonism profiles for KORs and DORs.

The gastrointestinal tract has a dense network of opioid receptors located throughout its course, and the opioid system is thought to play a role in normal bowel function ^{2 , 48} (Figure 2). During opioid agonist treatment, opioid receptors in the gut are stimulated, which results in decreased gastrointestinal motility that may lead to bowel dysfunction, especially in patients who require chronic, ongoing analgesia that opioid agonist treatment provides. ⁶ Adverse effects associated with decreased gastrointestinal motility include opioid-induced constipation and postoperative ileus. Because of their limited ability to reach the brain, peripherally acting opioid antagonists can treat opioid-induced constipation and postoperative ileus without compromising the analgesia that opioid agonists provide. ⁶

Peripherally acting opioid antagonists do not have the safety concerns associated with opioid agonists, such as physical dependence. ³ Their adverse effect profile is mild and may include abdominal pain, nausea, diarrhea, flatulence, and dyspepsia. ^{49 - 52} Despite acting preferentially on opioid receptors in the gut, peripherally acting opioid antagonists may precipitate acute withdrawal if taken by patients who have disruptions to the blood–brain barrier and are dependent on opioid agonists. ^{49 - 52} Drugs of this class should not be used in cases of known or suspected gastrointestinal obstruction. ^{49 - 52}

2017—Naldemedine (Symproic)

Naldemedine is a peripherally acting opioid antagonist available for the treatment of opioid-induced constipation in patients with chronic noncancer pain. ^{51 , 53} It is a MOR, DOR, and KOR antagonist and is available as an oral tablet. ^{51 , 53} Clinicians seeking to use naldemedine should not do so in patients who have a known or suspected gastrointestinal obstruction. In clinical trials, the use of naldemedine was associated with a higher incidence of adverse events versus placebo, but these events were generally mild or moderate in severity. ^{6 , 51} Abdominal pain, diarrhea, and nausea were the 3 most common adverse reactions reported.

2014—Naloxegol (Movantik)

Naloxegol is another peripherally acting opioid antagonist and a derivative of naloxone. ⁵⁴ Compared with its parent molecule, naloxegol has low blood–brain barrier permeability, and its actions are restricted to peripheral opioid receptors. Because it blocks opioid receptors located in the gut, naloxegol is used for the treatment of opioid-induced constipation in patients with chronic noncancer pain. ^{49 , 55}

Available as an oral tablet, naloxegol works as a MOR and DOR antagonist and a partial KOR agonist. ^{49 , 55} Similar to naldemedine, the medication is contraindicated in patients with known or suspected gastrointestinal obstruction. Despite naloxegol’s peripheral site of action, patients who have disruptions to the blood–brain barrier should be monitored for symptoms of opioid agonist withdrawal. ^{49 - 51}

In clinical trials, common adverse reactions of naloxegol included abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache. ⁴⁹

2008—Alvimopan (Entereg)

Postoperative ileus is caused by decreased gastrointestinal motility after abdominal and nonabdominal surgery and is associated with abdominal pain, bloating, nausea, and vomiting. ^{52 , 56} Several mechanisms, including inflammatory reactions and the use of opioid agonists, contribute to postoperative ileus.

Alvimopan, available as an oral capsule, is used to accelerate gastrointestinal recovery after surgery such as partial bowel resection. ⁵² Like the other peripherally acting opioid antagonists reviewed, alvimopan relieves the symptoms of postoperative ileus by blocking opioid receptors in the gut, and it is a MOR antagonist. ⁵⁷

Dyspepsia (indigestion) has been reported to occur with alvimopan use. In a long-term clinical trial, alvimopan use was associated with an incidence of myocardial infarction greater than that with placebo alone; thus, it is available for only short-term inpatient use through a risk evaluation and management strategy. ⁵²

2008—Methylnaltrexone (Relistor)

Methylnaltrexone was the first peripherally acting opioid antagonist to be approved for the treatment of opioid-induced constipation in patients with chronic noncancer pain and in patients with advanced illness who are receiving palliative care. ^{50 , 58} It is a derivative of naltrexone, but the addition of a methyl group renders it less lipid soluble than its parent molecule, and as such, it does not readily cross the blood–brain barrier. ⁵⁹

Methylnaltrexone is available in 2 formulations, as an oral tablet and a subcutaneous injection, and works as a MOR and KOR antagonist. ^{50 , 58} Methylnaltrexone should not be used in patients with known or suspected gastrointestinal obstruction. Symptoms consistent with opioid agonist withdrawal have been reported, and patients with disruptions to the blood–brain barrier may be at risk of opioid agonist withdrawal. ⁵⁰

In clinical trials, abdominal pain was the most common adverse event of methylnaltrexone when given orally or subcutaneously. Other adverse events were mild and included gastrointestinal symptoms such as diarrhea and nausea. ^{50 , 58}

Conclusions

Opioid antagonists are a class of medication that provide clinical benefits across several indications and have been used in clinical practice for years. They provide these benefits by blocking opioid receptors present in central and peripheral tissues. Thus, their respective sites of action influence their different therapeutic uses. For centrally acting opioid antagonists that preferentially bind to opioid receptors in the brain and spinal cord, these uses include mitigating olanzapine-associated weight gain, reversing opioid agonist overdose, and treating AUD and OUD. For peripherally acting opioid antagonists that preferentially bind to opioid receptors that reside in organs located in the periphery, these uses include treating opioid-induced constipation in patients with chronic noncancer pain and in patients with advanced illness who are receiving palliative care, and alleviating the symptoms of postoperative ileus. Importantly, opioid antagonists as a class are not addictive and do not have the safety concerns associated with opioid agonists. They are not associated with physical dependence or tolerance and possess no abuse potential. Knowledge of the different clinical indications and safety profiles of opioid antagonists facilitates their safe and effective use, making these drugs important tools in the treatment armamentarium for clinicians.