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Is nabumetone stronger than ibuprofen?

Is nabumetone stronger than ibuprofen?After 12 weeks of treatment, researchers found that nabumetone was similar in effectiveness to ibuprofen and other NSAIDs when treating osteoarthritis. However, the study found that nabumetone was more effective than the other NSAIDs for rheumatoid arthritis.

/Nabumetone is a naphthyl alkenone and non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, antipyretic, and analgesic activities. Nabumetone is a prodrug that upon hepatic catalysis converts into the active moiety 6-methoxy-2-naphthyl acetic acid (6MNA). 6MNA inhibits the activity of the enzymes cyclo-oxygenase I and II, resulting in decreased formation of precursors of prostaglandins and thromboxanes. The resulting decrease in prostaglandin synthesis is responsible for the therapeutic effects of nabumetone. The formation of thromboxane A2, by thromboxane synthase, is also decreased and results in an inhibition of platelet aggregation.

Nabumetone is a long-acting nonsteroidal anti-inflammatory drug (NSAID) that is available by prescription only and is used in the therapy of chronic arthritis. Nabumetone has been linked to rare instances of clinically apparent, idiosyncratic drug-induced liver disease.

Nabumetone is a methyl ketone that is 2-butanone in which one of the methyl hydrogens at position 4 is replaced by a 6-methoxy-2-naphthyl group. A prodrug that is converted to the active metabolite, 6-methoxy-2-naphthyl acetic acid, following oral administration. It is shown to have a slightly lower risk of gastrointestinal side effects than most other non-steroidal anti-inflammatory drugs. It has a role as a non-steroidal anti-inflammatory drug, a non-narcotic analgesic, a cyclooxygenase 2 inhibitor, and a prodrug. It is a methoxynaphthalene and a methyl ketone.

Mechanism of Action

Nabumetone’s active metabolite, 6-MNA, is an inhibitor of both COX-1 and COX-2 although it exhibits some COX-2 selectivity.[label, A178903] Inhibition of COX-1 and COX-2 reduces the conversion of arachidonic acid to PGs and thromboxane (TXA₂). This reduction in prostanoid production is the common mechanism that mediates the effects of nabumetone. PGE₂ is the primary PG involved in the modulation of nociception.[A179023] It mediates peripheral sensitization through a variety of effects.[T116, A179023] PGE₂ activates the G_q-coupled EP₁ receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE₂ also activates the EP₄ receptor, coupled to G_s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE₂ act via EP₃ to increase sensitivity to bradykinin and via EP₂ to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP₂ receptor which couples to G_s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI₂ is known to play a role via its G_s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain. PGI₂ and PGE₂ contribute to acute inflammation via their IP and EP₂ receptors.[T116, A179044] Similarly to β adrenergic receptors these are G_s-coupled and mediate vasodilation through the AC/PKA pathway. PGE₂ also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury.[T116] PGD₂ plays a role in the activation of endothelial cell release of cytokines through its DP₁ receptor.[A179044] PGI₂ and PGE₂ modulate T-helper cell activation and differentiation through IP, EP₂, and EP₄ receptors which are believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation. PGE₂ can cross the blood-brain barrier and act on excitatory G_q EP₃ receptors on thermoregulatory neurons in the hypothalamus.[T116] This activation triggers an increase in heat generation and a reduction in heat loss to produce a fever. NSAIDs prevent the generation of PGE₂ thereby reducing the activity of these neurons. The adverse effects of NSAIDs stem from the protective and regulatory roles of prostanoids which have been well-characterized.[T116] PGI₂ and PGE₂ regulate blood flow to the kidney by similar mechanisms to the vasodilation they produce in inflammation. Prevention of this regulation by NSAIDs produces vasoconstriction which limits renal function by reducing blood flow and hydrostatic pressure which drives filtration. PGE₂ also regulates gastric protection via EP₃ receptors which are, in this location, coupled to G_i which inhibits the AC/PKA pathway. This reduces the secretion of protons by H⁺/K⁺ ATPase in parietal cells and increases the secretion of mucus and HCO₃^– by superficial endothelial cells. Disruption of this protective action by NSAIDs leads to ulceration of the gastric mucosa. Lastly, disruption of PGI₂, which opposes platelet aggregation, generation by COX-2 selective agents leads to an imbalance with TXA₂ generated by COX-1, which promotes aggregation of platelets, leading to increased risk of thrombosis. Since nabumetone is somewhat COX-2 selective it is thought to promote this imbalance and increase thrombotic risk.

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Indications of Nabumetone

Indicated for Symptomatic relief in rheumatoid arthritis.
Symptomatic relief in osteoarthritis.
Nabumetone is a long-acting nonsteroidal anti-inflammatory drug (NSAID) that is available by prescription only and is used in the therapy of chronic arthritis. Nabumetone has been linked to rare instances of clinically apparent, idiosyncratic drug-induced liver disease.
Back Pain
Sciatica
Muscle Pain
Rheumatoid Arthritis
Frozen Shoulder

Contraindications of Nabumetone

Hypersensitivity to the active substance or to any of the excipients,
Nabumetone must not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Nabumetone is contraindicated in patients with severe hepatic failure.
Nabumetone is contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Nabumetone is contraindicated in patients with active, or history of recurrent, peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding).
Nabumetone is contraindicated in the third trimester of pregnancy and in nursing mothers.
Nabumetone is contraindicated in patients with severe heart failure, and in patients with current cerebrovascular or another hemorrhage.
a heart attack
chronic heart failure
abnormal bleeding in the brain resulting in damage to brain tissue, called a hemorrhagic stroke
a blood clot
an ulcer from too much stomach acid
stomach or intestinal ulcer
liver problems
bleeding of the stomach or intestines
kidney transplant
pregnancy
a rupture in the wall of the stomach or intestine
tobacco smoking
increased cardiovascular event risk
the time immediately after coronary bypass surgery
chronic kidney disease stage 4 (severe)
chronic kidney disease stage 5 (failure)
kidney disease with likely reduction in kidney function
aspirin-exacerbated respiratory disease
history of gastric bypass surgery
history of kidney donation

Dosage of Nabumetone

Strengths: 500 mg; 750 mg; 1000 mg

Osteoarthritis

Initial dose: 1000 mg orally once a day
Maintenance dose: 1500 to 2000 mg orally per day in 1 or 2 divided doses
Maximum dose: 2000 mg/day

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Rheumatoid Arthritis

Initial dose: 1000 mg orally once a day
Maintenance dose: 1500 to 2000 mg orally per day in 1 or 2 divided doses
Maximum dose: 2000 mg/day

Renal Dose Adjustments

Mild renal dysfunction (CrCl 50 mL/min or greater): No adjustment recommended.

Moderate renal dysfunction (CrCl 30 to 49 mL/min)

Initial dose: 750 mg orally once a day
Maximum dose: 1500 mg/day

Severe renal dysfunction (CrCl less than 30 mL/min)

Initial dose: 500 mg orally once a day
Maximum dose: 1000 mg/day

Side Effects of Nabumetone

The Most Common

shortness of breath (even with mild exertion);
swelling or rapid weight gain;
the first sign of any skin rash, no matter how mild;
signs of stomach bleeding–bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
liver problems–nausea, upper stomach pain, itching, tired feeling, flu-like symptoms, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
kidney problems–little or no urinating, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath; or
low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet.
stomach pain, indigestion, nausea;
diarrhea, constipation, gas;
swelling in your hands and feet;
headache, dizziness;
itching, skin rash; or
ringing in your ears.

Common

Acid or sour stomach
belching
loss of appetite
muscle pain
pain in lower back or side
pinpoint red spots on skin
puffiness or swelling of the eyelids or around the eyes, face, lips or tongue
rapid breathing
red irritated eyes
red skin lesions, often with a purple center
redness or other discoloration of skin
severe or continuing stomach pain
bloated full feeling
continuing ringing or buzzing or other unexplained noise in ears
excess air or gas in stomach or intestines
hearing loss
indigestion
mild diarrhea
passing gas

Rare

Increased sweating
sleepiness or unusual drowsiness
sleeplessness
trouble sleeping
unable to sleep
Bleeding gums
blistering, peeling, loosening of skin
bloody or black, tarry stools
bloody or cloudy urine
burning upper abdominal pain
changes in vision
chest pain
chills
clay-colored stools
general feeling of tiredness or weakness
greatly decreased frequency of urination or amount of urine
high blood pressure
hives or welts
increased sensitivity of skin to sunlight
increased thirst
joint pain, stiffness, or swelling
large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs

Drug Interactions of Nabumetone

Common medications that may interact with nabumetone include:

All other NSAID drugs except nabumetone
ACE inhibitors or ARBs, such as captopril, enalapril, or losartan
aminoglycosides, such as gentamicin
antibiotics, such as ciprofloxacin, norfloxacin, or vancomycin
anticoagulants (blood thinners) such as apixaban, dabigatran, fondaparinux, heparin, or warfarin
antidepressants, such as citalopram, escitalopram, fluoxetine, or paroxetine
antifungals, such as voriconazole
antiplatelets, such as clopidogrel or ticagrelor
beta-blockers, such as acebutolol, atenolol, bisoprolol, or carvedilol
bisphosphonates, such as alendronate
corticosteroids, such as dexamethasone or prednisone
cyclosporine
Aspirin Low Strength aspirin
diphenhydramine
duloxetine
omega-3 polyunsaturated fatty acids
cyclobenzaprine
escitalopram
fluticasone salmeterol
betamethasone
betaxolol
betrixaban
bisoprolol
captopril
carteolol
carvedilol
celecoxib
chlorothiazide
deflazacort
atorvastatin
pregabalin
metoprolol
esomeprazole
acetaminophen
hydrocodone
ciprofloxacin
citalopram
clofarabine
clomipramine
clopidogrel
cortisone
cyclosporine
albuterol
montelukast
levothyroxine
Vitamin B12 (cyanocobalamin)
Vitamin C (ascorbic acid)
Vitamin D3 (cholecalciferol)
alprazolam
cetirizine

Pregnancy Category of Nabumetone

US FDA pregnancy category: Not assigned

Pregnancy

There is no clinical trial experience with the use of nabumetone during human pregnancy.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with the dose and duration of therapy. During the first and second trimester of pregnancy, nabumetone should not be given unless clearly necessary. If nabumetone is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and the duration of treatment as short as possible.

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Lactation

Because no information is available on the use of nabumetone during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.

Before taking nabumetone,

tell your doctor and pharmacist if you are allergic to nabumetone, aspirin, or other NSAIDs such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn), or any other medications. Ask your doctor or pharmacist for a list of the ingredients.
tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: angiotensin-converting enzymes (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril, enalapril (Vasotec, in Vaseretic), fosinopril, lisinopril (in Zestoretic), moexipril (Univasc), perindopril (Aceon, in Prestalia), quinapril (Accupril, in Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); angiotensin receptor blockers such as candesartan (Atacand, in Atacand HCT), eprosartan (Teveten), irbesartan (Avapro, in Avalide), losartan (Cozaar, in Hyzaar), olmesartan (Benicar, in Azor, in Benicar HCT, in Tribenzor), telmisartan (Micardis, in Micardis HCT, in Twynsta), and valsartan (in Exforge HCT); medications are taken orally for diabetes; diuretics (‘water pills’); lithium (Lithobid);; phenytoin (Dilantin, Phenytek); and methotrexate (Otrexup, Rasuvo, Trexall). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if you have or have ever had asthma, especially if you also have frequent stuffed or runny nose or nasal polyps (swelling of the lining of the nose); heart failure; swelling of the hands, feet, ankles, or lower legs; or kidney or liver disease.
tell your doctor if you are pregnant, plan to become pregnant; or are breastfeeding. Nabumetone may harm the fetus and cause problems with delivery if it is taken around 20 weeks or later during pregnancy. Do not take nabumetone around or after 20 weeks of pregnancy, unless you are told to do so by your doctor. If you become pregnant while taking nabumetone, call your doctor.
if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking nabumetone.
plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Nabumetone may make your skin sensitive to sunlight.

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