University of Groningen
Neuropathic-like symptoms in hip and knee osteoarthritis
Blikman, Tim
DOI:
10.33612/diss.134434931
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2020
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Blikman, T. (2020). Neuropathic-like symptoms in hip and knee osteoarthritis. University of Groningen.
https://doi.org/10.33612/diss.134434931
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and Lawrence (KL) grading system, which is related to the development of osteophytes (bony spurs), joint space loss, subchondral sclerosis and cyst formation [7]. Clinical OA is typically defined by the American College of Rheumatology (ACR) criteria. These criteria incorporate joint pain and several other features like age [3]. Oddly, there is no strong relation between radiographic osteoarthritis and clinical OA [3]. This is indicative that some parts of the imaged joint lack nociceptive innervation, and that pain experience in symptomatic OA is more than simply a response to structural joint changes. Probably other factors, like neuropsychological factors, are playing a role in the process [3].
The epidemiology of OA is complex and multifactorial, ranging from genetic components to neuropathic alterations in the osteoarthritic joint [8]. These risk factors and related structural alterations (see Figure 1) could ultimately lead to symptomatic OA pain, which is the predominant factor guiding clinical treatment.
OA risk factors:
trauma, malalignment, mechanical overload, age, obesity, metabolic syndrome, genetic predisposition, gender
Release of cytokines/mediators/MMPs/ADAMTSs
OA pain
OA structural alterations: synovitis
angiogenesis nerve damage/ growth
degeneration of cartilage matrix
apoptosis of chondrocytes
sclerosis osteophyte bone marrow lesion
synovium cartilage bone
How?
Figure 1. Risk factors and pathological events leading to osteoarthritis (OA) [8]
The clinical treatment of OA is multidimensional and patient-specific. All available treatment modalities are initially conservative, as no curative disease-modifying treatments exists. Conservative treatment typically starts with non-pharmacological approaches. These are simple lifestyle modifications like weight loss in obese patients and exercises to improve muscle strength [9]. Other non-pharmacological approaches entail bracing to unload osteoarthritic compartments and surgical strategies to correct malalignment This thesis focuses on neuropathic-like symptoms in patients with lower limb
osteoarthritis (OA). The thesis starts with research on identification of these symptoms up to their treatment. Before jumping to these chapters it is essential to have some basic understanding of general concepts that will be discussed. This introduction first presents some basic characteristics of hip and knee osteoarthritis, then examines the definition of pain and pain pathways, including the role of neuropathic-like symptoms in osteoarthritis.
HIP AND KNEE OSTEOARTHRITIS
Osteoarthritis is a chronic, progressive degenerative synovial joint disease and the most common form of arthritis. Traditionally it is defined by loss of joint cartilage and subchondral bone, but nowadays it is considered a disease of the entire joint (subchondral bone, capsule, synovial membrane, ligaments) and surrounding periarticular muscles [1]. An osteoarthritic joint generally has the following characteristics to varying degrees [2]: 1. Cartilage damage, becoming less elastic and more brittle;
2. Bony spurs at the edge of the joint; 3. Swelling of the joint;
4. Poorly lubricating synovial fluid;
5. Breakdown of ligaments and tendons around the joint.
Symptomatic OA is typically characterized by joint pain, stiffness and deficits in joint function. It frequently has detrimental effects on a person’s psychological wellbeing [3]. Other major symptoms include joint instability, reduced movement, deformity, crepitus, swelling and muscle weakness [4]. OA most commonly affects the knees, hips and hands [1]. OA of the knees and hips cause the greatest burden, as these are large weight-bearing joints. In a study that investigated 291 diseases in 187 countries, hip and knee OA was ranked as the 11th highest contributor to global disability [5]. It is typically not a disease that occurs early in life – it usually presents after age 50 – but in case of joint injury it can start earlier [2]. Worldwide around 10% of men and 18% of women aged over 60 have symptomatic OA [1]. It is anticipated that the future burden of OA will become a major problem for health systems globally [5]. This is largely explained by population ageing and the global epidemic of overweight and obesity, which are risk factors for OA [6].
The diagnosis of OA is made either clinically or radiographically, usually a combination of both. Due to the ease of standardization, radiography is often used as the gold standard diagnostic tool [6]. Radiographic level of degeneration is usually expressed by the Kellgren
CHAPTER 1 GENERAL INTRODUCTION
be activated in the absence of pain perception [12]. Nociceptors are only triggered when a stimulus intensity reaches the noxious range. There are essentially two major classes of nociceptors. The first are myelinated (A-Õ) afferents, which become rapidly activated when there is acute, well-localized pain. The second class of nociceptors react later and are unmyelinated C-fibers that convey poorly localized “late” pain. Fast pain (A-Õ) gives rise to sharp pain, while the sensation from C-fibers is deep and prolonged [15]. The noxious stimuli are transmitted through neural pathways. These pathways include the peripheral nervous system, the central nervous system and the autonomic nervous system. The process starts with activation of the nociceptors, which pass the signal through the axons of the peripheral nerves terminating in the dorsal horn of the spine. From the dorsal horn the message goes through the spinothalamic tract up through the spinal cord to output on the thalamus, acting as a big “relay station” to the cerebral cortex [16]. The brain actively modulates the incoming information by influencing the dorsal horn via descending trajectories coming from the medulla/periaqueductal gray (see Figure 2). Due to the somatopic organization of the descending connections, it can alter signal transmission from specific body parts. Further, it can have both anti- and pro-nociceptive effects. It is believed that this system was essential to human evolution, as the fight-or-flight reaction is only possible when there is suppression of pain in a severely-injured individual [16].
Figure 2. Pain input and modulation
(osteotomy) [9]. Some experimental options pursue cartilage repair, yet there is little evidence that these techniques can alter the development of OA [9]. Pharmaceutical agents are frequently promoted parallel to non-pharmacological approaches, mostly paracetamol and/or non-steroidal anti-inflammatory drugs to control pain. Other frequently used agents are glucosamine and chondroitin, but studies show that they do not have any clinically relevant benefits [9]. Besides oral agents intra-articular injections, like anti-inflammatory steroids and hyaluronic acid, are also given to relieve symptoms [9]. Unfortunately, when conservative options for OA are ineffective joint replacement surgery is performed. This is a definitive procedure and a major surgery with all the risks involved. Dissatisfaction and residual pain after primary arthroplasty is common; up to 20% of patients experience unexplained chronic postsurgical pain and are dissatisfied [10,11].
PAIN
Pain is defined by the International Association for the Study of Pain (IASP) as “an
unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [12]. The IASP also states that
pain is always subjective and always unpleasant, therefore an emotional experience. “Experiences which resemble pain but are not unpleasant, e.g., prickling, should not be called pain”. The IASP definition avoids tying pain to the stimulus. “Activity induced in the
nociceptor and nociceptive pathways by a noxious stimulus is not pain, which is always a psychological state, even though we may well appreciate that pain most often has a proximate physical cause”[12]. Chronic pain is simply the chronicity of this experience,
namely persistent or recurrent pain lasting longer than three months [13]. Chronic pain is a major health problem. In Europe, chronic pain is experienced by around 20% of adults. It has serious negative effects on people’s quality of life. Another concern is that it is poorly managed in nearly half of cases, as inadequate pain management is received [14]. To further understand the transmission and processing of pain it is key to begin where it starts, nociception. Nociception is defined as “the neural process of encoding noxious stimuli” [12]. This can trigger autonomic processes like high blood pressure, or behavioral processes like a withdrawal reflex. In general the process starts with a stimulus that is damaging to normal tissues. This stimulus is noted by the nociceptor, which is a “high-threshold sensory receptor of the peripheral nervous system that is capable of transducing and encoding noxious stimuli” [12]. One must bear in mind that nociception and pain are linked but are not the same. This is because of the emotional and subjective nature of pain. Undoubtedly, activation of nociceptors can trigger pain but nociceptors can also
Figure 3. Neuronal changes in humans with OA [8]
In the field of pain, and especially in the musculoskeletal field including OA, there is an important ongoing shift in the classification and treatment of chronic pain, particularly centrally sensitized pain. The neural changes in OA are probably accountable for neuropathic-like symptoms [8]. Based on outcomes of questionnaires, such as the painDETECT, it is known that about 20% of hip and 20-67% of knee OA patients experience neuropathic pain-like symptoms [19-26]. Currently it is unclear whether neuropathic-like symptoms, probably a proxy for a sensitized pain system, have a clinically relevant influence on patient-specific outcome variables. Literature shows an association between OA pain severity and functional limitations, yet unambiguous evidence about the association between neuropathic-like symptoms, joint-specific function and health-related quality of life is lacking. Moreover, as indicated previously, a sensitized pain state could persist after arthroplasty. It is therefore essential to know whether preoperative neuropathic-like symptoms are predictive for long-term chronic postsurgical pain and dissatisfaction among hip and knee arthroplasty patients. If so, it would be essential to
TYPES OF OSTEOARTHRITIC PAIN
Joints are densely innervated with A-Õ- and C-fibers. Under normal conditions these respond only to strong mechanical circumstances, such as rotation against resistance, which causes a human to experience pain [8]. OA pain was traditionally considered as a purely nociceptive process, nowadays this is seen as a mixed type of pain. Neural changes at several levels could be in place in a subset of patients. These changes include peripheral sensitization and central sensitization (CS).
The IASP definition of peripheral sensitization is the “increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields” [17]. In the case of OA it means the peripheral nervous system experiences hyperexcitability from non-noxious stimuli. Experimental studies show that inflammatory mediators and tissue damage-associated substances reduce the threshold of high-threshold neurons. As a result joint nociceptors, which are normally silent and not active, are more likely to respond to noxious and non-noxious stimuli. This can already start after the first hours of inflammation and can last for weeks. Eventually the information travels to the central nervous system (CNS), where it is processed and subjectively interpreted as pain (see Figure 3) [1,8].
Pain is not only peripherally regulated. The increased peripheral input in the central nervous system can cause dysregulation of the CNS, which is called CS [8]. The IASP defines CS as an “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input” [17]. CS results from plasticity of the CNS and produces hypersensitivity throughout the whole body. This is due to spontaneous neural activity, reduced activation thresholds and expansion of the receptive field [1]. It involves both excess ascending signals from the periphery (OA joint) and deficits in the descending inhibitory system (see Figure 3)[1]. CS is maintained through peripheral nociceptive input (the OA joint), but it is believed that it can persist after removal of the peripheral nociceptive source [18].
CHAPTER 1 GENERAL INTRODUCTION
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find out whether these symptoms are modifiable and thus treatable in end-stage OA patients. This dissertation sheds further light onto these subjects, which could lead to better understanding and treatment of neuropathic-like symptoms in hip and knee OA.
SCOPE OF THE THESIS
The overall aim of this thesis is to further elucidate the role of neuropathic-like symptoms in symptomatic hip and knee OA. The first aim is to investigate the consequences of experiencing neuropathic-like symptoms in hip and knee OA patients. The focus will be on preoperative joint-specific function, health-related quality of life and chronic postsurgical pain. The second aim is to investigate whether a centralized pain state, defined as experiencing neuropathic-like symptoms, could be treated in OA patients awaiting joint arthroplasty.
OUTLINE OF THE THESIS
First, in Chapter 2 a questionnaire assessing neuropathic pain is translated and cross-culturally adapted to the Dutch language. This questionnaire is subsequently test-retested to gain insights into reliability. It will serve throughout the thesis as a tool to measure pain mechanisms. The results of the first aim are presented in Chapter 3 and
Chapter 4. Chapter 3 describes the sole influence of experiencing neuropathic-like
symptoms on joint function and health-related quality of life in hip and knee OA patients.
Chapter 4 presents the results of a longitudinal study describing the predictive value
of experiencing neuropathic-like symptoms preoperatively on chronic postsurgical pain and dissatisfaction after primary hip/knee arthroplasty.
The second aim, which is focused on the treatment of centralized pain, starts in Chapter
5. This chapter describes the design of the Duloxetine in OsteoArthritis (DOA) study, which
is a prospective, multicenter, pragmatic, open-label randomized controlled trial assessing the effect of preoperative pain treatment by means of duloxetine on postoperative outcome after total hip or knee arthroplasty. Chapter 6 presents the results of this study regarding the effectiveness of the preoperative treatment phase. In Chapter 7 the results of the different studies in this thesis are discussed and recommendations for future research are given.
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CHAPTER 1 GENERAL INTRODUCTION
