«I am getting better» and «I feel good»: searching for an objective criterion for a clinical response to analgesic therapy for rheumatic diseases

Analysis of the results of clinical trials should be based on the use of objective parameters that allow for assessing the significance of the data obtained for real medical practice. These parameters include Minimal Clinically Important Improvement (MCII) and Patient Acceptable Symptom State (PASS).
Objective: to determine the approximate value of the parameters MCII and PASS on the basis of data from the PARACELS (Regular Piascledine and Artrosilene Administration for osteoarthritis (OA): Expediency of the Unified Treatment Regimen) study.
Patients and methods. A study group consisted of 6,448 patients (70.9% female, 29.1% male) (mean age, 57.8±10.2 years) with knee OA and moderate or severe pain of ≥40 mm on a 100-mm visual analogue scale (VAS). All the patients took during 12 weeks avocado/soybean unsaponifiables 300 mg/day and a nonsteroidal anti-inflammatory drug (ketoprofen lysine salt) 320 mg/day, which was prescribed at the beginning of treatment for 10–14 days and then could be used on demand with more pain to come. Pain intensity was measured using the 100-mm VAS. Patient satisfaction with treatment results was also studied with a point scale, where 0 is worsening or no effect, while 5 is an excellent effect. The dynamics of pain was compared and treatment results were assessed by patients.
Results and discussion. After 12 weeks, most patients showed a substantial improvement: a mean pain intensity reduction of 77.7±29.6%. A satisfactory treatment result estimate (that can be considered as a surrogate measure of MCII) corresponded to an average pain reduction of 32.0±11.7 mm on VAS (a 47.3% improvement compared to the baseline level). A good treatment result estimate (that can be considered as a surrogate measure of PASS) corresponded to an average pain reduction of 41.0±13.3 mm on VAS (a 62.9% improvement compared to the baseline level).
Conclusion. The PARACELS study has shown that in Russian patients receiving analgesic therapy, MCII can correspond to a pain reduction of >30 mm on VAS (>40% of the baseline level), PASS can do to its reduction of >40 mm on VAS (>60% of the baseline level).

1. Nasonov EL, Yakhno NN, Karateev AE, et al. General principles of treatment for musculoskeletal pain: interdisciplinary consensus. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2016;54(3):247-65. (In Russ.). doi: 10.14412/1995-4484-2016-247-265

2. Borenstein D, Altman R, Bello A, et al. American College of Rheumatology Pain Management Task Force. Report of the American College of Rheumatology Pain Management Task Force. Arthritis Care Res (Hoboken). 2010 May;62(5):590-9.

3. Geenen R, Overman CL, Christensen R, et al. EULAR recommendations for the health professional's approach to pain management in inflammatory arthritis and osteoarthritis. Ann Rheum Dis. 2018 Jun; 77(6):797-807. doi: 10.1136/annrheumdis2017-212662

4. Karcioglu O, Topacoglu H, Dikme O, Dikme O. A systematic review of the pain scales in adults: Which to use? Am J Emerg Med. 2018 Apr;36(4):707-714. doi: 10.1016/j.ajem.2018.01.008. Epub 2018 Jan 6.

5. Bailly F, Fautrel B, Gossec L. Pain assessment in rheumatology – How can we do better? A literature review. Joint Bone Spine. 2016 Jul;83(4):384-8. doi: 10.1016/j.jbspin.2016.01.001. Epub 2016 Feb 15.

6. Englbrecht M, Tarner IH, van der Heijde DM, et al. Measuring pain and efficacy of pain treatment in inflammatory arthritis: a systematic literature review. J Rheumatol Suppl. 2012 Sep;90:3-10. doi: 10.3899/jrheum.120335

7. Doganay Erdogan B, Leung YY, Pohl C, et al. Minimal Clinically Important Difference as Applied in Rheumatology: An OMERACT Rasch Working Group Systematic Review and Critique. J Rheumatol. 2016 Jan;43(1):194-202. doi: 10.3899/jrheum.141150. Epub 2015 Jun 1.

8. Ostelo R, de Vet H. Clinically important outcomes in low back pain. Best Pract Res Clin Rheumatol. 2005 Aug;19(4):593-607.

9. Tubach F, Ravaud P, Beaton D, et al. Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders. J Rheumatol. 2007 May;34(5):1188-93.

10. Tubach F, Ravaud P, Martin-Mola E, et al. Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: Results from a prospective multinational study. Arthritis Care Res (Hoboken). 2012 Nov;64(11):1699-707. doi: 10.1002/acr.21747

11. Perrot S, Bertin P. «Feeling better» or «feeling well» in usual care of hip and knee osteoarthritis pain: determination of cutoff points for patient acceptable symptom state (PASS) and minimal clinically important improvement (MCII) at rest and on movement in a national multicenter cohort study of 2414 patients with painful osteoarthritis. Pain. 2013 Feb;154(2):248-56. doi: 10.1016/j.pain.2012.10.017. Epub 2012 Oct 30.

12. Machado G, Maher C, Ferreira P, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015 Mar 31;350:h1225. doi: 10.1136/bmj.h1225

13. Jevsevar D, Donnelly P, Brown GA, Cummins DS. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review of the Evidence. J Bone Joint Surg Am. 2015 Dec 16;97(24):2047-60. doi: 10.2106/JBJS.N.00743

14. Karateev AE, Lila AM, Pogozheva EYu, et al. What factors influence the effectiveness of long-term analgesic therapy for osteoarthritis? Analysis of data from a multicenter 3-month PARACELSUS study. Terapevticheskii arkhiv. 2019;91(5):68-75. (In Russ.).

15. Karateev AE. Factors that affect the effectiveness of analgesic therapy. Nevrologiya i psikhiatriya. 2013;(5):46-53. (In Russ.).

16. Bellamy N, Hochberg M, Tubach F, et al. Development of multinational definitions of minimal clinically important improvement and patient acceptable symptomatic state in osteoarthritis. Arthritis Care Res (Hoboken). 2015 Jul;67(7):972-80. doi: 10.1002/acr.22538

17. Olsen MF, Bjerre E, Hansen MD, et al. Minimum clinically important differences in chronic pain vary considerably by baseline pain and methodological factors: systematic review of empirical studies. J Clin Epidemiol. 2018 Sep;101:87-106.e2. doi: 10.1016/j.jclinepi.2018.05.007. Epub 2018 May 21.

18. Angst F, Aeschlimann A, Stucki G. Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. Arthritis Rheum. 2001 Aug;45(4):384-91.

19. Salaffi F, Stancati A, Silvestri C, et al. Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale. Eur J Pain. 2004 Aug;8(4):283-91.

20. Stauffer ME, Taylor SD, Watson DJ, et al. Definition of nonresponse to analgesic treatment of arthritic pain: an analytical literature review of the smallest detectable difference, the minimal detectable change, and the minimal clinically important difference on the pain visual analog scale. Int J Inflam. 2011; 2011:231926. doi: 10.4061/2011/231926. Epub 2011 May 5.

21. O'Donnell JB, Ekman EF, Spalding WM, et al. The effectiveness of a weak opioid medication versus a cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug in treating flare-up of chronic low-back pain: results from two randomized, doubleblind, 6-week studies. J Int Med Res. 2009 Nov-Dec;37(6):1789-802.

22. Lin HY, Cheng TT, Wang JH, et al. Etoricoxib improves pain, function and quality of life: results of a real-world effectiveness trial. Int J Rheum Dis. 2010 May;13(2):144-50. doi: 10.1111/j.1756185X.2010.01468.x

23. Lange B, Kuperwasser B, Okamoto A, et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther. 2010 Jun;27(6): 381-99. doi: 10.1007/s12325-010-0036-3. Epub 2010 Jun 11.