# Presentation: 632400

## Management of Acute Gout

**John J. Cush, MD**
**Presbyterian Hospital of Dallas**

## Who Manages Acute Gout

- Rheumatologists:musculoskeletal medicine specialists
- Tends to see minority of Gout patients, often those with severe, recalcitrant, chronic disease
- Compared with RA (similar prevalence), far fewer gout patients are seen/followed by rheumatologists
- Rheum referral more accurate dx, shorter Sx duration (3.1day), shorter hospitalization (7.4 days), lower hospitalization costs ($5995 less). Solomon DH. Ann Int Med 12:52, 1997
- Primary Care and Emergency Dept Physicians
- First line for acute gouty attacks
- Education is needed to optimize outcomes and limit toxicity
- Survey in Mexico shows significant drug misuse by non-rheumatologists (GP,IntMed,Ortho) Rev Invest Clin 55:621,2003
- Survey of N.Zealand Rheums and GPs: differences in NSAID, colchicine, allopurinol use. Stuart RD N Z Med J 104:115,1991

## Gout

- Disorder of urate metabolism, results in deposition of monosodium urate (MSU) crystals in joints and soft tissues.
- 1st described 5th century BC – Hippocrates described gout as “the king of diseases and the disease of kings”
- Burden: In 1981, 37 million lost work days in US*
- 2003 Kim et al estimates the annaul cost of Acute Gout is $27,378,494 in the USA (underestimate: women excluded & not all indirect and intangible costs included)

- * Roubenoff et al

## NHANES III 1988-94

- National Health Intv Survey (&PE) = 17,030 men/women

- (2.7%)

- (5.6%)

**NHANES III 1988-94**

## Prevalence of Gout

| Age (years) | Men 3.4 Million Population % | Women 1.7 Mill Population % |
| --- | --- | --- |
| 20-29 | 0.2 | 0.6 |
| 30-39 | 2.1 | 0.1 |
| 40-49 | 2.2 | 0.6 |
| 50-59 | 5.7 | 2.3 |
| 60-69 | 9.1 | 3.5 |
| 70-79 | 10.8 | 4.7 |
| >80  | 8.6 | 5.6 |

- NHANES III 1988-94

## Slide 6

## Gout

- Acute: intermittent/recurrent, LE, ascending, inflammatory mono/oligoarthritis, “Podagra”
- Intercritical gout: between attacks
- Tophaceous gout: chronic, accumulation of MSU crystals as “tophi” (may look like RA)
- Asymptomatic hyperuricema: elevated uric acid without evidence of gout, nephrolithiasis. Higher levels increase risk of these diseases
- Renal: nephrolithiasis, gouty nephropathy, uric acid nephropathy

## Slide 8

## Acute (Classic) Gout

- Acute, severe onset of pain, warmth, inflammation, Limited motion  cant walk, cant put sheet on it.
- Podagra (50-90%): pain, swelling warmth in 1st MTP
- Joints: MTP, tarsus, ankle, knee
- Associated with fever, leukocytosis, high ESR or C-reactive protein levels.
- Initially monarthritis (80-90%) and with repeated attacks ascends from the lower extremity (initial polyarthritis in elderly, women, myeloproliferative disorders, CyA)
- Precipitants: stress, trauma, excess alcohol, infection, surgery, drugs
- Chronology: untreated attacks last 7-14 days. Acute gout risk of repeat attack estimated to be 78% w/in 2 yrs

## Natural Hx of Acute AttackBellamy N, et al. Br J Clin Pharmacol 24:33-6, 1987

- 11 volunteers with acute podagra studied
- 2 withdrew on day 4 for severe pain
- 9 remaining showed improvement
- Pain by day 5
- Swelling by day 7
- Tenderness improved in 7/9 by day 7 (2 persisted)
- But only 3 noted resolution of pain during 7d study
- Implications for clinical trial endpoints?
- Pain improvement/resolution by day 3-5
- Resolution of symptoms, return to normal activity

## Acute Gout

- Laboratory Findings
- 40-49% will have normal uric acid levels
- Leukocytosis common
- ESR and CRP elevated
- No indices of chronic inflammatory disease (alb, Hgb)
- Measureable elevations in IL-6 and IL-1
- Radiographic findings
- Soft tissue swelling (Opacities = tophi)
- Normal Joint space and Normal ossification
- Erosions: nonarticular, punched out, Sclerotic margins, overhanging edge

## Slide 12

## Gouty Tophi

- Incidence has decreased over last few decades
- Seen in 25-50% of untreated patients (after 10-20yrs)
- Location: Olecranon, bursae, digits, helix of ear
- Damages bone, periarticular structures and soft tissues
- Palpable measure of total body urate load
- Other Extraarticular Complications
- Renal
- Uric acid calculi (seen in10-15% of gout pts)
- Chronic urate nephropathy (in those with tophi)
- Acute uric acid nephropathy (in pts undergoing chemotherapy)
- Hypertensive Renal disease is the most common cause of renal disease in gout

## Uric Acid

- Random hyperuricemia ≠ gout (likely CRI, diuretic use)
- Acute attack: Urate levels may be normal, low or high
- 40-49% of acute gouty attacks normouricemic
- Mechanism: increased excretion of uric acid
- Probably mediated by IL-6, inflammation
- Urano W, et al. J Rheumatol 29:1950-3, 2002
- Schlesinger N, et al. J Rheumatol 24: 2265-6, 1997
- Negative association between Gout – RA
- Few reports of both coexisting in literature
- RF preferentially binds MSU coated with IgG and inhibited neutrophil chemiluminescence (RF may block interaction of crystal bound IgG and Fc recpt)

## Diagnosis of Gout

- 1977 ARA criteria: Urate crystals*: IA or Tophus
- Any 6 of following: > 1 attack acute arthritis; Max. inflammation w/in 1day; Erythema over joint; Podagra; hx podagra; Unilateral tarsal involvement; Tophus; Hyperuricemia; Asymmetric swelling on xray; subcortical cyst w/o erosion; c/s neg. inflam arthritis
- Practical Approach: Acute or recurrent inflammatory monarthritis/oligoarthritis
- With evidence of MSU crystal identification **OR**
- One of the following:
- History of recurrent, intermittent similar attacks
- Evidence of hyperuricemia
- Xray evidence of antecedent gouty damage

- * Wallace et al 1977 (sensitivity 84.4%, specificity 100%)

## Slide 16

## Slide 17

## Overview: Gout Management

_**Acute Rx**_: NSAIDs > steroids > colchicine (oral only)
- Steroids: PO, IM, intraarticular
_**Chronic Rx**_: colchicine, probenecid, allopurinol
- > 2-3 attacks/year  initiate prophyllaxis (cost effective)
- Probenecid: uricosuric, promotes excretion
- Don’t use w/ CRI, nephrolithiasis, Tophaceous gout
- Colchicine: (diarrhea) decr. PMN motility, activity
- Allopurinol: decrease formation- use w/ CRF,  renal stones, Tophaceous gout, Uric acid > 11

- *

- * Adjust dose for renal insufficiency

## Limitations of Current Gout Drugs

- NSAIDs
- Colchicine
- Allopurinol
- Sulfinpyrazone

- ?Elderly
- ?Renal insufficiency
- ?Peptic Ulcer disease
- ?Hepatic dysfunction

- Need for
- Safer
- Agents

## Acute Gout Management

- Confirm Diagnosis
- Prevention: diet, weight reduction, avoid alcohol diuretic
- FDA approved therapies: indomethacin, naproxen, sulindac, colchicine, allopurinol, sulfinpyrazone
- Unapproved for Acute Gout:
- Variety of NSAIDs
- Corticotrophin, corticosteroids: for monarticular attacks (IA), polyarticular attacks (IM, PO), when NSAID contraindicated. ACTH has been used since 1949 and may be superior to indomethacin in some trials.
- AVOID Uricosuric drugs: Probenecid, Sulfinpyrazone
- (PotentiaL adjunctive agents: losartan (24%↑), fenofibrate
- Fenofibrate lowers Urate 19%, increases excretion 36%

## Regional Differences
NSAIDs Preferred: USA, Canada, N. Zealand, Australia
Colchicine Preferred: France, EU (diagnostic?)
Colchicine + NSAID in 32%
Minority use uricosurics (or test 24hr urine urate)
Duration of Therapy: 7-30 days
No formal guidelines advocated or studied

- NSAIDs Preferred: USA, Canada, N. Zealand, Australia
- Colchicine Preferred: France, EU (diagnostic?)
- Colchicine + NSAID in 32%
- Minority use uricosurics (or test 24hr urine urate)
- Duration of Therapy: 7-30 days
- No formal guidelines advocated or studied

- Acute Gout Management

## Acute Gout Management

| Drug | Dose | Common AE | SAE |
| --- | --- | --- | --- |
| NSAIDs | Indocin* 150 mg/d taper 5-7d | GI toxicity, CNS, HTN, LFTs | PUD, renal dz, bleeding, allerrxn |
| COX-2 inhibitors | Per PDR qd or bid | ?less GI toxicity?
RenalHTN,edem | PUD, renal, MI, CVA |
| Colchicine | 1.2 mg po then 0.6 q1-2h (not to exceed 8mg) | Diarrhea, N/V, abdominal pains | Neuromyopathy, ARF, BM suppression |
| Cortico-steroids | IA Methylpred 10-40 mg.
PO:30-60 qd | HTN, BS, fluid retention, insomnia | Risk of infection osteoporosis |
| ACTH | 40-80 IU IM q 6-12h | HTN, BS, fluid retention, insomn | Risk of infection osteoporosis |

- * or equivalent antiinflammatory dose

## Treatment Acute Gout

- _NSAIDs Contraindicated?_
-  Renal insufficiency
-  Peptic ulcer disease
-  Congestive heart failure
-  NSAID intolerance

- Are Corticosteroids
- Contraindicated?

- NSAIDs
- Antiinflamatory
- doses

- Corticosteroids

- Oral Colchicine

- Oral or
- Intraarticular
- Steroid

- Lipsky PE, Alarcon GS, Bombardier C, Cush JJ, Ellrodt AG, Gibofsky A, Heudebert G, Kavanaugh AF, et al. Am J Med 103(6A):49S-85S, 1997

- Intraarticular
- PO Steroid

## Colchicine

- Alkaloid of the *Colchicum *species
- Antiinflammatory effects mediated by ability to inhibit microtubule and PMN activity
- PK: mean terminal 1⁄2 life: 9hrs (IV 19 min – 16 hours). Tightly binds microtubules (PMNs). Concentrates liver, spleen & intestine.
- Excreted in urine and bile.  Undergoes enterohepatic recirculation
- Undergoes demethylation by CYP 3A4 (interacts with cimetadine, terfenidine, EES, ketoconazole, diltiazem, nifedipine, cyclosporine, statins
- May cross placent.  + found in breast milk
- Off label indications: gout, pseudogout, amyloidosis, familial mediterranean fever, hepatic cirrhosis, dermatitis herpetiformis, Behcets, Sweets syndrome
- Biologic effects: Binds tubules, inhibits cell migration, adherence, degranulation.  Inhibits IL-8, ICAM, E-selectin, L-Selectin., IL-1. Also decreases insulin, thyroid, TSH, amylase, catecholamine synthesis, lysosomal hydrolase release, fibroblast proliferation

## Colchicine Advantages

- Long history of use (acute and chronic Rxs)
- Diagnositic specificity (96%); Sensitivity (70%)
- Faster onset 6-12 hours (IV)
- Corticosteroids 12-24 hrs; NSAIDs: 24-48 hours
- Tx surgical (NPO) patients, NSAID intolerant/contraindic.
- Cost !
- Yu T. 20 yrs retrospective study 540 pts (518M)
- Results: Excellent 82%, Satisfactory 12%, Poor 5%
- Few were intolerant
- No cases of renal or hematologic toxicty w/ chronic use
- Semin Arthritis Rheum 12:256-64, 1982

## Clinical Trials in Gout

- 1939 Lockie: colchicine in gout (75) vs other(50)
- ALL gout responded (none of the other)
- Criteria for response not noted
- 1967 Wallace 120 pts w/ arthritis
- 58 acute gout (urate + recurrent arthritis) 15 tophi
- Colchicine orally (61 pts) or IV (59 pts)
- Criteria: Major resolution joint inflamm w/in 48 hrs and no worsening in 7 days
- Responders: Gout 76% vs Other 2/62 (3.2%)

## Colchicine Dosing

- PO: 1.2 mg initially then 0.6 mg q 1-2 hours till GI Sx and/or better (max 6 mg)
- Ahern et al. Placebo controlled trial shows colchicine 64% respond within 48 hrs (23% placebo same). Significant differences 18-36 hrs. Colchicine diarrhea developed @ median 24 hours (mean 6.7 mg)
- GI toxicity in 80% of pts w/in 48 hrs. Toxicity before improvement.
- Acute use reserved for when NSAIDs/Steroids contraindicated
- Wortman RL 2004 Prefers Colchicine when dx Gout  not established
- When to use IV Colchicine?  If rapid response, oral use precluded, NSAIDs or steroids contraindicated
- Problem is that there is no warning GI symptoms (as with PO).
- Toxicity depends on total dose over time, size of single dose
- Rec: 1) 2 mg initially, followed by 1 mg IV q 6 (max 4-5 mg); 2) 2 mg as single IV dose; or 3) 3 mg IV as single IV dose
- Death: 2% reported by Roberts et al.
- 20 deaths by Bonnel et al from ODS/FDA

## Carr AA. Colchicine toxicity.  Arch Int Med 115:29, 1965
Ellwood MG, Self poisoning with colchicine. Postgrad Med 47:129, 1971
Baum J, Colchicine use as a suicidal drug by females. J Rheumatol 7:124, 1980
Ferranini E, Marrow aplasia following colchicine in gout. Clin Exp Rheum 2:173,1984
Pasero G. Colchicine: should we still use it? Clin Exp Rheumatol 2:103-4, 1984
Roberts WN. Colchcine in acute gout: reasses risk/benefits. JAMA 257:1920-2, 1987
Wallace SL. Systemic toxicity assoc with the IV colchicine. J Rheum 15:495, 1988
Hoffman RS. Outpatient colchicine poisoning. Del Med J. 65: 257-60, 1993
Lee BI. Colchicine myopathy with cyclosporine.  J Korean Med Sci 12:160, 1997
Dawson TM. Colchicine induced rhabdomyolysis. J Rheumatol 24:2045, 1997
Maldonado MA, IV colchicine:retro analysis hosp patient. Clin Exp Rheum 15:487, 1997
Mullins ME. Fatal CVS collapse after acute colchicine. J Toxicol Clin Tox 38:51, 2000
Goldbart A. Fatal colchicine intox in a child.  Eur J Pediatr 159:895, 2000
Mullins ME. Troponin I cardiac toxicity w/ colchicine. Am J Emerg Med 18:743, 2000
Sanchez Munoz LA, Acute colchicine poisoning.  An Med Intern 17:109, 2000
Dogukan A. Fatal colchicine intoxication w/ CAPD. Clin Nephrol 55:181, 2001
Dixon AJ. Colchicine neutropenia, not overdose. Ann Pharmacother 35:192, 2001
Bonnel RA. Deaths assoc w/ IV colchicine. J Emerg Med 22:385-7, 2002
Jones GR. LC-MS analysis of colchicine fatality. J Anal Toxicol 26:365-9, 2002
Maxwell MJ, Accidental colchicine overdose. Emerg Med J 19:265-7, 2002
Debie K, Colchcine induced rhatbomyolysis in CHF.  Acta Cardiol  58: 561, 2003
Phanish MK, Colchicine induced rhabdomyolysis. Am J Med 114 (2) 2/1/03
Asuvdevan AR, Colchicine induced rhabdomyolysis.  Am J Med 115 (3) 8/15/03

- Ellwood MG, Self poisoning with colchicine. Postgrad Med 47:129, 1971
- Baum J, Colchicine use as a suicidal drug by females. J Rheumatol 7:124, 1980
- Ferranini E, Marrow aplasia following colchicine in gout. Clin Exp Rheum 2:173,1984
- Pasero G. Colchicine: should we still use it? Clin Exp Rheumatol 2:103-4, 1984
- Roberts WN. Colchcine in acute gout: reasses risk/benefits. JAMA 257:1920-2, 1987
- Wallace SL. Systemic toxicity assoc with the IV colchicine. J Rheum 15:495, 1988
- Hoffman RS. Outpatient colchicine poisoning. Del Med J. 65: 257-60, 1993
- Lee BI. Colchicine myopathy with cyclosporine.  J Korean Med Sci 12:160, 1997
- Dawson TM. Colchicine induced rhabdomyolysis. J Rheumatol 24:2045, 1997
- Maldonado MA, IV colchicine:retro analysis hosp patient. Clin Exp Rheum 15:487, 1997
- Mullins ME. Fatal CVS collapse after acute colchicine. J Toxicol Clin Tox 38:51, 2000
- Goldbart A. Fatal colchicine intox in a child.  Eur J Pediatr 159:895, 2000
- Mullins ME. Troponin I cardiac toxicity w/ colchicine. Am J Emerg Med 18:743, 2000
- Sanchez Munoz LA, Acute colchicine poisoning.  An Med Intern 17:109, 2000
- Dogukan A. Fatal colchicine intoxication w/ CAPD. Clin Nephrol 55:181, 2001
- Dixon AJ. Colchicine neutropenia, not overdose. Ann Pharmacother 35:192, 2001
- Bonnel RA. Deaths assoc w/ IV colchicine. J Emerg Med 22:385-7, 2002
- Jones GR. LC-MS analysis of colchicine fatality. J Anal Toxicol 26:365-9, 2002
- Maxwell MJ, Accidental colchicine overdose. Emerg Med J 19:265-7, 2002
- Debie K, Colchcine induced rhatbomyolysis in CHF.  Acta Cardiol  58: 561, 2003
- Phanish MK, Colchicine induced rhabdomyolysis. Am J Med 114 (2) 2/1/03
- Asuvdevan AR, Colchicine induced rhabdomyolysis.  Am J Med 115 (3) 8/15/03

**Colchicine Serious Toxicity, Suidice, & Death**

## Deaths associated with IV Colchicine

- Since 1990, AERS reports 90 deaths associated with IV colchicine use (429 allopurinol)
- Bonnel RA, et al. J Emerg Med 22:385-7, 2002
- 20 deaths 1983-2000 (13 AERS, 7 literature)
- 8F:11M; 17 gout pts (ages 50-91 yrs), 2 FMF(21,31)
- All exceed rec. dose (2-4 mg). Range 5.5-19 mg
- Adverse effects: thrombocytopenia (8), leukopenia (8), pancytopenia (3), agranulocytosis (2), aplastic anemia (2), acute renal failure (6), and DIC (4)
- Death within 1-40 days; 80% showed BM depression
- 13 risk factors: age > 65 yrs, preexisting medical cond, concomitant NSAIDs, recent oral colchicine use
- Warnings, precautions, contraindications, dosing NOT followed or were misinterpreted

## IV Colichicine Toxicity

- Acute Toxicity
- Local irritation  skin necrosis with extravasation
- Tightness in the chest, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhea,arthralgia, myalgia, myopathy, cyanosis, severe shock, hematuria, oliguria, ascending paralysis, delerium
- Labs: thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and DIC (4)
- Fatalities with as little as 1 mg IV
- Rhabdomyolysis: ESRD, 2 mos, other drugs
- @ risk: Elderly, renal failure, those taking colchicine po  & IV, Cyclosporine, grapefruit juice, statins

## Colchicine Intoxication

| Stage 1 (<24h) | Stage II (24-72h) | Recovery |
| --- | --- | --- |
| Abdominal pain
Nausea
Vomitiing
Diarrhea
Dehydration
Skin Irritation | Renal Failure
Respiratory failure
Cardiac failure
Pancytopenia
Aplastic anemia
Metabolic acidosis
Electrolyte disturb.
Rhabdomyolysis
DIC
Convulsions
Coma | Leukocytosis
Alopecia |

- *Ben-Chetrit E, Levy M. Sem AR 28:48,1998

## Colchicine:Guidelines for Use

- IV colchicine should be severely restricted if not banned
- Removed from licenced clinical use in Great Britain
- Removed from hospital formulary in many Hospitals
- Single IV dose < 2-3 mg and cumulative doses < 4-5 mg/7days
- Give via established intravenous catheter
- Following IV use, no PO colchicine for at least 7days
- Give REDUCED (<50%) doses in CRI, liver disease, elderly, prior PO colchicine therapy
- Lower Doses in elderly (2gm max) and pts w/ renal failure
- Contraindicated: pregnancy, combined renal and hepatic disease, Creat Clearance <10cc/min, extrahepatic biliary obstruction

## Treatment of IV Colchicine Toxicity

- Avoidance/prevention through intelligent use
- Drug cessation
- Not dialyzable (has occurred in pts on dialysis)
- Cytopenias Rx: with growth factors
- Rhabdomyolysis: fluids, alkalinzation of urine
- Experimental : Fab’ anti-colchicine Abs

## Slide 34

## Corticosteroids in Acute Gout

- Benefits: equal to NSAIDs, less toxic acutely, benefits of local use and aspiration (nonstandard dosing, forms, routes – po, IM, SC, IV)
- Often given w/ CHF, CRI, hx of GI bleed or Monarticular Gout
- Toxicity: hyperglycemia, hypokalemia, fluid retention, rebound flare
- Prednisone: 30-50 mg 3-7d then tapered over 10-14 days (rebound?)
- ACTH IM 40-80 U; Triamcinolone acetonide 60 mg;betamethasone 7

| Trial | Yr | N | Design | Control | Active | Outcome |
| --- | --- | --- | --- | --- | --- | --- |
| Axelrd | 1988 | 100 | OLRT | Ind200 | ACTH40 | ACTH fast onset, Ind more toxicity |
| Ritter | 1994 | 33 | Retro | - | ACTH 40-80U | 97% by 5.5 days |
| Siegel | 1994 | 31 | OLRT | ACTH40 | TCA60 | All resp by day 8. TCA few rebound |
| Werlen | 1996 | 27 | RCT | Diclofen | Betameth Methylpre | Steroids>Diclofen |

## NSAIDs in Acute Gout

- FDA approval:indomethacin, naproxen, sulindac
- Tested: etodolac, flurbiprofen, meclofenamic acid, indoprofen, carprofen, phenylbutazone, piroxicam, isoxicam, fentiazac, ketorolac, etoricoxib
- Benefits
- Faster onset of relief (compared with colchcine)
- Within 2-4 hours for indomethacin
- Less toxic (when prescribed appropriately); better tolerated
- Widespread use and familiarity
- Cost

## Etoricoxib vs Indomethacin in Acute Gout Dailch D, et al. Am Pain Society 2004

- Combined analyses of 2 prior studies
- N = 339  (Etor 178  vs Ind 161 for 6 weeks)
- 1o Outcome: Joint pain on days 2-5 (VAS)
- 2o Outcome: Pt/MD global response, Tender Jt
- 					     Etoricoxib		Indocin
- Moderate Pain reduced		1.14		0.99
- Severe Pain reduced		2.0		2.06
- AE:  dizziness			2.8%		14.3%
- 		HTN				5.6%		8.7%
- 		Diarrhea			2.8%		4.3%
- 		Headache			1.1%		6.2%

## Analgesics in Acute Gout

- Conventional thought: control inflammation yields control of pain
- Pain is the Dominant Symptom in Acute gout
- Trials
- Topical Ice: Schlesinger 2002
- RCT 19 pts: all recv colchcine + pred, 1⁄2 recv Ice packs.  Local ice associated with less pain, swelling
- Ketorolac
- Shresta Am J Emerg Med 12:454, 1994
- OL 9pts: Pain VAS improved >80% by 90 minutes
- Shresta Ann Emerg Med 26:682, 1995
- DBRCT 20pts: Pain improved 59-68% in 2hrs. “Some rebound in ketorolac group by 6 hours”

## Acute Gout: Open-Label Clinical Trials

| Trial | Yr | N | Design | Control | Active | Primary | Days |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Lockie | 1939 | 75 | OL | - | Colchicine | ??? |  |
| Wallace | 1967 | 58 | OL |  | Colchicine | Joint Exam | 2-7 |
| Karachalios | 1982 | 26 | Open label | - | Sulindac | Joints | 2-4 |
| Karachalios | 1985 | 28 | Open label | - | Piroxicam | Pain, Joints | 5 |
| Molina | 1985 | 27 | OL | - | Fentiazac | Pain, Global | 3 |
| Thomas | 1983 | 8 | OL | - | Azapropazone | Pain, Urate | 2-21 |
| Cobra | 1983 | 40 | OL | -  | Piroxicam | Pain, inflam, LOM | 1-6 |
| Shresta | 1994 | 9 | OL | - | Ketorolac | Pain VAS | 1 |

**Acute Gout: Open-Label Clinical Trials**

## Slide 40

| Trial | Yr | N | Design | Control | Active | Primary | Day |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Ahern | 1987 | 43 | DBRPCT | Placebo | Colchicine | 50%↓ Pain
Clinical score | 2d |
| Eberl | 1983 | 20 | DBCT | IND | Meclomen | Pain, Jt exam | 1- |
| Butler | 1985 | 33 | DBCT | Butazol | Flurbiprof | ?? | 2 |
| Lomen | 1986 | 29 | RCT | IND | Flurbiprof | Global Resp | 2,3,5 |
| Altman | 1988 | 59 | DBRCT | IND | Ketoprof | Pain, D/C, glob | 1-5 |
| Werlen | 1996 | 27 | RCT | Diclofen | Betameth Methylpre | Pt Global Resp Joint swelling | 1,3,6 |
| Schlesinger | 2002 | 19 | RCT | Pred, Colch | Ice+ Pred, Colch | Pain VAS, Jt exam, SF volm |  |
| Schumac | 2002 | 150 | DBRCT | IND | Etoricoxib | Pain 0-4, Jts | 2,5,8 |
| Cheng | 2004 | 62 | SBRCT | Diclofen
Meclom | Rofecoxib | Pt/MD Glob Response | 3-8 |
| Maccag | 1991 | 61 | DBRCT | Naprox | Etodolac | Pain, Jts, Glob | 2,4,7 |
| Shresta | 1995 | 20 | DBRCT | IND | Ketorolac | Pain 0-5 | 1,2,6h |

## Trial Issues: Acute Gout

- Diagnosis: by crystal Identification, ARA criteria, other
- Disease duration? ; > 1 yr.
- Duration of attack?  18 hours, 5-7 days
- Con Meds
- NSAIDs, Pain meds – discontinued/held
- Steroids: disallowed
- Allopurinol: +/- continuation
- Time of assessments
- Q 30”, Q 6h x 48 hrs, Days 1,2, 3,4,6,7, longer?
- Primary Outcomes: pain VAS, Joint scores, Global Responses
- Seconday: Global responses, serum urate, CRP/ESR, toxicity, time to resolution, need for rescue therapy
- Rescue? Acetaminophen, narcotics, steroids

## Suggested Trial Design

- ICH guidelines appropriate (300-600 for 6mo;>100 1 yr)
- Randomized, active control (IND, colchicine)
- DX: Gout by ARA criteria  or  + crystal identification?
- Acute Gout attack _<_ 3 days
- Trial Length: _<_ 2 weeks
- Visit Frequency: according to desired/expected onset of effect and/or complete resolution. (eg, 0, 1d, 3d, 7d, 14d)
- Longer: to assess rebound, toxicity, QOL, return to work
- Inclusion: 18, Dx Gout, Acute attack, Mono-, Oligoarthritis, Activity (3/4 Cardinal signs inflammation)
- Exclusion
- Polyarthritis, Alcohol excess, CRI, ASA(81,325), CyA, RA, Transplant, active infection, Dietary restriction,uncontrolled HTN
- ?? Diuretics, obesity, DM, CHF, tophi, Kidney stones, narcotics, anticoagulants, NSAID, allopurinol, probenecid, sulfinpyrazone, Hospitalized/Immobilized, Unwilling, Involved in litigation

## Primary Outcomes: Patient derived
Pain (Pt self-reported >> MD Tender Joint score)
Eg, use of real time PDA-assisted data capture
Secondary Outcomes: Pt & MD derived
Global assess. (0-4, mild, mod, severe, extreme)
Global response to drug
Complete resolution of symptoms
Time to symptom resolution
Index Joint Score (tender, swollen, erythema, warmth)
Swollen joint score, Tender Joint scores
Need for rescue analgesics
ESR/CRP, Uric acid
Functional measures (ie, 50 ft. walk time)
Safety/Toxicity w/ comparator

- Pain (Pt self-reported >> MD Tender Joint score)
- Eg, use of real time PDA-assisted data capture
- Secondary Outcomes: Pt & MD derived
- Global assess. (0-4, mild, mod, severe, extreme)
- Global response to drug
- Complete resolution of symptoms
- Time to symptom resolution
- Index Joint Score (tender, swollen, erythema, warmth)
- Swollen joint score, Tender Joint scores
- Need for rescue analgesics
- ESR/CRP, Uric acid
- Functional measures (ie, 50 ft. walk time)
- Safety/Toxicity w/ comparator

- Suggested Trial Design

## Gout Quotes

- “King of diseases and the disease of kings”
- Hippocrates 450 BC
- “Love and gout are incurable”  1623 Meridia
- “A disease of ancient and distinguished lineage”
- G Rodnan 1980
- “The best medicine for rheumatism is to thank the lord it aint gout”  Josh Billings~1850
- “Among all the diseases that infest our human bodies, there is not one known hitherto, that more deservedl is called opprobrium Medicorum, the Reproach of Physicians, than the Gout”  - John Marten, 1713

## REFERENCES
Arromdee E, et al. J Rheumatol 29:2403-6, 2002
Kim KY, et al.  Clin Therapeutics 25:1593, 2003
Ahern MJ, et al.  Aust NZ J Med 17: 301, 1987
Roubenoff R, et al. JAMA 266:2004-7, 1991
Wallace SL, et al. ARACriteria. Arth Rheum 20:895, 1977 
Roberts WN, et al. JAMA 257:1920-2, 1987
Wallace SL, et al. J Rheum 15:495, 1988
Bonnel RA, et al. J Emerg Med 22:385-7, 2002
Emmerson BT. N Engl J Med  334:445, 1996
Wortmann RL.  Curr Rheumatol Rep 6:235-9, 2004
Schumacher HR, et al. BMJ 324:1488, 2002
Lally EV, et al. Gout/women.Arch Int Med 146:2221,1986
Rott KT, Agudelo CA. JAMA 289:2857, 2003
Terkeltabu RA. Gout. N Engl J Med 349:1647, 2003

- Arromdee E, et al. J Rheumatol 29:2403-6, 2002
- Kim KY, et al.  Clin Therapeutics 25:1593, 2003
- Ahern MJ, et al.  Aust NZ J Med 17: 301, 1987
- Roubenoff R, et al. JAMA 266:2004-7, 1991
- Wallace SL, et al. ARACriteria. Arth Rheum 20:895, 1977
- Roberts WN, et al. JAMA 257:1920-2, 1987
- Wallace SL, et al. J Rheum 15:495, 1988
- Bonnel RA, et al. J Emerg Med 22:385-7, 2002
- Emmerson BT. N Engl J Med  334:445, 1996
- Wortmann RL.  Curr Rheumatol Rep 6:235-9, 2004
- Schumacher HR, et al. BMJ 324:1488, 2002
- Lally EV, et al. Gout/women.Arch Int Med 146:2221,1986
- Rott KT, Agudelo CA. JAMA 289:2857, 2003
- Terkeltabu RA. Gout. N Engl J Med 349:1647, 2003