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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NEUROPATHIC-LIKE SYMPTOMS
To date, neuropathic pain cannot be objectified in OA patients because of several conditions that should be met before pain is considered neuropathic. These conditions were drafted by the International Association of the Study of Pain (IASP) [1] and are currently not suitable for a condition like OA. The first condition to be met is that there should be a lesion or disease of the peripheral somatosensory nervous system [2]. While this is the case in OA, it is impossible to establish at the level of the individual patient. The typically small nerve lesions in OA are situated in/around the joint, so they are not easily accessible for examination. MRI scans are not yet sensitive enough to visualize these nerve lesions [3], but previous research has indicated their presence [3]. Research shows upregulation of neural damage markers in peripheral nerves that innervate periarticular and intraarticular structures (sodium monoiodoacetate rat model of OA) [4]. Samples obtained during knee replacement surgery reveal infiltration of immune cells, increased angiogenesis and increased growth factor expression at the osteochondral junction in OA joints compared to healthy joints [5]. This probably contributes to ectopic neurovascular innervation into the cartilage, which is normally a minimally innervated structure [3]. The second condition that must be met to call pain neuropathic is that the pain distribution should be neuroanatomically plausible [2]. This is again impossible to investigate in OA. As the affected nerves in OA are not cutaneous, they lack a skin-defined innervation territory, therefore pain will not follow a specific pattern [3]. Hence by definition, OA pain cannot be called neuropathic pain. The term neuropathic-like symptoms was thus introduced into the field of OA and is accordingly used throughout this thesis. In this thesis neuropathic-like symptoms are defined as experiencing ≥ 13 points [6] on the painDETECT questionnaire (one of the leading neuropathic pain questionnaires in the field [7,8]), which indicates a possible or likely neuropathic pain profile. The PainDetect questionnaire was developed to discriminate between nociceptive and neuropathic pain [7,8]. As this questionnaire can be filled in quickly, it is easy to implement in daily clinical practice [9].
Likely due to the incapability to test for definite neuropathic pain, there is currently insufficient awareness for neuropathic-like symptoms in OA patients. More awareness seems justified, as previous research and results from this thesis show that neuropathic-like symptoms are highly prevalent among knee and hip OA patients. Respectively 46% and 37% of these patients have experienced such symptoms (Chapter 3). Results in Chapter 3 also showed that neuropathic-like symptoms are associated with clinically relevant diminished physical functioning in knee OA patients and deteriorated pain-related quality of life in hip OA patients. Comparable negative impacts were seen in
INTRODUCTION
The overall aim of this thesis was to further elucidate the role of neuropathic-like symptoms in symptomatic hip and knee osteoarthritis (OA). An important step in this direction was the development of a Dutch version of the modified painDETECT Questionnaire (mPDQ), tailored to hip and knee OA patients. In Chapter 2 it was found that the Dutch modified version of the mPDQ seems to fit as a discriminative tool to identify knee and hip OA patients with a neuropathic pain profile. The first aim was to investigate the consequences of experiencing neuropathic-like symptoms (Chapters 3 and 4). In Chapter 3 it was found that knee OA patients who experience neuropathic-like symptoms encounter clinically relevant diminished joint-related function. By contrast, in hip OA the presence of neuropathic-like symptoms was only associated with a lower subjective rating of pain-related quality of life. Chapter 4 presented the results of a prospective cohort study. It was studied whether preoperatively experienced neuropathic-like symptoms act as an additional predictor for chronic postsurgical pain (CPSP) and dissatisfaction after total knee and hip arthroplasty (TKA/THA). The study showed that symptoms at least double the odds of CPSP one year after TKA/THA, and CPSP was more evident in hip patients. Dissatisfaction seems not to be related with preoperatively experienced neuropathic-like symptoms.
The second aim of this thesis was to investigate whether a centralized pain state, defined as experiencing neuropathic-like symptoms, could be treated in OA patients awaiting TKA/THA. This typically represents OA patients for whom conservative treatment options like acetaminophen and non-steroidal anti-inflammatory drugs failed (end-stage). In a pragmatic enriched randomized controlled trial (Chapter 5) it was found that adding duloxetine treatment to care-as-usual is beneficial for end-stage knee OA patients. End-stage hip OA patients seem to be non-responsive to duloxetine treatment though (Chapter 6).
This general discussion is structured around three themes. First the theme of neuropathic-like symptoms will be discussed. This theme will start with the term neuropathic pain and its relation with like symptoms. The impact of experiencing neuropathic-like symptoms in the preoperative setting will be also discussed, then its relation with CPSP. The second theme is dedicated to duloxetine and its role in the management of osteoarthritic pain. The third and final theme will put duloxetine in perspective with its legal framework, as the European regulatory authority has not yet approved duloxetine for the treatment of OA pain or discomfort.
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GENERAL DISCUSSION
(ESCEO) place duloxetine as their last pharmacological step, for patients who stay persistently symptomatic despite use of non-steroidal anti-inflammatory drugs and intra-articular injections [18]. ESCEO states that central sensitization may play a role in osteoarthritis pain and that duloxetine could have a role in the advanced management of the disease. In summary, the various research societies advise duloxetine treatment for symptomatic, relatively healthy OA patients who do not experience enough pain relief from conservative analgesics. ESCEO also states that duloxetine may be appropriate for OA patients with central sensitized pain, but notes that research into this specific subgroup is lacking. Our thesis (Chapters 5 and 6) adds new knowledge, as the pain-relieving effects of duloxetine were analyzed in hip and knee OA patients who were placed on a waiting list for arthroplasty. This implies that only persistently symptomatic (end-stage) and relatively healthy (fit for surgery) OA patients were selected (as advocated by the guidelines). What’s more, our intervention study (Chapter 6) was the first to solely include patients with some level of neuropathic-like symptoms, which could be seen as a proxy for a centrally sensitized pain status [6]. The results of this intervention study showed that additional duloxetine therapy is effective for end-stage knee OA patients with neuropathic-like symptoms. In hip OA patients, additional duloxetine treatment has no pain-relieving effect over care-as-usual.
As duloxetine treatment likely improves pain in end-stage knee OA patients with neuropathic-like symptoms (Chapter 6), it seems warranted to further investigate whether it could be implemented earlier in the OA process – in OA patients that experience the symptoms as a proxy for a centrally sensitized pain status. Earlier desensitization by duloxetine could lengthen the conservative treatment phase, but research is needed to confirm this hypothesis.
DULOXETINE TREATMENT AND THE LEGAL FRAMEWORK
As presented in Chapter 6 of this thesis, duloxetine seems effective in end-stage knee OA patients with neuropathic-like symptoms, yet its implementation to treat OA pain is currently not possible in the Netherlands. By contrast, the U.S. Food and Drug Administration (FDA) has approved duloxetine for the treatment of chronic musculoskeletal pain, including discomfort from osteoarthritis [19]. The European Medicines Agency (EMA) did not approve duloxetine due to lacking information regarding its safety in the elderly [20] and uncertainty as to whether the found treatment effects could be maintained over a substantial period of time [20]. Results presented in Chapter 6 show that additional duloxetine treatment is effective as an analgesic in end-stage knee other OA-related conditions like musculoskeletal pain, diabetic neuropathy and chronic
low back pain [10]. Based on these results, one could conclude that neuropathic-like symptoms are prevalent and invalidating in lower-limb OA, especially among knee OA patients. It therefore seems worthwhile to screen patients on their pain phenotype, as neuropathic-like symptoms seem to be modifiable with treatment (Chapter 6). Results in Chapter 6 showed that treatment was beneficial in terms of pain relief (end-stage knee OA). In theory this could lead to postponing or even aborting arthroplasty.
Next to its negative impact during the course of OA (Chapter 3), this thesis showed that preoperatively experienced neuropathic-like symptoms are associated with chronic postsurgical pain (CPSP; Chapter 4) after TKA and THA. CPSP is a highly unfavorable outcome after TKA/THA. Knowledge about the presence of neuropathic-like symptoms could thus be used to better predict if a patient is at risk for developing CPSP. This can help physician as well as patient when deciding about arthroplasty, especially in terms of expectation management. Moreover, identification of neuropathic-like symptoms and subsequent preoperative treatment could result in a reduction of CPSP. This research is ongoing, as our preoperative cohort (Chapter 6) will be followed for one year postoperatively (see Chapter 5 for the study protocol).
DULOXETINE AS TREATMENT OF NEUROPATHIC-LIKE
SYMPTOMS
It is thought that experienced neuropathic-like symptoms are the result of central nervous system sensitization (CS) [3,11,12]. Patients with these symptoms were almost six times more likely to have signs of CS [6]. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, seems effective in treating neuropathic pain conditions as well as chronic pain conditions in which central sensitization is one of the key underlying pain mechanisms [13-15]. Multiple international guidelines mention duloxetine in their OA treatment recommendations. Duloxetine is the only centrally acting agent endorsed by the 2014 Osteoarthritis Research Society International (OARSI) recommendations [16]. OARSI considered duloxetine appropriate for most clinical sub-phenotypes, however due to the associated adverse events and the availability of more targeted therapies it has uncertain appropriateness as a first-line analgesic in single-joint OA patients with comorbidities. The older 2012 recommendations by the American College of Rheumatology (ACR) state explicitly that they have no recommendations on the use of duloxetine for knee and hip OA, yet do not discourage it either [17]. Finally, the 2014 recommendations by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
2. Preoperatively experienced neuropathic-like symptoms are associated with CPSP. This can help the OA caregiver decide about arthroplasty. It gives both caregiver and patient better insight into what to expect after arthroplasty when experiencing neuropathic-like symptoms preoperatively (likely as an expression of a centralized pain state).
3. Based on this thesis it could be stated that adding duloxetine treatment to care-as-usual seems to be beneficial for end-stage knee OA patients with neuropathic-like symptoms, on whom it seems to have the potential to delay the process toward arthroplasty. In the long term this could even mean fewer primary and revision arthroplasties.
FUTURE RESEARCH
% Despite the potential of the modified-painDETECT questionnaire, it is currently unknown whether it is also suitable as an evaluative tool to record changes over time (responsiveness) or changes after an intervention. Future longitudinal studies are therefore needed.
% As stated earlier there are currently no non-invasive ways to objectify nerve disturbances in or around OA joints. Measuring proprioceptive deficiencies could be helpful toward gaining insight into nerve disturbances, since good proprioception requires adequate functioning of peri/intra-articular nerves. Explorative research is needed to detect any associations between proprioceptive acuity and neuropathic-like symptoms.
% This thesis showed the positive effects of duloxetine treatment in end-stage knee OA patients with neuropathic-like symptoms (likely as an expression of a centralized pain state). Future longitudinal studies with a more extensive follow-up should be conducted to investigate whether the positive effect of duloxetine in knee OA patients could be maintained over a longer period of time.
% Additional research is needed in early-stage OA patients with neuropathic-like symptoms. Earlier desensitization by duloxetine could lengthen the conservative treatment phase and thus postpone total knee replacement surgery.
% This thesis showed that preoperatively experienced neuropathic-like symptoms are associated with CPSP. Whether preoperative treatment of neuropathic-like symptoms could reduce the odds of experiencing CPSP remains unknown. This research is currently in progress, as our preoperative duloxetine cohort (Chapters 5 and 6) will be followed up to one year postoperatively.
OA patients with neuropathic-like symptoms. The results will not lead to a full registration by the EMA though, as the study was not aimed to study safety in the elderly nor the long-term effectiveness of duloxetine. Awaiting future studies, in the meantime the EMA could reconsider registration of duloxetine for a specific subgroup of patients. Especially end-stage knee OA patients with neuropathic-like symptoms not responding well to traditional first-line analgesics could benefit from this specific subgroup registration. It is quite possible that implementation of duloxetine treatment in this subgroup could postpone total knee replacement surgery. Registration in a specific subgroup would reduce the impact of adverse events, compared to a full registration, as the registration indication is strict and would only involve end-stage knee OA patients with neuropathic-like symptoms not responding well to first-line analgesics. This impact reduction is relevant, as nearly 95% of patients using duloxetine experienced adverse events (Chapter 5), albeit mostly mild and only apparent at the start of the intervention. Still, 20% of duloxetine patients discontinued due to AEs. This proportion is relatively high, but seems acceptable when duloxetine is used solely in knee OA patients with neuropathic-like symptoms who do not respond well to first-line analgesics and would otherwise need to turn to arthroplasty. It is moreover likely that the discontinuation rate due to adverse events would be lower in the “real-life” setting. Firstly, the trial design used in this thesis (Chapters 5 and 6) made it opportune for OA patients to discontinue relatively quickly, as participants were aware of the fact that they would soon undergo arthroplasty irrespective of continuation/ discontinuation. So a minor level of inconvenience due to any adverse event could already be a reason to discontinue. Secondly, our study population was relatively old. From previous research it is known that younger patients discontinue about half as often due to adverse events (11.8% versus 22.3%) [21].
To conclude, based on results of this thesis it seems reasonable to partially reconsider the earlier verdict given by the EMA; duloxetine should be an option for end-stage knee OA patients who experience some level of neuropathic-like symptoms and do not respond well to first-line analgesics. For the full registration it seems warranted to await results of studies that focus more in detail on the safety profile in elderly patients, including studies with a longer follow-up.
PRACTICAL IMPLICATIONS
This thesis offers some implications that can optimize clinical practice.
1. The modified-painDETECT questionnaire (mPDQ) is a discriminative tool that can serve to identify knee and hip OA patients with a neuropathic pain profile.
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CONCLUDING REMARKS
Research presented in this thesis has provided insight into neuropathic-like symptoms in hip and knee osteoarthritis. Firstly, neuropathic-like symptoms are highly prevalent and should not be ignored by OA caregivers. The symptoms are related with impaired function in knee OA patients and with deteriorated quality of life in hip OA patients. The negative effects of experiencing preoperative neuropathic-like symptoms were also apparent after arthroplasty. Patients with such symptoms were more likely to experience CPSP. These findings stress the need for additional awareness and treatment of neuropathic-like symptoms. Duloxetine treatment was particularly effective in reducing pain in end-stage knee OA patients who suffered from these symptoms. Future studies should be performed to confirm whether improvements in pain and function can persist after arthroplasty too.
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