Norepinephrine reuptake inhibitors (NRIs): Uses, common brands, and safety info

Norepinephrine reuptake inhibitors (NRIs), also known as noradrenaline reuptake inhibitors (NARIs), are prescription drugs that increase the amount of the neurotransmitter norepinephrine in the brain by preventing its reuptake in the synapses, or spaces, between nerve cells. 

NRI actions are specific to blocking the reuptake of norepinephrine and have virtually no action on other neurotransmitters. NRIs are used to treat major depression, seasonal affective disorder, attention-deficit hyperactivity disorder (ADHD), and pain relief. 

NRIs are sometimes used off-label for panic disorder and anxiety disorder. Zyban, a brand name for bupropion HCl sustained release tablets approved as an aid to smoking cessation, is no longer available however the generic form may be prescribed for that purpose.

The following table lists the NRI medications approved for use by the U.S. Food and Drug Administration (FDA), followed by information on how they work, what conditions they treat, safety, and cost.

Other norepinephrine reuptake inhibitors

Although not classified as true NRIs, some tetracyclic antidepressants and tricyclic antidepressants (TCAs) to treat depression work primarily by decreasing the reuptake of norepinephrine with minor activity on other neurotransmitters. Drugs with NRI-type activity include the following:

• Ludiomil (maprotiline)

• Vivactil (protriptyline)

• Norpramin (desipramine)

What are norepinephrine reuptake inhibitors?

Like other selective reuptake agents, NRIs target specific receptors, in this case within the norepinephrine system, while ignoring other receptors that may lead to unwanted side effects. In clinical trials, NRIs have been found to be safe and effective therapeutic

choices having low potential for abuse, favorable side effect profiles, and relatively minor withdrawal symptoms compared to other classes.

How do norepinephrine reuptake inhibitors work?

NRIs work by blocking the action of the norepinephrine transporter which causes the reuptake of norepinephrine in the synapses, or spaces, between the nerve cells. This allows more norepinephrine to remain active in the brain. 

Norepinephrine is a naturally occurring neurotransmitter, or brain chemical, in the central nervous system (CNS) that increases alertness and reaction time. Norepinephrine has also been shown to play a role in a person's mood and ability to concentrate. Low levels of norepinephrine can result in physical and mental symptoms, such as: 

• Anxiety

• Depression

• Changes in blood pressure

• Changes in heart rate

• Low blood sugar, or hypoglycemia

• Migraine headaches

• Problems sleeping

In the abbreviation NRI, the "RI" stands for "reuptake inhibitor." Reuptake inhibitors work by increasing the amount of certain brain neurotransmitters to cause the intended effect. There are several other classes of reuptake inhibitor drugs, including:

• Serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g., Cymbalta (duloxetine), Pristiq (desvenlafaxine), Fetzima (levomilnacipran), Savella (milnacipran), and Effexor (venlafaxine)

• Selective serotonin reuptake inhibitors (SSRIs), e.g., Prozac (fluoxetine), Paxil (paroxetine), Celexa (citalopram), and Zoloft (sertraline)

Although NRIs are sometimes noted as “selective” NRIs, they are not to be confused with “SNRIs,” or serotonin and norepinephrine reuptake inhibitors.

What are norepinephrine reuptake inhibitors used for?

NRI drugs are typically prescribed to patients who would benefit from increased levels of norepinephrine. Following is a list of approved indications for each individual product:

• Attention-deficit hyperactivity disorder (ADHD): Strattera (atomoxetine)

• Major depressive disorder: Wellbutrin (bupropion HCl), Wellbutrin SR (bupropion HCl sustained-release), Forfivo XL (bupropion HCl extended-release)

• Major depressive disorder and seasonal affective disorder: Wellbutrin XL (bupropion extended-release) and Aplenzin (bupropion hydrobromide extended-release)

• Aid to smoking cessation treatment: Bupropion HCl ER (extended-release)

• Relief of moderate to severe acute pain in patients 18 years of age or older: Nucynta (tapentadol)

Who can take norepinephrine reuptake inhibitors?

Adults

NRIs have been found to be an effective and well-tolerated therapy for both short- and long-term treatment in adults in the treatment of depression, attention-deficit hyperactivity disorder (ADHD), as an aid to smoking cessation, and for pain relief.  

Children and adolescents

The safety and effectiveness of bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, bupropion HCl ER, Aplenzin XL, and Forfivo XL) in the pediatric population have not been established and its use in a child or adolescent must balance the potential risks with the clinical benefits. All forms of bupropion have an FDA-mandated “boxed warning,” also called a black box warning, due to increased risk of suicidality in children, adolescents, and young adults (up to 24 years of age). 

The safety and effectiveness of Nucynta have not been established in pediatric patients less than 18 years old and its use is not recommended.

Strattera has been determined to be safe and effective for use in pediatric patients from ages 6 to 15 for the treatment of attention-deficit hyperactivity disorder (ADHD). Strattera also carries a boxed warning regarding the increased risk of suicidal thoughts in children and adolescents. 

Seniors

In clinical trials of bupropion no overall differences in safety or effectiveness were observed in patients greater than 65 years of age compared to younger patients. Because the elderly are more likely to have impaired kidney function, it is important when prescribing to consider reducing the dosage strength or frequency of dosing in those patients.

In general, dosing of Nucynta in elderly patients with normal kidney and liver function is the same as for younger adult patients. Older patients with decreased kidney and liver function should be started at the lower range of recommended doses.

The safety and effectiveness of Strattera have not been evaluated in elderly patients.

Women who are pregnant or breastfeeding

In a clinical study to determine the safety of bupropion use during pregnancy, the results suggested that it does not increase the risks for birth defects or spontaneous abortions. Because the results of this study have not been confirmed by other studies, it is recommended bupropion be used during pregnancy only if the potential benefit of treatment justifies the potential risk to the fetus. Bupropion has been found in human milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug based on the importance of continuing the drug to the mother.

There have been no adequate and well-controlled studies on the use of Strattera in  pregnant women and it should not be used unless the potential benefit justifies the potential risk to the fetus. Strattera was found to be excreted in milk in animal studies. It is unknown if it is excreted in human milk. Caution should be exercised if Strattera is given to a nursing woman.

There have been no adequate and well-controlled studies on the use of Nucynta in pregnant women and it should not be used unless the potential benefit justifies the potential risk to the fetus.

Are norepinephrine reuptake inhibitors safe?

All bupropion dosage forms and Strattera carry a boxed warning regarding a risk of increased suicidal thinking and behavior in some younger patients. Patients of all ages who are started on either drug should be monitored for signs of suicidal thoughts and behaviors.

Recalls

There are no current recalls as of August 2021. 

Restrictions

You should not take any NRI medicine if you are allergic to any of the active or inactive ingredients. The presence of other medical problems and conditions may affect the use of NRIs. You should not use bupropion medicines if you have any of the following conditions:

• A seizure disorder

• A current or prior diagnosis of bulimia or anorexia nervosa 

• Undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines such as Xanax or Valium)

• Currently on a monoamine oxidase inhibitor (MAOI) or have taken an MAOI within the past 14 days

You should not use Strattera if you have any of the following conditions:

• Narrow angle glaucoma

• Pheochromocytoma (a tumor that forms in the center of the adrenal gland that causes it to make too much adrenaline) 

• Currently on a monoamine oxidase inhibitor (MAOI) or have taken an MAOI within the past 14 days

You should not use Nucynta if you have any of the following conditions:

• Lung problems

• A gastrointestinal (GI) problem called paralytic ileus in which the intestines are not working normally

• Currently on a monoamine oxidase inhibitor (MAOI) or have taken an MAOI within the past 14 days

Stopping NRIs

Bupropion

The sudden discontinuation of any antidepressant, such as bupropion, may cause withdrawal-like symptoms. This is sometimes called discontinuation syndrome and may include the following symptoms:

• A general feeling of uneasiness

• Nausea

• Dizziness

• Lethargy

• Flu-like symptoms

A gradual reduction in the dose rather than abruptly stopping is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Your healthcare provider may continue decreasing the dose but at a more gradual rate.

Nucynta

Nucynta can cause physical dependence. The following withdrawal symptoms may occur:

• Feeling anxious

• Sweating

• Sleep problems

• Shivering, pain

• Nausea

• Tremors

• Diarrhea

• Upper respiratory symptoms

• Hallucinations

• Feeling that your hair is “standing on end”

To help lessen withdrawal symptoms, do not change the dose of Nucynta unless your healthcare professional advises you. Do not use Nucynta more often than prescribed and follow your doctor’s instructions about how to slowly stop taking it.

Serotonin syndrome risk

The development of a potentially life-threatening serotonin syndrome may occur with concomitant use of NRIs and serotonergic drugs that increase the levels of serotonin such as SNRIs (e.g., Cymbalta or Effexor XR), SSRIs (e.g., Prozac or Paxil), tricyclic antidepressants (TCAs), triptans, fentanyl, lithium, tramadol, tryptophan, buspirone, dextromethorphan, amphetamines, St. John’s Wort, and monoamine oxidase inhibitors (MAOIs) This may occur within the recommended dose. Symptoms of serotonin syndrome may include high fever, seizures, uneven heartbeat, or passing out. Emergency medical care may be needed if any of these symptoms occur.

Are norepinephrine reuptake inhibitors controlled substances?

Strattera and bupropion drugs are not controlled substances.

Nucynta is a Schedule II controlled substance and has an abuse potential similar to other opioid pain relievers. All patients treated with opioids require careful monitoring for signs of abuse and addiction because the use of opioid pain relievers carry the risk of addiction even under appropriate medical use.

Common norepinephrine reuptake inhibitors side effects

The following are potential common side effects when taking NRIs. This is not an exhaustive list and you should always consult a healthcare professional before taking an NRI.

• Weight loss

• Loss of appetite

• Constipation

• Dry mouth

• Skin rash

• Sweating

• Ringing in the ears

• Shakiness

• Stomach pain

• Agitation

• Anxiety

• Dizziness

• Trouble sleeping

• Muscle pain

• Nausea

• Fast heartbeat

• Sore throat

• Frequent urination

• Sexual dysfunction

How much do norepinephrine reuptake inhibitors cost?

NRIs have a wide price range depending on the specific drug, quantity, and dosage. Almost all Medicare and insurance plans will cover NRIs. Since most NRIs are available in generic formulations, they are much less expensive than their brand-name counterparts. A SingleCare discount card could reduce prescription costs up to 80% at participating pharmacies.