Peripheral opioid receptor antagonists

Definition and Classification
Peripheral opioid receptor antagonists (PORAs) are a subclass of opioid antagonists that selectively inhibit opioid receptors in the peripheral nervous system—particularly in the gastrointestinal tract—without significantly crossing the blood-brain barrier (BBB). Their primary purpose is to block the undesired peripheral effects of opioid drugs, especially opioid-induced constipation (OIC) and postoperative ileus, while preserving central analgesia mediated by the same opioids.

This pharmacological selectivity is critical for patients on chronic opioid therapy where constipation or bowel dysmotility impairs quality of life, and withdrawal of central analgesia is undesirable. PORAs are also known as peripherally acting μ-opioid receptor antagonists (PAMORAs) because they predominantly act on mu-opioid receptors (μ-opioid receptors) in the gut.

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1. Mechanism of Action

Peripheral opioid receptor antagonists work by selectively binding to and blocking peripheral μ-opioid receptors, especially those located in the enteric nervous system (myenteric and submucosal plexuses), without interfering with central receptors due to:

• Molecular modifications (e.g., quaternary ammonium structures)

• PEGylation or polar functional groups to reduce BBB penetration

• High affinity for peripheral receptors with poor CNS permeability

By inhibiting opioid binding in the gut, these agents reverse opioid-induced inhibition of gastrointestinal motility and secretion—restoring normal peristalsis and bowel function.

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2. Pharmacological Targets

Receptor Subtype	Action by PORAs
μ-opioid receptor (MOR)	Competitive antagonism (primary)
κ-opioid receptor (KOR)	Negligible activity
δ-opioid receptor (DOR)	Minimal relevance

Note: Some investigational agents show mixed receptor interactions, but approved PORAs are highly selective for peripheral MOR.

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3. Clinical Indications

A. Opioid-Induced Constipation (OIC)

• Most common indication

• Seen in patients using chronic opioids for cancer pain, chronic non-cancer pain, or palliative care

B. Postoperative Ileus (select agents)

• Used to promote GI recovery following bowel surgery or abdominal procedures

C. Other Off-label/Investigational Uses

• Opioid-induced nausea, gastroparesis, urinary retention

• Diagnostic adjuncts in assessing opioid bioavailability in GI tract

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4. Approved Drugs in This Class

Generic Name	Brand Name	Formulation	FDA Approval Year	Indication
Methylnaltrexone bromide	Relistor	SC injection, oral tablet	2008 (SC), 2016 (oral)	OIC in cancer and non-cancer
Naloxegol oxalate	Movantik	Oral tablet	2014	OIC in adults with chronic pain
Naldemedine tosylate	Symproic	Oral tablet	2017	OIC in chronic opioid use
Alvimopan	Entereg	Oral capsule (restricted)	2008	Postoperative ileus (hospital use only)

5. Comparative Pharmacokinetics

Parameter	Methylnaltrexone	Naloxegol	Naldemedine	Alvimopan
Route	SC, oral	Oral	Oral	Oral
CNS Penetration	Negligible	Minimal	Minimal	Minimal
Half-life	8–12 hours	6–11 hours	~11 hours	~10–17 hours
Metabolism	Minimal (SC), liver	CYP3A4	CYP3A4, UGT1A3	Gut flora, liver
Elimination	Renal & fecal	Renal	Fecal	Fecal
Bioavailability (oral)	Low (~50%)	~60%	~93%	~6% (active metabolite ~80%)

6. Dosage and Administration

Drug	Standard Adult Dose	Route	Frequency
Methylnaltrexone	12 mg SC once daily or 450 mg orally once daily	SC/Oral	Daily or as needed
Naloxegol	25 mg orally once daily (12.5 mg if renally impaired)	Oral	Once daily
Naldemedine	0.2 mg orally once daily	Oral	Once daily
Alvimopan	12 mg orally pre-op, then 12 mg twice daily (max 15 doses)	Oral	BID in hospital setting

7. Adverse Effects

Common (all agents)

• Abdominal pain

• Flatulence

• Nausea

• Diarrhea

• Hyperhidrosis (methylnaltrexone)

Less Common / Serious

• Gastrointestinal perforation (rare; methylnaltrexone, especially in cancer)

• Opioid withdrawal symptoms:

  • Sweating

  • Cramping

  • Chills

  • Lacrimation

• Cardiovascular events (Alvimopan: MI risk in long-term use)

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8. Contraindications

Drug	Contraindications
Methylnaltrexone	Known/suspected mechanical GI obstruction
Naloxegol	Use with strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole); GI obstruction
Naldemedine	Known/suspected GI obstruction; history of hypersensitivity
Alvimopan	Use of therapeutic opioids for >7 days preoperatively; cardiovascular disease history

9. Drug Interactions

Drug	Interacting Drug/Class	Effect/Concern
Naloxegol	Strong CYP3A4 inhibitors (e.g., ketoconazole)	Increased exposure, risk of withdrawal symptoms
Naldemedine	CYP3A4 inducers (rifampin), inhibitors	Decreased/increased effectiveness
Methylnaltrexone	Few interactions (non-CYP metabolism)	Minimal systemic interaction
Alvimopan	Opioid analgesics, P-gp inhibitors	Altered GI activity; increased absorption risk

10. Clinical Efficacy

Methylnaltrexone

• COMPOSE and RELIEF studies: rapid bowel movement within 4–12 hours

• Effective even in advanced cancer and palliative care populations

Naloxegol

• KODIAC-4, KODIAC-5: increased spontaneous bowel movements (SBMs) vs. placebo

• Onset: within 24 hours

Naldemedine

• COMPOSE-1 and COMPOSE-2: effective SBM response in chronic non-cancer OIC

• Well tolerated long-term (≥12 weeks)

Alvimopan

• GI Recovery After Surgery Trials: faster return of bowel function post-op

• REMS program required due to MI risk with long-term use

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11. Use in Special Populations

Population	Considerations
Elderly	Generally safe; monitor renal function
Renal impairment	Dose reduction (naloxegol); avoid in ESRD
Hepatic impairment	Monitor for withdrawal signs; use cautiously
Pregnancy	Category C (methylnaltrexone, naloxegol); avoid unless benefits outweigh risks
Pediatric	Not approved for routine use in children

12. Advantages of Peripheral Opioid Antagonists

• Selective action: Treats constipation without affecting pain control

• Faster symptom relief: Compared to laxatives

• Minimal CNS effects: Non-euphoric, non-addictive

• Safe in cancer and non-cancer populations

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13. Limitations and Considerations

Limitation	Impact
Cost	High (limited insurance coverage in some regions)
Risk of GI perforation	Rare but serious—caution in anatomical abnormalities
Not effective for non-opioid constipation	Ineffective if no opioid use is involved
May precipitate withdrawal	Especially if CNS penetration increases due to drug interaction or BBB dysfunction

14. Investigational and Emerging Agents

Agent	Mechanism	Status
Axelopran	Peripheral μ-antagonist	Phase II/III (IBD and OIC)
A3384	Oral peptide-based antagonist	Preclinical
Novel dual inhibitors	μ-antagonist + prokinetic	Conceptual research