|Systematic (IUPAC) name|
|Biological half-life||8 to 12 hours|
|CAS Registry Number|
|PDB ligand ID||1FL (, )|
|Molecular mass||250.198 g/mol|
Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971 after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a non-steroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.
- Mechanism of action 1
Medical uses 2
- Amyloidosis 2.1
Side effects 3
- Gastrointestinal 3.1
- Cardiovascular 3.2
- Ear, nose, throat, and eye 3.3
- Central nervous system 3.4
- Skin 3.5
- Contraindications 4
- Cautions 5
- Overdose 6
- Synthesis 7
- References 8
- External links 9
Mechanism of action
Like all NSAIDs, diflunisal acts by inhibiting the production of prostaglandins, hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug. Though diflunisal has an onset time of 1 hour, and maximum analgesia at 2 to 3 hours, the plasma levels of diflunisal will not be steady until repeated doses are taken. The long plasma half-life is a distinctive feature of diflunisal in comparison to similar drugs. To increase the rate at which the diflunisal plasma levels become steady, a loading dose is usually used. It is primarily used to treat symptoms of arthritis, and for acute pain following oral surgery, especially removal of wisdom teeth.
Effectiveness of diflunisal is similar to other NSAIDs, but the duration of action is twelve hours or more. This means fewer doses per day are required for chronic administration. In acute use, it is popular in dentistry when a single dose after oral surgery can maintain analgesia until the patient is asleep that night.
- Pain, mild to moderate
- Rheumatoid arthritis
- Injury to tendons
- ATTR amyloidosis
Both diflunisal and several of its analogues have been shown to be inhibitors of transthyretin-related hereditary amyloidosis, a disease which currently has few treatment options. Phase I trials have shown the drug to be well tolerated, with a small Phase II trial (double-blind, placebo-controlled, 130 patients for 2 years) in 2013 showing a reduced rate of disease progression and preserved quality of life. However a significantly larger Phase III trial would be needed to prove the drugs effectiveness for treating this condition.
The inhibition of prostaglandins has the effect of decreasing the protection given to the stomach from its own acid. Like all NSAIDS, this leads to an increased risk of stomach ulcers, and their complications, with long-term use. Elderly users of diflunisal are at greater risk for serious GI events.
- Increased risk of GI events including bleeding, ulceration, and stomach or intestine perforation.
- Abdominal pain or cramps
- Nausea and vomiting
- Irregular heart beat
- Possible increased risk of serious and potentially fatal cardiovascular thrombotic events, MI, and stroke
- Risks may increase with duration of use and for cardiovascular disease history
Ear, nose, throat, and eye
- Ringing in the ears
- Yellowing of eyes
Central nervous system
- Swelling of the feet, ankles, lower legs, and hands
- Yellowing of skin
- Hypersensitivity to aspirin/NSAID-induced asthma or urticaria
- Aspirin triad
- 3rd trimester pregnancy
- CABG surgery (peri-op pain)
- Cardiovascular diseases
- Cardiac risk factors
- Congestive heart failure
- Elderly or debilitated
- Impaired liver function
- Impaired kidney function
- Fluid retention
- History of gastrointestinal bleeds/PUD
- Smoker (tobacco use)
- Corticosteriod use
- Anticoagulant use
- Alcohol use
- Diuretic use
- ACE inhibitor use
Deaths that have occurred from diflunisal usually involved mixed drugs and or extremely high dosage. The oral LD50 is 500 mg/kg. Symptoms of overdose include coma, tachycardia, stupor, and vomiting. The lowest dose without the presence of other medicines which caused death was 15 grams. Mixed with other medicines, a death at 7.5 grams has also occurred. Diflunisal usually comes in 250 or 500 mg, making it relatively hard to overdose by accident.
Diflunisal is synthesized from a diazonium salt, which is synthesized from 2,4-difluoroaniline and isoamyl nitrite, anisole in the presence of copper (I) salts by the classic scheme of making diaryls, the so-called Gomberg–Bachmann reaction.
The resulting 4-(2,4-difluorophenyl)anisole is demethylated by hydrogen iodide into 4-(2,4-difluorophenyl)-phenol. This product is reacted with carbon dioxide in the presence of a base according to the Kolbe-Schmidtt phenol carboxylation method, giving diflunisal.
- Adams, S. S. (1999). "Ibuprofen, the propionics and NSAIDs: Personal reflections over four decades". Inflammopharmacology 7 (3): 191–197.
- Wallace, J. L. (1 October 2008). "Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself?". Physiological Reviews 88 (4): 1547–1565.
- Tempero, KF; Cirillo, VJ; Steelman, SL (Feb 1977). "Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans.". British Journal of Clinical Pharmacology. 4 Suppl 1: 31S–36S.
- Brogden, RN; Heel, RC; Pakes, GE; Speight, TM; Avery, GS (Feb 1980). "Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis.". Drugs 19 (2): 84–106.
- Lawton, GM; Chapman, PJ (Aug 1993). "Diflunisal--a long-acting non-steroidal anti-inflammatory drug. A review of its pharmacology and effectiveness in management of postoperative dental pain.". Australian dental journal 38 (4): 265–71.
- Tojo, Kana; Sekijima, Yoshiki; Kelly, Jeffery W.; Ikeda, Shu-ichi. "Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis". Neuroscience Research 56 (4): 441–449.
- Kingsbury, J. S.; Laue, T. M.; Klimtchuk, E. S.; Theberge, R.; Costello, C. E.; Connors, L. H. (6 March 2008). "The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal: DIRECT ANALYSIS BY FLUORESCENCE-DETECTED ANALYTICAL ULTRACENTRIFUGATION". Journal of Biological Chemistry 283 (18): 11887–11896.
- Adamski-Werner, Sara L.; Palaninathan, Satheesh K.; Sacchettini, James C.; Kelly, Jeffery W. (January 2004). "Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis". Journal of Medicinal Chemistry 47 (2): 355–374.
- Berk, John L.; Suhr, Ole B.; Sekijima, Yoshiki; Yamashita, Taro; Heneghan, Michael; Zeldenrust, Steven R.; Ando, Yukio; Ikeda, Shu-ichi; Gorevic, Peter; Merlini, Giampaolo; Kelly, Jeffrey W.; Skinner, Martha; Bisbee, Alice B.; Dyck, Peter J.; Obici, Laura. "The Diflunisal Trial: Study accrual and drug tolerance". Amyloid 19 (S1): 37–38.
- Berk, JL; Suhr, OB; Obici, L; Sekijima, Y; Zeldenrust, SR; Yamashita, T; Heneghan, MA; Gorevic, PD; Litchy, WJ; Wiesman, JF; Nordh, E; Corato, M; Lozza, A; Cortese, A; Robinson-Papp, J; Colton, T; Rybin, DV; Bisbee, AB; Ando, Y; Ikeda, S; Seldin, DC; Merlini, G; Skinner, M; Kelly, JW; Dyck, PJ; Diflunisal Trial, Consortium (Dec 25, 2013). "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.". JAMA 310 (24): 2658–67.
- Hannah, J.; Ruyle, W. V.; Jones, H.; Matzuk, A. R.; Kelly, K. W.; Witzel, B. E.; Holtz, W. J.; Houser, R. A.; Shen, T. Y. (1978). "Novel analgesic-antiinflammatory salicylates". Journal of Medicinal Chemistry 21 (11): 1093.
- Diflunisal: MedlinePlus Drug Information
- Dolobid Prescribing Information (manufacturer's website)
- Dolobid Medication Guide (manufacturer's website)
- "Single dose oral diflunisal for acute postoperative pain in adults"