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Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials

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Abstract

Evidence supports early use of non-biologic DMARDs to prevent irreversible damage in inflammatory arthritides, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and possibly ankylosing spondylitis (AS). However, there is a paucity of data exploring their effects on pain as a primary outcome in these conditions. This systematic literature review investigated the effect of non-biologic DMARDs on pain levels in IA and examined whether disease duration impacted efficacy. We searched Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews, abstracts from the 2008 to 2010 American College of Rheumatology annual congresses, and citation lists of retrieved publications. Only randomized, double-blind controlled trials were analyzed. Quality was assessed with the Risk of Bias tool. Descriptive statistics were used in meta-analysis. 9,860 articles were identified, with 33 eligible for inclusion: 8 in AS, 6 in PsA, 9 in early RA (ERA), and 10 in established RA. In ERA and established RA, all studies of DMARDs (monotherapy and combination therapies) consistently revealed statistically significant reductions in pain except three oral gold studies. In AS, sulfasalazine studies showed significant pain reduction, whereas use of other DMARDs did not. In PsA, 5 of 6 studies reported VAS-pain improvement. From the studies included, we were unable to assess the influence of disease duration on pain outcomes in these rheumatic conditions. DMARDs improve pain in early and established RA. Sulfasalazine may improve pain in AS and PsA. Further study is needed to assess the relationship between disease duration and DMARD efficacy in reducing pain in these conditions.

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Acknowledgments

Funded by 3e Initiative in Rheumatology (evidence, expertise, exchange) and from an unrestricted grant from Abbott Canada whereby no biologics were studied to avoid any perceived sponsor bias.

Conflict of interest

None of the authors declares a conflict of interest.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Toronto Western Hospital, University of Toronto, University Health Network, 399 Bathurst Street, Room 1E-420, Toronto, ON, M5T 2S8, Canada

    Amanda J. Steiman

  2. Division of Rheumatology, St. Joseph’s Hospital, Western University, 268 Grosvenor Street, London, ON, N6A 4V2, Canada

    Janet E. Pope

  3. London Kidney Clinical Research Unit, Division of Nephrology, Western University, London Health Sciences Centre, Room ELL-101, Westminster Tower, 800 Commissioners Road East, London, ON, N6A 4G5, Canada

    Heather Thiessen-Philbrook

  4. London Kidney Clinical Research Unit, Division of Nephrology, Western University, London Health Sciences Centre, Room ELL-112, Westminster Tower, 800 Commissioners Road East, London, ON, N6A 4G5, Canada

    Lihua Li

  5. Division of Rheumatology, University of Calgary, 3330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada

    Cheryl Barnabe

  6. Division of Rheumatology, Montreal General Hospital, McGill University, Room A6-123, 1650 Cedar avenue, Montreal, QC, H3G 1A4, Canada

    Fares Kalache

  7. Division of Rheumatology, Mount Sinai Hospital, University of Toronto, The Joseph and Wolfe Lebovic Building, Second Floor, 60 Murray Street, Toronto, ON, M5T 3L9, Canada

    Tabitha Kung & Vivian Bykerk

  8. Division of Rheumatology, Laval University, CHUQ, CHUL, 2705, boul. Laurier, Suite H-1365, Quebec City, QC, G1V 4G2, Canada

    Louis Bessette

  9. Division of Rheumatology, University of British Columbia, Suite#403, 301 East Columbia, New Westminster, BC, V3L 3W5, Canada

    Cathy Flanagan

  10. Division of Rheumatology, CHUM, Notre-Dame Hospital, Université de Montréal, 1560 Rue Sherbrooke East, Montréal, QC, H2L4M1, Canada

    Boulos Haraoui

  11. Women’s College Hospital and Research Institute, University of Toronto, 76 Grenville Street, 10th floor, Room 1001, Toronto, ON, M5S 1B2, Canada

    Jacqueline Hochman

  12. Division of Rheumatology, Rockyview General Hospital, University of Calgary, 7007-14 Street SW, Calgary, AB, T2V 1P9, Canada

    Sharon Leclercq

  13. Division of Rheumatology, Department of Medicine, University of Calgary, 1403 29 St NW, Calgary, AB, T2N 2T9, Canada

    Dianne Mosher

  14. Division of Rheumatology, University of Toronto, 43 Lundys Lane, Newmarket, ON, L3Y 3R7, Canada

    Carter Thorne

  15. Division of Rheumatology, Hospital for Special Surgery, 535 East 70th St., 6th Floor, New York City, NY, 10021, USA

    Vivian Bykerk

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  1. Amanda J. Steiman
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  2. Janet E. Pope
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Corresponding author

Correspondence to Vivian Bykerk.

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Appendix 1: Search strategy employed

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237. Arabloc.mp.

238. Arava.mp.

239. Artrimod.mp.

240. Leflucross.mp.

241. hwa 486.mp.

242. hwa486.mp.

243. rs 34821.mp.

244. rs34821.mp.

245. su 101.mp.

246. su101.mp.

247. 599-79-1.rn.

248. or/199-247

249. Cyclosporin$.mp.

250. Immunosuppressive Agents/

251. Peptides, Cyclic/

252. limit 251 to yr = ”1971–1981”

253. Peptides/

254. limit 253 to yr = ”1966–1970”

255. 252 or 254

256. 250 and 255 (112)

257. Gengraf.mp.

258. Neoral.mp.

259. Sandimmun$.mp.

260. Sangcya.mp.

261. adi 628.mp.

262. adi628.mp.

263. cicloral.mp.

264. ciclosporin$.mp.

265. consupren.mp.

266. ol 27400.mp.

267. ol27400.mp.

268. pulminiq.mp.

269. sang 35.mp.

270. sang35.mp.

271. neoral.mp.

272. restasis.mp.

273. cya-nof.mp.

274. csa-neoral.mp.

275. ol 27-400.mp.

276. 59865-13-3.rn.

277. or/249,256-276

278. gold.mp.

279. sodium aurothiomalate.mp.

280. mercaptobutanedioic acid monogold.mp.

281. sodium thiomalatoaurate.mp.

282. aurolate.mp.

283. disodium thiomalate.mp.

284. myocrysine.mp.

285. miocrisin.mp.

286. myocrisin.mp.

287. aurothiomalate.mp.

288. miocrin.mp.

289. myochrisin$.mp.

290. myochrysin$.mp.

291. shiosol.mp.

292. tauredon$.mp.

293. aurothioglucose.mp.

294. thioglucosoaurate.mp.

295. aureotan.mp.

296. solganal.mp.

297. gold50.mp.

298. auromyose.mp.

299. aurumin$.mp.

300. goldthioglucose.mp.

301. goldtioglucose.mp.

302. oronol.mp.

303. solganol.mp.

304. Organogold.mp.

305. Auranofin.mp.

306. sk&f d 39162.mp.

307. sk&f-39162.mp.

308. sk&f39162.mp.

309. ridauran.mp.

310. crisinor.mp.

311. ridaura.mp.

312. 12244-57-4.rn.

313. or/278-312

314. methotrexat$.mp.

315. mexate.mp.

316. a methopterine.mp.

317. abitrexate.mp.

318. amethopterin$.mp.

319. ametopterine.mp.

320. antifolan.mp.

321. cl 14377.mp.

322. cl14377.mp.

323. emt?exat$.mp.

324. enthexate.mp.

325. folex.mp.

326. mtx.mp.

327. ledertrexate.mp.

328. methohexate.mp.

329. methotrate.mp.

330. methotrexat$.mp.

331. methrotrexate.mp.

332. methylaminopterin.mp.

333. methylaminopterine.mp.

334. metothrexate.mp.

335. metotrexat.mp.

336. metotrexate.mp.

337. mpi 5004.mp.

338. mpi5004.mp.

339. novatrex.mp.

340. nsc 740.mp.

341. nsc740.mp.

342. rheumatrex.mp.

343. trexall.mp.

344. Atrexel.mp.

345. Biometrox.mp.

346. Brimexate.mp.

347. emt?exat$.mp.

348. Ebetrexat.mp.

349. Farmitrexat.mp.

350. Fauldexato.mp.

351. Hextrate.mp.

352. ifamet.mp.

353. lantarel.mp.

354. leulin.mp.

355. lumexon.mp.

356. maxtrex.mp.

357. medsatrexate.mp.

358. metex.mp.

359. methobax.mp.

360. methobion.mp.

361. methoblastin$.mp.

362. metoject.mp.

363. Metolate.mp.

364. Metotab.mp.

365. Metrexato.mp.

366. Metrotex.mp.

367. mexate.mp.

368. miantrex.mp.

369. Neotrexat.mp.

370. otamex.mp.

371. O-trexat.mp.

372. Pterin.mp.

373. Reutrexato.mp.

374. Rhodamer.mp.

375. tecnomet.mp.

376. texate.mp.

377. tremetex.mp.

378. trexan.mp.

379. trexeron.mp.

380. trixilem.mp.

381. unitrexate.mp.

382. xaken.mp.

383. zexate.mp.

384. 59-05-2.rn.

385. or/314-384 (37575)

386. dmard$.mp.

387. (disease modif$ adj2 agent$).mp.

388. Antirheumatic Agents/

389. ANTI-INFLAMMATORY AGENTS/

390. limit 389 to yr = ”1987-1994”

391. (disease modify$ adj3 anti$ drug$).mp.

392. or/386-388, 390-391

393. 118 or 131 or 180 or 198 or 248 or 277 or 313 or 385 or 392

394. (inflam$ adj2 joint$ adj2 disease$).mp.

395. (rheum$ adj2 arthr$).mp.

396. (caplan$ adj2 syndrome$).mp.

397. (caplan$ adj2 disease$).mp.

398. (felty$ adj2 syndrome$).mp.

399. (felty$ adj2 disease$).mp.

400. rheumatoid$.mp.

401. (rheumat$ adj2 nodule$).mp.

402. still$ disease$.mp.

403. still$ syndrome$.mp.

404. (sicca adj2 syndrome$).mp.

405. sicca adj2disease$.mp.

406. rheumatism.mp.

407. (psori$ adj2 arthri$).mp.

408. (psori$ adj2 arthrop$).mp.

409. (psori$ adj2 polyarthr$).mp.

410. (psori$ adj2 rheumat$).mp.

411. (reactive adj2 arthrit$).mp.

412. (arthrit$ adj2 postinfect$).mp.

413. (reiter$ adj2 syndrome$).mp.

414. (reiter$ adj2 disease$).mp.

415. (ankyl$ adj2 spond$).mp.

416. (marie$ strumpell$ adj2 disease$).mp.

417. (marie$ strumpell$ adj2 syndrome$).mp.

418. (marie$ struempell$ adj2 disease$).mp.

419. (marie$ struempell$ adj2 syndrome$).mp.

420. (bechterew$ adj2 disease$).mp.

421. (bechterew$ adj2 syndrome$).mp.

422. (bekhterev$ adj2 disease$).mp.

423. (bekhterev$ adj2 syndrome$).mp.

424. morbus bechterew$.mp.

425. spondylarthr$.mp.

426. (spondy$ adj2 rheum$).mp.

427. (spin$ adj2 ankylosis).mp.

428. (spin$ adj2 arthrit$).mp.

429. vertebral ankyl$.mp.

430. inflammatory arthrit$.mp.

431. exp rheumatoid arthritis/

432. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

433. (sjogren$ adj2 syndrome).mp.

434. exp Spondylitis, Ankylosing/

435. (ankylos$ or spondyl$).tw.

436. (bekhterev$ or bechterew$).tw.

437. (Marie adj struempell$).tw.

438. exp Arthritis, Psoriatic/

439. (psoria$ adj (arthriti$ or arthropath$)).tw.

440. ((arthriti$ or arthropath$) adj psoria$).tw.

441. (arthrit$ and psoriasis).tw.

442. (arthrit$ and psoriatic).tw.

443. (arthropath$ and psoriasis).tw.

444. exp Spondylarthropathies/

445. exp Arthritis, Infectious/

446. ((sexual$ or chlamydia or yersinia or postyersinia or postdysenteric or salmonella or shigella or b27 or postinfectious or post infectious) adj5 arthrit$).tw.

447. undifferentiated oligoarthritis.tw.

448. ((enteropath$ or crohn$ or colitis or inflammatory bowel) adj5 arthrit$).tw.

449. Reiter$.tw.

450. enthesitis.tw.

451. exp Reiter Disease/

452. exp arthritis, reactive/

453. (arthritis adj2 reactive).tw.

454. undifferentiated oligoarthritis.tw.

455. exp Inflammatory Bowel Diseases/

456. (inflamm$ adj5 (arthriti$ or arthropath$)).tw.

457. Inflammatory bowel disease$.tw.

458. ibd.tw.

459. (Crohn$ adj disease).tw.

460. Ileocolitis.tw.

461. ((terminal or regional) adj ileitis).tw.

462. ((granulomatous or regional) adj enteritis).tw.

463. ((granulomatous or ulcerative) adj colitis).tw.

464. or/394-463

465. 27 and 393 and 464

466. from 465 keep 1-500

467. from 465 keep 501-1000

468. from 465 keep 1001-1500

469. from 465 keep 1501-1760 (260)

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Steiman, A.J., Pope, J.E., Thiessen-Philbrook, H. et al. Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials. Rheumatol Int 33, 1105–1120 (2013). https://doi.org/10.1007/s00296-012-2619-6

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  • DOI: https://doi.org/10.1007/s00296-012-2619-6

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