Phenylephrine vs Pseudoephedrine - How do they compare?

The most important difference between phenylephrine and pseudoephedrine is that phenylephrine is ineffective at relieving nasal congestion, whereas there is some evidence that oral pseudoephedrine is effective.

The main reasons for a lack of effectiveness of phenylephrine include:

• Although both phenylephrine and pseudoephedrine are well absorbed from the gut, phenylephrine is extensively metabolized in the gut wall. This means only about 40% of a dose reaches the bloodstream and only 3% is excreted unchanged. Pseudoephedrine is not metabolized in the gut wall, so almost 100% of a dose reaches the bloodstream and 43 to 96% of a dose is excreted unchanged
• phenylephrine was approved by the FDA based on in-house studies provided by pharmaceutical companies, not as a result of clinical trials. These unpublished studies ranged from mild successes to total failures, and a recommendation that phenylephrine should not be accepted as a nasal decongestant was made in 1994 but ignored. However, the efficacy of phenylephrine as a nasal spray for nasal congestion is supported by several studies
• The only study¹ that involved phenylephrine found that it was no more effective than placebo (a pretend pill). Expert reviews² have also questioned the substitution of phenylephrine for pseudoephedrine considering the lack of data for its effectiveness, which deprives the public of a relatively safe effective nasal decongestant.
• On September 14, 2023, the FDA Drug Advisory Committee concluded that current data does not support the effectiveness of phenylephrine as a nasal decongestant, although there were no concerns about any toxicity at recommended dosages.

Other significant differences between phenylephrine and pseudoephedrine include:

• Pseudoephedrine has restrictions on its sale. In some states (such as Oregon, Mississippi, and some parts of Missouri and Tennessee), a prescription from a doctor is required before it can be purchased. In other states, your driver’s license or another form of suitable ID must be shown, and some details recorded before it can be sold. Quantities are also limited
• Pseudoephedrine has a greater potential for misuse compared with phenylephrine. This is because it can be used to make methamphetamine. Pseudoephedrine itself is not addictive, although it may cause some central nervous system effects (CNS), such as insomnia, at dosages used to relieve a cold. However, studies have indicated that restricting the sale of pseudoephedrine to the public has little impact on illegal methamphetamine manufacture because it fails to target the large-scale production of methamphetamine
• Pseudoephedrine has a greater incidence of central nervous system (CNS) stimulant effects than phenylephrine, such as insomnia. This is because it is more lipid-soluble and more likely to cross into the brain than phenylephrine because of its chemical structure.

There are also some similarities between phenylephrine and pseudoephedrine:

• Both are available as oral tablets and an oral liquid. Pseudoephedrine is also available as long-acting extended-release tablets
• Both are FDA approved for use in children four years of age and older (except for the pseudoephedrine extended-release tablets which cannot be used in children under the age of 12). Note that internationally, many countries do not recommend pseudoephedrine or phenylephrine be used at all in children
• Both may be used short-term to relieve the symptoms of a common cold, such as sinus or nasal congestion and pressure
• Both have minimal effects on the cardiovascular system at usual oral dosages, although pseudoephedrine at 60mg may cause a slight increase in heart rate with no noticeable change in blood pressure. Recommendations are that neither phenylephrine or pseudoephedrine should be taken by people with high blood pressure, hyperthyroidism, heart disease, prostate problems or Raynaud’s syndrome unless on the advice of a doctor
• Both have a good safety record when taken at the recommended dosage for sinus and nasal congestion.

Both phenylephrine and pseudoephedrine are vasoconstrictors, this means that they narrow blood vessels, relieving congestion. Nasal blood vessels are about five times more sensitive than those in the heart, which explains why pseudoephedrine is effective at relieving nasal congestion in the low doses used in OTC medicines with few cardiac effects.

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