Gout medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
- The medical therapy of Gout differs for acute flares, chronic condition and maintenance therapy for prevention of acute flares.
- The main stay of therapy is pain managament, ideally achieved with NSAIDS[1] and oral or intra articular Glucocorticoids.[2]
- Colchicine is usually used for maintainance therapy, however; within 24 hours of symptom onset, low dose colchicine can be used.[3]
- For treatment resistant Gout, lesinurad with Xanthine oxidase inhibitors as a combination is used. [4]
- Other, less standard methods of treatment include the use of topical creams, ice packing[5] and increasing mobility for reducing pain.
Medical Therapy
Following medications are used in management of gout.
Glucocorticoids
Oral glucocorticoids are always preferred over parental glucocorticoids due to benefit/risk profile. Glucocorticoids are proven to be equally effective as NSAIDs [6] and associated with fewer adverse side effects[7].
Oral glucocorticoids include
- Prednisone - 40mg for 4-5 days and then gradually tapered off over 7-10 days[8].
Intra articular Glucocorticoids: Septic arthritis should be ruled out before initiating intra articluar glucocorticoids.
- Triamcinolone acetate - dosage varies depending on the size of joint. Usually used in monoartiular or oligoarticular(1 or 2-3 joints) involvement.
- 40 - 60 mg(large joints), 30 mg(medium joints), 10 mg(small joints)
Parental glucocorticoids include:
- Intramuscular - Triamcinolone acetate 40 - 60mg[9], Betamethasone 7mg[10]
- Intravenous - Methylprednisolone 30mg
| Patients | Interventions | Results | ||
|---|---|---|---|---|
| Steroid | NSAID | |||
| Janssens et al 2008[11] | 120 total patients with uric acid crystals on arthrocentesis | Prednisolone 35 mg once daily for 5 days | Naproxen 500 mg twice daily for 5 days | NSAID trended better (88% versus 80% response; p=0.3) No differences in rates of drug toxicity. |
| Man et al 2007[6] | 90 total patients with clinical diagnosis of gout† | Initially prednisolone 30 mg Followed by prednisolone 30 mg daily for 5 days and as needed acetaminophen |
Initially diclofenac 75 mg with indomethacin 50 mg Followed by indomethacin 50 mg every 8 hrs for 2 days then 25 mg every 8 hrs for 3 days and as needed acetaminophen. |
Steroids faster reduction in pain. Steroids used more acetaminophen. More adverse effects from indomethacin. Indomethacin trended to more relapses at 2 weeks (11% vs 17%). |
| Notes: † Clinical diagnosis of gout was "pain and warmth in a joint, and presented within 3 days of the onset of pain and also had 1 or more of the following: metatarsal-phalangeal joint involvement; knee or ankle joint involvement and aspirate containing crystals; or typical gouty arthritis, with either gouty tophi present or previous joint aspiration confirming the diagnosis of gout." Seven patients allowed arthrocentesis and all were positive for gout. | ||||
Non-steroidal anti-inflammatory agents
NSAIDs have proven efficacy than placebo according to Randomized controlled trial[12] but proven to be equally efficacious( in particular, indomethacin[11],) compared to Glucocorticoids [6] . Can be given within 48hrs in patients age less than 60 with no Comorbidity and used as an alternative to glucocorticoids. Current FDA approved NSAIDS[13] include:
- Indomethacin - 50 mg PO q8h
- naproxen - 500 mg PO q12h
- Sulindac - 200 mg PO q12hr.
COX-2 selective inhibitors are proven to have similar benefits as NSAIDs with an added advantage of protection from NSAIDs induced Gastritis[14] [15] but yet to be approved by FDA.
Colchicine
Colchicine is better than placebo according to a systematic review by the Cochrane Collaboration[16] that found a single randomized controlled trial of 43 patients[17]. In this study, colchicine 1 mg orally, followed by 0.5 mg every two hours led to a 50% reduction in pain in about 70% of patients compared to about 35% of patients who received placebo. However, all patients had drug toxicity from colchicine and in 90% of the patients toxicity occurred before 50% reduction in pain.
Regarding the best dose, 1.2 mg followed by 0.6 mg in 1 hour may be as effective as higher dose.[18]
To avoid drug toxicity, lower doses of colchicine (0.6 per day) have been used in combination with glucocorticoids.[5] The UK National Library for Health recommends 0.5 mg two to four times a day.[19]
Anti-cytokines
The monoclonal antibody against interleukin-1 beta, canakinumab, may help according to a randomized controlled trial.[20]
Local ice
Ice packs, applied for 30 minutes 4 times per day, can help according to a randomized controlled trial without allocation concealment.[5]
Clinical treatment guidelines for management of Gout is set up by American College of Rheumatology.[21] Goal of Gout therapy is to
- Treat Gout flares.
- Provide maintenance therapy to prevent flares and, dietary and life style modifications.
Management of acute gout attack:
Acute gout attacks are self limited, hence only symptomatic treatment is indicated. Appropriate choice of medications should be made based on the general condition of the patient, assessment of Comorbidities and duration of the symptom onset. Initiation of treatment with exact dosage of Medication within the earliest possible time frame i.e., preferentially within first 12- 24 hours of onset may result in complete resolution of symptoms. It is important to note that there is no isolated best medication for gout and, depending on patients, choice between single and combination therapy may vary.
· Access the intensity of the attack based on severity of pain and the number of joints involved.
· For a mild/moderate gout severity (6 of 10 on a 0 –10 pain visual analog scale) involving 1 or a few small joints or 1 or 2 large joints, initiating monotherapy with options being oral nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, or oral colchicine (evidence A for all drug categories).
o NSAIDs: Approved medications are naproxen, indomethacin (both evidence A), and sulindac (evidence B). They should be initiated at their full dosing at either the Food and Drug Administration (FDA)– or European Medical Agency–approved anti-inflammatory/ analgesic doses. It should not be tapered with symptomatic improvement; instead full dose should be administered till complete resolution.
o Colchicine: Acute gout can be treated with a loading dose of 1.2 mg, followed by 0.6 mg 1 hour later (evidence B). This can then be followed by a gout attack prophylaxis dosing beginning 12 hours or later and continued till the attack resolves (evidence C). If the patient was already on prophylactic colchicine and received acute gout regimen in the last 2 weeks, then consider other therapeutic options i.e. corticosteroid, NSAID.
o Corticosteroids: Corticosteroids can be given as an initial monotherapy. Prednisone, or prednisolone at a starting dosage of at least 0.5 mg/kg per day for 5–10 days and then discontinued (evidence A). Alternatively, a full dose for 2–5 days can be given, followed by tapering for 7–10 days, and then discontinued (evidence C). While oral corticosteroid is the preferred route, intra-articular route can be considered for acute gout of 1 or 2 large joints (evidence B).
· For a severe acute gout attack (7 of 10 on a 0 –10 pain visual analog scale) and in patients with an acute polyarthritis or involvement of more than 1 large joint, combination therapy should be considered. Recommendation is to initiate simultaneous use of full doses (or, where appropriate, a full dose of 1 agent and prophylaxis dosing of the other) of 2 of the pharmacologic modalities as recommended above.
· If the patient was previously on an established pharmacologic uric acid lowering therapy (ULT), it is recommended to be continued without interruption during an acute attack (evidence C), i.e. do not stop ULT therapy during an acute flare.
Prophylaxis to prevent acute gout flares 16339094, 21846852, 20370912, 21353107, 15570646
It is recommended that for all cases of gout, where urate lowering therapy is started, a prophylaxis for acute flares should be started as well, given that gout attacks are common in early ULT (evidence A). 16339094, 21846852, 20370912, 21353107
The first-line for this purpose is oral colchicine (evidence A) 21353107, 15570646, or low-dose NSAIDs (evidence C).
A low-dose of colchicine as 0.5 mg or 0.6 mg taken orally once or twice a day is the recommendation, with dosing further adjusted downward for moderate to severe renal function impairment and potential drug–drug interactions) 21480191.
The duration of treatment should be greater of at least 6 months (evidence A) 16339094 20370912, 21353107, 3 months after achieving target serum urate levels in patient with no tophi on physical exam (evidence B), or 6 months after achieving desired urate levels appropriate for the patient with one of more tophi (evidence C).
Management of chronic gout/chronic tophaceous gouty arthropathy:
Once the diagnosis of gout is established, a systematic pharmacologic as well as non-pharmacologic management approach should be initiated. A set of baseline recommendations for all patients are:
· Patient education on the disease, its treatment options and their objectives, including the particular role of uric acid excess in gout and as the key long-term treatment target (evidence B) 22679303.
· Consider diet and lifestyle modification
· Always consider elimination of serum urate– elevating prescription medications e.g. thiazide and loop diuretics, niacin, and calcineurin inhibitors (evidence C)
· Always consider secondary causes of hyperuricemia for all gout patients
· A clinical evaluation of gout disease activity and its burden should be done for each patient by history and a thorough physical examination for symptoms of arthritis and signs such as tophi and acute and chronic synovitis (evidence C).
Nonpharmacological urate lowering therapy
Certain diet and lifestyle measures are advised for the majority of patients with gout (evidence B and C for individual measures). Many of them are recommended for decreasing the risk and frequency of acute gout attacks (20035225) and also to lower serum urate levels.
This emphasis on diet and lifestyle choices is to promote and maintain ideal health as well as for the prevention and optimal management of comorbidities in gout patients, which include cardiovascular diseases 16871533, 18504339, diabetes mellitus, hyperlipidemia, and hypertension.
Gout patients should limit their consumption of purine-rich meat and seafood (evidence B) (22648933) as well as high fructose corn syrup–sweetened soft drinks and energy drinks (evidence C), and encouraged the consumption of low-fat or nonfat dairy products (evidence B) (21285714).
Alcohol intake is advised to be reduced for all gout patients, especially of beer (evidence B). In CTGA and in patients with inadequate control of disease, abstinence is recommended during periods of active arthritis (evidence C).
Pharmacological urate lowering therapy (ULT) and serum urate target
Pharmacological therapy to lower serum uric acid levels is indicated in any patient with established diagnosis of gout with
· Prior gout attacks (2 or more per year) and current hyperuricemia (evidence A )
· Tophus or tophi by clinical exam or imaging study (evidence A)
· CKD stage 2–5 or end-stage renal disease, which by itself, is an appropriate indication for pharmacologic ULT (evidence C)
· Past urolithiasis (evidence C)
The goal is to attain a serum urate level at a minimum of less than 6 mg/dl (evidence A). Serum urate level should be lowered sufficiently so to have a dependable improve in signs and symptoms of the disease, including palpable and visible tophi detected by physical examination, and that this may involve therapeutic serum urate level lowering to below 5 mg/dl (evidence B).
The recommended first line is xanthine oxidase inhibitor therapy with either allopurinol or febuxostat (evidence A). There is no preference of either XOI over the other XOI drug. ULT can be started during an acute gout attack, provided an effective anti-inflammatory therapy has already been initiated (evidence C)
· Allopurinol should be started with a dose no greater than 100 mg/day (50 mg/day in stage 4 or worse CKD) (evidence B), then gradually titrate maintenance dose upward every 2–5 weeks to appropriate maximum dose in order to achieve desired serum uric acid level (evidence C) Prior to initiation, in selected patient subpopulations at higher risk for severe allopurinol hypersensitivity reaction (e.g., Koreans with stage 3 or worse CKD, and Han Chinese and Thai irrespective of renal function), consider HLA–B*5801 (evidence A)
· Probenecid is the first choice among uricosuric agents (evidence B). It is recommended to monitor urinary uric acid levels during its therapy (evidence C). With a creatinine clearance of 50 ml/minute, it is not recommended as first-line ULT monotherapy (evidence C). History of urolithiasis and elevated uric acid level in urine also contraindicates its use (evidence C). Monitor urinary pH and consider urine alkalinization (e.g., with potassium citrate), in addition to increased fluid intake, as a risk management strategy for urolithiasis (evidence C).
Probenecid was recommended as an alternative first-line option in case of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (evidence B). However, probenecid should not be used as a first-line monotherapy when creatinine clearance is below 50 ml/minute.
It is recommended that regular monitoring of serum urate levels be done every 2–5 weeks during drug titration; including continued measurements every 6 months once the desired level is achieved (evidence C).
Clinical practice guidelines address treatment. However, trials comparing glucocorticoids (steroids) and non-steroidal anti-inflammatory agents (NSAIDs) were not published till after the guidelines.
A nurse-led protocol with treatment goal of 6 mg/dL was beneficial.
Regarding medications, if there are no mitigating factors in choosing a drug, glucocorticoids, non-steroidal anti-inflammatory agents (NSAIDs), and colchicine all work; however, colchicine consistently causes drug toxicity.
A combination treatment is ice four times a day with oral prednisone 30 mg orally tapered over 6 days (30 mg for two days, 20 mg for two days, 10 mg for two days) and colchicine 0.6 mg/day. An advantage of this regimen is the reduced toxicity from the low dose of colchicine and that the colchicine helps prevent flares if allopurinol is later started. Colchicine has been combined with NSAIDs that are not metabolized by the CYP3A4 isoenzyme of cytochrome P-450 (naproxen is not metabolized by CYP3A4). Combining glucocorticoids with NSAIDs increased the risk for gastrointestinal drug toxicity
References
- ↑ van Durme CM, Wechalekar MD, Buchbinder R, Schlesinger N, van der Heijde D, Landewé RB (2014). "Non-steroidal anti-inflammatory drugs for acute gout". Cochrane Database Syst Rev (9): CD010120. doi:10.1002/14651858.CD010120.pub2. PMID 25225849.
- ↑ Wechalekar MD, Vinik O, Schlesinger N, Buchbinder R (2013). "Intra-articular glucocorticoids for acute gout". Cochrane Database Syst Rev (4): CD009920. doi:10.1002/14651858.CD009920.pub2. PMID 23633379.
- ↑ Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH (2018). "Update on colchicine, 2017". Rheumatology (Oxford). 57 (suppl_1): i4–i11. doi:10.1093/rheumatology/kex453. PMC 5850858. PMID 29272515.
- ↑ Engel B, Just J, Bleckwenn M, Weckbecker K (2017). "Treatment Options for Gout". Dtsch Arztebl Int. 114 (13): 215–222. doi:10.3238/arztebl.2017.0215. PMC 5624445. PMID 28434436 PMID: 28434436 Check
|pmid=value (help). - ↑ 5.0 5.1 5.2 Schlesinger N, Detry MA, Holland BK, Baker DG, Beutler AM, Rull M; et al. (2002). "Local ice therapy during bouts of acute gouty arthritis". J Rheumatol. 29 (2): 331–4. PMID 11838852.
- ↑ 6.0 6.1 6.2 Man CY, Cheung IT, Cameron PA, Rainer TH (2007). "Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial". Annals of emergency medicine. 49 (5): 670–7. doi:10.1016/j.annemergmed.2006.11.014. PMID 17276548.
- ↑ Man CY, Cheung IT, Cameron PA, Rainer TH (2007). "Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial". Ann Emerg Med. 49 (5): 670–7. doi:10.1016/j.annemergmed.2006.11.014. PMC 7115288 Check
|pmc=value (help). PMID 17276548. Review in: Evid Based Med. 2007 Dec;12(6):175 - ↑ Prasad S, Ewigman B (2008). "Acute gout: oral steroids work as well as NSAIDs". J Fam Pract. 57 (10): 655–7. PMC 3183840. PMID 18842190.
- ↑ Alloway JA, Moriarty MJ, Hoogland YT, Nashel DJ (1993). "Comparison of triamcinolone acetonide with indomethacin in the treatment of acute gouty arthritis". J Rheumatol. 20 (1): 111–3. PMID 8441139.
- ↑ Zhang YK, Yang H, Zhang JY, Song LJ, Fan YC (2014). "Comparison of intramuscular compound betamethasone and oral diclofenac sodium in the treatment of acute attacks of gout". Int J Clin Pract. 68 (5): 633–8. doi:10.1111/ijcp.12359. PMID 24472084.
- ↑ 11.0 11.1 Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C (2008). "Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial". Lancet. 371 (9627): 1854–60. doi:10.1016/S0140-6736(08)60799-0. PMID 18514729. Review in: J Fam Pract. 2008 Sep;57(9):576 Review in: J Fam Pract. 2008 Oct;57(10):655-7
- ↑ García de la Torre, Ignacio. (1987) Estudio doble-ciego paralelo, comparativo con tenoxicam vs placebo en artritis gotosa aguda (A comparative, double-blind, parallel study with tenoxicam vs placebo in acute gouty arthritis). Invet Med Int '14:'92–7 [Abstract in Spanish]
- ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID https://doi.org/10.1007/s40674-015-0013-8 Check
|pmid=value (help). - ↑ Schumacher HR, Boice JA, Daikh DI, Mukhopadhyay S, Malmstrom K, Ng J; et al. (2002). "Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis". BMJ. 324 (7352): 1488–92. doi:10.1136/bmj.324.7352.1488. PMC 116444. PMID 12077033.
- ↑ Fam AG (2002). "Treating acute gouty arthritis with selective COX 2 inhibitors". BMJ. 325 (7371): 980–1. doi:10.1136/bmj.325.7371.980. PMC 1124536. PMID 12411331.
- ↑ Schlesinger N, Schumacher R, Catton M, Maxwell L (2006). "Colchicine for acute gout". Cochrane Database Syst Rev (4): CD006190. doi:10.1002/14651858.CD006190. PMID 17054279.
- ↑ Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M (1987). "Does colchicine work? The results of the first controlled study in acute gout". Aust N Z J Med. 17 (3): 301–4. doi:10.1111/j.1445-5994.1987.tb01232.x. PMID 3314832. Unknown parameter
|month=ignored (help) Summary at Bandolier - ↑ Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (2010). "High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study". Arthritis Rheum. 62 (4): 1060–8. doi:10.1002/art.27327. PMID 20131255.
- ↑ CKS (2007) Gout - Management (Topic Review). Clinical Knowledge Summaries. http://cks.library.nhs.uk/gout/management [Accessed: Date]
- ↑ So A, De Meulemeester M, Pikhlak A, Yücel AE, Richard D, Murphy V; et al. (2010). "Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study". Arthritis Rheum. 62 (10): 3064–76. doi:10.1002/art.27600. PMID 20533546.
- ↑ FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM; et al. (2020). "2020 American College of Rheumatology Guideline for the Management of Gout". Arthritis Care Res (Hoboken). 72 (6): 744–760. doi:10.1002/acr.24180. PMID 32391934 Check
|pmid=value (help).