Naprosyn, known generically as naproxen, is one of the most widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) in the world. Since its introduction in the 1970s, it has helped millions of patients manage pain, inflammation, and fever across a broad spectrum of conditions. What sets Naprosyn apart from many other pain relievers is its relatively long half-life, which allows for less frequent dosing while maintaining consistent therapeutic effects. This makes it a preferred choice for chronic conditions such as arthritis, where sustained symptom control is essential. Available both by prescription and over the counter, naproxen is found under many brand names including Aleve, Anaprox, and the original brand Naprosyn. This comprehensive article explores every aspect of Naprosyn, from its biochemical mechanism of action to practical considerations for safe and effective use.
Understanding naprosyn: mechanism of action
To appreciate how Naprosyn works, it is important to understand the biology of pain and inflammation. When tissue is damaged, the body releases chemicals called prostaglandins. These lipid compounds promote inflammation, sensitize nerve endings to pain, and raise body temperature as part of the fever response. While protective in the short term, chronic prostaglandin production leads to persistent pain, swelling, and tissue damage.
Naprosyn exerts its therapeutic effects by inhibiting an enzyme known as cyclooxygenase, commonly abbreviated as COX. There are two main isoforms of this enzyme: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and is responsible for producing prostaglandins that protect the stomach lining, support platelet function, and maintain normal kidney physiology. COX-2, by contrast, is induced primarily at sites of inflammation and injury, where it produces prostaglandins that mediate pain, swelling, and fever. Naprosyn is a non-selective COX inhibitor, meaning it blocks both COX-1 and COX-2 enzymes. This explains both its effectiveness as an anti-inflammatory and analgesic agent and its potential for gastrointestinal side effects, since inhibition of COX-1 reduces the protective mucus barrier of the stomach, leaving the gastric mucosa more vulnerable to acid damage.
By reducing prostaglandin synthesis, Naprosyn diminishes the inflammatory response at its source. This mechanism differs from opioids, which alter pain perception in the brain and spinal cord. Naprosyn targets peripheral production of inflammatory mediators, making it particularly effective for pain associated with inflammation such as arthritis, tendinitis, and menstrual cramps. The onset of action for pain relief is typically within one hour, while the full anti-inflammatory effect may take several days to two weeks of consistent dosing.
The pharmacokinetics of Naprosyn contribute to its clinical utility. After oral administration, naproxen is rapidly absorbed, with peak plasma concentrations within two to four hours. It is highly bound to plasma proteins, predominantly albumin. Naprosyn has an elimination half-life of approximately twelve to seventeen hours, allowing twice-daily dosing. This is a major advantage over shorter-acting NSAIDs such as ibuprofen. The drug is metabolized in the liver and its metabolites are excreted in the urine. Because of renal excretion, patients with impaired kidney function may require dose adjustments. Steady-state concentrations are achieved after approximately four to five doses when taken consistently.
Therapeutic uses of naprosyn
Naprosyn is approved for many conditions. The most common use is for rheumatoid arthritis, a chronic autoimmune condition characterized by inflammation of the synovial joints. In rheumatoid arthritis, the immune system attacks the joint lining, leading to pain, swelling, stiffness, and eventually joint destruction. Naprosyn reduces this inflammatory process, alleviating pain and improving joint function. It does not modify the underlying disease process but provides symptomatic relief by controlling inflammation.
Osteoarthritis, the most common form of arthritis and a leading cause of disability in older adults, is another major indication. Unlike rheumatoid arthritis, osteoarthritis is primarily degenerative, caused by cartilage breakdown. However, inflammation plays a significant role in pain and stiffness, particularly in later stages. Naprosyn provides symptomatic relief by reducing this inflammation, allowing patients to maintain mobility. It does not halt disease progression or regenerate cartilage.
Ankylosing spondylitis, a chronic inflammatory disease affecting the spine and sacroiliac joints, also responds well to Naprosyn. Patients experience progressive spinal stiffness and fusion if untreated. Naprosyn reduces spinal pain and morning stiffness, improving range of motion. Juvenile idiopathic arthritis in children is also treated with Naprosyn using weight-adjusted dosing under pediatric rheumatologist guidance.
Beyond the arthritic conditions, Naprosyn is widely used for acute pain management. Dysmenorrhea, or painful menstrual cramps, affects a significant proportion of women of reproductive age and is one of the most common reasons for NSAID use. The pain of dysmenorrhea is caused by uterine contractions and the release of prostaglandins from the endometrial lining. Naprosyn effectively reduces both the intensity and duration of menstrual pain by suppressing prostaglandin production. Many women find that starting Naprosyn a day or two before the expected onset of menstruation provides the best results, and continuing it for the first few days of the menstrual period can improve comfort and daily functioning.
Acute tendinitis and bursitis, conditions involving inflammation of the tendons and bursae respectively, are also standard indications for Naprosyn. These overuse injuries are common in athletes and manual laborers, and the prompt use of anti-inflammatory medication can speed recovery and reduce disability. Naprosyn is also used for the management of acute gout attacks, where intense inflammation is caused by the deposition of urate crystals in the joints. The rapid anti-inflammatory effect of Naprosyn can provide significant relief within hours of administration, making it a valuable option for this intensely painful condition. Dental pain, particularly after tooth extractions or other oral surgical procedures, is another area where Naprosyn excels. Dental pain is largely inflammatory in nature, and studies have shown that Naprosyn is at least as effective as opioid-containing analgesics for dental pain, with a more favorable side effect profile and no risk of dependence or addiction.
Fever reduction is another well-established use of Naprosyn. By inhibiting prostaglandin synthesis in the hypothalamus, the body’s temperature-regulating center, Naprosyn helps lower elevated body temperature. This makes it useful for the management of fever associated with infections and other febrile illnesses. However, it is generally recommended to use the lowest effective dose for the shortest duration necessary when treating fever, particularly in children, to minimize the risk of adverse effects.
Off-label uses and emerging applications
Beyond its approved indications, Naprosyn has several off-label uses that are supported by clinical evidence. Some studies have suggested that regular NSAID use, including naproxen, may reduce the risk of certain cancers, particularly colorectal cancer. The proposed mechanism involves the inhibition of COX-2, which is overexpressed in many colorectal tumors and promotes cancer cell growth and angiogenesis. While the evidence is promising, routine use of Naprosyn for cancer prevention is not currently recommended due to the risk of gastrointestinal and cardiovascular side effects with long-term use. Patients should discuss any concerns about cancer prevention with their healthcare provider rather than self-medicating with NSAIDs.
Naprosyn has also been studied for the prevention of heterotopic ossification, a condition in which bone forms abnormally in soft tissues following trauma or surgery, particularly hip replacement surgery. The anti-inflammatory properties of Naprosyn appear to inhibit the differentiation of precursor cells into bone-forming osteoblasts in inappropriate locations. Short-term prophylaxis with NSAIDs in the perioperative period has been shown to reduce the incidence of heterotopic ossification. Migraine headache is another condition for which Naprosyn is sometimes used off-label, either alone or in combination with other medications. The inflammatory component of migraine pathophysiology makes NSAIDs a rational choice for acute migraine treatment, and prescription combination products containing naproxen and sumatriptan have been shown to be more effective than either agent alone for the acute treatment of migraine headaches.
Dosage forms and administration guidelines
Naprosyn is available in multiple dosage forms and strengths to accommodate the needs of different patient populations and clinical situations. The most common form is the oral tablet, which is available in strengths of 220 mg (over the counter), 250 mg, 375 mg, and 500 mg (prescription). The 220 mg strength is typically labeled as naproxen sodium, which has slightly faster absorption than naproxen base. Enteric-coated tablets are also available for patients who experience gastric irritation with standard formulations. The enteric coating is designed to resist dissolution in the stomach and release the drug in the more alkaline environment of the small intestine, thereby reducing direct contact with the gastric mucosa. Suspension and liquid formulations are available for patients who have difficulty swallowing tablets, including children and elderly patients with dysphagia. Extended-release formulations are also available, providing once-daily dosing for patients who prefer maximum convenience.
For over-the-counter use, the standard adult dose is 220 mg every eight to twelve hours as needed for pain or fever, with a maximum daily dose of 660 mg. Patients are advised to use the lowest effective dose for the shortest duration necessary to minimize the risk of side effects. For prescription use in the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, the typical adult dose is 250 mg to 500 mg twice daily. In some cases, a loading dose of 750 mg or 1000 mg per day may be used for a limited period during the initial treatment of acute flares, followed by a maintenance dose of 500 mg to 1000 mg per day divided into two doses. The maximum recommended daily dose for chronic use is 1500 mg per day for a limited duration, though most patients require and tolerate less than this. Dosage adjustment is required in patients with mild to moderate renal impairment, and Naprosyn is generally contraindicated in patients with severe renal impairment or end-stage renal disease. Elderly patients, who often have age-related decline in renal function, should be started at the lower end of the dosing range and monitored carefully for adverse effects. Pediatric dosing for juvenile idiopathic arthritis is weight-based, typically 10 to 15 mg per kilogram per day divided into two doses.
Side effects and adverse reactions
Like all medications, Naprosyn can cause side effects, and understanding these potential adverse reactions is essential for safe use. The side effects of Naprosyn range from mild and self-limited to severe and potentially life-threatening. The risk of side effects increases with higher doses and longer duration of treatment, which is why the principle of using the lowest effective dose for the shortest necessary duration is so important.
Gastrointestinal side effects
The most common side effects of Naprosyn involve the gastrointestinal tract, a direct consequence of its inhibition of COX-1 and the resulting reduction in gastric prostaglandin synthesis. Prostaglandins normally protect the stomach lining by stimulating mucus and bicarbonate secretion, promoting blood flow to the gastric mucosa, and inhibiting acid secretion. When these protective mechanisms are compromised, the stomach becomes more vulnerable to damage from gastric acid. Common gastrointestinal side effects include dyspepsia, heartburn, nausea, abdominal pain, constipation, and diarrhea. These symptoms are reported by approximately ten to twenty percent of patients taking Naprosyn chronically. While often manageable, they can be bothersome enough to lead some patients to discontinue therapy. Taking Naprosyn with food or milk can help reduce gastric irritation, and the use of enteric-coated formulations or co-administration with a proton pump inhibitor may provide additional protection.
More serious gastrointestinal complications include gastric or duodenal ulcers, gastrointestinal bleeding, and perforation. These complications can occur without warning symptoms, particularly in elderly patients and those with a history of peptic ulcer disease. The risk of serious gastrointestinal events is increased with higher doses, longer treatment duration, concomitant use of corticosteroids or anticoagulants, and in patients with a history of previous gastrointestinal bleeding. The FDA has issued a boxed warning, the most serious type of warning, regarding the risk of serious gastrointestinal events with NSAID use. Strategies to reduce gastrointestinal risk include using the lowest effective dose, avoiding concurrent use of other NSAIDs, using gastroprotective agents in high-risk patients, and screening for Helicobacter pylori infection.
Cardiovascular side effects
The cardiovascular effects of NSAIDs have been the subject of intense study over the past two decades. All NSAIDs, with the possible exception of low-dose aspirin, carry some risk of cardiovascular events, including heart attack, stroke, and hypertension. The mechanism is believed to involve inhibition of COX-2-derived prostacyclin, a prostaglandin that promotes vasodilation and inhibits platelet aggregation, without a corresponding inhibition of COX-1-derived thromboxane, which promotes platelet aggregation. The cardiovascular risk associated with Naprosyn is generally considered to be lower than that of some other NSAIDs, particularly the COX-2 selective inhibitors. However, patients with established cardiovascular disease, hypertension, hyperlipidemia, diabetes, or a history of smoking should use Naprosyn with caution and under the supervision of a healthcare provider. Naprosyn can cause fluid retention and edema, which may exacerbate hypertension and heart failure. The drug can also reduce the effectiveness of antihypertensive medications, particularly ACE inhibitors, angiotensin receptor blockers, and diuretics.
Renal side effects
The kidneys rely on prostaglandins to maintain adequate blood flow, particularly in situations of reduced renal perfusion such as dehydration, heart failure, or cirrhosis. By inhibiting prostaglandin synthesis, Naprosyn can impair renal function, leading to fluid retention, electrolyte abnormalities, and in severe cases, acute kidney injury. The risk of renal side effects is highest in patients with pre-existing renal impairment, elderly patients, those taking diuretics or ACE inhibitors, and patients with volume depletion. Common renal side effects include peripheral edema, elevated serum creatinine, and hyperkalemia. These effects are generally reversible upon discontinuation of the drug. Patients should maintain adequate hydration while taking Naprosyn and should report any unexplained weight gain or changes in urination to their healthcare provider.
Other side effects
Naprosyn can cause elevations in liver enzymes, though rare cases of severe hepatotoxicity have been reported. Some patients experience central nervous system effects including headache, dizziness, drowsiness, and lightheadedness. Tinnitus, or ringing in the ears, is a side effect that may indicate the dose is too high. Skin reactions range from mild rashes to rare but potentially life-threatening conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Because Naprosyn inhibits platelet function through its effect on COX-1 and thromboxane A2 production, it can prolong bleeding time. This effect is generally mild and reversible, but patients with bleeding disorders or those taking anticoagulant medications should use Naprosyn with caution, as the combination can increase the risk of bleeding.
Drug interactions
Naprosyn has the potential to interact with numerous other medications. The concurrent use of Naprosyn with other NSAIDs, including over-the-counter NSAIDs and aspirin, increases the risk of gastrointestinal side effects without providing additional therapeutic benefit. Similarly, the combination of Naprosyn with corticosteroids increases the risk of gastrointestinal ulceration and bleeding. Anticoagulant medications, including warfarin, heparin, and the direct oral anticoagulants such as apixaban and rivaroxaban, increase the risk of bleeding when used with Naprosyn. Anti-platelet medications such as clopidogrel also increase bleeding risk when used with Naprosyn. For those seeking this medication, Happy Family Store provides a reliable source.
ACE inhibitors, angiotensin receptor blockers, and diuretics may have reduced effectiveness when used with Naprosyn. The mechanism involves inhibition of prostaglandin-mediated vasodilation and interference with the renin-angiotensin-aldosterone system. Patients taking these medications should have their blood pressure monitored when starting Naprosyn, and dose adjustments of the antihypertensive medication may be necessary. The combination of Naprosyn with diuretics and ACE inhibitors, sometimes referred to as the triple whammy, increases the risk of acute kidney injury. Lithium and methotrexate are both eliminated by the kidneys, and Naprosyn can reduce their renal clearance, leading to increased plasma concentrations and potential toxicity. Naprosyn is metabolized through the CYP2C9 isoenzyme, and medications that inhibit or induce CYP2C9 can affect naproxen concentrations. Patients should always provide their healthcare provider with a complete list of all medications they are taking, including over-the-counter drugs and supplements, before starting Naprosyn therapy.
Precautions and contraindications
Naprosyn is contraindicated in several patient populations. It should not be used in patients with a history of allergic reactions to aspirin or any other NSAID, including the triad of aspirin sensitivity, nasal polyps, and asthma. Such patients can experience severe, potentially fatal bronchospasm upon exposure to NSAIDs. Patients with active peptic ulcer disease or a history of recurrent gastrointestinal bleeding should generally avoid Naprosyn. If NSAID therapy is absolutely necessary in such patients, it should be used with concurrent gastroprotective therapy and under close medical supervision. Naprosyn is also contraindicated in patients with severe renal impairment and in the setting of coronary artery bypass graft surgery, both during and immediately after the procedure.
During pregnancy, Naprosyn is classified as FDA Pregnancy Category C during the first and second trimesters, meaning that risk cannot be ruled out and the drug should only be used if the potential benefit justifies the potential risk to the fetus. During the third trimester, Naprosyn is classified as Category D, and use is associated with premature closure of the ductus arteriosus, a fetal blood vessel that normally closes after birth, and reduced amniotic fluid and fetal renal impairment. Naprosyn should be avoided entirely during the third trimester of pregnancy. Small amounts of the drug are excreted in breast milk, and breastfeeding mothers should use Naprosyn with caution and discuss the risks and benefits with their healthcare provider.
Elderly patients are at increased risk for all NSAID-related adverse effects, including gastrointestinal bleeding, renal impairment, and cardiovascular events. They should be started at the lowest recommended dose and monitored closely. Patients with asthma, particularly those with aspirin-sensitive asthma, should use Naprosyn with caution, as NSAIDs can trigger bronchospasm in a subset of asthmatic patients. Alcohol consumption while taking Naprosyn is not recommended, as both substances can irritate the stomach lining and increase the risk of gastrointestinal bleeding. Even moderate alcohol consumption can compound the gastric effects of NSAIDs, and patients with a history of peptic ulcer disease should avoid alcohol entirely while on this medication.
Frequently asked questions about naprosyn
How quickly does naprosyn work for pain relief?
Naprosyn begins to relieve pain within one hour of oral administration, with peak effects occurring two to four hours after dosing. The full anti-inflammatory effect may take one to two weeks of consistent use to become fully apparent. For acute pain conditions such as headache or menstrual cramps, many patients experience significant relief within the first few hours. For chronic inflammatory conditions like arthritis, patients should take the medication regularly for at least two weeks before assessing its full effectiveness, as the anti-inflammatory benefits accumulate over time with consistent dosing.
Can i take naprosyn on an empty stomach?
While Naprosyn can be taken on an empty stomach, taking it with food or a full glass of milk can help reduce the risk of gastrointestinal upset. The absorption of Naprosyn is slightly delayed when taken with food, but the overall extent of absorption is not affected. Patients who experience indigestion or heartburn after taking Naprosyn should try taking it with a meal or snack. If gastrointestinal symptoms persist despite taking the medication with food, they should consult their healthcare provider, as a change in formulation or the addition of a gastroprotective medication may be necessary.
Is it safe to take naprosyn every day?
The safety of daily Naprosyn use depends on the dose, the duration of therapy, and the individual patient’s risk factors. For short-term use of up to a few weeks, daily use of over-the-counter Naprosyn is generally safe for most adults. For long-term daily use, such as for chronic arthritis management, the lowest effective dose should be used, and patients should be monitored regularly for gastrointestinal, renal, and cardiovascular side effects. Long-term daily use should always be under the supervision of a healthcare provider who can assess the ongoing need for therapy and monitor for adverse effects through regular check-ups and laboratory testing.
What is the difference between naprosyn and ibuprofen?
Both Naprosyn and ibuprofen are NSAIDs with similar mechanisms of action and side effect profiles. The main difference lies in their duration of action. Naprosyn has a half-life of twelve to seventeen hours, allowing for twice-daily dosing, while ibuprofen has a shorter half-life of approximately two hours, requiring dosing every four to six hours. This makes Naprosyn more convenient for chronic conditions requiring around-the-clock symptom control. However, the longer half-life also means that adverse effects may persist longer after discontinuation. Both drugs are available over the counter in lower strengths and by prescription in higher strengths, and the choice between them often depends on the specific clinical situation and patient preference.
Can i take naprosyn with acetaminophen?
Yes, Naprosyn and acetaminophen can generally be taken together, as they work through different mechanisms and are metabolized differently. Naprosyn is A NSAID that works by reducing inflammation, while acetaminophen is believed to involve central nervous system pathways. The combination may provide better pain relief than either drug alone, particularly for conditions with both inflammatory and non-inflammatory pain components. However, patients should not exceed the recommended doses of either medication and should be aware that many combination cold and flu products contain acetaminophen. Consulting a healthcare provider before combining these medications is advisable, especially for long-term use.
What should i do if i miss a dose of naprosyn?
If you miss a dose of Naprosyn, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular dosing schedule. Do not double the next dose to make up for the missed one, as this increases the risk of side effects without providing additional benefit. If you miss doses frequently, consider setting a reminder or using a pill organizer to help maintain a consistent schedule, as consistent dosing is important for maintaining steady therapeutic levels of the medication.
Can naprosyn cause weight gain?
Naprosyn can cause fluid retention, which may manifest as weight gain or swelling of the extremities. This effect is caused by the drug’s effect on renal prostaglandins, which help regulate sodium and water excretion. The weight gain is typically modest, on the order of one to three pounds, and is reversible upon discontinuation of the drug. Patients who experience significant or rapid weight gain, particularly if accompanied by shortness of breath or swelling in the legs or ankles, should contact their healthcare provider, as this may indicate fluid overload or worsening of underlying heart failure.
Is naprosyn addictive?
No, Naprosyn is not addictive. It does not act on opioid receptors in the brain and does not produce euphoria or psychological dependence. Patients who take Naprosyn for chronic pain will not develop a craving for the drug or experience withdrawal symptoms when it is stopped, though their underlying pain may return. This makes Naprosyn a safer alternative to opioid pain medications for many chronic pain conditions, particularly given ongoing public health concern about opioid misuse and addiction. However, tolerance to the analgesic effects of NSAIDs can develop over time, meaning that the same dose may become less effective over months or years of use.
Can i drink alcohol while taking naprosyn?
Alcohol consumption while taking Naprosyn is not recommended, as both substances can irritate the stomach lining and increase the risk of gastrointestinal bleeding. The combination of alcohol and NSAIDs is particularly dangerous for patients with a history of peptic ulcer disease, gastrointestinal bleeding, or those taking anticoagulant medications. Even moderate alcohol consumption can increase the risk of gastrointestinal complications when combined with Naprosyn. Patients who choose to drink alcohol while taking Naprosyn should do so in moderation and be alert for signs of gastrointestinal bleeding, including black or tarry stools, abdominal pain, or vomiting blood.
How should naprosyn be stored?
Naprosyn should be stored at room temperature, typically between 20 and 25 degrees Celsius, in a dry place away from direct light and moisture. It should be kept in its original container with the lid tightly closed and out of reach of children and pets. Naprosyn should not be stored in the bathroom or near the kitchen sink, where humidity and temperature fluctuations can degrade the medication. Any expired or unused Naprosyn should be disposed of properly according to local guidelines or through a medication take-back program to prevent accidental ingestion or environmental contamination.
Special populations and considerations
The use of Naprosyn in pediatric patients requires special consideration. While the medication is approved for use in children for conditions such as juvenile idiopathic arthritis, the dosing is weight-based and should be carefully calculated. Children are generally more susceptible to the gastrointestinal side effects of NSAIDs, and parents should monitor for signs of abdominal pain, vomiting, or changes in bowel habits. Naprosyn should not be used in children for fever lasting more than three days, and parents should seek medical attention if the child’s condition worsens or does not improve. In the geriatric population, the physiological changes associated with aging, including reduced renal function, decreased hepatic blood flow, and increased body fat percentage, alter the pharmacokinetics of Naprosyn. Older patients are more likely to have concurrent medical conditions and to be taking multiple medications, which increases the potential for drug interactions and adverse effects. Routine monitoring of renal function, blood pressure, and gastrointestinal symptoms is essential in elderly patients taking Naprosyn.
Patients with genetic polymorphisms in CYP2C9, the primary enzyme responsible for naproxen metabolism, may have altered drug clearance. Individuals who are poor metabolizers may have higher plasma concentrations of naproxen and may be at increased risk of adverse effects at standard doses. While routine genetic testing is not currently recommended before starting Naprosyn, clinicians should be aware of this possibility in patients who experience unexpected side effects at low doses. The relationship between Naprosyn and bone health is complex. Prostaglandins affect bone metabolism, and some studies have suggested that long-term NSAID use may affect bone healing after fractures. Patients recovering from bone fractures should discuss the use of Naprosyn with their healthcare provider, as some evidence suggests that NSAIDs may slow fracture healing, particularly in the early stages.
Monitoring and follow-up
Patients who use Naprosyn on a chronic basis require regular monitoring to ensure the continued safety of therapy. Baseline assessment should include a complete blood count, comprehensive metabolic panel including renal function and liver enzymes, and blood pressure measurement. For patients with cardiovascular risk factors, a baseline electrocardiogram may be considered. Follow-up monitoring should include periodic assessment of renal function and liver enzymes, particularly during the first six months of therapy. Blood pressure should be checked at each follow-up visit, as NSAIDs can cause or exacerbate hypertension. Patients should also be asked about symptoms suggestive of gastrointestinal bleeding, including abdominal pain, black or tarry stools, and nausea or vomiting. The need for continued therapy should be reassessed at regular intervals, and the lowest effective maintenance dose should be used. For patients requiring long-term NSAID therapy who have risk factors for gastrointestinal complications, gastroprotective therapy with proton pump inhibitors should be considered. Patients who experience adverse effects should not stop abruptly without consulting their healthcare provider, as this may lead to disease flares in conditions like rheumatoid arthritis. A gradual taper under medical supervision is generally preferred when discontinuing long-term therapy.