MENARINI symposiumFriday, June 14th 08:15 – 09:45

N117/N118 Room

MC

-I305

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in rheumatological diseasesA therapeutic strategyChairman: Prof. Serge Perrot

PAINFUL CONDITIONS

MAIN FEATURES

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Musculoskeletal conditions are the most common cause of severe long- term pain and physical disability, and they affect hundreds of millions of people around the world1. Musculoskeletal diseases encompass a spectrum of conditions, from those of acute onset and short duration to lifelong disorders, including osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis, and low back pain (LBP)1. In surveys carried out in Canada, the USA, and Western Europe, the prevalence of physical disabilities caused by a musculoskeletal condition repeatedly has been estimated at 4–5% of the adult population1. The prevalence of musculoskeletal conditions is higher among women and increases markedly with age. Moreover, the pain and physical disability brought about by musculoskeletal conditions affect social functioning and mental health, further hampering the patient’s quality of life1. Pain is an ubiquitous symptom in osteoarticular diseases, occurring much more commonly than stiffness or disabi-lity2. Pain related to OA is considered as the prototypical nociceptive pain condition3. OA is one of the most costly and disabling forms of joint disease, being far more common than RA and other forms of joint disease4. OA can arise in any synovial joint in the body, but is more common in the hands, knees, hips, and spine. A single joint could be involved, but more commonly several joints are affected5 (Figure 1).

Knee

Hand

Spine

Hip

Osteoarthritis pain = prototypical nociceptive pain condition

Joint Pain: multiple sites - multiple pain

Figure 1. Multiple sites of joint pain. Graphical eleboration from text in5.

Foot

LBP, low back pain; OA, osteoarthritis; RA, rheumatoid arthritis.

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Joint pain is usually the main aspect of symptomatic OA that leads patients to seek medical attention6

For a long time, studies in OA have focused on joint architecture and local de-gradation, considering pain as only a symptom, a consequence of joint damage. However, OA-related pain is a specific disease, with a complex pathophysiology, including neuropathic peripheral and central abnormalities, together with local inflammation involving all joint structures2. Clinical findings emphasize that it is not a stable and linear condition, that pain experience is independent of structural modifications, and that the quality of pain in OA is important to consider, aside from its intensity2. Infact, current evidence suggests that OA joint damage predi-sposes to pain but that little correlation between pain severity and the extent of joint damage exists7.Instead of being a pure cartilage disorder, OA is now consi-dered as a whole-joint disease that affects various anatomical structures in and around the joint capsule. These include muscle, ligaments, entheses, synovial tissue and the subchondral bone8. Inflammatory symptoms such as joint effusion or articular stiffness are common in OA and synovial inflammation detected by sonography occurs in more than half of the patients with early OA8. Joint inflam-mation is a well-recognised feature of OA, notably in the early stage9. Inflamma-tion in OA can be triggered by malalignment, overuse, trauma, crystal formation, trauma or idiopathy. Moreover, several studies pointed out the importance of mechanical factors in the destructive cascade of this disease9.

OA pain should be considered as a complex and not unique pain condition, where precise clinical assessment may drive specific therapeutic approaches3

Pain is the primary outcome measurement in OA, and its assessment is mostly based on its intensity; however, pain analysis should not be restricted to inten-sity as pain is not adequately assessed by a single intensity rating10. Of note, a recent initiative from Osteoarthritis Research Society International (OARSI) and Outcome Measures in Rheumatology (OMERACT) has investigated several di-mensions in OA pain, leading the development of ICOAP (Intermittent and Con-stant OsteoArthritis Pain), a questionnaire including pain intensity, frequency, and impact on mood, sleep, and quality of life2,11. The ICOAP questionnaire eva-luated both constant and intermittent pain and took into account not only pain intensity but also related distress and the impact of OA pain on quality of life11. Two distinct pain conditions in OA, related to the context of OA progression, were defined with intermittent and intense pain having the greatest impact on quality of life3,10. However, an extensive description of OA pain quality is urgely needed. To this end, Cedraschi et al. developed a framework for a patient-cente-red evaluation of OA pain, allowing an in-depth description of pain, and in further steps, the development of a specific questionnaire, the OsteoArthritis Symptom Inventory Scale (OASIS) for assessing OA pain quality, as a complement to the ICOAP questionnaire10. Seven dimensions of OA pain were identified as shown in Figure 2.

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Subgrouping patients with OA pain on the basis of pain quality, as assessed by patient-centered questionnaires, may facilitate the development of more accurate and effective pain management10.

Following joint disorders including OA, back problems ranked third among the top 10 reasons for seeking medical help with about 90% of people suffering from them at some point in their lives12,12b (Figure 3).

Figure 2. Seven pain dimensions identified through qualitative analysis. OASIS, OsteoArthritis SymptomInventory Scale. Modified from Table 4 in10.

Joint pain quality: OASIS study Osteoarthritis Symptom Inventory Scale

• Seven dimensions of OA pain emerged: 1. pain sensory description, 2. OA-related symptoms, 3. pain variability profile, 4. pain-triggering factors, 5. pain and physical activity, 6. mood and image, 7. general physical symptoms.

• Ongoing validation and patients’ phenotypes to be determined

Figure 3. Ten most prevalent disease groups according to the Rochester Epidemiology Project (REP). Using the resources of the Rochester Epidemiology Project (REP), a study to identify the prevalence of the most common non-acute conditions in a defined US population, was carried out. The REP records-lin-kage system provides an ideal opportunity to quantify the prevalence of all medical conditions in an entire population, across age, sex, and ethnic groups, regardless of socioeconomic or insurance sta-tus. A total of 142,377 subjects were included (53% women). Graphical elaboration of Figure 3 in12.

Top 10 most common reasons for seeing a doctor (Survey on 140,000 patients)

1. Skin disorders, including cysts, acne and dermatitis.2. Joint disorders, including osteoarthritis.3. Back problems.4. Cholesterol problems.5. Upper respiratory conditions.6. Anxiety, bipolar disorder and depression.7. Chronic neurologic disorders.8. High blood pressure.9. Headaches and migraines.10. Diabetes.

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For nearly all people with low back pain (LBP), it is not possible to identify a spe-cific nociceptive cause. Only a small proportion of people have a well understood pathological cause; id est, a vertebral fracture, malignancy, or infection13. Most episodes of LBP are short-lasting with little or no consequence, but recurrent episodes are common and LBP is increasingly understood as a long-lasting con-dition with a variable course rather than episodes of unrelated occurrences13.

A paradigm shift is greatly needed in our thinking that LBP is usually a simple self-limiting condition, to a broader conceptualization of it as a persistent or recurrent problem14

Around half the people seen with LBP in primary care have a trajectory of continu-ing or fluctuating pain of low-to moderate intensity, some recover, and some have persistent severe LBP13. Thus, LBP natural course needs to be better understood by both clinicians and researchers in order to optimize treatment15. Four trajectories were initially identified for LBP patients representing different paths over time: persistent mild, recovering, severe chronic and fluctuating16. Further delineation of these trajec-tories may lead to better early intervention strategies, tailored treatment plans, and better outcomes for patients. Moreover, better understanding of the trajectories will also provide insight into the mechanisms of pain, and the pathways from acute injury to chronic conditions14. The approach to low back pain has changed dramatically in the past decades. According to a classical disease model, all classifications of low back pain (LBP) used to consider its patho-anatomic basis and consequently proposed treatments but the increasing burden on society in terms of costs and disability lead to a revolution in the understanding of the problem. In this way, LBP must be consi-dered as a bio-psycho-social syndrome that consequently requires a multidisciplinary bio-psycho-social treatment approach (Figure 4)17.

LOW BACK PAIN

FDC:TRAM/DKP

NEUROPATHIC

NOCICEPTIVE SOCIAL

PSYCHOLOGICAL

Acute Chronic

BIO – PSYCHO – SOCIAL

Low back pain: Treat according to the stage We can change the lives of our patients with low back pain

Figure 4. Multimodal treatment approach to low back pain.

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There is an almost endless list of treatment options currently available to patients with LBP16 including oral medications, topical medications, exercise, manual therapy, traction, acupuncture,transcutaneous electrical nerve stimulation (TENS), spinal cord stimulators, mattresses, orthotics, back supports, biofeedback, spinal injections and surgery. As a result, LBP patients may be offered treatments from the full range of conservative, pharmacological, non-pharmacological, traditional and complementary healthcare iinterventions16. Figure 5 illustrates the pain treatment arsenal for acute LBP. The choice of medication depends on a number of factors, including the duration of symptoms, severity of symptoms, expected benefits, prior response to medica-tions, adverse effect profile, presence of co-morbidities, costs and degree of suppor-ting evidence18. Recently, a review of practice guidelines for patients with LBP has been conducted to explore how evidence-based recommendations have changed du-ring the last decade19.

Most guidelines endorse recommendations for patient education, reassurance about a favourable prognosis and advice on returning to normal activities, avoiding bed rest, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids for short periods when there is contraindication or lack of improvement with NSAIDs19

Our understanding of pain mechanisms is increasing but remains incomplete. Pain treatments remain inadequate in efficacy and associated with a variety of toxicities. Despite this situation, rheumatologists continue to treat patients with painful rheuma-tic disorders on a daily basis21. Effective management of pain therefore requires an

PHARMACOLOGICALPAIN TREATMENTS

FDC:TRAM/DKP

STEROID INJECTIONS

OPIOIDS

ANTIDEPRESSANTSANTICONVULSANTS

NSAIDs

TOPICAL

• Non-opioids, NSAIDs• Opioids• Steroids• Topicals• Adjuvants

• Anti-anxiety• Anti-depressant• Neuropathic pain treatments

• Anticonvulsants (i.e. gabapentin)

• Side effect management

Pain treatment arsenal in acute LBP

Figure 5. Pain treatment arsenal in acute low back pain. LBP, low back pain; NSAIDs, non-steroidal antinflammatory drugs. Graphical elaboration from text in20.

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integrated strategy taking into account the pathological process, psychosocial factors that affect the response to pain, and associated medical and pharmacologic conside-ration22. Figure 6 illustrates the strategic pillars for an improved rheumatic pain mana-gement. In line with other pain conditions, ideal treatment of rheumatic pain should be through a multimodal approach, integrating non-pharmacologic as well as pharmaco-logic treatments. In the light of this new concept of pain mechanisms, future pharma-cologic treatment options may encompass a wider scope than the use of traditional analgesics and NSAIDs22.

It is well established that combining drugs with different mechanisms and sites of action would yield a better pain relief, with the fewest side-effects; this concept is at the base of multimodal analgesia24

Moreover, the IASP Council has released the new definition of multimodal therapy: aimed at clarifying terminology for different multicomponent treatment approaches: multimodal therapy is now defined as the concurrent use of separate therapeutic inter-ventions with different mechanisms of action within one discipline aimed at different pain mechanisms25. The fixed-dose combination of tramadol (75 mg) and dexketopro-fen (25 mg) (TRAM/DKP) provides a comprehensive multimodal approach for mode-rate-to-severe acute pain, thanks to the central analgesic effect, peripheral analgesic action, and anti-inflammatory activity24. In the context of rheumatological painful condi-tions, it has been suggested that TRAM/DKP may represent an attractive medication for acute exacerbations of OA pain due to its pharmacological profile. Of note, the combination of dexketoprofen and tramadol, targeting different sites of action, is, the-refore, suitable for OA type of pain, arising from different body structures (joints, mu-scles, ligaments, etc.)24. Recently, the analgesic efficacy of TRAM/DKP was compared in a head-to-head study (DAVID* study) to that of TRAM/paracetamol combination thus showing the greatest sustained analgesia during the 6-hour post dose period as demonstrated by the total pain relief at 6 h (TOTPAR6) primary endpoint26 (Figure 7).

Figure 6. Proposed strategy to improve outcome in rheumatological pain management. Graphical elaboration of text in22,23.

Can we improve outcome of rheumatic pain?

• Better Understanding - Mechanisms, pain & drugs - Disease modifying

• Eliminate Risk Factors - Identify (age /gender) - Target (Individualize therapy)

• Multi-Modal Therapy

* DAVID study: Dexketoprofen Analgesic eVolution with tramaDol

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* DAVID study: Dexketoprofen Analgesic eVolution with tramaDol

Moreover, the time course of the mean pain relief (PAR) and pain intensity (PI)scores showed that TRAM/DKP provided a more rapid onset of action compa-red with TRAM/paracetamol as differences were statistically significant already 30 min postdose26. Furthermore, patients in the TRAM/DKP arm constantly had greater analgesia and lower PI, in a statistically and clinically significant fashion, at each pre-specified time points until 6 hours after drug intake, in comparison to those in the comparator arm26 (Figure 8).

The rapid onset of analgesic effect of DKP, with its anti-inflammatory activity, associated to the sustained (mean duration: 8.1h) action of TRAM, makes this combination a valuable tool to achieve multimodal analgesia26. Collectively, the results of the DAVID study added further evidence for the potential role of TRAM/DKP as a valuable option to achieve an effective multimodal analgesia thus broa-dening TRAM/DKP utility already documented in previous trials27-29.

TOTPAR2 TOTPAR4 TOTPAR6 TOTPAR8

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20

16

12

8

4

0

ME

AN

SC

OR

E

Placebo TRAM/paracetamol

Primary Endpoint

*p<0.0001

TRAM/DKP

*

**

*

Figure 7. Mean TOTPAR at 6 hours (primary endpoint) and at 2, 4 and 8 hours for TRAM/DKP, TRAM/paraceta-mol and placebo with PAR being measured on a 5-point Verbal Rating Scale (0=‘no relief’ to 4=‘complete relief’). *Statistically significant comparison of TRAM/DKP versus TRAM/ paracetamol (p<0.0001). A randomized, double blind, placebo active-controlled, parallel group trial in patients scheduled to undergo standard impacted 3rd molar extraction and experiencing a postoperative pain of at least moderate intensity. Three possible treatment arms: TRAM/DKP 75/25 mg (n=260), TRAM/paracetamol 75/650 mg (n=262) and placebo (n=131). PAR, pain relief; TRAM/DKP, tramadol/dexketoprofen; TOTPAR6, total pain relief. Modified from Figure 2 in26.

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T15m T30m T1h T1.5h T2h T4h T6h T8h

3

4

3

2

2

1

1

0

ME

AN

PA

R

TIME

Placebo TRAM/paracetamol TRAM/DKP

** *

*

†

††

Figure 8. Time course of mean PAR over 8 hours for TRAM/DKP, TRAM/paracetamol and placebo with PAR measured on a 5-point Verbal Rating Scale (0=‘no relief’ to 4=‘complete relief’). The area under the curve for pain relief at a given time point corresponds to TOTPAR at the same time point. *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0001); †Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0006); ††Statistically significant TRAM/DKP versus TRAM/ paracetamol (p<0.00086). A randomized, double blind, placebo active-controlled, parallel group trial in patients scheduled to undergo standard impacted 3rd molar extraction and experiencing a postoperative pain of at least moderate intensity. Three possible treatment arms: TRAM/DKP 75/25 mg (n=260), TRAM/paracetamol 75/650 mg (n=262) and placebo (n=131). PAR, pain relief; TRAM/DKP, tramadol/dexketoprofen; TOTPAR, total pain relief. Modified from Figure 3 in26.

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Key Points

• Pain is an ubiquitous symptom in osteoarticular diseases, occurring much morecommonly than stiffness or disability2

• Joint pain is usually the main aspect of symptomatic OA that leads patients toseek medical attention6

• Clinical findings emphasize that OA-related pain is not a stable and linear condi-tion, that pain experience is independent of structural modifications, and that thequality of pain in OA is important to consider, aside from its intensity2

• Pain treatments in OA are poorly effective, and outcome measures are basedmostly on pain VAS or on questionnaires assessing pain purely in terms of itsintensity, without taking into account its quality10

• Subgrouping patients with OA pain on the basis of pain quality, as assessed bypatient-centered questionnaires, may facilitate the development of more accura-te and effective pain management10

• Back problems ranked third among the top 10 reasons for seeking medical helpwith about 90% of people suffering from them at some point in their lives12,12b

• Most episodes of LBP are short-lasting with little or no consequence, but recur-rent episodes are common and LBP is increasingly understood as a long-lastingcondition with a variable course rather than episodes of unrelated occurrences13

• The complexity of chronic LBP management highlights the need for early inter-vention in patients with acute LBP in order to prevent progression to chronicLBP30

• In line with other pain conditions, ideal treatment of rheumatic pain should bethrough a multimodal approach, integrating non-pharmacologic as well as phar-macologic treatments22

• The fixed-dose combination of tramadol (75 mg) and dexketoprofen (25 mg)(TRAM/DKP) provides a comprehensive multimodal approach for modera-te-to-severe acute pain, thanks to the central analgesic effect, peripheral analge-sic action, and anti-inflammatory activity24

• The rapid onset of analgesic effect of DKP, with its anti-inflammatory activity,associated to the sustained action of TRAM, makes TRAM/DKP combination avaluable tool to achieve multimodal analgesia27

DKP, dexketoprofen; LBP, low back pain; OA, osteoarthritis TRAM, tramadol;VAS, visual analogue scale

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References

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2. Trouvin AP and Perrot S. Pain in osteoarthritis. Implications for optimal management. Joint Bone Spine 2018; 85:429-434.

3. Perrot S. Osteoarthritis pain. Best Practice & Research Clinical Rheumatology 2015; 29: 90-97.4. Mobasheri A et al. Osteoarthritis Year in Review 2016: biomarkers (biochemical markers). Osteoarthritis and

Cartilage 2017; 25: 199-208.5. Dieppe A and Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet 2005; 365:

965–73.6. Salaffi F et al. The sources of pain in osteoarthritis: a pathophysiological review. Reumatismo 2014; 66: 57-71.7. Kidd B. Mechanisms of pain in osteoarthritis. HSS Osteoarthritis Symposium: Frontiers in OA. HSSJ 2012; 8:

26-28.8. Hugle T and Geurts J. What drives osteoarthritis?—synovial versus subchondral bone pathology. Rheumatolo-

gy 2017;56:1461-1471.9. Egloff C et al. Biomechanics and pathomechanims of osteoarthritis. Swiss Med Wkly 2012; 142: w13583.10. Cedraschi C et al. “Let’s Talk about OA Pain”: A Qualitative Analysis of the Perceptions of People Suffering

from OA. Towards the Development of a Specific Pain OA-Related Questionnaire, the Osteoarthritis Sympto-mInventory Scale (OASIS). PLoS One 2013; 8: e79988.

11. Hawker GA et al. Development and preliminary psychometric testing of a new OA pain measure – an OARSI/OMERACT initiative. Osteoarthritis Cartilage 2008; 16: 409-414.

12. Sauver St JL et al. Why do patients visit their doctors? Assessing the most prevalent conditions in a define US population. Mayo Clin Proc. 2013; 88: 56–67.

12b.Nasser MJ. How to approach the problem of low back pain: an overview. J Family Community Med. 2005; 12: 3–9.13. Hartvigsen J et al. What low back pain is and why we need to pay attention. Lancet 2018; 391:2356-2367.14. Gatchel RJ et al. Transitioning from Acute to Chronic Pain: An Examination of Different Trajectories of Low

Back Pain. Healthcare 2018; 6: 48; doi:10.3390.15. Tamcan O et al. The course of chronic and recurrent low back pain in the general population. Pain 2010; 150:

451-457.16. Foster NE. Barriers and progress in the treatment of low back pain. BMC Med 2011; 9: 108.17. Negrini S, et al. Low back pain: state of art. Eur J Pain Suppelments 2008; 2: 52-56.18. Chou R. Pharmacological Management of Low Back Pain. Drugs 2010; 70: 387- 402.19. Oliveira CB et al. Clinical practice guidelines for the management of non specific low back pain in primary care:

an updated overview. Eur Spine J 2018; 27: 2791-2803.20. Helander EK et al. Multimodal analgesia, current concepts, and acute pain considerations. Curr Pain Headache

Rep 2017; 21:3.21. Borenstein DG et al. Pain management in rheumatology research, training, and practice. Clin Exp Rheumatol

2017; 35 (Suppl 107): S2-S7.22. Fitzcharles MA et al. Management of chronic pain in the rheumatic diseases with insights for the clinician. Ther

Adv Musculoskel Dis 2011; 3: 179-190.23. Kidd BL et al. Current approaches in the treatment of arthritic pain. Arthritis Research& Therapy 2007; 9: 214.24. Varrassi G et al. Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexke-

toprofen and tramadol. Curr Med Res Opin. 2017; 3:1165-1173.25. IASP website http://www.iasp-pain.org/PublicationsNews/NewsDetail.aspx?I temNumber= 6981.26. Gay-Escoda C et al. Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/ paracetamol in moderate

to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study). BMJ Open 2019; 9: e023715.

27. Moore RA et al. Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to- severe acute pain after abdominal hysterectomy. BMC Anesthesiol 2016; 16:9.

28. McQuay HJ et al. Randomized clinical trial of dexketoprofen/tramadol 25mg/75mg in moderate-to-severe pain after total hip arthroplasty. Br J Anaesthesia 2016; 116: 269-276.

29. Moore RA et al. Dexketoprofen/tramadol: randomised double-blind trial and con formation of empirical theory of combination analgesics in acute pain J Headache Pain 2015; 16: 541.

30. Morlion B. Pharmacotherapy of low back pain: targeting nociceptive and neuropathic pain components. CMRO 2011; 27: 11-33.

MC-I305-7-2019

in rheumatological diseasesA therapeutic strategy

PAINFUL CONDITIONS

To whom it may concernFor the correct use of this product please do refer to the technical

documents (e.g. patient information leaflets and SmPC) approved in your country by the competent local regulatory authorities.

Information for physiciansPlease do not hesitate to request a copy of any said technical documentation

to our local representative. Please be informed that the contents of this material may be used only if compliant with local laws and regulations.

Drawn from the speeches by

Prof. Serge PerrotPain Center, Cochin-Hôtel Dieu Hospital, Assistance Publique-Hôpitaux de Paris; Inserm U987, Paris

Descartes University, France.

Prof. Magdi HannaAnalgesics and Pain Research Unit, London, UK.

Supported by The Menarini groupduring the EULAR Congress, held in Madrid 12-15 June 2019.