We have a common expectation that when prescribed a medication, it will work in a certain way.

In the worst case, we will experience no effect at all or a list of known side effects.

There is another possible outcome, known as a paradoxical reaction, which is when our symptoms increase instead of decrease.

What Is a Paradoxical Reaction?

A paradoxical reaction happens when a person experiences the opposite of what the drug is intended to do.

It might be quite surprising that when taking a medication for a certain condition that the medication could actually increase the symptoms instead of making them go away.

This is a well-known possibility and is known as a paradoxical reaction. Many factors can cause this to happen, and many times, the reason why a certain person experiences this is unknown.

A paradoxical reaction is different from known side effects. For instance, an anti-nausea medication might cause the person to become nauseous or more nauseous.

In some cases, a medication might aggravate other conditions that are known side effects of another medication the person is taking.

Paradoxical reactions fall into three categories. The first is the opposite effect of the explicit purpose of the drug.

The second is when it has the opposite effect when used off-label, and the third is when the unexpected response is unrelated to the usual use of the drug or it causes the side effect of another medication to occur.

What Causes a Paradoxical Effect?

In some cases, the reason for the paradoxical response is not known, but some factors have been identified that are associated with this phenomenon.

Some paradoxical responses are common in certain drug categories, while others seem to occur only in rare cases. One reason for a paradoxical reaction is what is known as hormesis.

Hormesis refers to the effects of certain doses of medicines on the body. For instance, small doses of ionizing radiation can help treat cancer, but higher doses can be damaging.

Paradoxical reactions can mean the person does not tolerate the dose of the medication they are on, and it needs to be reduced.

Even if the dosage is according to recommendations, some people's bodies seem to respond almost too well. Others have bodies that do not respond at all to the same dosage. Everyone is different, and dosage recommendations are made based on how the average person responded while the drug was being tested.

One of the most difficult aspects of getting the dosage of a medication right is that people's bodies might respond differently to the same dose.

If two people are the same weight and height, they could be expected to require the same dosage of medicine, but it does not always work that way. For one person, the dosage might be right, but for the other, it might be too high or too low.

Several factors have been found to influence how a person will react to certain medications.

Drug Tolerance

Over time, the body builds up a tolerance to some medications, and they are no longer as effective as they were in the beginning. It takes higher and higher doses of medication to get the same effect.

In some cases, higher doses of medication might cause an unwanted reaction even though it still does not seem to affect the targeted condition.

Genetics

Genetics also affect how a person responds to certain medications. The challenge is that you do not always know how those in your family responded to certain medications, especially if they never took them.

Pharmacogenomics is a branch of medicine that studies how a person's genetic makeup affects how they respond to certain medications.

The field of pharmacogenomics is a rapidly growing field that seeks to understand how genes affect drug response.

The eventual goal is to be able to anticipate how a person is likely to react to a certain medication based on their genetic makeup. This knowledge hopes to gain a better understanding of adverse reactions and how to prevent them.

State of The Body Before Taking Drugs

The response to a certain medication is an interplay between the state of the person's body and the environment.

Factors, such as a person's stress level, lack of sleep, or emotional state can affect the effectiveness or reactions to a certain medication. Other factors, such as a person's diet and overall health can affect how they react to medications.

Underlying Infections or Medical Conditions

The presence of an underlying infection or undiagnosed medical condition can trigger an adverse reaction to medications. For instance, a medication that has a known side effect of causing heart arrhythmias might cause a heart attack in a person with existing undiagnosed arrhythmias.

Another example might be a drug that is known to raise blood sugar levels causing abnormally high glucose levels in someone with undiagnosed or uncontrolled Type II diabetes.

ADHD

Paradoxical reactions seem to be more common among those with diagnosed and undiagnosed ADHD. At one time, it was thought that all persons with ADHD would calm down when given stimulants.

This belief was so common that giving a person stimulants to see if it calmed them down was used as a diagnostic tool.

Now, we know that the paradoxical response to stimulants among people with ADHD does not occur in everyone. We also know that the dose of the stimulants and individual factors influence the effect.

In some people with ADHD, giving them stimulants will make their brains even more reactive, while in others, it calms them down.

Clinical Features Of Paradoxical Reactions

Paradoxical reactions come in many different forms. They range from mild to severe. Any medication has a chance of producing a paradoxical effect, and it is important to monitor yourself or someone else closely when you begin taking any new medication.

The clinical features of a paradoxical reaction depend on the condition and the medication used to treat it. One example of this is a person who begins taking antidepressants and develops new or worsening suicide ideation.

Another example is when a person taking migraine medication might experience worsening migraines.

In cases where the condition under treatment shows signs of worsening, the question should always be whether the medication caused the condition to worsen or something else. It might be that the condition did not respond to the medication and the condition worsened on its own.

The question then becomes whether the person needs a higher dose of the medication or whether this would create an even bigger problem.

The clinical features of a paradoxical reaction can resemble those of a dangerous drug interaction, so you need to rule this out. If the person is on another medication, then it could be the reason for the reaction.

True paradoxical reactions can occur, so it is important to make sure the symptoms being experienced are not from another cause.

Neurobiology Of Paradoxical Reactions

In some cases, the neurobiology of paradoxical reactions is understood, but in others, it is a mystery. One example where it is understood is in the case of benzodiazepines. In this case, a medication that is supposed to calm a person down causes them to become more agitated.

In this reaction, the drugs act by activating GABA receptors that inhibit the ability of a nerve cell to transmit information. Increased GABA should create a calming effect on the person. Instead, in some people, the medication fails to stimulate GABA receptors or blocks their ability to function.

Approach for Managing Reactions

When a person seems to be experiencing a paradoxical reaction, it is important to determine whether it is a true paradoxical reaction or whether the condition is worsening because the dosage of the medication is not high enough.

It is important to monitor a person closely any time they begin a new medication or a medication dosage is increased.

If you or a loved one is taking medication and experiences an unwanted reaction, it is important to contact your physician immediately to ask them what to do.

It is also essential to take any medications exactly as directed by your physician. If a severe reaction occurs, you should stop the medication immediately and contact your physician. Tests might provide clues as to whether this is a paradoxical reaction or from some other cause.

Paradoxical Reaction Examples

Certain drug categories and substances have a higher incidence of paradoxical reactions than others do.

Anytime a drug or substance has the opposite effect expected or has an effect that seems completely related, a paradoxical reaction should be considered. Here are some of the more common drugs known to cause these types of reactions.

Drug Categories

• Depressants
• Stimulants
• Hallucinogens
• Dissociative Anesthetics
• Narcotic Analgesics
• Inhalants
• Cannabis

Substances

• Amphetamines
• Antibiotics
• Antidepressants
• Antipsychotics
• Barbiturates
• Benzodiazepines
• Caffeine
• Naltrexone
• Alcohol

You can find many examples of paradoxical reactions in the world of medicine. That is one of the reasons why finding a medication that works for an individual and getting the dosage adjusted can take time. Paradoxical reactions are something every clinician, patient, and caregiver should be aware of any time a new medication begins or the dosage is adjusted.

References

1. https://www.benzoinfo.com/paradoxical-reactions/
2. https://pubmed.ncbi.nlm.nih.gov/15460178/
3. https://en.wikipedia.org/wiki/Paradoxical_reaction
4. https://nigms.nih.gov/education/fact-sheets/Pages/pharmacogenomics.aspx