Örebro University School of Medicine Degree project, 15 ECTS January 2018
Descriptive study on self-reported pharmacological and
non-pharmacological substances in patients with symptomatic hip osteoarthritis
___________________________________
Author: Patricia Goro
School of Medicine, Örebro University, Sweden
Supervisors: Lillemor A. Nyberg, MD, GP, PhD
Institution of medicine, Örebro university, Sweden Ewa M. Roos, PT, PhD, Professor University of Southern Denmark, Odense, Denmark Örebro, Sweden
Abstract
Introduction: Osteoarthritis (OA) is a leading cause of disability and the incidence is
expected to rise in the future. The knee and hip are the most commonly affected joints, this study is focused on hip OA. The diagnosis is based on clinical criteria. As cure is not achievable yet, the treatment is focused on the primary symptom - pain. The core in hip OA treatment is physical activity. Medical treatment is complementary and the options are many and diverse, resulting in differences among patients.
Objective: Descriptive analysis of the usage of non- and pharmacological substances in
patients with symptomatic hip OA.
Method: The extracted data from the Good Life with osteoArthritis in Denmark (GLA:D)
data base on 5481 hip OA patients self-reported substance use, obtained from the study population (7129), were processed from a questionnaire. The free text column was categorised separately into 66 new categories.
Results: The two most common substances out of 80 were acetaminophen (71.1%) and
NSAID (44.9%). Representing the third and fourth categories were naturopathic drugs/dietary supplements (27.7%) and glucosamine (16.5%). The remaining categories were represented in a falling scale from 5.6% to 0.5%. The substance frequency (10310) was higher than the patient frequency (5481).
Conclusion: Among the studied hip OA patients, 15 different categories of non- and
pharmacological substances were used by ³0.5%. The two most common categories were acetaminophen and NSAID, but non-pharmacological naturopathic drugs/dietary supplements and glucosamine were more commonly used than opioids.
Abbreviations
ASA – acetylsalicylic acid BMI – body mass indexCAM – complementary and alternative medicine COX inhibitor – cyclooxygenase inhibitor
FOF – musculoskeletal function and physiotherapy GI – gastrointestinal
GLA:D – good life with osteoarthritis in Denmark
GRADE – Grading of Recommendations Assessment, Development and Evaluation NSAID – non-steroidal anti-inflammatory drugs
OA – osteoarthritis
OARSI – osteoarthritis research society international PG – prostaglandin
RA – rheumatoid arthritis
SDU – university of southern Denmark WHO – world health organization
Contents
1. INTRODUCTION 5
1.1 NON-PHARMACOLOGICAL TREATMENT 6
1.2 PHARMACOLOGICAL TREATMENT 7
2. OBJECTIVE 8
3. MATERIAL AND METHODS 9
3.1 STUDY DESIGN 9
3.2 PATIENTS AND CLINICAL CHARACTERISTICS 9
3.3 STATISTICS 10 3.4 ETHICS 10 4. RESULTS 11 5. DISCUSSION 12 6. CONCLUSION 16 7. ACKNOWLEDGEMENTS 16 8. REFERENCES 18
1. Introduction
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA can affect all the joints in the body but the most commonly affected are the knee, hip, hands and the first metatarsophalangeal joint [1]. The world-wide estimation of OA is that 18% women and 9.6 % men have symptomatic OA, which indicates a higher incidence in women [2]. The incidence of OA increase with age and obesity. Therefore, with an aging population and as the prevalence of obesity increases, the incidence of OA is expected to rise in the future [3,4].
This study is focused on hip OA. It is estimated that 25% of people by the age of 85 will develop symptomatic hip OA [5]. The life time risk of knee OA is even higher [6]. Which possibly contributes to the fact that the clinical guidelines for hip OA is generally based on recommendations for knee OA [7,8]. However, it is important to differ them apart as OA is considered a heterogeneous disease [9].
There have been numerous ways to define the disease throughout history. The current definition emphasise that OA is not a single disease. Although the diseases share the same biological, morphological and clinical features, they differentiate from each other etiologically. The biological mechanism includes destabilization in the synthesis and degradation of the articular cartilage. Consequently, the morphological features include degeneration of the articular cartilage. Hip arthrosis canbe diagnosed with a combined assessment of symptoms, anamnesis and clinical findings. The most common symptoms in hip OA are hip pain, stiffness and physical disability. The clinical findings are reduced flexion and internal rotation of the hip. With these three criteria, diagnosis can be made supported by Level 2 evidence, according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [9]. Radiological examinations are not a part of the criteria for diagnosing OA as the correlation between the patients symptoms and radiographic picture is weak [10].
Joint pain is one of the primary and the most dominant symptoms in OA [11]. It is still unclear which structural change causes the joint pain. There is also ambiguity whether the pain is of inflammatory or nociceptive nature [12]. The articular cartilage is not innervated by sensory nerves, hence the origin of the pain cannot be labelled to the cartilage [13]. However the joint capsule and the ligaments surrounding the joint are innervated by nociceptive fibers. There are
three different nociceptors that respond to different stimuli, such as mechanical, chemical and pathological stimulus. Inflammation and tissue damage can lead to peripheral sensitization of these nociceptors, which results in an exaggerated response to a stimulus. Furthermore, the central nervous system is also sensitized to mechanical stimuli. However, OA is not defined as an inflammatory disease as not all patients have an inflammatory component in their joint. Therefor inflammatory pain only explains some of the symptoms. Whereas peripheral sensitization explain pain in harmless movements and central sensitization explain radiating pain [12].
As there is no cure for OA yet the treatment is based on symptomatic pain relief. Primarily, pain relief can be achieved with non-pharmacological and pharmacological therapies. Optimal treatment includes a combination of both. Secondly, surgical management can be considered if the patient does not respond to any other treatment [14]. Besides, patients also use unconventional treatments named complementary and alternative medicine (CAM) [15].
1.1 Non-pharmacological treatment
Osteoarthritis research society international (OARSI) was developed to provide international guidelines in the treatment of hip and knee OA. The most important non-pharmacological treatment for OA is exercise therapy and patient education. The education should include how changes in lifestyle and exercise influence the disease [16]. For example, the Good Life with Osteoarthritis in Denmark (GLA:D) project was established to stress the importance of combining exercise and education as the core treatment of patients with OA [17]. Regarding exercise, bode strengthening and aerobic exercise is recommended [14]. According to three systematic reviews exercise can improve pain, function and may reduce progression of hip OA. Further, exercise is recommended as obesity is a risk factor for the development of OA. However, there is moderate associations between obesity and hip OA, compared to OA of the knee. Weight-loss recommendations for patients with hip OA is so far not based on evidence, but rather on expert opinion [14].
The pain-relieving mechanism that is achievable with exercise is yet not fully understood. Aerobic exercise gives release of endorphins which affects the central nervous system through inhibition of pain. Strength training has a pain-relieving effect as increased muscle strength leads to decreased load in the joint [18].
CAM’s are medical therapies that are not a part of the conventional medical therapy [19]. The use of CAM is high among patients with OA [15]. A population-based study found that patients with OA most commonly used glucosamine and chondroitin as nutritional supplements [20]. Both of these occur naturally in the cartilage and was earlier recommended for patients with knee OA [16]. According to an update in OARSI’s international guidelines these supplements are no longer recommended as there is no evidence in their pain reducing mechanism [21].
1.2 Pharmacological treatment
Pharmacological treatment should be used as a complement to the core-treatment of OA, which is exercise and weight-loss [16]. Pharmacological treatment of OA is based on the world health organization (WHO) ladder, originally developed for treating cancer pain. The ladder is a step care approach based on the severity of pain. Firstly, acetaminophen is recommended, thereafter non-steroidal anti-inflammatory drugs (NSAID), weak opioids and lastly strong opioids. A combination of analgesics is recommended for optimal pain relief [22].
The recommended first line-treatment of OA is acetaminophen. This core recommendation should be applied on patients with mild to moderate pain. Acetaminophen is preferred as a long-term treatment considering its safety and efficacy. However, the use of this analgesic has lately starting to be questioned. This is, as studies have shown a small reduction in pain with acetaminophen.
The recommendation of second line pharmacological treatment is NSAID. Patients with OA should be treated with the lowest effective dose and for as short period as possible. Caution regarding the use of NSAID should also be taken into account, considering patients with increased GI-risk [16]. There are two different isoforms of cyclooxygenase inhibitor (COX), COX-1 and COX-2. NSAID inhibits either both, non-selective NSAID, or each respectively, selective NSAID. Inhibition of COX-1, involves a decrease in prostaglandin (PG) production which cause an increased gastrointestinal (GI) risk [23]. Furthermore, NSAID is in general associated with more adverse effects in the GI-tract compared to acetaminophen.
The recommended third line treatment of OA is opioids. In case of refractory pain the use of weak opioids should be considered, whereas severe pain is treated with stronger opioids. The
reduction of pain achieved with opioids are associated with adverse effects, such as nausea, constipation and dizziness. Concerning the addictive issue with opioids, there are no studies on the long term use of opiates in patients with OA [16].
A recent cross-sectional study found that in a study group of patients with hip and/or knee OA 50% used acetaminophen, 30% NSAID and 12% opioids. Which coincide with the current step care approach in patients with OA [24]. These findings are confirmed by other studies [25,26]. Although other studies have found a variety of differences in use of these painkillers that does not correspond with the step care approach [24].
New therapeutic approaches for pain relief in OA are the use of antidepressant and anticonvulsant drugs. The use of these drugs is based on the findings that the central nervous system is a part of the processing of pain [27]. Both antidepressant and anticonvulsive drugs are commonly used in patients with arthritis and therefor it has been proposed to describe them as “pain-modifying drugs”. However, their mechanism is not fully understood and they have not been studied in patients with OA. Further, the limiting aspect is the fact that both of these drugs have adverse effects that are not suitable for elder patients [28].
Medical treatment of hip OA includes a variety of options, which is why it is of importance to analyse the use of these treatments among the patients. To get a comprehensible picture, both pharmacological and non-pharmacological substances used by patients with hip OA will be examined in this study.
2. Objective
The purpose of this study on the GLA:D project is (i) to make a descriptive analysis of the usage of pharmacological and non-pharmacological substances in patients with hip OA; and (ii) subsequently evaluate the most commonly used substances among patients with hip OA.
3. Material and methods
3.1 Study Design
Descriptive data was extracted from the GLA:D registry. GLA:D was established in 2013 by the “Research institute for musculoskeletal function and physiotherapy” at university of southern Denmark (SDU). The aim of GLA:D was to implement guidelines for the treatment of patients with hip- and knee OA. GLA:D consists of three different elements; education for physiotherapists, education and exercise for patients with hip- and knee OA and the national GLA:D registry. The registry is composed as a pre-post design by showing the patients at baseline and after the GLA:D intervention. Some of the outcomes that were evaluated were; pain, intake of painkillers, physical function, physical activity and joint-related quality of life. The variable “intake of painkillers” in patients with hip OA was collected from the GLA:D registry. This information was examined through a questionnaire (see Appendix 1) together with a physiotherapist. The physiotherapist asked if the patient had taken any joint-related medication at baseline or during the last 3 months. Firstly, the patients answer was documented with “Yes” or “No”. Secondly, the patients were asked which type of substance they were taking. Each patient could report taking several substances. The answer was reported in a questionnaire with 14 different options and a free text column.
The free text column was processed separately in this study. Out of 7129 patients 368 patients had written one or more substances in the free text column. Some of the substances written in the free text column could be included in one of the 14 options in the questionnaire, whereas some of them could not. Therefor the free text column was processed to be able to determine the definitive number of use of the 14 options in the questionnaire. The substances that could not fit into one of the 14 options was arranged into 66 new categories (see Appendix 2). Subsequently, some of the new categories were merged together with corresponding categories in the questionnaire. See Appendix 3 for which categories that were merged together.
3.2 Patients and clinical characteristics
The population that was studied included 7129 patients with hip OA that participated in the GLA:D project between 2013 and 2017. The inclusion criteria in the GLA:D project for the patients was “joint problems from knee and/or hip that have resulted in contact with the health
care system”. Exclusion criteria was another reason causing their joint problems, such as a
tumour or fibromyalgia[17].
The clinical characteristics for patients with hip OA are presented in table 1. In total, there was 7129 patients with hip OA. Out of 7129 patients, 77% reported that they were taking some sort of medicine. There was no remarkable difference in clinical characteristics between the patients taking medicine and patients not taking medicine. Overall there was more women in both groups. Both groups were overweight according to their mean body mass index (BMI). Patients taking medicine had a higher BMI score than patients not taking medicine.
Table 1. Clinical characteristics of the total hip OA study group.
All patients Medicine ”Yes” Medicine ”No”
Total (%) 7129 5481 (77%) 1648 (23%) Sex (%) F= female M= male 5222 (73) F 1907 (27) M 4127 (75) F 1354 (25) M 1095 (66) F 553 (33) M Mean age (years) 66 66 66 Mean BMI 27 27 26
3.3 Statistics
Descriptive statistics were calculated regarding the patient’s clinical characteristics and their usage of different substances. In total there was 80 categories, including the 14 categories from the questionnaire. These categories were arranged in most commonly used to least commonly used. Subsequently, substances used in ³ 0.5% of the patients was used as a cut-off for which categories to be presented in this study. One diagram was made for total use of substances in patients and the other diagram was related to substance frequency.
3.4 Ethics
An ethical approval was not required according to the local ethics committee of the North Denmark Region. The GLA:D registry have been approved by the Danish Data Protection agency. All the patients approved to hand in data to the registry and furthermore the data is de-identified. Therefor there is no risk of circulation of private information.
4. Results
This study found that out of 7129 patients, 5481 patients (77%) was taking one or multiple medicines. In the questionnaire, there were 14 different substances and in the free text column we found 66 new categories of different substances. In total, 15 different categories were used by ³ 0.5% of the patients answering “yes” to taking medicine (n=5481). As seen in table 2 acetaminophen (3898) and NSAID with or without acetyl salicylic acid (ASA) (2460), naturopathic drugs/dietary supplements (1519) and glucosamine (907) were the most commonly used among the patients.
Table 2. Substance frequency in patients answering “yes” to taking medicine (n=5481).
Substance Total %
Acetaminophen 3898 71.1
NSAID with or without ASA 2460 44.9
ND/DS* 1519 27.7
Glucosamine 907 16.5
Morphine and other opioids 307 5.6
Tramadol 203 3.7 Topical NSAID 189 3.4 Other 176 3.2 Codeine 119 2.2 Cortisone injection 111 2.0 Fish oil 71 1.3 Ginger 44 0.8 Anticonvulsive drugs 39 0.7 Calcium 33 0.6 Methotrexate 29 0.5
*Naturopathic drugs/dietary supplements
As seen in Table 2 acetaminophen (71.1%), NSAID with or without ASA (44.9%),
naturopathic drugs/dietary supplements (27.7%) and glucosamine (16.5%) were the four most commonly used in patients (n=5481). Within the most commonly used substances
anticonvulsive drugs (0.7%), calcium (0.6%) and methotrexate (0.5%) were among the least commonly used by the patients.
In Figure 1 the most commonly used substances in relation to all substances (n=10310) can be viewed. These findings verify the findings in Table 2, as the ranking of substances in the figures correlates to each other. Further, there was almost twice as many substances (10310) as patients (5481), due to combined medications in several patients
Figure 1. Substance frequency in relation to all substances (n=10310). The substances in Table
2 were used to calculate substance frequency among all substances.
The categories including those used by < 0.5% of the patients can be viewed in Appendix 4.
5. Discussion
This study found that patients with hip OA are using a variety of both non- and pharmacological substances. The 0.5% cut-off resulted in 15 different categories, where acetaminophen, NSAID with or without ASA, naturopathic drugs/dietary supplements and glucosamine were amongst the most commonly used.
In total, we found that the patients used 80 different categories of substances. In general drugs with similar mechanism of action were arranged together and substances that was mentioned more than once were arranged in separate categories. Each category with respective substances can be viewed in Appendix 2. Considering the fact that there were 80 different categories, a cut-off at 0.5% was set to be able to present a comprehensible picture of the results. Based on this cut-off, the results presented in this study shows the substances used in ³ 0.5% of the patients. The categories not presented in the results can be viewed in Appendix 4.
37.8 23.9 14.7 8.8 3.0 2.0 1.8 1.7 1.2 1.1 0.7 0.4 0.4 0.3 0.3 0 5 10 15 20 25 30 35 40 % SUBSTANCES Substance frequency Substances (n=10310)
Acetaminophen was most commonly used in patients (71.1%), secondly NSAID with or without ASA (44.9%) and thirdly naturopathic drugs/dietary supplements (27.7%). These results reflect that the use of substances only partly converge with the international guidelines for treating patients with OA. The use of acetaminophen and NSAID, which are referred to as first- and second line treatment in OA [16], does converge with the recommendations. These results may be explained by the fact that these analgesics are recommended by the international guidelines. Further, acetaminophen might be the most commonly used pain killer as it has fewer adverse effects compared to NSAID. Arthrosis most often affects elderly patients, which also is true for the population in this study (mean age = 66). Elder patients suffer from other comorbidities [28] as well and therefor it is important to prescribe medicine that is safe and have few adverse effects.
The category “naturopathic drugs/dietary supplements” was used by almost a third of the study population. This category might include a variety of different naturopathic drugs and supplements as there is no specification about which particular substances that are included. More specifically we found dietary supplements such as fish oil and ginger that was used by 1.3% and 0.8% of the patients. These are not a part of the international treatment recommendations. However, there are studies evaluating their possible anti-inflammatory effects [29,30]. The study about fish oil found that the supplement inhibit the production of the pro-inflammatory cytokine, IL-1b in patients with rheumatoid arthritis (RA) [29]. The study looking at ginger found that it inhibited the production of nitric oxide in immune cells. Nitric oxide is produced during chronic infection and inflammation [30]. Therefore, it is possible that these supplements have effects on inflammation in the joint. Additionally, these supplements are available for patients to purchase in health stores which might also contribute to their common use amongst patients. Overall, the use of these substances, collectively known as CAM’s, might indicate inadequately pain-relief with the recommended treatment including analgesic drugs.
The fourth most commonly used treatment was glucosamine (16.5%). Glucosamine was earlier recommended for patients with knee OA as it was believed it had an effect on the patient’s symptoms [16]. According to the updated international recommendations glucosamine is no longer recommended for treatment of knee OA. Further, there are no recommendations indicating benefit of treatment with glucosamine in patients with hip OA [21]. The high use of glucosamine might be explained by several factors. Due to the background of glucosamine,
with its earlier believed symptomatic relief, this might still be the general view of it. The fact that glucosamine can be bought in health stores and pharmacies, might also contribute to the common use in patients.
The fifth most commonly used treatment is morphine and other opioids (5.6%), whereas tramadol (3.7%) and codeine (2.2%) were less frequent in the study population. Even though one would merge these into one “opioid-category”, they still would not converge with the guidelines. Strong opioids are more commonly used in this study population than weak opioids. This does not coincide with the international guidelines, where weak opioids are recommended in first place [16]. This might reflect that the patients suffer from symptoms where treatment with weak opioids is not sufficient. Further, tramadol was used more compared to codeine. A possible explanation could be that some people are unable to metabolise codeine to its active metabolite, which causes an ineffective analgesic effect [31].
Interestingly, topical NSAID (3.4%) were among the most commonly used substances. Topical agents are usually a complement to the patient’s systemic treatment of pain. There are also benefits in using topical NSAID as GI adverse effects are less likely compared to oral NSAID [28]. However, the recommendation of treatment with topical NSAID only concern patients with knee OA [16]. Nonetheless, topical NSAID are used by some patients in this study population. The fact that Voltaren, which is a topical NSAID, can be purchased without a prescription, might contribute to its use among hip OA patients. Topical NSAID does not have any further side effects compared to placebo, which is another possible reason for their usage. Further, from a patient point of view this treatment might be considered an easy and practical way to target the joint locally.
The substances in the category “other” (3.2%) are unknown, which make it difficult to analyse underlying cause to its place in the list. This category was an option in the GLA:D questionnaire. As it was placed relatively high amongst the patient’s usage, it is of interest to modify the questionnaire to be able to asses which specific substances that might be included in this category.
Cortisone injection were used in 2% of the patients. Injections in the hip involves several difficulties, compared to knee injections. These difficulties are injection technique and the requirement of ultrasound guidance. Beyond these difficulties cortisone injection gives none or
short-lived effect on symptomatic hip OA [10]. Evidence demonstrate that intraarticular injections with corticosteroids should only be a complement to the core treatment of OA [32]. It is also discussed whether repeated injections might cause joint destruction, however evidence for this hypothesis is limited [33]. Patients might use cortisone injection when their joint pain is unbearable to achieve immediate pain relief, even though it is short-lived.
Anticonvulsive drugs were used by 0.7% of the patients. These drugs inhibit the release of excitatory neurotransmitters in the central nervous system, which may provide a pain-relieving effect. The use of anticonvulsive drugs might reflect that some patients have developed central sensitization caused by chronic pain. However, as mentioned, the effects of anticonvulsive drugs in patients with OA have not been studied [28].
Calcium was used in 0.6% of the patients. This nutrient is regulated by vitamin D and affects many different processes in the body, such as release of neurotransmitters and endocrine hormones. Calcium also have a key role in chondrocytes through matrix synthesis and cell death [34]. As calcium is regulated by vitamin D, it is suggested that low levels of vitamin D might affect calcium metabolism which may contribute to the progression of OA [9]. With this taken into consideration, the use of calcium in patients with OA might be supportable.
Methotrexate (0.5%) was the least common used amongst the 15 categories. Methotrexate is believed to inhibit synovitis in inflammatory arthritis. There are two studies regarding treatment with methotrexate in patients with OA. One study found no reduction in pain and the other found significant improvement in pain. However, these studies concerned knee and hand OA. A more recent study found an important reduction in pain in patients with knee OA treated with methotrexate. Thus, there seem to be evidence that might justify the use of methotrexate in treatment of patients with OA, but not specifically hip OA [35].
The WHO treatment ladder has lately been reviewed. According to OARSI’S recent recommendations many of the substances in the ladder have little scientific evidence to support their usage in treatment of OA. The use of acetaminophen in patients with comorbidities was found to be uncertain. The reason was concerns about its toxcicity. Opioids were also found to be uncertain for all patient groups, because of their many and serious adverse effects [21]. These findings are important to highlight as today the ladder is used for other purposes than the original one. It would probably be beneficial to reassess this ladder to make it specifically
applicable on OA patients. However, these findings are not equal to withdrawal of the recommendations of OA treatment.
It is important to discuss the design of the GLA:D questionnaire as a possible source of error in this study. Firstly, it cannot be confirmed whether all the substances reported by the patients was joint-related treatments. For example, in the free text column patients reported taking heart- and asthma medication, which contributes to questioning of the results in this study. Secondly, there was two identical “Other” categories in the questionnaire. One was supposed to be a part of the free text column whereas the other category was unspecified, which might have been confusing to the patients. Hence, there is room for modification of the questionnaire to be able to get more reliable results in the future.
In total, there was a various usage of pharmacological as well as non-pharmacological
substances. One third used naturopathic drugs/dietary supplements, which indicate the need of alternative treatment. These results might also indicate that pharmacological pain-relieving medicine does not adequately treat the perceived needs of patients with hip OA. As pain relief, plausibly is not fully achieved, this supports the importance of exercise as the core treatment in OA.
6. Conclusion
Among the 5481 studied patients with symptomatic hip OA reporting to take medicine we found 15 different categories of non- and pharmacological substances used by ³ 0.5%. The pharmacological drugs acetaminophen and NSAID with/without ASA and the non-pharmacological substances naturopathic drugs/dietary supplements and glucosamine were most commonly used, followed by the category morphine and other opioids.
7. Acknowledgements
Firstly, I would like to give my sincere appreciation to my supervisors Lillemor Nyberg and Ewa M. Roos. Without their genuine interest and commitment in this field of research, this study would not have been successful. Secondly, I am very grateful for all the support and guidance from the members in musculoskeletal function and physiotherapy (FOF) research
group at SDU. Altogether, each of all have made this the perfect balance between a challenge and a chance to develop; both within a fundamental area and professionally.
8. References
1. Atkinson MH. Osteoarthrosis. Can Fam Physician. 1984 Jul;30:1503–7.
2. WHO Chronic rheumatic conditions. WHO. [cited 2017 Nov 23]. Available from: http://www.who.int/chp/topics/rheumatic/en/
3. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body Weight, Body Mass Index, and Incident Symptomatic Osteoarthritis of the Hand, Hip, and Knee.
Epidemiology. 1999 Mar 1;10(2):161–6.
4. Englund M, Turkiewicz A. Artros allt vanligare folksjukdom. Läkartidningen.
2014;111:CSDU. Available from: http://lakartidningen.se/Klinik-och-vetenskap/Klinisk-oversikt/2014/05/Artros-allt-vanligare-folksjukdom/
5. Murphy LB, Helmick CG, Schwartz TA, Renner JB, Tudor G, Koch GG, et al. One in four people may develop symptomatic hip osteoarthritis in his or her lifetime. Osteoarthr Cartil OARS Osteoarthr Res Soc. 2010 Nov;18(11):1372–9.
6. Murphy L, Schwartz TA, Helmick CG, Renner JB, Tudor G, Koch G, et al. Lifetime Risk of Symptomatic Knee Osteoarthritis. Arthritis Rheum. 2008 Sep 15;59(9):1207–13. 7. Fernandes L, Hagen KB, Bijlsma JWJ, Andreassen O, Christensen P, Conaghan PG, et
al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis. 2013 Jul 1;72(7):1125–35.
8. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of
nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012 Apr 1;64(4):465–74.
9. Brandt K, Doherty M, Lohmander S. Osteoarthritis. Second edition. Oxford university press; 2003. 1, p. 294.
10. Socialstyrelsen. Nationella riktlinjer för rörelseorganens sjukdomar. 2012. (2012-5–1). Available from:
http://www.socialstyrelsen.se/nationellariktlinjerforrorelseorganenssjukdomar 11. Arden N, Nevitt MC. Osteoarthritis: Epidemiology. Best Pract Res Clin Rheumatol.
2006 Feb 1;20(1):3–25.
12. Felson DT, Schaible H-G. Pain in osteoarthritis. First edition. Wiley-Blackwell; 2009. p. 234-236
13. Sophia Fox AJ, Bedi A, Rodeo SA. The Basic Science of Articular Cartilage. Sports Health. 2009 Nov;1(6):461–8.
14. Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI recommendations for the management of hip and knee osteoarthritis: Part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage. 2010 Apr 1;18(4):476–99.
15. Kaboli PJ, Doebbeling BN, Saag KG, Rosenthal GE. Use of complementary and alternative medicine by older patients with arthritis: a population-based study. Arthritis Care Res. 2001 Aug 1;45(4):398–403.
16. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines - Osteoarthritis and Cartilage. 2008 Feb;16(2):137-62. Available from: http://www.oarsijournal.com/article/S1063-4584(07)00397-4/fulltext#sec6
17. Skou ST, Roos EM. Good Life with osteoArthritis in Denmark (GLA:DTM): evidence-based education and supervised neuromuscular exercise delivered by certified
physiotherapists nationwide. BMC Musculoskelet Disord. 2017 Feb 7;18:72. 18. Roos EM, Ageberg E. Träning är en grundsten i behandlingen. Läkartidningen.
2014;111:CRST. Available from: http://lakartidningen.se/Klinik-och-vetenskap/Klinisk-oversikt/2014/05/Traning-ar-en-grundsten-i-behandlingen/
19. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL.
Unconventional Medicine in the United States -- Prevalence, Costs, and Patterns of Use — NEJM. 1993 Jan 28;328(4):246-52. Available from:
http://www.nejm.org/doi/full/10.1056/NEJM199301283280406#t=articleResults 20. Herman CJ, Allen P, Prasad A, Hunt WC, Brady TJ. Use of Complementary Therapies
Among Primary Care Clinic Patients With Arthritis. Prev Chronic Dis. 2004 Oct ;1(4):A12. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277952/ 21. McAlindon T., Bannuru R., Sullivan M., Arden NK, Berenbaum F, Bierma-Zeinstra S.,
et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014 Marc;22(3):363-88.
22. Arendt-Nielsen L. Pain in the joints. First edidtion. Wolters Kluwer; 2017. 219-221 p. 23. Crofford LJ. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther.
2013;15(Suppl 3):S2.
24. Knoop J, van Tunen J, van der Esch M, Roorda LD, Dekker J, van der Leeden M, Lems WF. Analgesic use in patients with knee and/or hip osteoarthritis referred to an
outpatient center: a cross-sectional study within the Amsterdam Osteoarthritis Cohort. Rheumatol Int. 2017 Oct;37(10):1747-55. Available from:
https://link.springer.com/article/10.1007%2Fs00296-017-3785-3
25. McHugh GA, Luker KA, Campbell M, Kay PR, Silman AJ. A longitudinal study exploring pain control, treatment and service provision for individuals with end-stage lower limb osteoarthritis. Rheumatology. 2007 Apr 1;46(4):631–7.
26. Fisher JE, Ballantyne PJ, Hawker GA. Older Adults Living with Osteoarthritis: examining the relationship of age and gender to medicine use. Can J Aging Rev Can Vieil. 2012 Sep;31(3):323–33.
27. Hudson B, Williman JA, Stamp LK, Alchin JS, Hooper GJ, Mangin D, et al.
controlled trial. Trials. 2015 Oct 9;16:488. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600280/
28. van Laar M, Pergolizzi JV, Mellinghoff H-U, Merchante IM, Nalamachu S, O’Brien J, et al. Pain Treatment in Arthritis-Related Pain: Beyond NSAIDs. Open Rheumatol J. 2012 Dec 13;6:320–30.
29. Kremer J, Lawrence D, Petrillo G, Litts L, Mullaly P, Rynes R, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Am Coll Rheumatol. 1995 Aug;(8):8.
30. Ippoushi K, Azuma K, Ito H, Horie H, Higashio H. [6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages and prevents peroxynitrite-induced oxidation and nitration reactions. Life Sci. 2003 Nov 14;73(26):3427–37.
31. Dean L. Codeine Therapy and CYP2D6 Genotype. In: Pratt V, McLeod H, Dean L, Malheiro A, Rubinstein W, editors. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012 [cited 2017 Dec 5]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK100662/
32. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop. 2014 Jul
18;5(3):351–61.
33. Raynauld J-P, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2003 Feb 1;48(2):370–7.
34. Li H, Zeng C, Wei J, Yang T, Gao S-G, Li Y-S, et al. Serum Calcium Concentration Is Inversely Associated With Radiographic Knee Osteoarthritis. Medicine (Baltimore). 2016 Feb 12;95(6):e2838.. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753953/
35. Wenham CYJ, Grainger AJ, Hensor EMA, Caperon AR, Ash ZR, Conaghan PG. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology. 2013 May 1;52(5):888–92.
