Which oral (PO) opioid is least likely to cause severe constipation?

Oral Opioids and Constipation: Comparative Risk Assessment

Tapentadol is the oral opioid least likely to cause severe constipation due to its dual mechanism of action as both a μ-opioid receptor agonist and norepinephrine reuptake inhibitor. 1, 2, 3

Mechanism of Opioid-Induced Constipation

Opioid-induced constipation (OIC) is one of the most common and persistent side effects of opioid therapy. Unlike other opioid side effects that typically improve over time, constipation generally persists throughout treatment 4. This occurs because:

• Opioids bind to μ-receptors in the gastrointestinal tract
• This reduces peristalsis and intestinal secretions
• Increases fluid absorption from the bowel
• Results in harder, drier stools and delayed transit time

Comparative Risk of Constipation Among Oral Opioids

Lower Risk Options

1. Tapentadol

   • Dual mechanism: μ-opioid receptor agonist + norepinephrine reuptake inhibitor
   • Clinical studies show significantly lower incidence of constipation compared to oxycodone at equianalgesic doses 1, 2
   • Results in softer stools despite increasing colonic volume 1
   • Associated with significantly lower treatment discontinuation rates due to GI side effects 3

2. Transdermal Fentanyl

   • While not an oral opioid, worth noting that transdermal fentanyl has lower constipation rates than oral morphine 4
   • Cochrane Database review supports reduced opioid-related constipation compared to oral morphine regimens 4

Higher Risk Options

1. Morphine

   • Considered standard starting opioid but has high constipation potential 4
   • Produces active metabolite morphine-6-glucuronide that can worsen side effects 4

2. Oxycodone

   • Associated with higher rates of constipation, straining during defecation 1
   • In comparative studies with tapentadol, showed significantly higher GI side effect profile 2, 3

3. Hydrocodone

   • Available in various formulations but has significant constipation potential 4

4. Codeine

   • Metabolized to morphine and has significant constipation potential 4
   • Effectiveness varies due to CYP2D6 polymorphism between individuals 4

Clinical Approach to Preventing Opioid-Induced Constipation

For patients requiring opioid therapy, preventive measures should be implemented:

• Prophylactic laxative regimen: Stimulant laxative with or without stool softener, or polyethylene glycol 4
• Avoid ineffective agents: Fiber supplements like psyllium (Metamucil) are unlikely to control opioid-induced constipation 4
• Maintain adequate fluid intake and physical activity as tolerated 4
• Consider opioid rotation to less constipating options if constipation persists 4

Management of Established Opioid-Induced Constipation

If constipation develops despite preventive measures:

1. Rule out bowel obstruction or impaction 4
2. Titrate laxatives with goal of one non-forced bowel movement every 1-2 days 4
3. Consider adding osmotic laxatives (magnesium hydroxide, lactulose, polyethylene glycol) 4
4. For refractory cases: Consider methylnaltrexone (peripheral μ-opioid receptor antagonist) 4

Common Pitfalls and Caveats

• Don't rely on fiber supplements: They are ineffective for opioid-induced constipation and may worsen symptoms 4
• Don't wait for constipation to develop: Prophylactic treatment is essential as patients don't develop tolerance to this side effect 4
• Don't ignore renal function: Morphine, hydromorphone, hydrocodone, oxymorphone, and codeine should be used with caution in patients with fluctuating renal function due to potential accumulation of renally cleared metabolites 4
• Beware of acute effects: Even tapentadol can delay gastric emptying and small bowel transit in acute administration 5, though chronic use shows better GI tolerability than pure μ-agonists

Conclusion

When selecting an oral opioid with minimal constipation risk, tapentadol offers the best profile due to its dual mechanism of action, resulting in effective analgesia with significantly lower rates of constipation compared to traditional μ-opioid receptor agonists like oxycodone or morphine.