Best Practice & Research Clinical Rheumatology 29 (2015) 90e97

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

Osteoarthritis pain
Serge Perrot, Prof, MD, PhD *
^pital Cochin-Ho
Centre de la douleur, Ho ^tel Dieu, Assistance Publique Ho
^pitaux de Paris,
Universit
e Paris Descartes, INSERM U987, Paris, France

a b s t r a c t
Keywords:
Pain Osteoarthritis (OA) represents one of the most frequently occurring
Osteoarthritis painful conditions. Pain is the major OA symptom, involving both
Joint peripheral and central neurological mechanisms. OA pain is initi-
Pathophysiology ated from free axonal endings located in the synovium, periosteum
Assessment bone, and tendons, but not in the cartilage. The nociceptive message
involves not only neuromediators and regulating factors such as
neuronal growth factor (NGF) but also central modifications of pain
pathways. OA pain is a mixed phenomenon where nociceptive and
neuropathic mechanisms are involved in both the local and central
levels. OA pain perception is influenced by multiple environmental,
psychological, or constitutional factors, and OA pain intensity is not
correlated with joint degradation. OA pain may present with
different clinical features: constant and intermittent pain, with or
without a neuropathic component, and with or without central
sensitization. Finally, OA pain should be considered as a complex
and not unique pain condition, where precise clinical assessment
may drive specific therapeutic approaches.
© 2015 Elsevier Ltd. All rights reserved.

Introduction

In Europe, 20% of chronic pain is related to osteoarthritis (OA) [1] and pain is the main symptom in
OA. Furthermore, pain related to OA is considered as the prototypical chronic nociceptive pain con-
dition, and this is used as a major clinical model for the development of new analgesics dedicated to
treating chronic pain.

* Corresponding author. Service de Me decine Interne et The

rapeutique, Centre de la douleur Ho
^tel Dieu, 1 Place du Parvis
Notre Dame, 75004 Paris, France. Tel.: þ33 1 42 34 78 50; fax: þ33 1 42 34 78 62.
E-mail address: serge.perrot@htd.aphp.fr.

http://dx.doi.org/10.1016/j.berh.2015.04.017
1521-6942/© 2015 Elsevier Ltd. All rights reserved.
 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97 91

In 420 BC, Hippocrates described the “rheuma theory: joints are driven by the brain.” This
theory suggests that when the brain sends more liquid to the lower parts of the body pain is
induced in the hip, which finally reaches all the joints (in Ref. [2]). This theory is now being
revisited in the 21st century with neurosciences, describing all influences of the neurologic system
in joint disorders.
Pain is a ubiquitous symptom in osteoarticular diseases [3], especially in OA [4], much more
prevalent than stiffness and disability. OA frequency is increasing, mostly related to age and obesity.
Paradoxically, compared to inflammation and immunity research, for many years, joint pain patho-
physiology has not been extensively studied. OA pain has been considered as a prototypical nociceptive
pain condition, and clinicians have expected that pain can be an alarm signal, correlating with the
intensity of joint degradation [5]. In OA, most authors have focused their studies more on joint ar-
chitecture and local degradation than on pain; however, the present study shows that it may have a
neuropathic component, and it is not a stable and continuous symptom [6].
OA pain pathophysiology is a recent subject for researchers, and, as in other clinical pain conditions,
OA pain pathophysiology includes four different processes:

- Transduction: conversion of energy induced by a painful stimulus (mechanical, thermal, and

chemical) into electrical energy by specific receptors
- Transmission: from periphery to centers (spinal cord and brain), with specific pathways
- Perception in the brain cortical zones
- Modulation by brain and spinal structures, by inhibiting and facilitating ways, this phenomenon
being crucial for reducing pain sensation

It can be seen that OA pain is a complex phenomenon, involving peripheral and central mecha-
nisms, modulated by many factors, including psychological [7] and genetic factors [8]. Recent findings
of neuroimaging have improved knowledge in these mechanisms, and new treatments may be pro-
posed in the coming future for better management.

Experimental pain models: is there a model of OA pain?

In OA, as in any pain condition, animal models have tried to be as close as possible to the human
condition in OA. In fact, experimental studies on OA pain have been mostly developed from inflam-
matory models, from arthritis, comparing data in arthritis and control animals. Several models of OA
have been described, but most OA models have been initially developed to analyze structural joint
changes rather than to analyze nociceptive sensations in animals. Recently, few models have also been
developed to analyze nociceptive pain behavior, after cruciate ligament transection, meniscectomy,
and monoiodoacetate injection [9,10]. However, the most frequent animal models of chronic joint pain
are inflammatory models such as the models of Freund's adjuvant injection [11], carrageenan plantar
injection, [12] or urate joint injection [13].
Experimental tests that can assess nociceptive behavior in animals are mostly represented by
mechanical stimuli, such as the Randall and Selitto test [14], or thermal stimuli, for example, by
immerging the hind paw in different temperatures. Other tests are based on observations of sponta-
neous behavior: motility, writhing, etc. As in all animal studies, the translation to the human context is
limited, and many animal findings have not been confirmed in humans [15]. Some studies investigate
nociception in animals, and others investigate pain only in humans.

Neuroanatomy of joint and peripheral mechanisms of OA pain

The origin of joint pain has been unknown for a long period of time. In 1945, Davies reported the
first experimental joint pain and noted that synovium was insensitive to pressure but that needle
puncture induced diffuse intra-articular pain. [16] In 1950, Kellgren and Samuel [17] studied pain
induced by needles in the knee of healthy volunteers: the authors demonstrated that synovium was
insensitive to needle punctures, but that the capsule and ligaments were sensitive to pain.
92 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97

Immunostaining has demonstrated the type of innervation of the joint [18]. The capsule, ligaments,
meniscus, periosteum, and subchondral bone are largely innervated by a dense network of myelinic
and amyelinic fibers. The synovium is mostly innervated by amyelinic fibers, although cartilage has no
innervation [19]. In the joint, there are four types of sensory organs [18]: type I and type II receptors,
which are corpuscular organs (Paccini, Golgi, and Ruffini), are localized in the capsule, ligaments, and
meniscus, but not in the synovium. These are mechanoreceptors, sensitive to pressure and traction,
transmitting the message by myelinic fibers. Type III receptors, formed by thin Ad myelinic fibers, are
located on the ligament surface and they act as mechanoreceptors of high threshold, answering to
strong mechanical stimuli and to a lower degree to thermal stimuli.
Type IV receptors, also called polymodals, are formed by free terminals of unmyelinated C fibers,
and they represent the most important type of joint receptors, in all structures except in the cartilage.
They are normally not activated and are called polymodals as they are activated by mechanical,
thermal, and chemical stimuli, in pathological conditions such as inflammation. Type III and IV re-
ceptors are involved in pain sensation induced by joint lesions. They are also sensitized by increased
intra-articular pressure and by chemical local changes.

Transduction: peripheral stimuli and receptors in OA pain

More than 80% of the fibers in the joint are unmyelinated fibers, equally distributed between C
fibers and sympathetic fibers [18,20].

Mechanical stimuli induce joint pain

One important component of OA pain is mechanical pain. In a normal joint, the intra-articular
pressure is between 2 and 10 mm Hg [21]. In the case of inflammation or local articular lesion, the
pressure can increase up to 20 mm Hg. Cartilage damage may induce hyperpressure of the subchondral
bone [22]. In the joint, there are specific nociceptors that are specifically activated by mechanical
stimulus [23].

Inflammatory stimuli induce OA pain

In the joint, even in OA, local inflammation with the release of phospholipases, cyclooxygenases,
lipo-oxygenases, leukotrienes, free radicals, and NO [24] is involved in pain mechanisms.

Joint receptors and pain mediators

In the joint, C fibers, also called peptidergic, express the tropomyosin receptor kinase A (TRKA)
receptor for NGF (neuronal growth factor), the P2X3 receptor for ATP, and also the GDNF (glial-derived
neurotrophic factor) receptor. The mediators of these fibers are substance P, calcitonin gene-related
peptide (CGRP), neuropeptide Y (NPY) [25], and vasoactive intestinal peptide (VIP) [26] in all joint
structures, except in the cartilage. NGF is an important component of the C fibers, with an important
role in joint pain [27,28], currently targeted by new biological therapies [29].
Recently, receptors that play a role in neuropathic pain have also been found in the joint: TRPV
receptors are present in many joint structures and can be the target of descending inhibitory mech-
anisms [30].
Apart from nociceptors, other receptors in the joint that may take part in the mechanisms of joint
pain, and can represent putative targets for analgesic therapies, include opioid receptors present in the
joint [31], as well as cannabinoid receptors [32], both increased with inflammation. This has suggested
the possible use of local morphine in joint pain [33].

Transmission of pain: from periphery to the brain

Pain has a complex pathophysiology, and in OA, recent findings have demonstrated the important
role of central mechanisms. In OA, there is increasing evidence that central mechanisms play a role in
 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97 93

pain sensation. When injecting a saline solution in the anterior tibialis muscle, patients with knee OA
experience more intense and more diffuse pain compared to normal controls [34].
In fact, there are probably both peripheral and central mechanisms at different stages: peripheral
mechanisms more in the early stage and central mechanisms more in the late and chronic stages [35].
Interactions between the central and peripheral systems suggest a general plasticity of the nociceptive
system in OA pain [36,37]. This plasticity may depend on different factors, for example, emotional
factors.

Brain activation in OA pain

Recent findings have demonstrated that different types of pain could be related to some activation
in different brain regions: spontaneous pain could be mainly related to medial prefrontalelimbic
cortical areas, which are regions involved in emotional status. Conversely, stimulus-evoked pain could
be more related to somatosensory nociceptive processing regions [38].

Brain sensitization

The most striking recent findings in OA pain have been the demonstration of brain activation and
brain modifications in patients with pain related to OA. Some studies have analyzed brain activation
and have demonstrated that OA pain, as most chronic pain states, is associated with central sensiti-
zation. Clinically, central sensitization related to joint pain induces pain in response to stimuli that
currently do not induce pain (allodynia), with a larger area of pain activation and longer duration of
pain [35]. Central sensitization in OA has been confirmed by both quantitative sensory testing (QST)
analyses and functional magnetic resonance imaging (MRI) [39].

Brain modifications

More recent studies have analyzed brain volume, and, specifically in some areas, these studies have
found some modifications in the gray matter: as in other chronic pain states, OA is associated with a
decrease in gray matter [40,41], but this decrease may not be permanent, as gray matter is regenerated
6e9 months after effective hip or knee surgery [39,40].

Perception of OA pain and correlation with joint damage

One constant question in OA, for both patients and physicians, is related to the correlation between
pain and joint damage. Many patients and their physicians believe that pain is correlated with joint
damage and that intense pain may reflect a high degree of joint degeneration.
Cohort studies have demonstrated that there is a poor correlation between pain intensity in OA and
the degree of joint degeneration. In a study pooling two cohorts, the MOST and the Framingham cohort,
Neogi et al. [42]s demonstrated that pain was more correlated with joint space narrowing than with
the presence of osteophytes. They also found that only high degrees of joint deterioration were
associated with higher pain levels. A more precise study has analyzed all joint components by MRI
study to investigate which structural changes were mostly associated with pain in OA [43]. The authors
demonstrated that synovitis and bone marrow edema were the structural changes that were most
correlated with pain, whereas osteophytes, bone cysts, meniscal changes, and ligament tears were not
associated with OA pain. In conclusion, to this question, one may answer that, on an individual basis, it
is still not relevant to correlate pain with joint damage.

Clinical expression of OA pain: how is pain measured in OA? is this nociceptive, neuropathic, or
mixed?

Very few papers have described pain dimensions in OA, with little consensus on its dimensions [44].
Pain intensity in OA is currently assessed by numerical and visual analog scale, to assess its intensity
[45]. The MacGill Pain Questionnaire (MPQ) has two different subscales, sensorial and emotional, that
94 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97

may be used to differentiate both components, and it has been validated in patients with hip and knee
OA [46].
Some authors have analyzed night pain in knee OA [47] and prevention of knee pain [48]. A recent
initiative from the Osteoarthritis Research Society International (OARSI) and OMERACT has investi-
gated several dimensions in OA pain, providing Intermittent and Constant OsteoArthritis Pain (ICOAP),
a new questionnaire including pain intensity; frequency; and impact on mood, sleep, and quality of
life [49]. This qualitative approach explored changes in pain characteristics over time, in relation with
priorities and concerns of individuals living with hip or knee pain. The authors of this study have
defined two distinct pain conditions in OA, related to the context of OA progression, with intermittent
and intense pain having the greatest impact on the quality of life. Although several pain descriptors
are proposed in the paper, these descriptors were not intended to be specifically used to define pain
phenotypes in OA, as it has been done in neuropathic pain. In this line, we have developed a quali-
tative analysis of OA pain with a new questionnaire, the OsteoArthritis Symptom Inventory Scale
(OASIS), to characterize pain quality in OA, and in the future, to help define different phenotypes of OA
pain [50].
Pain assessment has recently integrated more comprehensive measurements such as QST. In OA,
several studies have analyzed pain thresholds and pain sensitivity to different stimuli [51], with most
studies confirming central sensitization [52].

OA pain is influenced by numerous factors

One major OA pain specificity is the influence of exercise and movement on OA pain. Movement
may increase pain, but exercise is a major non-pharmacological approach of OA pain. Thus, exercise
type and dose are very important points to be considered [53].
Pain is a subjective experience, with different strategies to cope with OA pain [54], regarding the site
of OA pain. OA pain, more than other pain conditions, is a condition where several influences have been
reported by patients. Weather conditions may influence OA pain sensitivity, with differences according
to age, gender, and countries [55].
Hormonal changes may also represent a factor that increases the severity of pain [56], as seen at a
menopausal age. Vitamin D deficiency has been considered as a putative factor for OA pain flares [57],
but this has not been confirmed in prospective studies [58]. Genetic factors may also modify pain, and
morphine consumption is also required for analgesic purposes in knee OA [59].
Lastly, OA pain is a condition where mutual influences between pain and mood disturbances should
be analyzed in the management of patients [60].

Conclusion

Pain in OA has a complex pathophysiology, related but distinct from OA pathophysiology. In this
pathophysiology, the joint is as important as the brain and as all modulating systems. It is only recently
that pain physicians and rheumatologists are sharing their research to better understand this major
symptom in OA. This has led to the better description of multiple mechanisms. All mechanisms
important to consider when treating OA, for better management of patients, may be taken into account
in the research of specific analgesic treatments.

Practice points

 OA pain intensity is not correlated with joint damage

 OA pain has both peripheral and central mechanisms
 OA pain has nociceptive, neuropathic, and central mechanisms
 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97 95

Research agenda

 Pathophysiological mechanisms of OA pain should determine the importance of central

mechanisms, especially central sensitization in chronic OA states.
 The development of more precise assessment of OA pain may allow determination of spe-
cific pain profiles
 Future analgesic therapy should be targeted at each pain profile

Disclosure

The author has received consultant fees from Pfizer, Lilly, Grunenthal, Astellas, Sanofi, BMS, and
Roche in the last 5 years.

Conflict of interest

No conflict of interest related to this paper.

References

[1] O'Brien T, Breivik H. The impact of chronic pain e European patient's perspective over 12 months. Scandinavian Journal of
Pain 2012;3:23e9.
[2] Grossman BJ. Rheumatoid arthritis from prehistory to Hippocrates. The Proceedings of the Institute of Medicine of
Chicago 1966 Sep;26(5):114e5.
[3] Hawley DJ, Wolfe F. Pain, disability and pain/disability relationships in seven rheumatic disorders: a study of 1,522 pa-
tients. Journal of Rheumatology 1991;18:1552e7.
[4] Bellamy N, Sothern RB, Campbell J. Rhythmic variations in pain perception in osteoarthritis of the knee. Journal of
Rheumatology 1990;17:364e72.
*[5] Claessens AAMC, Schouten JSAG, Van den Ouweland FA, et al. Do clinical findings associate with radiographic osteoar-
thritis of the knee? Annals of Rheumatic Diseases 1990;49:771e4.
[6] Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use
of primary health care. Annals of Rheumatic Diseases 2001;60:91e7.
[7] Edwards RR, Bingham 3rd CO, Bathon J, et al. Catastrophizing and pain in arthritis, fibromyalgia, and other rheumatic
diseases. Arthritis and Rheumatism 2006;55:325e32.
*[8] Thakur M, Dawes JM, McMahon SB. Genomics of pain in osteoarthritis. Osteoarthritis Cartilage 2013;21:1374e82.
[9] Mapp PI, Sagar DR, Ashraf S, et al. Differences in structural and pain phenotypes in the sodium monoiodoacetate and
meniscal transection models of osteoarthritis. Osteoarthritis Cartilage 2013;21:1336e45.
[10] Zhang RX, Ren K, Dubner R. Osteoarthritis pain mechanisms: basic studies in animal models. Osteoarthritis Cartilage
2013;21:1308e15.
[11] Calvino B, Crepon-Bernard MO, Le Bars D. Parallel clinical and behavioural studies of adjuvant-induced arthritis in the rat:
possible relationship with chronic pain. Behavioral and Brain Research 1987;24:11e29.
[12] Lam FY, Ferrel WR. Inhibition of carageenan induced inflammation in the rat knee joint by substance P antagonist. Annals
of Rheumatic Diseases 1989;48:928e32.
[13] Coderre TJ, Wall PD. Ankle joint urate arthritis (AJUA) in rats. An Alternalternative animal model of arthritis to that
proposed by Freund's adjuvant. Pain 1987:379e93.
[14] Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Archives of International
Pharmacodynamics 1957;111:409e19.
[15] Casey KL, Dubner R. Animal models of chronic pain, scientific and ethical issues. Pain 1989;38:249e52.
[16] Davies DV. Anatomy and physiology of diarthrodial joints. Annals of Rheumatic Diseases 1945;5:29e35.
[17] Kellgren JH, Samuel EP. The sensitivity and innervation of the articular capsule. Journal of Bone and Joint Surgery, British
1950;32:84e92.
[18] Mapp PI. Innervation of the synovium. Annals of Rheumatic Diseases 1995;54:398e403.
[19] Grigg P. Properties of sensory neurons innervating synovial joints. Cells Tissues Organs 2001;169:218e25.
[20] Catre MG, Salo PT. Quantitative analysis of the sympathetic innervation of the rat knee joint. Journal of Anatomy 1999;
194:233e9.
[21] Levick JR. An investigation into the validity of subatmospheric pressure recordings from synovial fluid and their
dependence on joint angle. Journal of Physiology 1979;289:55e67.
96 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97

*[22] Taljanovic MS, Graham AR, Benjamin JB, et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative
assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and
histopathology. Skeletal Radiology 2008;37:423e31.
[23] Heppelmann B, McDougall JJ. Inhibitory effect of amiloride and gadolinium on fine afferent nerves in the rat knee: ev-
idence of mechanogated ion channels in joints. Experimental Brain Research 2005;167:114e8.
[24] Karsdal MA, Woodworth T, Henriksen K, et al. Biochemical markers of ongoing joint damage in rheumatoid arthri-
tisecurrent and future applications, limitations and opportunities. Arthritis Research Therapy 2011;13(2):215.
[25] Ahmed M, Bjurholm A, Schultzberg M, et al. Increased levels of substance P and calcitonin gene-related peptide in rat
adjuvant arthritis. A combined immunohistochemical and radioimmunoassay analysis. Arthritis Rheumatism 1995;38:
699e709.
[26] McDougall JJ, Watkins L, Li Z. Vasoactive intestinal peptide (VIP) is a modulator of joint pain in a rat model of osteoar-
thritis. Pain 2006;123:98e105.
[27] Thompson SWN, Dray A, McCarson KE, et al. Nerve growth factor induces mechanical allodynia associated with novel A
fibre-evoked spinal reflex activity and enhanced neurokinin-1 receptor activation in the rat. Pain 1995;62:219e32.
[28] Ashraf S, Mapp PI, Burston J, et al. Augmented pain behavioural responses to intra-articular injection of nerve growth
factor in two animal models of osteoarthritis. Annals of Rheumatic Diseases 2014;73:1710e8.
[29] Hefti FF, Rosenthal A, Walicka PA, et al. Novel class of pain drug based on antagonism of NGF. Trends In Pharmacological
Sciences 2005;27:85e91.
[30] Chu KL, Chandran P, Joshi SK, et al. TRPV1-related modulation of spinal neuronal activity and behavior in a rat model of
osteoarthritic pain. Brain Research 2011;1369:158e66.
[31] Mousa SA, Straub RH, Scha €fer M, et al. Beta-endorphin, Met-enkephalin and corresponding opioid receptors within
synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Annals of Rheumatic Diseases 2007;66:
871e9.
[32] La Porta C, Bura SA, Aracil-Ferna ndez A, et al. Role of CB1 and CB2 cannabinoid receptors in the development of joint pain
induced by monosodium iodoacetate. Pain 2013;154:160e74.
[33] Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. New
England Journal of Medicine 1991;325:1123e6.
*[34] Bajaj P, Bajaj P, Graven-Nielsen T, et al. Osteoarthritis and its association with muscle hyperalgesia: an experimental
controlled study. Pain 2001;93:107e14.
[35] Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain 2010;149:
573e81.
[36] Graven Nielsen T, Arendt Nielsen L. Peripheral and central sensitisation in musculoskeletal pain disorders: an experi-
mental approach. Current Rheumatology Reports 2002;4:313e21.
[37] Imamura M, Imamura ST, Kaziyama HH, et al. Impact of nervous system hyperalgesia on pain, disability, and quality of life
in patients with knee osteoarthritis: a controlled analysis. Arthritis and Rheumatism 2008;59:1424e31.
*[38] Parks EL, Geha PY, Baliki MN, et al. Brain activity for chronic knee osteoarthritis: dissociating evoked pain from spon-
taneous pain. European Journal of Pain 2011;15:843.
[39] Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysical and functional imaging evidence supporting the presence of
central sensitization in a cohort of osteoarthritis patients. Arthritis and Rheumatism 2009;61:1226e34.
[40] Rodriguez-Raecke R, Niemeier A, Ihle K, et al. Brain gray matter decrease in chronic pain is the consequence and not the
cause of pain. Journal of Neurosciences 2009;29:13746e50.
*[41] Ruscheweyh R, Deppe M, Lohmann H, et al. Pain is associated with regional grey matter reduction in the general pop-
ulation. Pain 2011;152:904e11.
*[42] Neogi T, Felson D, Niu J, et al. Association between radiographic features of knee osteoarthritis and pain: results from two
cohort studies. British Medical Journal 2009;339:b2844.
[43] Torres L, Dunlop DD, Peterfy C, et al. The relationship between specific tissue lesions and pain severity in persons with
knee osteoarthritis. Osteoarthritis Cartilage 2006;14:1033e40.
[44] Burckhardt C. The use of the Mc Gill Pain Questionnaire in assessing arthritis pain. Pain 1984;19:305e14.
[45] Hawker G, Mian S, Kendzerska T. Measures of adult pain. Arthritis Care Research 2011;63:S240e52.
[46] Gandhi R, Tsvetkov D, Dhottar H, et al. Quantifying the pain experience in hip and knee osteoarthritis. Pain Research
Management 2010;15:224e8.
[47] Woolhead G, Gooberman-Hill R, Dieppe P, et al. Night pain in hip and knee osteoarthritis: a focus group study. Arthritis
Care Research (Hoboken) 2010;62:944e9.
[48] Jinks C, Ong BN, O'Neill T. Well, it's nobody's responsibility but my own. A qualitative study to explore views about the
determinants of health and prevention of knee pain in older adults. BMC Public Health 2010;10:148.
*[49] Hawker GA, Davis AM, French MR, et al. Development and preliminary psychometric testing of a new OA pain measure:
an OARSI/OMERACT initiative. Osteoarthritis Cartilage 2008;16:409e14.
*[50] Cedraschi C, Dele zay S, Marty M, 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 symptom
inventory scale (OASIS). PLoS ONE 2013;8(11):e79988.
[51] Suokas AK, Walsh DA, McWilliams DF, et al. QST in painful osteoarthritis: a systematic review and meta-analysis.
Osteoarthritis and Cartilage 2012;20:1075e85.
[52] Wylde V, Palmer S, Learmonth I, et al. Test-retest reliability of Quantitative Sensory Testing in knee osteoarthritis and
healthy participants. Osteoarthritis and Cartilage 2011;19:655e8.
[53] Juhl C, Christensen R, Roos EM, et al. Impact of exercise type and dose on pain and disability in knee osteoarthritis: a
systematic review and meta-regression analysis of randomized controlled trials. Arthritis and Rheumatology 2014;66(3):
622e36.
*[54] Perrot S, Poiraudeau S, Kabir-Ahmadi M, et al. Correlates of pain intensity in men and women with hip and knee
osteoarthritis. Results of a national survey: the French ARTHRIX study. Clinical Journal of Pain 2009;25:767e72.
 S. Perrot / Best Practice & Research Clinical Rheumatology 29 (2015) 90e97 97

[55] Timmermans EJ, van der Pas S, Schaap LA, et al. Self-perceived weather sensitivity and joint pain in older people with
osteoarthritis in six European countries: results from the European Project on OSteoArthritis (EPOSA). BMC Musculo-
skeletal Disorders 2014;15:66.
[56] Cauley JA, Kwoh CK, Egeland G, et al. Serum sex hormones and severity of osteoarthritis of the hand. Journal of Rheu-
matology 1993;20:1170e5.
[57] Muraki S, Dennison E, Jameson K, et al. Association of vitamin D status with knee pain and radiographic knee osteoar-
thritis. Osteoarthritis Cartilage 2011;19(11):1301e6.
[58] McAlindon T, LaValley M, Schneider E, et al. Effect of vitamin D supplementation on progression of knee pain and
cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial. Journal of American
Medical Association 2013;9:155e62.
[59] Chou W, Yang L, Lu H. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine
consumption for analgesia after total knee arthroplasty. Acta Anaesthesiologica Scandinavica 2006;50:787e92.
[60] Goldenberg D. The interface of pain and mood disturbances in the rheumatic diseases. Seminars in Arthritis Rheumatism
2012;40:15e31.